Sclerosis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

SCLEROSIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

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. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2003 by ICON Group International, Inc. Copyright 2003 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., 1960Sclerosis: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83639-6 1. 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 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 Eli Lilly Chair Professor of Innovation, Business and Society 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. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON SCLEROSIS ................................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Sclerosis....................................................................................... 12 E-Journals: PubMed Central ..................................................................................................... 136 The National Library of Medicine: PubMed .............................................................................. 146 CHAPTER 2. NUTRITION AND SCLEROSIS ..................................................................................... 281 Overview.................................................................................................................................... 281 Finding Nutrition Studies on Sclerosis ..................................................................................... 281 Federal Resources on Nutrition ................................................................................................. 289 Additional Web Resources ......................................................................................................... 289 CHAPTER 3. ALTERNATIVE MEDICINE AND SCLEROSIS ............................................................... 299 Overview.................................................................................................................................... 299 The Combined Health Information Database............................................................................. 299 National Center for Complementary and Alternative Medicine................................................ 300 Additional Web Resources ......................................................................................................... 324 General References ..................................................................................................................... 338 CHAPTER 4. DISSERTATIONS ON SCLEROSIS ................................................................................. 339 Overview.................................................................................................................................... 339 Dissertations on Sclerosis .......................................................................................................... 339 Keeping Current ........................................................................................................................ 345 CHAPTER 5. CLINICAL TRIALS AND SCLEROSIS ............................................................................ 347 Overview.................................................................................................................................... 347 Recent Trials on Sclerosis .......................................................................................................... 347 Keeping Current on Clinical Trials ........................................................................................... 370 CHAPTER 6. PATENTS ON SCLEROSIS ............................................................................................ 373 Overview.................................................................................................................................... 373 Patents on Sclerosis ................................................................................................................... 373 Patent Applications on Sclerosis................................................................................................ 431 Keeping Current ........................................................................................................................ 456 CHAPTER 7. BOOKS ON SCLEROSIS................................................................................................ 457 Overview.................................................................................................................................... 457 Book Summaries: Federal Agencies............................................................................................ 457 Book Summaries: Online Booksellers......................................................................................... 458 The National Library of Medicine Book Index ........................................................................... 478 Chapters on Sclerosis ................................................................................................................. 480 Directories.................................................................................................................................. 482 CHAPTER 8. MULTIMEDIA ON SCLEROSIS ..................................................................................... 485 Overview.................................................................................................................................... 485 Video Recordings ....................................................................................................................... 485 Bibliography: Multimedia on Sclerosis ...................................................................................... 486 CHAPTER 9. PERIODICALS AND NEWS ON SCLEROSIS .................................................................. 489 Overview.................................................................................................................................... 489 News Services and Press Releases.............................................................................................. 489 Newsletter Articles .................................................................................................................... 492 Academic Periodicals covering Sclerosis.................................................................................... 493 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 495 Overview.................................................................................................................................... 495 U.S. Pharmacopeia..................................................................................................................... 495 Commercial Databases ............................................................................................................... 497

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Researching Orphan Drugs ....................................................................................................... 497 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 503 Overview.................................................................................................................................... 503 NIH Guidelines.......................................................................................................................... 503 NIH Databases........................................................................................................................... 505 Other Commercial Databases..................................................................................................... 509 The Genome Project and Sclerosis ............................................................................................. 509 APPENDIX B. PATIENT RESOURCES ............................................................................................... 515 Overview.................................................................................................................................... 515 Patient Guideline Sources.......................................................................................................... 515 Associations and Sclerosis ......................................................................................................... 524 Finding Associations.................................................................................................................. 537 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 539 Overview.................................................................................................................................... 539 Preparation................................................................................................................................. 539 Finding a Local Medical Library................................................................................................ 539 Medical Libraries in the U.S. and Canada ................................................................................. 539 ONLINE GLOSSARIES................................................................................................................ 545 Online Dictionary Directories ................................................................................................... 545 SCLEROSIS DICTIONARY......................................................................................................... 547 INDEX .............................................................................................................................................. 667

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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 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 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 sclerosis, from the essentials to the most advanced areas of research. 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 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 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. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on sclerosis. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON SCLEROSIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on sclerosis.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and sclerosis, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “sclerosis” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Botulinum Toxin Injection in the Treatment of Vocal Fold Paralysis Associated with Multiple Sclerosis: A Case Report Source: Journal of Voice. 13(2): 274-279. June 1999. Contact: Available from Singular Publishing Group, Inc. 401 West 'A' Street, Suite 325, San Diego, CA 92101-7904. (800) 521-8545 or (619) 238-6777. Fax (800) 774-8398 or (619) 238-6789. E-mail: [email protected]. Website: www.singpub.com. Summary: Botulinum toxin has been demonstrated clinically to be an effective treatment for a variety of laryngeal problems, most notably spasmodic dysphonia. This article is a case report of the first successful treatment of vocal fold paralysis using botulinum toxin to treat vocal fold fixation in a patient with multiple sclerosis. As in other movement disorders, the theory behind the injection of this substance in the larynx has been a

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weakening of the vocal fold musculature to relieve uncoordinated and spasmodic movement of the vocal folds, presumably rebalancing the forces within the intralaryngeal musculature. A number of investigators have shown that immobile, clinically paralyzed vocal folds may still have partial voluntary motor unit activity. This voluntary activation may not produce clinically evident movement but may be sufficient to produce tone within the fold. If the voluntary motor units in the abductor musculature of the paralyzed fold are weakened with botulinum toxin, the continued pull of the functioning adductor musculature may be sufficient to medialize the paralyzed fold. The case report involves a patient with fold immobility secondary to multiple sclerosis who was treated in an attempt at laryngeal rebalancing, using botulinum toxin to medialize the fold. However, instead of simply having the fold return fixed to the midline, the patient regained normal laryngeal mobility and voice. While it is unclear whether the botulinum toxin alone was responsible, the coincidence of the occurrence certainly requires reporting. 4 figures. 17 references. •

Gingival Overgrowth in Cyclosporine A: Treated Multiple Sclerosis Patients Source: Journal of Periodontology. 65(8): 744-749. August 1994. Summary: Correlations have been reported between cyclosporine A (CsA) induced gingival overgrowth (OG) and plaque induced gingivitis, duration of CsA therapy, and blood and tissue drug levels. This article reports on a study that evaluated the relative importance of such factors using data from a 2 year, double blind study of CsA therapy in multiple sclerosis (MS) patients. Ninety subjects (40 taking CsA; 50 placebo) were evaluated for plaque, calculus, gingivitis, probing depths, attachment levels, and CsA levels in blood and saliva. OG was determined by a panel of 11 calibrated examiners from standardized clinical photographs taken at the end of the study. Four (17 percent) out of 23 CsA patients with CsA trough blood levels less than 400 ng per ml exhibited OG. In contrast, 10 (59 percent) out of 17 CsA patients with CsA trough blood levels greater than 400 ng per ml were affected with OG. The study did not reveal a relationship between plaque and OG or calculus and OG. This result may be explained by the generally poor oral hygiene of the participants in the present study, reflecting a lack of manual dexterity often observed with MS patients. 6 tables. 36 references. (AAM).

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Oral and Maxillofacial Manifestations of Multiple Sclerosis Source: Journal of the Canadian Dental Association. 66(11): 600-605. December 2000. Contact: Canadian Dental Association. 1815 Alta Vista Drive, Ottowa, ON K1G 3Y6. (613) 523-1770. E-mail: [email protected]. Website: www.cda-adc.ca. Summary: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) which mostly affects young adults living in the northern hemisphere. Dentists should be familiar with the clinical manifestations of MS that affect the oral and maxillofacial areas as well as patients' general health. This article reviews two cases of MS, highlights the orofacial manifestations of the disease, and discusses the related dental implications. Three of the most frequent orofacial symptoms are trigeminal neuralgia, trigeminal sensory neuropathy, and facial palsy. Dentists should also be aware of the importance of this disease in the diagnosis, treatment, and prognosis of certain orofacial lesions or conditions. In the two cases presented, the principal symptoms of MS were facial numbness and pain, and the dentist was the first health professional to be consulted. 4 figures. 2 tables. 26 references.

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Mandibular Resorption Due to Progressive Systemic Sclerosis: A Case Report Source: Journal of Oral and Maxillofacial Surgery. 59(5): 565-567. May 2001. Contact: Available from W.B. Saunders Company. Periodicals Department, P.O. Box 629239, Orlando, FL 32862-8239. (800) 654-2452. Website: www.harcourthealth.com. Summary: Progressive systemic sclerosis (PSS), also known as scleroderma, is a connective tissue disorder of unknown origin, characterized by fibrosis of the skin and other visceral organs. The disease generally occurs between 30 and 50 years of age, and women are mostly affected. The disease progresses with the firmness of the skin leading to limitation of mobility of the fingers. The tight sclerotic skin causes extrinsic pressure and the overproduced collagen in the small arteries leads to the obliteration of the vessels and eventually induces destruction of the bone. This article reports a case of PSS with general and facial findings, and extensive mandibular (lower jaw) resorption. The patient, a 45 year old white woman, presented with a complaint of mobility of her anterior mandibular teeth. Her PSS had been diagnosed 21 years previously. The oral opening was reduced to 32 mm because of atrophy of the lip muscles and tightening of the skin. Intraoral examination revealed poor oral hygiene, loss of teeth, and periodontitis that was especially localized to the anterior mandibular region. After extensive evaluation, results revealed no other pathology, metabolic bone disease or neoplasia that could be causing her bone resorption. Esophageal involvement, with dysphasia (swallowing difficulty) and pulmonary (lung) involved were also diagnosed in this patient. 5 figures. 1 table. 18 references.

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Bladder Dysfunction and Management in Multiple Sclerosis Source: Mayo Clinic Proceedings. 72(12): 1176-1183. December 1997. Contact: Available from Dowden Publishing Company, Inc. 110 Summit Avenue, Montvale, NJ 07645. (800) 707-7040 or (201) 782-5714. Fax (201) 391-2778. Summary: Symptomatic bladder dysfunction occurs at some time in most patients with multiple sclerosis (MS). This article reviews the problem of bladder dysfunction and its management in these patients. The relapsing, remitting course of MS and progressive loss of mobility associated with MS make management of urinary urgency and incontinence difficult. Urodynamic evaluation serves as a guideline for appropriate treatment. After accurate diagnosis of bladder dysfunction, a management program is developed with use of fluid schedules, voiding techniques, neuropharmacologic manipulation, intermittent catheterization, surgical treatment, and other adjunctive measures as indicated. The goals of treatment are to protect and preserve renal function, relieve symptomatic voiding dysfunction, and avoid subsequent urinary complications. A management program should be individualized, dynamic, and monitored with periodic, systematic urologic review to maintain these goals. 1 figure. 31 references. (AA).

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Olfactory Dysfunction in Multiple Sclerosis Source: The New England Journal of Medicine, Vol. 336:1918-1919, June 26, 1997. Number 26. Contact: Available from Dr. Richard L. Doty, Smell and Taste Center, 5 Ravdin Pavilion, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104. Summary: This article describes the testing and outcome conducted with 26 subjects with confirmed multiple sclerosis (MS) to see if the number of multiple sclerosis-related

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plaques in olfactory regions correlates with scores on the University of Pennsylvania Smell Identification Test (UPSIT), a standardized 40-odorant quantitative test of olfactory function. 1 figure. 5 references. •

Enamel Pitting: A Common Symptom of Tuberous Sclerosis Source: Oral Surgery, Oral Medicine, Oral Pathology. 71(1): 63-67. January 1991. Summary: This article explores dental enamel pitting as a diagnostic sign of tuberous sclerosis and describes a protocol for the oral examination of patients and persons at risk. Tuberous sclerosis is a neurocutaneous genetic disease. The author reports on a study of 50 patients with tuberous sclerosis and 250 control patients who were examined for dental enamel pitting. A simple clinical protocol was established for examination with the use of a dental disclosing solution swabbed on dry teeth. The incidence of enamel pitting in the adult dentition of patients with tuberous sclerosis was 100 percent, whereas the incidence in the control group was 7 percent. The author concludes that simplicity of the test and the high probability of occurrence in tuberous sclerosis make such an examination useful in the diagnosis of this serious genetic disease. 8 figures. 1 table. 15 references. (AA-M).

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Anaesthesia for Dental Conservation in a Patient with Tuberous Sclerosis Source: European Journal of Anaesthesiology. 13(4): 413-415. July 1996. Summary: This article presents a case report of anesthesia for dental conservation in a patient with tuberous sclerosis, complicated by epilepsy. Tuberous sclerosis is an inherited condition characterized by seizures, learning difficulties, and behavioral problems in which adenomatous lesions may occur in the skin, heart, and kidneys. The clinical onset is usually in early childhood. Phenytoin and epanutin required to control seizures can cause gingival hypertrophy, tenderness and bleeding. Routine dental examination and care is often impossible without sedation or general anesthesia. The choice of drugs was related to the patient's seizures and intercurrent therapy. Thiopentone, vecuronium, and nitrous oxide with isoflurane were satisfactory. The procedure lasted 90 minutes and included full examination, dental x-rays, scaling, filling, and extraction of teeth. The authors discuss this case and how their findings can be extrapolated to similar patients.

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Crohn's Disease in a Patient with Multiple Sclerosis Source: Journal of Clinical Gastroenterology. 13(3): 331-334. June 1991. Summary: This article presents a case study of an occurrence of Crohn's disease in a patient with well-established multiple sclerosis. A relationship between inflammatory bowel disease and multiple sclerosis is supported by a higher than expected coexistence of these diseases among families and individuals, as well as similar accepted and proposed mechanisms of pathogenesis and therapy. The authors report the case study and then review the medical literature in this area. The authors note that further investigation of shared genetic factors in the expression of these diseases will likely clarify common pathogenic mechanisms and perhaps lead to more effective treatment strategies. 2 figures. 17 references. (AA-M).

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Nausea, Vomiting and Diarrhea: An Unusual Presentation of Multiple Sclerosis Source: Canadian Journal of Gastroenterology. 11(4): 367-370. May-June 1997.

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Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Summary: This article presents the case of a young woman who presented with nausea, vomiting, and diarrhea. The etiology turned out to be a first attack of multiple sclerosis (MS). MS is a multifocal demyelinating disorder that usually affects young adults with subacute onset of focal neurological symptoms. The majority (80 percent) of patients present with visual, sensory or gait disturbances; patients older than 40 years more commonly exhibit symptoms of progressive myelopathy. The 33-year-old woman presented to the emergency room with a two-week history of nausea, vomiting and intermittent (one to four times per day) loose watery stools without blood. The vomiting and diarrhea were not associated with cramps, fever, or chills. She experienced mild light- headedness, especially on arising, and complained of mild left neck pain. There was no history of alcohol or substance abuse. The patient's mother died of disabling MS and a younger brother was recently diagnosed with MS. Physical examination at admission disclosed a thin woman in no acute distress, with normal vital signs; general and neurological examinations were entirely within normal limits. The gastroenterologic workup was normal. Because symptoms persisted and nausea was a prominent feature, and because of the family history, neurological consultation was obtained and supported the diagnosis of MS. The authors describe her treatment and subsequent improvement. She has been well without gastrointestinal or neurological symptoms for the five years of followup. The authors conclude that cases such as these should alert non-neurology physicians that persistent upper and lower gastrointestinal symptoms may, on occasion, be a consequence of primary central nervous system pathology. 1 figure. 23 references. (AA-M). •

Preliminary Study Into the Dental Health Status of Multiple Sclerosis Patients Source: Special Care in Dentistry. 13(3): 96-101. 1993. Contact: Available from Academy of Dentistry for People with Disabilities. 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2661. Summary: This article reports on a preliminary study that examined the dental health status of 22 volunteer patients with Muscular Dystrophy (MS). A questionnaire collected data regarding medical and dental histories and socio-demographic information. Extraoral and intra-oral examinations were carried out on all subjects to determine the particular dental treatment needs of this group. Instruments used included the Decayed, Missing, or Filled Teeth Index (DMFT) and the Community Periodontal Index of Treatment Needs (CPITN). The DMFT and CPITN scores for this group did not indicate that MS patients were more susceptible to dental caries or periodontal disease. However, the prevalence of trigeminal neuralgia and symptoms of Temporomandibular Joint (TMJ) dysfunction in the group studied indicated that these conditions may be manifest in persons with MS and warrant further investigations. 8 tables 25 references. (AA-M).

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Analysis of the Oral Manifestations of Systemic Sclerosis Source: Oral Surgery, Oral Medicine, Oral Pathology. 77(2): 141-146. February 1994. Summary: This article reports on a study in which the oral signs and symptoms in 32 patients with systemic sclerosis (SSc) were evaluated. A complete analysis of the orofacial abnormalities in SSc was performed, including the evaluation of the salivary secretion, visual investigation of oral soft tissue changes, and analysis of the signs of fibrosis or Sjogren's syndrome (SS) and capillary abnormalities in labial biopsy

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specimens. Oral mucosal telangiectasia was present in 18 cases (56.3 percent) and was not restricted to the limited form of systemic sclerosis. Two cases with inflammatory signs characteristic of SS were found, and six patients showed the histologic signs of labial gland fibrosis. Three of the cases investigated by electron microscopy belonged to the patients with disease onset within 2 years, showing that capillary vascular lesion is present in the early cases and that vascular injury affects even those tissues that do not seem to be involved by clinical examination. 3 figures. 4 tables. 33 references. (AA-M). •

Hearing Loss in Progressive Systemic Sclerosis Patients: A Comparative Study Source: Otolaryngology-Head and Neck Surgery. 124(5): 522-525. May 2001. Contact: Available from Harcourt Health Sciences, Subscription Customer Service, 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Fax (407) 363-9661. Website: www.harcourthealth.com. Summary: This article reports on a study that investigated the middle and inner ear involvement in patients with progressive systemic sclerosis (PSS). The authors prospectively evaluated 34 PSS patients. All patients underwent a complete ear nose throat physical examination and audiological evaluation with pure tone, impedance, and speech audiometry. In addition, systemic manifestations of the disease and drug therapy were recorded. Finally, all patients were tested for the presence of autoantibodies. The results were compared with those of 45 age matched healthy subjects. The authors found a sensorineural health loss (SNHL) in 20 percent and mixed type hearing loss in 3.3 percent of the patients. There was no correlation of hearing loss with age, systemic manifestations of the disease, presence of autoantibodies, and drug therapy. Ten percent of the patients had patulous (open) Eustachian tubes. The authors concluded that one fourth of the PSS patients had a hearing loss affecting the middle and mainly the high frequencies. This is a lower percentage than that reported by previous investigations. A significant percentage of bilateral (both sides) patulous Eustachian tubes was noticed as well. The authors call for further study to obtain a better understanding of the mechanism of ear damage in PSS patients. 1 figure. 2 tables. 19 references.

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Communication in Context: A Qualitative Study of the Experiences of Individuals with Multiple Sclerosis Source: American Journal of Speech-Language Pathology. 10(2): 126-137. May 2001. Contact: Available from American Speech-Language-Hearing Association (ASHA). Subscription Sales Coordinator, 10801 Rockville Pike, Rockville, MD 20852-3279. (888) 498-6699. Fax (301) 897-7358. Website: www.asha.org. Summary: This article reports on a study undertaken to examine an insider's perspective on communication in multiple sclerosis (MS), a disease of the central nervous system in which scattered lesions or plaques produce varying combinations of motor, sensory, and/or cognitive impairments. Qualitative research methods were used because they are designed to provide a systematic way of exploring complex issues, such as communication, that cannot be separated from the context in which they occur. Seven participants, all of whom had mild communication impairments, described their everyday experiences of communication and the impact of MS on these experiences. Themes derived via inductive analysis of verbatim transcripts included: 'watching the communication changes', 'it's about participating in my life', and 'communicating is unpredictable.' Using the World Health Organization model of disablement, the participants' communication impairments were mild. However, participants reported

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major lifestyle changes characterized by important limitations in communicative participation. Whereas some of the limitations were attributed to changes in speech and language, others were thought to be the result of changes in cognition, vision, mobility, and susceptibility to fatigue. Clinical implications from this study include the need to develop assessment protocols and outcome measures that capture issues related to communicative participation in natural contexts and participation in society. 1 figure. 2 tables. 36 references. •

Olfactory Dysfunction in Multiple Sclerosis: Relation to Longitudinal Changes in Plaque Numbers in Central Olfactory Structures Source: American Academy of Neurology, Neurology 1999; 53:880. Contact: Available from Dr. Richard L. Doty, Smell and Taste Center, 5 Ravdin Pavilion, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104. Full text of this article is available at http://www.neurology.org/cgi/content/abstract/53/4/880 with subscription or for a fee. Summary: This article reports on the findings of a study conducted with five multiple sclerosis (MS) patients over an 18- to 20-month period. Scores on the University of Pennsylvania Smell Identification Test (UPSIT), as well as the numbers of MRIdetermined plaques within the inferior frontal and temporal lobes, were obtained on three or four separate occasions in each subject. A close association was observed, longitudinally, between the remission and exacerbation of plaque numbers and UPSIT scores, with higher plaque numbers reflecting lower UPSIT scores. The authors report that these observations further support the hypothesis that olfactory loss in MS is associated with fluctuations in plaque numbers in central olfactory brain regions. 2 figures.

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Primary Focal Segmental Glomerulosclerosis: A Treatable Lesion with Variable Outcomes Source: Nephrology. 6(2): 47-56. April 2001. Contact: Available from Blackwell Science Asia. P.O. Box 378, Carlton South, Victoria 3053, Australia. Fax 61-3-9347-5001. Email: [email protected]. Summary: This article reviews the care and management of patients with primary focal segmental glomerulosclerosis (FSGS), a clinical syndrome characterized by proteinuria (protein in the urine), and scars in the kidney glomeruli (a cluster of the nephrons or filtering mechanisms of the kidney). Primary FSGS accounts for 7 to 20 percent of glomerular lesions seen in children and adults with proteinuria; the prevalence of this lesion in black patients (36 to 80 percent) is two to four times the prevalence found in white patients (14 to 24 percent). The progressive nature of primary FSGS and its high recurrence rate in transplanted kidneys has led to an increasing interest in the therapeutic approach to patients with this lesion. The authors review classic FSGS symptoms, histological variants of FSGS, the location of the segmental scar within the glomerulus (tip lesion), the cellular lesion (variant) of FSGS, presenting features, clinical course, remission, initial treatment, treatment of relapses, treatment of steroid resistant patients, and pathogenesis of the disease. Based on current data, a trial of steroid therapy in primary FSGS is warranted in nephrotic patients with reasonably well preserved renal (kidney) function in whom it is not otherwise contraindicated. The comparatively favorable prognosis of non nephrotic patients with FSGS does not support the use of steroids or other immunosuppressive agents. However, the

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progressive nature of FSGS in some non nephrotic patients, many of whom have hypertension (high blood pressure), underlines the importance of close followup, good blood pressure control, and use of ACE inhibitors. 4 figures. 5 tables. 69 references. •

Oklahoma Choctaw and Systemic Sclerosis: The Founder Effect and Genetic Susceptibility Source: Arthritis and Rheumatism. 41(10): 1725-1728. October 1998. Summary: This editorial addresses the issue of the high prevalence of systemic sclerosis (SSc) in the Choctaw residing in Oklahoma. SSc is absent or virtually absent in the Eastern Choctaw, so something about the environment of Oklahoma or the genetic composition of the Oklahoma Choctaw must be increasing their risk of SSc. Genealogy data support a genetic explanation. These data are interpreted as showing that the Oklahoma Choctaw with SSc are descended from a single person, a founder, who lived about 10 generations ago. Researchers have found a haplotype that tends to be shared more frequently among the Oklahoma Choctaw who have SSc than among controls who do not have it. The assumption is that this haplotype consisting of the alleles of genes in and around fibrillin 1 contains a susceptibility gene for SSc and that this gene originated from the founder. The editorial highlights research on this genetic susceptibility. 1 figure, 1 table, and 10 references.

•

Relationship Between Cutaneous and Pulmonary Involvement in Systemic Sclerosis Source: Journal of Rheumatology. 24(1):81-85; 1997. Summary: This journal article for health professionals describes a study that investigated the relationship between cutaneous and pulmonary involvement in a series of patients affected by systemic sclerosis (SSc). Participants were 46 female and 6 male nonsmoking patients affected by SSc. Twenty-eight had the diffuse form of the disease and 24 the limited form. All participants underwent pulmonary function studies, high resolution computed tomography (HRCT) of the lungs, and complete echocardiographic examination. Pulmonary artery systolic pressure was measured by Doppler echocardiography. Pulmonary interstitial fibrosis and skin fibrosis were evaluated using a point system. Results show that mean percentages of predicted values of forced vital capacity and total lung capacity were significantly reduced in patients with diffuse SSc compared to those with limited SSc. The overall HRCT score was 6.1 plus or minus 4.9, with no significant differences between disease subgroups. However, a HRCT score of 10 or more was present in 10 patients with diffuse SSc versus 2 patients with limited SSc. Pulmonary hypertension was present in 27 patients, 15 with limited SSc and 12 with diffuse SSc. No significant correlation was observed between skin score and lung volumes, carbon monoxide diffusing capacity, HRCT score, or pulmonary artery systolic pressure for all patients and subgroups. Results demonstrate that the extent and severity of cutaneous and pulmonary involvement in SSc were not related. Nevertheless, a slightly different pattern of pulmonary involvement between disease subgroups was present. 30 references, 1 figure, and 3 tables. (AA-M).

•

Recognizing an Index Case of Tuberous Sclerosis Source: American Family Physician. 61(3): 703-708. February 1, 2000. Contact: American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237 or (913) 906-6000. E-mail: [email protected]. Website: www.aafp.org.

Studies 11

Summary: This journal article provides health professionals with information on the epidemiology and clinical features of tuberous sclerosis. This disorder is the most common neurocutaneous syndrome after neurofibromatosis. Tuberous sclerosis is an autosomal dominant disorder with almost complete penetrance but a wide range of clinical severity. Genetic research has identified two tuberous sclerosis genes. One is located on chromosome 9 and the other on chromosome 16. About 68 percent of cases occur as a result of new gene mutations. Dermatologic manifestations may be the only clues the family physician has to the diagnosis of the disorder, which is also marked by childhood seizures and mental retardation. Characteristic signs of tuberous sclerosis vary widely in severity and can include hypopigmented ash leaf spots, fibrous plaques on the forehead, angiofibromas on the face, a shagreen patch on the lower back, and fibromas of the nails. Computed tomographic scanning or magnetic resonance imaging reveal subependymal nodules or cortical tubers in the brain. Associated cardiac, retinal, renal, and pulmonary pathology can increase morbidity and mortality. Genetic counseling is helpful but has limited use because of the variation in genetic expression and the frequency of new gene mutations that cause this disorder. The article includes an illustrative case. 5 figures, 1 table, and 16 references. (AA-M). •

Multiple Sclerosis and Urinary Incontinence Source: Informer. 12: p.[1-2]. December 1996. Contact: Available from Canadian Continence Foundation. P.O. Box 30 Vitoria Branch, Westmount, QC, H3Z 2V4. (514) 488-8379. Fax (514) 488-1379. Website: www.continence-fdn.ca. E-mail: [email protected]. Summary: This newsletter article explores the problem of urinary incontinence in people with multiple sclerosis (MS). Multiple sclerosis is a neurological condition that affects different people in different ways. Over 80 percent of individuals with MS will have some kind of urinary problem during the illness. The urinary symptoms will wax and wane, as do the other neurological symptoms. This article reviews the common urinary symptoms, including frequency, urgency, urge incontinence, and nocturia (night time frequency); and explores the treatment options, including drug therapy, lifestyle changes (avoiding caffeine, for example), and clean intermittent catheterization. The author concludes that most people who experience MS can manage the urinary symptoms they may encounter since effective treatment and management options for incontinence are available. The article includes the contact information for the Multiple Sclerosis Society of Canada (800-268-7582 or [email protected]).

•

Hepatoportal Sclerosis Source: Seminars in Liver Disease. 15(4): 329-339. November 1995. Contact: Available from Thieme Medical Publishers, Inc. 381 Park Avenue South, New York, NY 10016. (800) 782-3488. Summary: This review article discusses hepatoportal sclerosis (HPS), a clinicopathological condition responsible for noncirrhotic portal hypertension. The authors focus on some areas of controversy about HPS and related disorders. Topics include the definitions of idiopathic portal hypertension (IPH) and HPS; the relationship, in the liver, between the vein, the artery, and the bile duct; the pathological manifestations of HPS; the role of nodular regenerative hyperplasia (NRH) in the HPS entity; the pathology of HPS/IPH; incomplete septal cirrhosis (ISC); factors affecting the prognosis of HPS; and diagnostic difficulties in HPS. The authors conclude with a

12 Sclerosis

summary of their reasons for preferring the term HPS over IPH, and a discussion of the uses of the term HPS. 9 figures. 3 tables. 32 references. •

Urodynamics and Multiple Sclerosis Source: Urologic Clinics of North America. 23(3): 475-481. August 1996. Contact: Available from W.B. Saunders Company, Periodicals Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 654-2452. Summary: Voiding dysfunction in multiple sclerosis is common, and the irritative and obstructive symptoms can be disabling to the patient. This article focuses on the central role played by urodynamic studies in the initial assessment and management of the lower urinary tract. The authors note that voiding symptoms alone are unreliable predictors of bladder and urethral dysfunction secondary to multiple sclerosis. Detrusor hyperreflexia is the most common urodynamic finding in these patients. However, a variety of urodynamic patterns can be seen, and voiding function may change over time with this chronic neurologic disorder. 4 figures. 2 tables. 46 references. (AA-M).

Federally Funded Research on Sclerosis The U.S. Government supports a variety of research studies relating to sclerosis. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) 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 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 sclerosis. The following is typical of the type of information found when searching the CRISP database for sclerosis: •

Project Title: 1H MRSI OF AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Weiner, Michael W. Professor of Medicine, Radiology, Psychi; Northern California Institute Res & Educ San Francisco, CA 941211545 Timing: Fiscal Year 2001; Project Start 11-SEP-2000; Project End 31-JUL-2003 Summary: The primary goal of this project is to establish an 1H MRSI measurement of N-acetylaspartate (NAA) as a surrogate marker for quantitative measurements of upper motor neuron (UMN) loss in amyotrophic lateral sclerosis (ALS), and to detect ALS in an early stage of the disease. This proposal uses a newly developed short TE multislice 1H MRSI method with high test retest reproducibility, which samples surface cerebral cortex with minimal lipid contamination and which provides atrophy corrected [NAA],

2

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).

Studies 13

[creatine(Cr)], (choline (Cho)], and [myo-inositol (mI)]. MRI segmentation quantifies the gray and white matter, and cerebrospinal fluid in each MRSI voxel. A pilot study showed significant decreases in NAA (-11.9%), Cre (-10.7%), and Cho (-19.5%) in motor cortex of ALS after 3 months of enrollment in our study. This technique will be used to study the following subject groups in a longitudinal fashion. Clinically definite or probable ALS (n=20) and clinically possible or suspected ALS (n=20) will have MRI/1H MRSI every 3 months. Age and sex matched controls will have one MRI/1H MRSI. Hypotheses: l) Regional metabolic changes: The greatest neuron loss (assessed from [NAA] loss) in ALS brain occur in the primary motor cortex and the corticospinal tract (CST), 2) NAA as a surrogate marker of UMN function: Neuron loss (assessed from [NAA] loss) in motor cortex and CST of ALS patients correlates with clinical measures of UMN dysfunction, 3) Prediction of course of ALS: The long term time course of motor cortex neuron loss (assessed from (NAA]) in an individual can be predicted from 2-3 measurements in 6-9 months, 4) Early detection of UMN impairment: UMN loss (assessed from (NAA] loss) occurs before clinical UMN dysfunction is apparent. In addition to these hypotheses, changes in metabolites other than NAA, especially mI, will be explored. The ability of arterial spin labeled perfusion MRI to detect changes in motor and other brain regions and a small pilot study to determine the effects of oral creatine supplementation will be explored. It is expected that this project will lead to the development of improved diagnostic techniques for assessment, screening of subjects at risk for, monitoring progression of, and quantifying treatment effects of ALS and other motor neuron disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A CONTROLLED TRIAL OF CBT FOR MS INFLAMMATION Principal Investigator & Institution: Mohr, David C.; Northern California Institute Res & Educ San Francisco, CA 941211545 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): MS is a frequently disabling autoimmune disease affecting approximately 350,000 people in the United States. It is among the most disabling diseases in the United States, with 81% of all patients out of the workforce. More that two decades of research has consistently shown a relationship between stressful life events (SLEs), in particular non-traumatic family and work stressors, and subsequent clinical exacerbation. Furthermore, we have shown that non-traumatic SLEs increase the risk of the subsequent appearance of new gadolinium enhancing (Gd+) magnetic resonance imaging (MRI) brain lesions, an early marker of MS inflammation and blood-brain barrier (BBB' breakdown. The purpose of this study is to determine the efficacy of cognitive behavioral therapy for MS (CBT. MS), a stress management program we have developed specifically for MS, in reducing the occurrence of new brain lesions in people with relapsing-remitting multiple sclerosis (RRMS). RRMS was selected over other types, because it is the most common form of MS and it is more likely than other types to be associated with clinical exacerbation and Gd+ MRI. One hundred and twelve patients will be enrolled for 2 years. To ensure equivalent medical treatment across patients and treatment arms, all patients will receive neurological care through the University of California, San Francisco (UCSF) MS Center. Patients will be randomly assigned to either CBT-MS or treatment as usual (TAU). The stress management program will consist of 26 weekly group stress management training sessions followed by 12 monthly booster sessions to encourage maintenance of behavioral changes, Because MS exacerbation is episodic, with annual prevalence rates of.61 - 1.68, longer maintenance of behavioral changes will greatly increase the power to

14 Sclerosis

detect effects. Patients will be followed for 6 months following cessation of treatment and booster sessions. To encourage retention, TAU patients will be offered 26 weeks of CBT-MS after completing the study. Consistent with Phase II clinical trials in MS, the primary outcome will be Gd+ MRI brain lesions acquired at screening, and months 3, 6, 12, 18, and 24. Secondary neuroimaging outcomes will include T2-weighted MRI and brain parenchymal fraction (BPF). Secondary clinical outcomes will include MS exacerbation rate, progression of disability, and neuropsychological impairment. Quality of life will be examined as a secondary outcome to evaluate clinical utility. We also wilt enhance our understanding of mechanisms by examining potential psychosocial, immune, and endocrine mediators of the relationship betweenSLEs and clinical and neuroimaging markers of MS inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SCLEROSIS

A

DROSOPHILIA

MODEL

OF

AMYOTROPHIC

LATERAL

Principal Investigator & Institution: Jackson, Stephen M. Acting Assistant Professor; Genome Sciences; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile onset ALS characterized by spasticity of limb and facial muscles resulting from degeneration of motor neurons in the central nervous system. A gene responsible for ALS2 disease has recently been cloned that encodes a protein (termed alsin) with domains suggestive of functions in cell signaling, intracellular trafficking, and cytoskeletal organization. To gain further insight into the normal biological function of this gene, we propose to create a model of this disorder in the fruit fly Drosophila melanogaster. The Drosophila ALS2 gene (DALS2) encodes a polypeptide with 23% amino acid identity (38% similarity) to the human alsin polypeptide and is broadly expressed in a variety of tissue types throughout development. We propose to generate mutations in DALS2 using gene-targeting and double stranded RNA interference methods. Resulting DALS2 mutants will be characterized for signs of progressive motor neuron dysfunction and defects in cell signaling, intracellular trafficking, and cytoskeletal assembly. Additionally, we will conduct screens for genetic modifiers of the DALS2 phenotypes to elucidate the biochemical pathways leading to neuronal dysfunction and death in this Drosophila ALS2 disease model. Results from this work should clarify the normal cellular role of the ALS2 gene and may reveal strategies for treatment of ALS disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A NEW GENE OVER-EXPRESSED IN AUTOIMMUNE DISEASE Principal Investigator & Institution: Greene, Carolyn L. Microbiology and Immunology; Georgetown University Washington, DC 20057 Timing: Fiscal Year 2001; Project Start 28-SEP-2001 Summary: (provided by the applicant): Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system that is thought to be an autoimmune consequence of a microbial infection in a genetically susceptible host. MS patients tend to be immune hyper-responders to a variety of microbial and self antigens, suggesting an element of immune dysregulation in this disease. Little is known about the mechanisms through which this pathologic inflammatory response is generated and maintained. Differential display was performed to screen peripheral blood mononuclear

Studies 15

cells (PBMCs) from identical twins that are discordant for MS. An initial screen of a gene amplified only from the MS twin demonstrated an expression rate of 78 percent of MS patients, but only 33 percent of healthy controls. The more precise examination of this gene?s expression using real-time RT-PCR will be followed by a characterization of the gene, including its tissue and organ distribution, the completion of its sequencing, and the identification of the introns and exons in the genomic DNA. Following these studies, the 5? regulatory region of the gene will be characterized and an in vitro transcription and translation product will be generated. Treatments aimed at correcting the overexpression of this gene in MS patients may serve to lessen disease severity or even halt disease progression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SCLEROSIS

ACQUIRED

&

GENETIC

DETERMINANTS

OF

MULTIPLE

Principal Investigator & Institution: Mack, Thomas M. Professor; Preventive Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, CA 90033 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: The long-term goal of this proposal is to identify links between specific environmental exposures and/or specific gene alleles, and multiple sclerosis onset and progression. A cohort of 1294 pairs of North American twins affected by multiple sclerosis was assembled from 1980-92, detailed medical records, exposure and disability information were gathered independently from affected and unaffected individuals, and follow-up for new diagnoses and new records has subsequently proceeded. An additional set of 195 pairs of affected California native resident twins has been identified within a cohort of 41,000 twins participating in a population-based registry. The up-date on all cases will be completed, diagnoses will be systematically validated using the additional records, and age-specific disability information will be gathered. Blood specimens from both members of each pair and from specific family members as controls will be collected. The affected twins will be compared to their unaffected cotwins with respect to historical evidence of infection and other exposures and characteristics such as reproductive evidences of endogenous estrogen production. Cases will be compared to both co-twins and family member controls with respect to serological evidence of past infection with Chlamydia pneumoniae and members of the herpes virus family. We will compare cases to relatives with respect to the prevalence of alleles at the HLA (DR) locus as well as at various other candidate loci, found by genome-wide screening or that affect immune competence, myelin basic protein, and other pertinent functions. Within the set of cases only, both environmental and genetic factors will be assessed as determinants of age at onset and age-specific progression. If links to both acquired exposure and genome are identified, given adequate power, specific gene- environment interactions will be assessed. Analyses for both etiology and progression will consist of logistic regression and sub-analyses stratified on gender, zygosity, and HLA (DR) status. Additional descriptive evidence of environmental etiology will also be sought. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACUTE EXACERBATIONS OF MULTIPLE SCLEROSIS Principal Investigator & Institution: Sriram, Subramaniam; Vanderbilt University 3319 West End Ave. Nashville, TN 372036917 Timing: Fiscal Year 2001

16 Sclerosis

Summary: Multiple sclerosis is a chronic disease characterized by recurrent attacks of neurologyc dysfunction, due to lesions in the whate matter of the center nervous system. MS lesions evolve over time. "Active" lesions contain inflammatory cells such as lumphocytes, plasma cells, and macrophages in areas of demyelination, with evidence of phagocytosis of myelin and its breakdown products by macrophages. In contrast "inactive" lesions are hypocellular with scarring and loss of oligodendrocytes, the cells that produce myein. The presence of leukobytes in the CNS, where thay are normally absent, together with their early association with the demyelinating process, suggests that inflammation is involved in the pathogenesis of MS. Although the cause of MS is unknown, data from the published literature support immunologic or infectious factors leading to the state of chronic CNS inflammation. Migration of lymphocytes across the blood brain barrier and development of CNS inflammation is a hallmark of acute symptoms of multiple sclerosis. We will test the hypotheses that agents which interfere with the migration of cell by preventing adhesion of lymphocytes to capillary endothelium of the brain, will retard the inflammatory process and reduce or prevent the development of neurologic symptoms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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 92093 Timing: Fiscal Year 2001; Project Start 01-MAR-1997; Project End 31-MAY-2002 Summary: Amyotrophic lateral sclerosis (ALS), parkinsonism-dementia complex (PDC), and dementia, assumed to be a single disease entity, are highly prevalent, age-related neurodegenerative disorders among the people of Guam. Characteristically all show neuronal loss in the substantia nigra and/or anterior horn cells and severe hippocampal and neocortical neurofibrillary tangle formation. The tangles are identical to those encountered in Alzheimer disease (AD). Thus, clinically and pathologically this disease shows many aspects of the three major age- related neurodegenerative disorders encountered elsewhere in the world (ALS, AD, and Parkinson disease). Contrary to what has been reported, - the disease is not disappearing. Currently over 200 cases of ALSIPDC are in the Guam Patient Registry among an atrisk population of 17,000 individuals. However, the characteristics of the epidemic have changed. Fewer cases of ALS are seen, a greater proportion of patients present with presenile dementia, and the age of onset of necrologic impairment has increased by about 10 years. These changes support an environmental hypothesis with declining exposure, but other studies strongly suggest that an inherited gene(s) defect plays a significant role in susceptibility to this disease. The most likely model is that a gene- environment-interaction is responsible for ALS/PDC and dementia. The proposed program project, using epidemiologic, genetic, pathologic, and molecular biologic approaches, address i three major issues, 1) relevant genetic and environmental risk factors, 2) the pathogenesis and development of tau pathology, and 3) the potential role of oxidative stress and mitochondrial dysfunction. An important aspect involves the recognition that many relatively young Chamorros who die without a clinical diagnosis of ALSfPDC, show neuropathologic changes typical of ALS/PDC. This suggests that they have yet to accumulate a sufficient lesion burden to show clinical symptomatology. The study of brains of such individuals provides a truly unique opportunity to identify and characterize relevant pathogenetic features which are operative in the earliest phases of

Studies 17

the disease. The proposed research will provide critical insights into the etiology and pathogenesis of this major public health problem for the people of Guam, while also serving as a model for the study of analogous conditions seen elsewhere in the world. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AN ENU SCREEN OF THE MOUSE GENOME FOR NEW OF ALS Principal Investigator & Institution: Roder, John C. Professor; Samuel Lunenfeld Research Institute Research Office - Rm 850 Toronto, ON M5G 1X5 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant) We would like to understand the genetic basis of amyotrophic lateral sclerosis (ALS). For the familial form of the disease, mutations in SOD1 are implicated in pathogenesis but account for only a minority of cases (approx 15-20%). It is our goal to identify new genes that contribute to the etiology of ALS. We recently responded to an RFA from NIH with this goal (NIMDS-RFA-NS-01-004). We propose a novel, forward genetic screen in mice treated with ethly-nitroso-urea for mutants showing signs of ALS. This proposal is part of a large collaborative centre recently funded by the Canadian Foundation for Innovation and the MRC genome program which is now generating 5000 ENU mice per year. No one in the USA or elsewhere is carrying out such a screen. Our goal in this R21 is to generate pilot data that will show the feasibility of a screen for the clinical signs of ALS. This will include changes in gait and stride, loss of limb function and paralysis. Offspring of those mutants will be screened for neuropatholgy that includes a loss of motor neurons and muscle denervation. We will count Chat+ and Nissl+ cells in the facial nucleus and level T12-L3 of the spinal cord. Axon counts will be made on the facial nerve and the L4 ventral roots. A loss in cell number should be paralleled by an increase in Caspase+ve, Tunnel +ve cells. We will also measure disease onset. Mutants with both a decline in motor function and a loss of motorneurons will be selected for further study. Mutant mice will be crossed to C3H/HeJ for rough mapping to a chromosomal position by the core. We will focus on novel genes that do not map to the Sod 1 locus. In future years, we will carry out fine mapping to 0.1 cm and BAC contigs spanning this region will be generated. Candidates will be confirmed by transgenic rescue of ALS mutant mice by gene replacement with the mutated gene. Candidate genes will be sequenced and screened for loss of mRNA in affected tissue: motor cortex and spinal-motor neurons. In future years additional mutant alleles will be cloned and eventually sequenced. We will isolate suppressors and enhancers and elaborate the entire genetic pathway leading to ALS in mice. We will ultimately establish if the mechanism of gene action that leads to motorneuron loss involves oxygen radical toxicity, glutamate excitotoxicity, loss of trophic support or novel pathways Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANTISENSE INHIBITORS FOR TREATMENT OF MULTIPLE SCLEROSIS Principal Investigator & Institution: Ruffner, Duane E.; Salus Therapeutics 615 Arapeen Dr, Ste 102 Salt Lake City, UT 84108 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-JUL-2003 Summary: Multiple sclerosis (MS) is a debilitating neurodegenerative disease affecting greater than 300,000 Americans. The annual cost of MS. is in excess of 52.5 billion and the cost in terms of human suffering is immeasurable. Current treatments are few, and due to serious side -effects, their use is limited. There exists no cure for MS. Gelatinase-B

18 Sclerosis

also known as matrix metalloproteinase 9 (MMP-9), has been implicated in the pathogenesis of MS. Its secretion by lymphocytes is believed to be necessary for invasion and-breakdown of the blood brain barrier. Although broad spectrum inhibitors of all MMPs help to ameliorate the symptoms. they also produce severe side effects. Here we propose to develop anti-MMP-9 antisense therapeutics for the treatment of MS. The high specificity of these agents is expected to result in few or no side effects. Suitable targets for anti-MMP-9 antisense therapeutics will be identified and verified as outlined in specific aims l through 3. These studies will lead to the development of potent MS therapeutics in Phase II. l. Produce anti-MMP-9 antisense RNA and ribozyme libraries. 2. Use the libraries to identify effective anti~MMP-9 antisense RNA or ribozymes. 3. Verify the activity of effective antisense molecules by zymography. PROPOSED COMMERCIAL APPLICATIONS: Multiple sclerosis afflicts greater than 350,000 Americans at a cost in excess of $2.5 billion annually. The cost in terms of human suffering is immeasurable. Currently there are no truly effective therapies, nor is there a cure. Most, if not all MS therapeutics produce serious side effects limiting their use. This is likely due to their non-specific interactions on non-MS targets. In contrast, antisense therapeutics are highly specific. Antisense therapeutics for MS can be developed as highly potent, non- toxic therapeutics, with little or no side effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SCLEROSIS

APATHY

AND

COGNITIVE

IMPAIRMENT

IN

MULTIPLE

Principal Investigator & Institution: Christodoulou, Christopher; Neurology; State University New York Stony Brook Stony Brook, NY 11794 Timing: Fiscal Year 2001; Project Start 28-AUG-2001; Project End 31-JUL-2003 Summary: (Adapted from Applicant's Description): While researchers have searched for a relationship between the cognitive deficits and depression that are both common in multiple sclerosis (MS), numerous investigations have failed to find an association. This failure may stem from the multifaceted nature of depression. Measures of depression tap a spectrum of symptoms (e.g., dysphoric/depressed mood, somatic complaints), and some may be more relevant to cognition than others in neurological disorders such as MS. While apathy has been historically associated with depression, recent evidence indicates that apathy represents an important and distinct neuropsychiatric phenomenon in its own right. Researchers recently found that apathy played a key role in predicting cognitive dysfunction in a variety of neurological disorders (e.g., Parkinson's disease, progressive supranuclear palsy). In contrast, no link was found between cognitive impairment and dysphoric mood, a core feature of depression. While a relationship between apathy and cognitive impairment has been identified in over half a dozen neurological populations, it has not been adequately examined in MS. Apathy has been associated with neuroanatomical damage to regions that are often affected by the MS disease process (e.g., prefrontal cortex). In addition, apathy has been linked to neuropsychological deficits commonly found in MS (e.g., in working memory, executive functions). The proposed study will demonstrate how apathy, when separated from other factors traditionally associated with depression, can serve as a key marker of cognitive dysfunction in persons with MS. Subjects will consist of 80 MS patients. Apathy will be measured with the Apathy Evaluation Scale and the Apathy subscale of the Neuropsychiatric Inventory. Subjects will complete a battery of cognitive tasks focussed on executive functioning and working memory. It is hypothesized that apathy will correlate negatively with performance on tests of executive functioning and working memory, and that apathy will significantly add to the explanation of variance

Studies 19

in such performance beyond that accounted for by other neuropsychiatric variables measuring depression, fatigue, pain, and sleep disturbance. Empirical support for the initial hypotheses will lay the foundation for further rehabilitative research designed to improve both apathy and cognitive functioning in persons with MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ARGINASE AND REGULATION OF NITRIC OXIDE SYNTHASE IN ALS Principal Investigator & Institution: Ratan, Rajiv R. Director; Beth Israel Deaconess Medical Center St 1005 Boston, MA 02215 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 31-JUL-2005 Summary: (Adapted from applicant's abstract): Amyotrophic lateral sclerosis is a prevalent neurological disorder characterized by inexorable muscle weakness leading to death. The principal pathological finding in amyotrophic lateral sclerosis is loss of nerve cells in the anterior horns of the spinal cord, the motor nuclei of the brainstem, and the upper motor neurons of the cerebral cortex. Investigations aimed at preventing or limiting progression of amyotrophic lateral sclerosis have thus focused on the mechanisms by which neurons degenerate. A transgenic mouse model has been developed that possesses many of the pathological and clinical features of human familial and sporadic amyotrophic lateral sclerosis. As nitric oxide (NO) has been shown to mediate neuronal loss in other neurodegenerative conditions, several groups have investigated the role that NO may play in disease progression | in the transgenic model. The results have been conflicting likely because currently available inhibitors of nitric oxide synthase do not permit optimal control of NO generation within particular cell types and subcellular compartments. A novel potential strategy for regulating nitric oxide synthesis involves the enzyme arginase that can | regulate availability of arginine in the cytoplasm or mitochondria. In preliminary studies, we have shown that: 1) extracellular arginase blocks neuronal apoptosis and 2) arginase immunoreactivity is, upregulated in the spinal cord of ALS transgenic mice as well as humans with the sporadic and familial forms of amyotrophic lateral sclerosis. These preliminary results lead to the overall hypothesis to be tested in this proposal: about Interventions aimed at promoting arginase activities in microglia, astrocytes and/or motor neurons will limit availability of cell arginine for toxic NO generation and thereby diminish cell death and disease progression in amyotrophic lateral sclerosis but permit NO to, mediate its survival promoting effects in each of these cell types. We propose to test this hypothesis by: 1) determining the cell types and subcellular compartments where arginase is expressed in the normal central nervous system of humans and mice, and how the localization and levels of these isoforms change in amyotrophic lateral sclerosis as well as in a transgenic mouse! Model of amyotrophic lateral sclerosis and how this compares to the localization of NOS (all forms) in these tissues; and 2) determining whether increased arginase activity in microglia, astrocytes or neurons from control mice or mice over expressing SOD1 mutant (G93A) will abrogate NO mediated toxicity of motor neurons induced by growth factor deprivation, excitotoxins or LPS/IFN-gamma treatment. These studies promise to enhance our understanding of how arginine about metabolism, including the synthesis of NO, is regulated in the normal and abnormal nervous system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AUTOIMMUNITY CENTERS OF EXCELLENCE Principal Investigator & Institution: Chess, Leonard; Professor; Medicine; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2003; Project Start 28-SEP-1999; Project End 31-MAR-2008 Summary: (provided by applicant): The overall goals of this ACE renewal application will be to further develop our interdisciplinary basic and clinical research program at Columbia primarily focused on the evaluation of novel therapeutic approaches to human autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid and psoriatic arthritis (RA), multiple sclerosis (MS), type I diabetes mellitus (TIDM), biliary cirrhosis and scleroderma. In each of these diseases, there are ongoing basic and clinical research programs involving pathophysiologic and/or clinical immunotherapeutic studies. We hypothesize that there are four principal events involved in the immunopathogenesis of these diseases: (1) predisposing genes establish a T-cell repertoire capable of recognizing self peptides intrinsic to the autoimmune process; (2) previously tolerant autoreactive T-cell clones are activated, expand to change the T cell repertoire to reflect autoreactive effector T cells and migrate to sites of inflammation; (3) regulatory mechanisms, including cytokines and CD4+ and CD8+ regulatory T cells fail and (4) pathogenic autoantibodies and T cells effect tissue injury. We predict that reducing the clonal expansion and migration of relevant autoreactive T cells by blockade of TCR signaling with agents like anti-CD3 or interruption of the signaling and migration of autoreactive memory T cells with agents like anti-VLA-1 could down-modulate disease activity. We propose to test these hypotheses during the natural history of disease and during specific immune intervention. In this ACE renewal, we plan to continue ongoing studies of anti-CD3 therapy of TIDM, initiate trials of biliary cirrhosis employing Mycophenolate Mofetil and continue pre-clinical assessment of the VLA-1 pathway as a prelude to clinical trials with anti-VLA-1 moAbs anticipated to begin in 2004. During these studies, we will: (1) identify by PCR based CDR3 length techniques and TCR sequencing, autoantigen-driven expansions in the CD4 and CD8 cz_ TCR repertoire; (2) Identify changes in the T cell functional response to autoantigens and (3) directly study the regulatory interactions of TH1, TH2 as well as CD4+ and CD8+ T cells in controlling the TCR repertoire. In select patients, we will directly study cells at the site of inflammation (CNS, skin, kidney, joints) using HVS immortalization techniques as well as by laser capture technology for repertoire and microarray analysis of activated genes. In addition, we plan new basic studies of the control of the autoreactive T cell repertoire in autoimmune disease by analysis of EAE in the mouse and studies of human regulatory cells in TIDM. PROJECT 1: The Role of Human Cd8+ T Cells in Regulating the Self Reactive CD4+T Cell (Chess, L) PROJECT 1 (provided by applicant): During the past several years, we have defined a novel pathway of immunoregulation effected by CD8+ T cells which recognize and control the outgrowth of autoreactive CD4+ T cells expressing certain T cell receptor (TCR) V beta molecules (reviewed in Jiang, H., and L. Chess. Annu. Rev. Immunol. 18:185, 2000.). Interestingly, these TCR V beta specific regulatory CD8+ T cells have recently been shown to control the autoimmune CD4+ TCR V beta repertoire at a clonal level during the development of autoimmunity in mice. Moreover, the regulatory CD8+ T cells also cognitively discriminate between TH1 and TH2 cells and in vivo control the balance of TH1 and TH2 autoreactive T cells that emerge following autoantigen triggering. The precise specificity of these regulatory CD8+ T cells is not known, however, in mice they are restricted by MHC class Ib molecule, Qa-1. In this proposal, which is interactive with the Jiang project and relies on clinical material in the Herold anti-CD3 project, we will test the hypothesis that these CD8+ regulatory T cells control the emergence of autoreactive CD4+ T cells in type I human diabetes (Dr. Chess, PI) by specifically

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deleting or inactivating unique clones of autoreactive CD4+ TH1 cells. In man, we have developed evidence that TCR V beta specific CD8+ T cells can be identified and cloned from normal individuals. Interestingly, these CD8+ T cells can be restricted by HLA-E, the human homologue of Qa-1. We also have shown that these CD8+ T regulatory cells emerge during the course of human multiple sclerosis which are capable of specifically down regulating autoantigen (MBP) specific CD4+ T cells in a T cell receptor (TCR) V beta specific manner in vitro. In this project, we will extend these studies to type I diabetes (T1D) and determine if regulatory CD8+ T cells regulate diabetic activity and control the outgrowth of the autoreactive T cell repertoire and the TH phenotype in human T1D. Initially, we will concentrate on the control of CD4+ T cells reactive with putative diabetes associated antigens GAD and later extend this analysis to other islet cell specific or other T1D antigens including insulin and HSP. Moreover, because recent evidence suggest that certain HLA-E genotypes predict disease susceptibility to human T1D, we plan to identify known polymorphisms of HLA-E alleles in the T1D patients and correlate HLA-E polymorphic variations with the capacity to generate CD8+ regulatory cells and with clinical course. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AUTOIMMUNITY--MECHANISMS OF UNRESPONSIVENESS Principal Investigator & Institution: Fathman, C Garrison. Professor; Medicine; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2001; Project Start 01-SEP-1994; Project End 31-AUG-2004 Summary: The goal of this Program Project Grant (PPG) is to develop innovative immunotherapies for the treatment or prevention of the murine model of multiple sclerosis, experimental allergic encephalomyelitis (EAE). The first project studies the use of gene therapy to treat EAE. This project centers on delivery of regulatory proteins (cytokines and blockade of TNFalpha) to lesions of EAE. The second project tests another model of gene therapy using retroviral delivery of protein inhibitors to interfere with the function of NFAT and NFkappaB. The goals of the second project interrelate with those of the first project through the attempt to target the autoimmune T cells in lesions of EAE as potential targets of immune intervention. The third project proposed DNA vaccination as a potential immunotherapy of EAE. This project will assess the development of and regulatory effects of DNA vaccination on the development of immune response to various cell surface molecules involved in the inflammatory cascade in EAE. We believe these three projects provide an integrated attempt to explore fundamental issues in the development of immunotherapy of EAE. Insights gained from these studies may have enormous application to the future treatment of several different autoimmune diseases. Importantly, the three investigators have worked together developing the expertise and rationale for this proposal. The combined effort of these three investigators should provide the model of a successful PPG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AVIDITY MATURATION OF T CELLS IN MUTIPLE SCLEROSIS Principal Investigator & Institution: Forsthuber, Thomas G. Assistant Professor; Pathology; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS), which is thought to be mediated by an erroneous attack of T cells on myelin autoantigens present in the central

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nervous system (CNS). Characterization of the T cell epitopes targeted in MS patients has remained technically challenging, and the functional characteristics of the neuroantigen-specific T cells, particularly in the CNS, have remained unresolved. We have obtained preliminary results showing vigorous T cell responses to MOG peptides in PBL of MS patients by cytokine ELISPOT assay. Based on these results, we want to examine the MOG- specific T cell response in individual patients longitudinally over the course of MS, and test the epitope specificity and functional avidity of these cells. To overcome the difficulties that arise when examining M0G responses directly ex vivo from the brain of MS patients, we propose to study T cell responses in the CNS of "humanized" HLA-DR2 and -DR4 transgenic mice. Our preliminary studies have indicated that T cell responses in HLA-DR transgenic mice are directed against similar MOG epitopes as T cell responses in MS patients with this HLA-DR haplotype. We will test the hypothesis that MOG-specific T cells undergo avidity maturation over the course of MS, and high-avidity T cells accumulate in the peripheral blood of patients prior to relapses or exacerbation of disease. Furthermore, we will test the function of MOG-specific T cells by studying the fine specificity and functional avidity of these cells in the CNS. We will test this hypothesis in the fol1owing aims: In Aim 1 we will examine the MOG epitope-specific T cell response over time in MS patients by cytokine ELISPOT. In Aim 2 we will test the avidity maturation of MOG-specific T cells over the course of disease in MS patients. In Aim 3 we will test the MOG-specific T cell repertoire in the CNS of HLA-DR2 and -DR4 transgenic mice over the course of EAE. In Aim 4 we will test the avidity maturation of MOG-specific T cells in the CNS and blood of the transgenic mice over the course of EAE. At the end of this project, we will have learned whether MOG-specific T cells undergo avidity maturation in MS patients and how this relates to relapses/remissions. The experiments in the HLA-DR transgenic mice will complement the human studies and define the specificity and function of MOG-reactive T cells in the CNS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AVONEX (IFN B1A) IN SUBJECTS AT HIGH RISK FOR DEVELOPMENT OF MULTIPLE SCLEROSIS Principal Investigator & Institution: Brod, Staley A. Associate Professor; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, TX 77225 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 28-FEB-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AXONAL OLIGODENDROCYTE SIGNALING IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Devries, George H. Professor of Cell Biology,; Cell Bio & Neurobio & Anatomy; Loyola University Medical Center Lewis Towers, 13Th Fl Chicago, IL 60611 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Our long-term objective is to determine the axonal factors involved in the failure to remyelinate in diseases such as multiple sclerosis (MS). In the studies proposed here, we will isolate and characterize axonal factors that control the migration, proliferation, and survival of oligodendrocyte precursor cells (OPC cells). We focus on the initial stages of developmental myelination to gain an understanding of the molecular functions and factors that lead to normal development of a myelin sheath.

Studies 23

Then we will investigate those same functions and factors in MS brains to determine which factors are inappropriately expressed. We hypothesize that imbalances of axonalrelated growth factors contribute to the failure of remyelination in MS. In Specific Aim 1 we will characterize a process by which axonal molecules are released from a membrane fraction enriched in axonal plasma membrane. We will use medium that has been conditioned with OPC cells to stimulate the axonal-enriched fraction. Western blotting will be used to characterize the nature of the axonal factors (e.g., growth factors of different types) that are released from the axonal surface membrane. We will also characterize the types of receptors that have been activated. In Specific Aim 2 we will investigate the influence of axonal factors and how axons regulate migration, proliferation, and survival of OPC cells. Preliminary studies found that solubilized factors can stimulate proliferation. Migration assays using both soluble and particulate fractions will allow us to determine whether axonal contact and/or soluble factors released from axonal membrane are responsible for initiation and cessation of migration and proliferation. Specific Aim 3 directly tests the hypothesis that the axonoligodendrocyte balance is altered in MS. Demyelinated areas from MS brain will be analyzed for growth factor composition (both type and ratio among them) in order to understand why oligodendrocytes migrate to the demyelinated region, proliferate, but do not remyelinate the demyelinated axons. We will obtain important information about the axonal molecules that control the early events of myelination (i.e. migration, proliferation, and survival of OPC cells), which eventually will enable researchers to pinpoint areas for therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AXONAL PATHOLOGY DURING THE COURSE OF MULTIPLE SCLEROSIS Principal Investigator & Institution: Trapp, Bruce D. Professor; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, OH 44195 Timing: Fiscal Year 2002 Summary: This proposal is based on the hypothesis that axonal loss is the major cause of irreversible neurological signs and symptoms in multiple sclerosis patients. The principal investigator has designed a series of experiments to address fundamental questions regarding axonal loss and other axonal lesions in multiple sclerosis plaques and in two animal counterparts (Aims 1-3); he also intends in Aim 4 to assess the status of oligodendrocytic precursor cells in and around multiple sclerosis plaques. Multiple sclerosis spinal cord, almost exclusively postmortem, will be obtained by rapid autopsy; axonal counts from these patients versus controls will be collected by morphometric techniques and subjected to statistical analyses. Similar manipulations will be performed on animal models of inflammatory demyelination and experimental spinal cord trauma. The investigator proposes in Aim 1 to quantify axons, terminal ovoids, and myelin sheaths in MS spinal cord sections immunostained with antibodies to neurofilaments, both phosphorylated and non-phosphorylated, proteolipid protein and MHC class II molecules through a morphometric analysis of the demyelinative plaques, as well as periplaque proximal and distal axonal reactions. These measurements will be made in acute to chronic plaques and compared to each other and to controls. Confocal microscopy of double-labeled fluorescent preparations will be a major source of this data. The axonal lesions will be correlated with tissue levels of N-acetyl-aspartic acid, utilizing HPLC, in sections serial to the ones studied morphologically. This same approach will be used in rat spinal cord (Aim 2), which has been transected and examined at 2, 7, 14, 16, and 120 days post-transection. Aim 3 is to do a comparable

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analysis utilizing a mouse model of chronic relapsing EAE that has been induced through the administration of a portion of the proteolipid protein. The final series of experiments (Aim 4) will attempt to characterize the distribution and determine the functional subpopulations of oligodendrocytic precursor cells in acute and chronic multiple sclerosis lesions by using antibodies to NG2, PDGFar, GRO-ar, erbB 2,3,4, P75 plus Trk A, p75 minus Trk A, fas, and activated caspase 3. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: B CELL RESPONSES IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Gilden, Donald H. Professor; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, CO 800450508 Timing: Fiscal Year 2001 Summary: Increased IgG and oligoclonal bands (OGBs) are found exclusively in the CSF of patients with infectious and inflammatory diseases of the CNS, particularly multiple sclerosis (MS). Although their specificity in MS is unknown, in infectious diseases of the CNS, OGBs are specific for the agent that causes disease, thus providing a rationale for our hypothesis that OGBs in MS brain and CSF are directed against the antigen that causes disease. To distinguish between a specific versus a random humoral response, we sequenced IgG heavy (V/H) and light (V/L) chain variable regions expressed in multiple acute MS plaques and found a restricted response consisting primarily of V/H4 germline genes. Some V/H sequences were over-represented, clonally expanded, and displayed a non-random accumulation of somatic mutations, features indicative of an antigen driven B cell response. A parallel analysis of subacute sclerosing panencephalitis (SSPE) brain also revealed over-represented and somatically mutated V/H and V/L sequences. We co-expressed these sequences in mammalian expression vectors and showed that the recombinant IgG was specific for measles virus (the cause of SSPE) in infected tissue culture cells. We will exploit our success with recombinant measles virus specific antibody to identify measles antigen in SSPE brain. Information accumulated from SSPE will be used to synthesize recombinant antibodies from candidate MS sequences to demonstrate their immunologic specificity, for either protein or carbohydrate antigens. Once specificity is established, we will screen phage display cDNA libraries from MS brain to identify and characterize cDNAs whose protein products react with MS recombinant antibodies or with IgG purified from acute MS plaques. We will also continue to sequence V/H regions from acute MS plaques to determine if restricted use of specific V/H4 or other family germlines is characteristic of MS. We are well-prepared to conduct these studies because we have: (a) pathologically verified acute MS brains and non-MS neurologic disease brains; (b) a demonstrated ability to identify disease- relevant IgG sequences from human brain, and to use these sequences to generate recombinant IgG specific for the agent that causes disease; (c) the expertise in molecular biology to construct and screen complex cDNA libraries; and (d) CSF containing OGBs from patients with MS and other CNS inflammatory diseases. Identification of an MS-specific antigen will have wide application, not only for early definitive diagnosis, but also for developing strategies for modulation, if not prevention, of disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOBEHAVIORAL MODEL OF STRESS AND MULTIPLE SCLEROSIS Principal Investigator & Institution: Ackerman, Kurt D. Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260

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Timing: Fiscal Year 2001; Project Start 01-JUL-1997; Project End 30-JUN-2004 Summary: The applicant has a long-standing interest in behavioral medicine research, with particular emphasis on the role of stress and mental health in the development of medical disorders. He has received an M.D. and Ph.D. in Neurobiology and Anatomy and is Board Certified in General Psychiatry. His previous research has involved identification of communication, routes between the central nervous system (CNS) and the rodent immune system, which may be involved m stress-related immune changes and the development of immune-mediated disorders. This Mentored Research Scientist Development Award is designed to provide him with the skills necessary to pursue his long-term goals of conducting longitudinal human studies of stress-related health changes, understanding the psychological and biological factors which govern this relationship, and developing appropriate treatment strategies for prevention of stressrelated medical illness. To achieve these goals, the applicant has proposed a series of career development activities and research studies under the mentorship of Dr. Andrew Baum, exploring the role of stress in the autoimmune disorder multiple sclerosis (MS). MS is one of the most common neurologic disorders, produced by immune-mediated destruction of the CNS. Since the earliest descriptions of MS, stress has been considered an important factor contributing to the progression of the disorder; however, there have been few systematic studies in this area. During the award period, the candidate will conduct a prospective longitudinal study of stress and health in MS patients, while monitoring mental health and biological factors which may play a role in stress- related exacerbations. This research experience will be supplemented by career development activities supervised by pioneering researchers at the University of Pittsburgh, Ohio State University, University of Chicago, and University of California, Los Angeles. The proposed training program is designed to develop the candidate's expertise in: 1) longitudinal study design and analysis; 2) autonomic and neuroendocrine regulation of the immune system; 3) use of animal models of autoimmune disorders; 4) statistical modeling of stress and disease; and 5) the development of interventions for stressrelated medical disorders directed at physical and mental health; and will give him the skills necessary to pursue an independent academic career in behavioral medicine research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIODEMOGRAPHY OF GENETIC DISEASE Principal Investigator & Institution: Carnes, Bruce A.; National Opinion Research Center 1155 E 60Th St Chicago, IL 60637 Timing: Fiscal Year 2001; Project Start 01-MAY-1999; Project End 30-APR-2004 Summary: This Independent Scientist Award derives from an ongoing effort to investigate age patterns of mortality in populations from a biological perspective. Evolution theory predicts natural selection's ability to influence gene expression begins a decline at the age of sexual maturity that reaches negligible levels by the ages when reproduction ceases. This age gradient for selection permits the life span to be partitioned into biologically meaningful age ranges-a pre-reproductive period, a reproductive period, and a post-reproductive period. Biodemographic research influenced by evolution theory has led to a mortality classification that distinguishes between genetic and non-genetic causes of death and has generated predictions and testable hypotheses about the age distribution of deaths with a genetic etiology. Emerging research on the molecular etiology and pathogenesis of disease suggests that genetic diseases can be further partitioned into those that are heritable and those thought to arise from the accumulation of acquired genetic damage. This award is

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designed to permit the PI to permanently leave his position as a radiation biologist, move into research and teaching in the field of aging full-time, receive training in subjects relevant to biodemographic research, and pursue a series of research projects associated with the training that initially focus on the biodemography of genetic diseases in humans. The results derived from this award will have relevance for the estimation of lower limits to age-specific death rates, upper limits to human longevity, and forecasting life expectancy and the size of the older population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOLOGICAL ROLES OF COPPER IN HUMAN NUTRITION Principal Investigator & Institution: Gitlin, Jonathan D. Professor; Pediatrics; Washington University Lindell and Skinker Blvd St. Louis, MO 63130 Timing: Fiscal Year 2001; Project Start 30-SEP-1992; Project End 29-SEP-2005 Summary: Copper is an essential trace element with a critical role in the biochemistry of cellular respiration, iron homeostasis and antioxidant defense. The long-term objective of these studies is to define the cellular and molecular determinants of human copper metabolism. Recent studies have revealed that the delivery of copper to specific pathways within the cell is mediated by a unique class of intracellular carrier proteins termed copper chaperones. The studies in this proposal are intended to elucidate the role of the copper chaperone for superoxide dismutase (CCS) in intracellular copper homeostasis and in the pathogenesis of familial amyotrophic lateral sclerosis (FALS) in patients with inherited mutations in Cu/Zn superoxide dismutase (SOD1). Structure/function studies will be accomplished using site-directed mutagenesis and expression of CCS in cells from mice with a germline deletion of the CCS gene. The interaction of CCS and SOD1 in intact, living single cells will be analyzed using blue and green fluorescent fusion proteins and fluorescence resonance energy transfer microscopy. The molecular and cellular mechanisms determining copper trafficking to CCS from cytoplasmic or storage sites will be elucidated by identification and characterization of novel CCS interacting proteins. Finally, the precise role of CCS in the pathogenesis of FALS will be evaluated by examining disease onset and progression in FALS SOD1 transgenic mice bred onto the genetic background of CCS deficiency. Taken together the results of these studies will permit new insights into the mechanisms of intracellular copper homeostasis and may allow for novel nutritional strategies to prevent or ameliorate human disease. The long-range objective of these studies is to define the cellular and molecular determinants of human copper metabolism. Four specific aims are identified: 1. To perform a detailed structural and functional analysis of the copper chaperone for superoxide dismutase (CCS). 2. To define the spatial and temporal interaction of CCS and SOD1 in living cells. 3. To elucidate the mechanisms of intracellular copper trafficking to CCS. 4. To examine the role of CCS in the pathogenesis of neuronal degeneration in familial amyotrophic lateral sclerosis (FALS). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOMARKER OF NEUROPROTECTANT EFFICACY IN ALS Principal Investigator & Institution: Gabbita, Somasundar P.; Phase 2 Discovery, Inc. 3130 Highland Ave, 3Rd Fl Cincinnati, OH 45219 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2004 Summary: (provided by applicant): The objective of this Phase I feasibility study is to develop a reliable biomarker of neuronal damage in a validated mouse model of amyotrophic lateral sclerosis (ALS). Currently, there is no widely accepted biomarker to

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quantify ALS-induced motor neuron injury. Previously, we have shown that neuronal degeneration in rodents and humans results in cleavage of the cytoskeletal protein MAP-tau. Our laboratory has developed a sensitive ELISA that specifically measures cleaved MAP-tau (C-tau) in rodent models of traumatic brain injury and bacterial meningitis. Using this C-tau ELISA assay, our preliminary studies demonstrate that spinal cord C-tau levels are tenfold higher in late stage symptomatic ALS (G93A-SOD1 mutation) mice as compared to control mice. Using a rotorod motor performance assay, Hensley et al. have recently demonstrated that administration of Nor-dihydroguaiaretic acid (NDGA) to ALS mice delays onset of neurologic deficits. We hypothesize that 1) Ctau is a reliable biomarker of motor neuron injury in ALS mice and 2) C-tau can serve as a screening tool to identify neuroprotectant drags for treating ALS. We will test these hypotheses by determining the relationship between C-tau levels and progression of neurologic deficits in ALS mice. Furthermore, we will test whether the demonstrated neuroprotectant effect of NDGA that delays onset of neurologic deficits in ALS mice also exerts expected effects on C-tau levels. Our Specific Aims are: Specific Aim 1: Compare spinal cord C-tau levels in ALS mice and control mice at 120 days. Specific Aim 2: Determine the relationship between C-tau levels and neurologic deficits in ALS mice as compared to controls. Neurologic deficits and spinal cord C-tau levels will be determined in ALS and age-matched control mice and statistically compared from the presymptomatic stages to late symptomatic stages of disease progression. Specific Aim 3: Determine if C-tau levels reliably quantify the effect of a demonstrated neuroprotectant drag intervention in ALS mice. C-tau levels and rotorod performance will be determined and compared as a function of NDGA treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BONE MARROW DERIVED MESANGIAL CELL PROGENITORS IN AGING Principal Investigator & Institution: Striker, Gary E. Professor; Medicine; University of Miami Box 016159 Miami, FL 33101 Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 30-APR-2006 Summary: (Adapted from the Applicant's Abstract): Our preliminary data suggests that mesangial cell precursors are derived from the bone marrow. The purpose of this proposal is to determine if the mesangial sclerosis that characterizes accelerated aging originates in bone marrow precursors. A gradual loss in renal function during aging is not inevitable. It occurs in those elderly individuals who are sclerosis-prone and who have intercurrent diseases such as hypertension or diabetes. Thus, there are two aging populations, one that may develop renal disease (sclerosis-prone) and one that does not (sclerosis-resistant). We developed strains of sclerosis-resistant (C57) and sclerosis-prone (ROP) mice that model these two populations. Kidney lesions were mild or absent in aging C57 mice. Aging ROP mice had modest glomeruloscierosis, in the absence of an injury, but the process was sharply accelerated, and occurred at an earlier age with a reduced nephron number (due to the Os gene) or diabetes mellitus. We propose that the glomeruloscierosis found in sclerosis-prone mice with reduced renal mass (ROP Os/+) mice could be used as a model of accelerated aging. The glomeruloscierosis in ROP Os/+ mice was restricted to the mesangial regions and was characterized by a stable mesangial cell phenotypic changes. We hypothesize that the phenotypic changes arise in the bone marrow. We propose to confirm the bone marrow origin of mesangial cell progenitors and to determine if the site of the phenotypic change induced by rapid aging in sclerosis-prone mice is in the marrow or the kidney. We will determine if mesangial cell progenitors can be isolated from the bone marrow and/or the circulation.

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We will also assess the effect(s) of donor and recipient age on the number and ability of mesangial precursors to repopulate and induce/reduce glomerular lesions. Finally, we will examine the gene expression pattern of the phenotypic changes in mesangial cells by DNA microarrays. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CALPAIN ACTIVATION OF T CELLS IN DEMYELINATING DISEASE Principal Investigator & Institution: Banik, Naren L. Professor; Neurology; Medical University of South Carolina 171 Ashley Ave Charleston, SC 29425 Timing: Fiscal Year 2001; Project Start 15-JAN-2001; Project End 30-NOV-2005 Summary: (adapted from applicant's abstract): Although the cause of multiple Sclerosis (MS) remains unknown, there is strong evidence that demyelination and inflammation are mediated by a 7 cell autoimmune mechanism. Since CD4 7 ceils are important in the etiology and pathogenesis of MS, the mechanisms by which these cells become activated are crucial to understanding and treating demyelinating diseases. This proposal examines the role of calpain, a calcium-activated neutral proteinase, in activation of peripheral blood mononuclear cells (PBMC) cultures. One important factors involved in T cell activation is a transcription factor, nuclear kappa B (NFkB). The activation of NFicB promotes interleukin-2 (IL-2) synthesis, CD25 expression, T cell proliferation, and T cell survival, It has been suggested that NFB is activated by neutral proteinase(s) calpain may be one such participant. Calpain has been shown to be involved in T cell proliferation and integrinmediated cell migration. Also, in demyelinating diseases (i.e., MS), the content and activity in inflammatory cells, such as CD4+ T cells, is significantly increased. From these findings, we propose the following hypotheses: (I) Calpain has a central mle in the activation of PBMCs, degradation of IkBa, and activation of NFkB promoting IL-2 synthesis; (II) Calpain activity and expression may be altered in PBMC and myelin basic protein (MBP) -specific T cells of MS patients during the course (relapse and remission) of the disease; (HI) Released calpam from activated MBPspecific T cells may contribute to epitope spreading and demyelination. These specific aims will be used to investigate these goals: (1) Examine and characterize the role that calpain plays in IL-2 synthesis and CD25 expression; (2) Examine 1KB degradation and NFkB activation and characterization of calpain interaction with 1KB in normal PBMCs; (3) Measure the expression and activity of calpain in PBMCs of MS patients and the susceptibility of these cells to calpain inhibition; (4) Measure the expression and activity of calpain in MBP-specific T cells of MS patients and the ability of calpain to produce immunogenic peptides from intact human MBP. Understanding the mechanisms involved in T cell activation and proliferation and the progression of demyelination may help to develop therapeutic strategies for the treatment of MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CANNABINOID SIGNALING SYSTEM IN MICROGLIAL CELL Principal Investigator & Institution: Stella, Nephi; Pharmacology; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-APR-2006 Summary: Delta9-tetrahydrocannabinol (THC) is best known as a psychotropic agent. Yet, this agent also produces multiple non- psychotropic effects; in particular reducing immunologic competence. These effects raise the possibility that cannabinoids regulate inflammations occurring within the CNS. The work proposed here addresses the role of

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cannabinoids in the regulation of microglial cell activation. Microglial cells are immune cells that reside in the CNS and become activated in diseases such as multiple sclerosis and HIV encephalopathy. Activated microglial cells release toxins and cytokines that lead to remodeling of affected tissue. By analogy with peripheral macrophages, we hypothesize that the engagement of cannabinoid receptors on microglial cells tempers their activation process. This hypothesis is supported by the observation that cannabinoids inhibit CNS inflammation associated with experimental allergic encephalomyelitis, an animal model of multiple sclerosis. In addition, several small clinical studies indicate that patients with multiple sclerosis experience relief from symptoms with marijuana use. We propose to identify and characterize the cannabinoid signaling system in microglial cells. The specific aims are: 1: What types of cannabinoid receptors do resting or activated microglial cells express? 2: How are endocannabinoids generated by microglial cells? 3: Do microglial cells inactivated endocannabinoids? Understanding how cannabinoids interact with microglial cells is of particular interest because patients with multiple sclerosis and HIV encephalopathy often use these drugs for medicinal purposes, and because recent evidence implicates cannabinoid signaling pathways in the symptomatology of these diseases. Finally, because cannabinoids are immunoactive, characterization of the cannabinoid signaling system in microglial cells might lead to new pharmaceutical targets that could specifically temper inflammation of the CNS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CD24 AS A THERAPEUTIC TARGET FOR MULTIPLE SCLEROSIS Principal Investigator & Institution: Zhou, Qunmin; Oncoimmune, Ltd 1474 Bridgeton Dr Columbus, OH 43220 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2003 Summary: (provided by the applicant): A major long-term goal of the OncoImmune LLC is to develop therapeutic agents for the treatment of multiple sclerosis. Compelling evidence indicates that autoreactive T cells are involved in pathogenesis of Multiple Sclerosis (MS). Since the MS patients have accumulated large numbers of autoreactive T cells, a major challenge is to prevent the effector function of pre-existing autoreactive T cells by targeting the molecules involved in the effector function of T cells regardless of their antigen-specificity. In this regard, we have recently established that the CD24 gene is a critical checkpoint, beyond induction of self-reactive T cells, in the development of acute experimental autoimmune encephalomyelitis (A-EAE), a murine model of human MS. More importantly, the fusion protein consisting of the extracellular domain of the CD24 and the Fc portion of the human immunoglobulin (Ig), drastically reduces the clinical symptoms of acute EAE when administrated after self-reactive T cells are produced. In this phase I application, we wish to extend our observation into the relapsing EAE (R-EAE) model that closely resembles the clinical course of human MS. We will produce a large amount of CD24Ig fusion protein or soluble CD24 and test their efficacy in treating relapsing EAE in SJL mice. In addition, the ability of CD24Ig or soluble CD24 to prevent "epitope-spreading" in antigen recognized by T cells will also be evaluated. Our study will provide solid evidence for the therapeutic potential of CD24-based drugs. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CEREBROSPINAL STUDIES IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Weiner, Howard L. Robert L. Kroc Professor of Neurology; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115

30 Sclerosis

Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 30-NOV-2001 Summary: The purpose of this protocol is to develop new laboratory tests in order to both diagnose and follow the course of multiple sclerosis patients. These tests could potentially lead to new treatments for multiple sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHARACTERIZATION OF AUTOIMMUNE T CELL RESPONSES IN MS Principal Investigator & Institution: Karandikar, Nitin J. Pathology; University of Texas Sw Med Ctr/Dallas Dallas, TX 753909105 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2004 Summary: (provided by applicant): Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS) and is responsible for long-term morbidity in 250350,000 people in the United States. Although the precise etiology of MS is unknown, this inflammatory disorder is associated with histologic features suggestive of autoimmune destruction. Myelin-specific immune responses are demonstrable in the peripheral blood and cerebrospinal fluid of MS patients. Autoimmune T cell responses may be directed against various target antigens in the CNS, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG). To understand the pathogenesis of MS, it is crucial to elucidate the fine specificity and exact nature of autoantigen specific responses. Recent powerful methodologies emerging in other areas of Immunology have enabled us to sensitively and specifically characterize human immune responses. We propose to apply these techniques to address important questions regarding the fine specificity, cytokine profile, and the T cell repertoire of responses in MS. In addition, dynamic evolution of these responses will be studied longitudinally in MS patients at different clinical stages of the disease, to study the pathogenic role of "epitope spreading." CNS antigen-specific responses may sometimes be observed in healthy individuals, although these responses are qualitatively different. Prior work suggests that responses from healthy individuals may differ in their costimulatory requirements. Building on these results, we will elucidate the costimulatory requirements of autoreactive T cells and address intrinsic differences in the T cell repertoire in different sets of T cells. The Candidate will be primarily responsible for the formulation of experiments and data analysis and interpretation. His co-Mentors are well-established investigators in distinctive areas of Immunology. The University of Texas Southwestern Medical Center has an excellent environment for basic and clinical research. The Candidate has doctoral experience in Immunology research, specifically in an autoimmune murine model of multiple sclerosis and has recently finished residency and fellowship training in Hematopathology. He will utilize this career development award to further develop new expertise in cutting-edge technology and learn newer approaches in human Immunology, at the same time logically building on his past experience in autoimmunity, in a related area of human disease. This will greatly facilitate his eventual transition into an independent physician-scientist at an academic medical center. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHEMOKINE RECEPTOR EXPRESSION ON MBP REACTIVE T CELLS Principal Investigator & Institution: Calabresi, Peter A. Associate Professor; Neurology; University of Maryland Balt Prof School Baltimore, MD 21201 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2003 Summary: (Adapted from the Investigator's Abstract): Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) of unknown etiology. It is the most common non-traumatic cause of neurologic disability in young adults. Although three drugs have been approved to treat the symptoms of MS, they are not a cure. Development of more effective treatment strategies will be improved by a greater understanding of the pathogenic events in this disease. The pathology of MS is characterized by perivascular infiltration of mononuclear cells. Several lines of evidence suggest that costimulation independent (memory) myelin basic protein (MBP) reactive T cells exist preferentially in MS patients' blood and may be involved in initiating the inflammatory response. T cell activation requires at least two signals: antigen presented in the context of major histocompatibility complex (MHC) class II and a second, costimulatory, signal of binding the CD28 receptor on the T cell. In MS, it is thought that the activated T cell then preferentially produces specific Th1 cytokines that upregulate adhesion molecules on endothelial cells and promote migration into the CNS, where demyelination occurs. Chemokines (CK) are chemoattractant cytokines that mediate tissue specific migration of T cells that express certain chemokine receptors (CKR). In MS, CK and CKR expression are thought to be an important mechanism by which antigen driven T cells migrate to sites of inflammation, but there is little data to support this concept. The investigators will examine CKR expression, function, and correlation with cytokine profiles through the following specific aims: Specific Aim 1. To determine whether MBP reactive memory T cells express more CCR5 and CXCR3 than MBP reactive naive T cells or TT reactive memory cells: a) using primary proliferation assays to isolate the MBP and TT reactive memory T cells that are costimulation independent (do not require CD28 signal) from MS patients, as compared to ONDs and controls; and b) quantifying CKR expression on these cells (by FACS ) and function (by migration studies). Specific Aim 2. To evaluate whether memory MBP reactive T cells that express CCR5 and CXCR3 produce more of the Th1 cytokines: a) isolating T cell subsets with specific CKR profiles by FACS and migration analysis; and b) quantifying cytokine production by intracytoplasmic staining (using flow cytometry). Specific Aim 3. To investigate whether VCAM binding to VLA-4 on T cells alters the expression of CKR on MBP reactive T cells by: co-culturing MBP reactive T cells with VCAM expressing endothelial cells or VCAM-Ig, and analyzing CKR expression by FACS or ELISA. The results from these aims will enhance our understanding of MBP reactive T cells as a model for the pathogenic events in MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL RESEARCH PROGRAM FOR THE PARTIAL EPILEPSIES Principal Investigator & Institution: Engel, Jerome J. Professor; Neurology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2001; Project Start 01-JAN-1985; Project End 31-AUG-2005 Summary: The UCLA clinical neurophysiology program project (CNP) is composed of tightly-coordinated, interactive, multi-disciplinary investigations into the fundamental mechanisms of human temporal lobe epilepsy by the collaborative efforts of a team for clinical and basic neuroscientists who have been working together for a number of

32 Sclerosis

years. The CNP is currently in its 38th year of NIH funding, and has continued to take advantage of the unique opportunities offered by an epilepsy surgery facility to carry out invasive research on patients with epilepsy. Emphasis was placed initially on clinical research, but by 1981 the program project became devoted entirely to basic research on normal and abnormal function of the human temporal lobe. Beginning with our last renewal, we further narrowed our focus to investigate only epileptic mechanisms of the hippocampus, particularly hippocampal sclerosis, and also began to include experimental animal models of human temporal lobe epilepsy. With this application, all subprojects integrate studies of temporal lobe epilepsy in patients, with parallel studies in the intra-hippocampal kainate rat model, which morphologically, electrophysiologically, and behaviorally resembles human mesial temporal lobe epilepsy with hippocampal sclerosis. Experimental protocols include in vivo electrophysiology and microdialysis, as ell as in vitro neurochemistry and molecular microanatomy, molecular and cellular physiology, and local circuit physiology, in patients and animals, with a particular emphasis on elucidating the role of the dentate gyrus in the epileptogenic properties of sclerotic hippocampus. We propose three subjects to investigate: i) molecular alterations in glutamate receptors on interneurons and their functional correlates; ii) changes in cellular excitability resulting from altered intracellular neurochemistry, neurotransmitter receptor function, and network characteristics; and iii) the neuroanatomical and neurochemical substrates of unique interictal and ictal epileptiform electrophysiological events recorded from the intact brain. We anticipate that elucidation of fundamental mechanisms underlying epileptic abnormalities of mesial temporal lobe epilepsy, the most common, and most refractory, form of human epilepsy, will ultimately result in new approaches to diagnosis, therapy and prevention of epilepsy, and its adverse biological consequences. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLINICAL TRIAL OF TOPIRAMATE IN ALS Principal Investigator & Institution: Cudkowicz, Merit E. Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, MA 02114 Timing: Fiscal Year 2001; Project Start 29-JUL-2000; Project End 30-JUN-2003 Summary: Amyotrophic lateral sclerosis (ALS) is a progressive, uniformly lethal neurodegenerative disorder. Recent genetic and biochemical studies implicate glutamate excitotoxicity, free radical toxicity, and mitochondrial dysfunction as possible causes of familial ALS and sporadic ALS. This study will test the hypothesis that glutamate excitotoxicity plays a role in the pathogenesis of ALS. If this hypothesis is correct, pharmacological agents that block glutamate receptors may be therapeutic in ALS. The proposed study will determine whether therapeutic intervention with the topiramate, a glutamate receptor blocking agent, will slow the progressive deterioration of motor function in subjects with ALS. Topiramate is a FDA approved agent for epilepsy. Topiramate has modulatory effects on glutamate neurotransmission by blocking kainate/alpha-amino-3-hydroxy-5- methyl-4-isoxazole-propionic acid (AMPA) excitatory receptors. Topiramate protected motor neurons in an in vitro model of chronic glutamate toxicity in a dose dependent fashion. The applicant will conduct a double-blind, randomized, placebo- controlled, study of the safety and efficacy of Topiramate therapy in slowing of disease progression in 288 patients with ALS. All patients will be recruited from the Massachusetts General Hospital and 15 other clinical sites. The primary outcome measure is change in upper extremity motor function after twelve months of experimental therapy as tested with quantitative neuromuscular examination. Secondary outcome measures include grip strength, forced vital capacity,

Studies 33

the ALS functional rating scale, and the safety and tolerability of topiramate in this population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLONAL SELECTION IN DIABETIC NEPHROPATHY Principal Investigator & Institution: Lenz, Oliver; Medicine; University of Miami Box 016159 Miami, FL 33101 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): The prevalence of diabetic nephropathy,the leading cause of end-stage renal failure, has been rising over the past years; despite recent advances in the management of diabetic patients.We have previously shown that the susceptibility to develop progressive glomerulosclerosis varies between mouse strains as it does between different ethnic groups. We identified both sclerosis-prone (ROP) and sclerosis-resistant (C57BL/6) mouse strains, and found that mesangial cells from these strains respond differently to glucose. Our preliminary data show that different subpopulations exist among mesangial cells isolated from sclerosis prone mice. They are characterized by a different length in the d(CA) repeat in the MMP-9 promoter, which recently has been linked to the risk of developing diabetic nephropathy. Rather than using this dinucleotide repeat for linkage studies, we propose that it can be used as a marker for mesangial cell sub-populations. In ROP mesangial cells, we identified single cell clones with d(CA)20 and d(CA)24 repeats. After exposure to high glucose levels, all mesangial cells isolated from ROP mice contained the d(CA)24 dinucleotide repeat. No heterogeneity in the d(CA) dinucleotide repeat length was detected at baseline in mesangial cells isolated from sclerosis-resistant C57BL/6 mice, and no change was observed after exposure to high glucose levels. This led us to propose that in susceptible individuals, diabetes mellitus leads to the clonal expansion of one of the mesangial subpopulations responsible for progressive glomerulosclerosis, and that the length of the d(CA) repeat in the MMP-9 promoter is a suitable marker to distinguish the different sub-populations. We will test the hypothesis that exposure to high glucose levels leads to a clonal selection in mesangial cells cultured from sclerosis-prone ROP mice. We will analyze the differences in gene expression that characterize sub-populations of mesangial cells in low and high glucose levels. The long-term goal of our proposal is to characterize the role of clonal selection in glomerular disease, and identify new targets for screening, prevention, and intervention in the pathogenesis of diabetic nephropathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLONING PROLIFERATION

GENES

THAT

REGULATE

MYOCARDIOCYTE

Principal Investigator & Institution: Field, Loren J. Professor; Medicine; Indiana UnivPurdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, IN 462025167 Timing: Fiscal Year 2001; Project Start 01-JUL-1990; Project End 28-FEB-2003 Summary: Cardiomyocytes in the adult mammal exhibit little if any capacity to undergo cell division. Consequently cardiomyocyte loss due to injury or disease is irreversible. Identification of the gene products which regulate cardiomyocyte proliferation and terminal differentiation might provide useful molecular targets with which to induce therapeutic myocardial growth in the adult heart. We have used cardiomyocyte cell lines derived from transgenic mouse tumors to identify 3 proteins (p193, p107 and p380) which bind either directly or indirectly to the SV40 Large T-Antigen (T-Ag) oncoprotein. In addition, we have cloned the mouse cDNA and genes from the Tuberous Sclerosis

34 Sclerosis

Complex (TSC) 1 and 2 loci: TSC is an autosomal dominant familial cancer which affects a variety of organs including the heart. We hypothesize that these proteins participate in the regulation of cardiomyocyte proliferation and/or terminal differentiation. In support of this, experiments performed during the current funding period have shown that p193 exhibits tumor suppressor activity in NIH-3T3 cells, and that p107 and TSC2 impact upon cardiomyocyte terminal differentiation and proliferation, respectively. In this competitive renewal application, we propose to further test our hypotheses with additional gain and loss of function models. Four Specific Aims are proposed. In Aim number 1, we will generate gain and loss of function transgenic mice to ascertain the role of p193 in normal and pathologic cardiac development, as well as identify the cellular proteins which interact with p193. In Aim 2, we will establish the molecular mechanism by which p107 expression renders the hearts of transgenic mice resistant to isoproterenol-induced hypertrophy, as well as determine if these animals are resistant to other hypertrophic stimuli. In Aim 3 we will isolate and clone p380, a novel myocardial p53 binding protein, and will generate gain and/or loss of function transgenic models to directly test its role in cardiac growth and development. Finally, in Aim 4 we will generate TSC1 deficient ES cells to test the role of this gene product in the regulation of cardiomyocyte proliferation in vitro and in vivo. We will also generate transgenic mice which express TSC2 dominant negative mutants in the myocardium. If the putative regulatory roles for these proteins are confirmed, they may serve as intracellular targets for therapeutic myocardial growth in the adult heart. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COARTICULATION IN DYSARTHRIA Principal Investigator & Institution: Tjaden, Kristin K. Communicative Disorders & Scis; State University of New York at Buffalo 402 Crofts Hall Buffalo, NY 14260 Timing: Fiscal Year 2001; Project Start 15-JAN-2001; Project End 31-DEC-2005 Summary: Coarticulation has been studied extensively in neurologically normal speakers and figures prominently in theories of normal speech production. In so far as coarticulation presumably would have a similar status in a speech production theory of dysarthria, and a basic understanding of coarticulation is essential for elaborating such a theory, research investigating coarticulation in dysarthria appears warranted. The idea that coarticulation influences perceptual impressions of precision further indicates that studies investigating coarticulatory patterns in dysarthria may suggest articulatory characteristics that could be targeted in therapy to improve precision. The current project aims to study anticipatory coarticulation for speakers with Amyotrophic Lateral Sclerosis (ALS), Parkinson disease (PD), and Multiple Sclerosis (MS), as inferred from the acoustic signal. Neurologically healthy speakers will be studied for comparison purposes. The Perceptual-Acoustic Theory (PAT), a theory of normal speech production theory, will be used as a starting point for studying anticipatory coarticulation in PD, ALS, and MS. Specific predictions that the PAT suggests concerning anticipatory coarticulation for neurologic speakers will be tested. One goal of the project is to characterize anticipatory coarticulation for the typical or habitual speech of individuals with ALS, MS, and PD. A second goal is to determine the effects of two treatment techniques - slowed articulatory rate and increased vocal intensity- on anticipatory coarticulation in ALS, MS, and PD. A third goal is to document the relationship between perceptual impressions of precision and coarticulation. Second formant (F2) frequency values, first moment coefficients, and consonant F2 measures will be used to infer coarticulation. Scaled estimates of precision also will be related to select acoustic measures of coarticulation.

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

Project Title: COGNITIVE SPEED AND WORKING MEMORY IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Sweet, Lawrence H.; Miriam Hospital Providence, RI 02906 Timing: Fiscal Year 2001; Project Start 11-SEP-2001 Summary: (provided by applicant): Every year 5,200 women and 3,600 men receive a diagnosis of multiple sclerosis (MS) in the United States. MS is the most common nontraumatic disabling neurological disorder in 20-59 year-olds. A variety of cognitive deficits are present in 43-65 percent of cases. Information processing speed and working memory (WM) deficits are common. The relationship between slowed information processing and other impaired cognitive functions such as verbal WM remains unclear. Slowed processing might account for remaining cognitive deficits. This study aims to 1) confirm processing speed and verbal WM deficits by comparing MS patients and healthy volunteers; 2) demonstrate significant correlations between these abilities; 3) determine if verbal WM impairments can be solely attributed to slowed processing by treating processing speed as a covariate in group comparisons; and 4) demonstrate differential deficits of verbal WM components processes (e.g., rehearsal, executive control) in group comparison across these components. If processing speed accounts for verbal WM deficits, a diffuse brain process resulting in global cognitive inefficiency would be supported. Alternatively, unique verbal WM deficits that are not attributable to the effects of cognitive slowing would support the idea of more focal neural disconnections, or the differential effects of information processing speed upon verbal WM components. These outcomes would have a clear impact on our understanding of the process by which MS cognitive deficits occur and help us better predict underlying brain systems involved. This is where I hope to direct my future research with a F32 award. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMBINATION THERAPY IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Lublin, Fred D. Professor; Neurology; Mount Sinai School of Medicine of Nyu of New York University New York, NY 10029 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-AUG-2002 Summary: This proposal is for a Clinical Trial Planning Grant to develop a protocol and manual of operations for a randomized, controlled clinical trial comparing the efficacy of combining interferonbeta (IFN) with glatiramer acetate (GA) to treat relapsing forms of multiple sclerosis (MS). At present, both IFN and GA are available, individually, for treatment of relapsing forms of MS. Pivotal trials combining agents have not yet been performed, although this approach would offer the hope of improving upon the modest efficacy results obtained in clinical trials of the agents individually. Further, there are no properly randomized, Controlled studies comparing the efficacy of IIFN to GA. The planned trial will allow for a comparison of the relative efficacy of each agent alone and in combination against the pooled results of single agent therapy or the better of the single agents. As these are expensive therapies and the results with the agents alone are modest, it is of great importance to develop better therapeutic modalities. There are currently no new agents in phase III testing for relapsing MS; thus, combination therapy is the best hope of improving treatment options for patients with relapsing MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CONTROL OF MHV INFECTION IN THE CENTRAL NERVOUS SYSTEM Principal Investigator & Institution: Buchmeier, Michael J. Professor; Scripps Research Institute 10550 N Torrey Pines Rd La Jolla, CA 920371000 Timing: Fiscal Year 2001; Project Start 01-FEB-1998; Project End 31-JAN-2003 Summary: (Adapted from Applicant's Summary): Multiple sclerosis (MS) is the most common autoimmune neurodegenerative disease of adults in the United States, affecting approximately 250,000 individuals. Available evidence suggests that MS etiology and pathogenesis may involve two events, the first being exposure to an environmental agent, likely a virus, early in life, followed by a second event in early adulthood which triggers disease. Links with host genetics, particularly MHC-class II antigens and gender have been shown, but a definitive pathogenetic sequence linking the early and late events has not been shown, therefore animal model systems are of value in providing insight into the pathogenesis of MS. This project seeks to understand the mechanisms of CD4+ T cell mediated immune responses in the pathogenesis of CNS demyelinating disease, the signals which trigger influx of inflammatory cells, and the state and sites of virus persistence within the CNS. Intracerebral inoculation of C57B1/6 mice with the neurotropic murine coronavirus MHV-JHM and variants such as V5A13.1 derived from it results in a reproducible encephalomyelitis which usually resolves within 7-14 days but is followed by acute or chronic episodes of demyelination. Restriction of virus replication and spread within the brain is controlled by elements of the T cell response, and is accompanied by induction of multiple cytokine and chemokine mRNAs in the CNS compartment. Evidence suggests that CD4+ T cell responses are central to both control of infection and demyelinating disease, hence Dr. Buchmeier proposes three specific aims to elucidate details of this virus-host interaction. These are: 1) to investigate in CD4 knockout mice the requirements for demyelination; 2) to investigate in C57B1/6 and B6CD4 knockout mice the pathogenesis of virus-induced acute and chronic demyelinating disease and to seek evidence of an antiself response against components of the myelin sheath triggered by virus infection; and 3) to analyze by in situ hybridization, immunohistochemistry and PCR the state and cellular sites of viral persistence within the CNS following infection. Coronaviruses are widespread upper respiratory and enteric pathogens in man and animals, and coronavirus RNA has recently been described in the brains of human multiple sclerosis patients. The studies proposed will reveal basic information in interpreting the host-virus relationship in coronavirus infections, how they cause persistent infections, and the mechanisms of pathogenesis of demyelinating disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--PATIENT /TISSUE Principal Investigator & Institution: Dhir, Rajiv; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001; Project Start 22-AUG-2001; Project End 30-JUN-2006 Summary: The aims of Core B are the recruitment of appropriate SCI and MS patients for the intravesical RTX trial in Project 4, bladder imaging for the four Projects, and collection of urine needed for Project 3. Dr. Rajiv Dhir of the Department of Pathology will be the Principal Investigator of Core B. Dr. Dhir has extensive experience with clinical and basic research. As part of his responsibility, he will oversee the proper scientific handling of patient specimens with proper informed consent, maintenance of patient confidentiality and adherence to proper medical research ethics. The Tissue

Studies 37

Resource and Morphology Core at the University of Pittsburgh is also a part of this Core. It will be responsible for the storage and handling of bladder tissues and urine to be obtained form the SCI patients. Their main tasks include: biological material collection, banking, and processing; data collection; histology and morphology support; and quantitative image analysis and morphometry. Additionally, three institutions that will aid the Program Project by patient recruitment and other services are: The University of Pittsburgh Medical Center SCI Center (John Horton, M.D., Principal Investigator and Director of SCI Program); The University of Pittsburgh Medical Center Multiple Sclerosis Center (Rock Heyman, M.D., Principal Investigator); and Harmarville Rehabilitation Hospital SCI Center (Gilbert Brenes, M.D., Principal Investigator). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COURSE OF DISEASE PROGRESSION IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Griggs, Robert C. Professor and Chair; University of Rochester Orpa - Rc Box 270140 Rochester, NY 14627 Timing: Fiscal Year 2001 Summary: A) Natural History: To collect information for up to six months on muscle strength and functional ability in ALS. B) Drug Trial: To determine the safety of BDNF given by daily injection subcutaneously for 28 days, and then if a patient consents, for an additional five months. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CREATINE IN AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Rosenfeld, Jeffrey; Carolinas Medical Center Box 32861 Charlotte, NC 28203 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-MAY-2005 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.

38 Sclerosis

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

Project Title: CYTOKINE REGULATION OF CIITA AND CLASS II MHC IN GLIA Principal Investigator & Institution: Benveniste, Etty N. Professor and Chair; Department of Cell Biology; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 30-JUN-2005 Summary: (Verbatim from the Applicant's Abstract) Class II MHC antigens regulate the immune response by presenting antigen to CD4+ T cells, leading to their activation. The expression of class II MHC genes is regulated by a non-DNA binding protein, class II transactivator (CIITA) the "master control factor" for class II MHC transcription. Appropriate constitutive and inducible expression of class II MHC antigens is essential for normal immune function, while aberrant expression has been correlated with autoimmune diseases, including multiple sclerosis. The costimulatory molecule, CD40, upon interaction with its cognate ligand CD154 on T cells, promotes the expression of numerous cytokines/chemokines by the CD40 expressing cells. In the inflamed CNS, class II MHC and CD40 molecules are aberrantly expressed by microglia and macrophages, allowing them to function as antigen presenting cells. This leads to activation of autoreactive CD4+ T cells, and subsequent inflammation and demyelination. IFNgamma is the most potent inducer of class II MHC and CD40 expression, and plays a pivotal role in the initiation of intracerebral immune responses. We hypothesize that aberrant CIITA, class II MHC and CD40 expression in microglia/macrophages results in detrimental immunologic activities in the CNS. As a corollary, we propose that downregulation of these molecules will result in a reduction of immune responsiveness in the CNS. Restricting expression of class II MHC and CD40 molecules in the CNS can be achieved by a new family of proteins termed Suppressors of Cytokine Signaling (SOCS). SOCS proteins function as negative regulators of cytokine signaling, especially those such as IFNgamma that utilizes the JAK/STAT pathway. Currently, there is no information regarding the expression or function of SOCS proteins within the CNS. In this study, we will examine the ability of microglia/macrophages to express SOCS proteins, both constitutive and cytokine-inducible expression (AIM 1). Next, SOCS gene expression in MS brain will be examined (AIM 2). We will determine the cellular localization of SOCS proteins within the CNS, the disease specificity of SOCS expression, and the extent of SOCS expression in different stages of MS lesions. Lastly, the ability of SOCS proteins to modulate IFNgamma-induction of class II MHC and CD40 in microglia/macrophages will be tested by stable transfection of SOCS-1 and SOCS-3 proteins in these cells (AIM3). Our studies will provide the first biological assessment of SOCS production and function in cells of the CNS, thereby setting the foundation for future therapeutic manipulations of these critical immunoregulatory proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CYTOKINE REGULATION OF GLIAL REACTIVITY Principal Investigator & Institution: John, Gareth R. Pathology; Yeshiva University 500 W 185Th St New York, NY 10033 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Although central nervous system (CNS) remyelination in multiple sclerosis (MS) is well documented, that its occurrence and extent are not more widespread has perplexed investigators for many years. It is now

Studies 39

accepted that MS lesions contain appreciable numbers of premyelinating oligodendrocytes, indicating that the potential for remyelination is not limited by the loss of these cells. These data would suggest that interactions between oligodendrocytes and their surrounding environment may determine the success or failure of remyelination. Reactive astrocytes are a prominent pathological feature of MS, and have been shown to interact with nonmyelinating oligodendrocytes in lesions. We have explored links between astrocyte reactivity and lesion repair using primary cultures of human astrocytes, and have found that treatment of these cultures with TGFBeta1, a cytokine upregulated in MS lesions, induces expression of Jagged1, a ligand for the Jagged/Notch/Hes developmental signaling pathway. Activation of Notch signaling is considered to be one of the mechanisms used in the developing CNS to maintain migrating oligodendrocytes in an immature state. Within and around active MS plaques lacking remyelination, we have found that Jagged1 is expressed by hypertrophic astrocytes, while its receptor Notch 1 and the downstream effector Hes5 localize to cells with an immature oligodendrocyte phenotype, and TGFBeta1 is associated with perivascular extracellular matrix. In contrast, there is negligible Jagged1 expression in remyelinated lesions. In addition, we have found that culturing immature primary human oligodendrocytes on either Jagged1-transfected 3T3 cells or TGFBeta1-treated astrocytes leads to a significant reduction in process outgrowth from these cells. In this application, we will test the hypothesis that events triggered by TGFBeta1 in the astrocyte culminate in Notch-mediated inhibition of oligodendrocyte maturation. Three specific aims are proposed. In the first specific aim, we will define the major signaling pathways used by TGFBeta1 to induce Jagged1 in primary human astrocytes. In the second specific aim, we will determine whether TGFBeta1-treated astrocytes inhibit oligodendrocyte maturation via Notch signaling. In the third specific aim, we will correlate expression of TGFBeta1, Jagged1, and downstream Notch effectors with multiple sclerosis lesion activity. The experiments proposed in this application complement and parallel ongoing work in our laboratory using animal models, and our long-term goal will be to identify novel therapeutic avenues designed to encourage remyelination in the multiple sclerosis lesion. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEMYELINATION DISEASE--VIRAL AND IMMUNE FUNCTION Principal Investigator & Institution: Stohlman, Stephen A. Professor; Neurology; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, CA 90033 Timing: Fiscal Year 2001; Project Start 01-APR-1982; Project End 31-MAR-2003 Summary: The long term goals of this program project are an understanding of an inflammatory demyelinating disease of the central nervous system (CNS) induced and associated with viral infection. To this end, the projects in this program are analyzing the mechanisms of a defined model of CNS demyelination induced by the neurotropic JHM strain (MHV-4) of mouse hepatitis virus (JHMV). This model provides a means to understand the interactions between a pathogen and host that result in either an acute or persistent CNS infection. The persistent or chronic form of this infection is associated with ongoing primary demyelination a pathology similar to that seen in multiple sclerosis. Virus can not be isolated from chronically infected animals and the demyelinating lesions eventually begin to resemble a chronic plaque in multiple sclerosis. Multiple sclerosis raises many questions related to both the role of virus in induction and the immune response in the pathogenesis of demyelination. The JHMV model provides a mechanism to address fundamental questions of viral persistence, neurotropism, and immune responses, both as protective mechanisms and as inducers

40 Sclerosis

of demyelination. The core principle investigators have been stable and are actively collaborating. The program consists of four projects. These projects include a molecular analysis of CNS tropism via analysis of the viral receptor and mechanism of entry, an analysis of the effective mechanisms used to control virus replication in specific CNS cell types, the basis for T cell migration, the acquisition of effector phenotypes with the CNS parenchyma, and the molecular basis of viral persistence leading to chronic demyelination. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEPRESSION AND END OF LIFE CARE IN ALS Principal Investigator & Institution: Albert, Steven M. Gertrude H Sergievsky Center; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2001; Project Start 20-AUG-2000; Project End 31-JUL-2004 Summary: (Adapted from investigator's abstract) Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in death, usually from respiratory insufficiency or aspiration, within 3 to 5 years of diagnosis. The disease affects all voluntary motor function except eye movement and sphincter control. In the final 6-9 months of life, patients must choose (either explicitly or by default) palliation or tracheostomy and long-term mechanical ventilation (LTMV). In this 4 year project, we will follow 140 patients diagnosed with definite or probable ALS who face a high likelihood of death within 6-9 months, as defined by poor pulmonary function, dysphagia and weight loss, or hospice certification or eligibility. These patients will be followed with bimonthly in-home assessments, and with an additional assessment in the last weeks of life. We will also interview the primary family caregiver on the same schedule and once after the patient's death, as well as conduct a survey of medical providers' influence on end-of-life decisions. In this observational cohort study, we propose (1) to assess the prevalence and course of depressive disorders and symptoms in ALS patients in the final months of life and its relevance for decision-making at the end of life; (2) to identify predictors of tracheostomy/LTMV use; (3) to examine the degree to which patients and families take steps to control the timing of death by adopting a strict palliative care regime; and (4) to examine associations between patient and caregiver distress in the final months of life. Key questions include the following: Do levels of distress and depressive symptoms increase as patients approach death, and does this relationship differ according to choice of palliative care or LTMV? What maintains hope in these patients, who are, in a medical sense, hopelessly ill? Of patients who receive LTMV, in what proportion is LTMV consciously planning for, as opposed to an unplanned emergency procedure? Is patient mental health or caregiver burden associated with decisions to forego or undergo LTMV? To what degree does use of noninvasive, temporary nasal ventilation (Bi-Pap) prevent use of LTMV? These questions have not been investigated in a prospective study. We will be able to address them through repeated, detailed assessments of patients and caregivers. This information will be critical for understanding the experience of patients with terminal disease as they and their families face end-of-life care decisions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEVELOPMENT OF CARBOXYFULLERENE DRUGS TO TREAT ALS Principal Investigator & Institution: Alford, John M.; Tda Research, Inc. 12345 W 52Nd Ave Wheat Ridge, CO 800331916 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-AUG-2004

Studies 41

Summary: (provided by applicant): Studies show that fullerene-based antioxidants make excellent neuroprotectants, and they have demonstrated good efficacy in models for a wide array of oxidative neurological disorders including arnyotrophic lateral sclerosis (ALS), Parkinson's disease and brain injury resulting from ischemic stroke. These results suggest that neuroprotective pharmaceuticals are one of the most unique, yet important and commercially viable applications of fullerenes to date. Although it shows great promise as a neuroprotectant drug useful in treating ailments such as ALS and Parkinson's disease for which better treatments are desperately needed, the derivatized fullerene compounds are currently too expensive and cannot be produced in sufficient quantities for clinical testing or to treat patients. During Phase I, we developed several new techniques that allow efficient production of a carboxyfullerene pharmaceutical compound. With continued development, we anticipate that by the completion of the project, it will be possible to economically manufacture enough of the fullerene- based neuroprotectant for clinical trials to begin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPMENTAL REGULATION OF THE NERVE GROWTH FACTOR RECEPTOR GENE Principal Investigator & Institution: Chao, Moses V. Professor; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, NJ 08854 Timing: Fiscal Year 2001 Summary: Neurotrophins are secreted proteins which influence the proliferation, differentiation, survival and death of neuronal and non-neuronal cells during vertebrate development. It is likely that the information concerning the mechanism of action of neurotrophin receptors will lead to a greater understanding of how the multiple actions and specificity are encoded in these trophic factors. NGF, BDNF, NT-3 and NT-4 exert their actions through two types of receptors, the trk family of tyrosine kinase receptors and a unique receptor termed p75. While the effects of NGF upon neuronal cell survival and differentiation are well documented, recent evidence indicates that NGF may be involved in promoting programmed cell death in the nervous system. The purpose of this subproject is to elucidate the mechanism by which neurotrophins act through the p75 and trk receptors in regulating apoptosis. Downstream signaling pathways involving activation and time course of the stress-activated kinase (c-jun kinase) activity and Nfkappab transcription activity will be assessed. This investigation will yield new insights which may lead to the development of strategies to counter several neurodegenerative diseases, such as amyotrophic lateral sclerosis, Alzheimer's disease and multiple sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIETARY PARKINSONS

ETIOLOGIES

OF

MULTIPLE

SCLEROSIS

AND

Principal Investigator & Institution: Ascherio, Alberto; Associate Professor; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, MA 02460 Timing: Fiscal Year 2001; Project Start 01-APR-1997; Project End 31-MAR-2002 Summary: We propose to document the occurrence of multiple sclerosis (MS) and Parkinson's disease (PD) among male and female participants of three large ongoing prospective studies and to examine prospectively the association between several dietary and non-dietary risk factors and the incidence of these diseases. The studies are the Nurses' Health Study I (121,000 women), Nurses' Health Study II (116,000 women),

42 Sclerosis

and the Health Professionals Follow-up Study (52,000 men). Diet has been assessed repeatedly by a semiquantitative food frequency questinnaire developed and refined by our group over the last 15 years; detailed studies in subsamples of participants demonstrate that this questionnaire performs well, and that the study populations have substantial various in dietary intakes. Several follow-up cycles have been completed, with responses over 90 percent. Numerous non-dietary variables of potential interest as risk factors for MS and Parkinson's disease or as potential confounders of the associations between diet and these diseases have also already been collected at baseline and during the follow-up. We will evaluate the association between history of childhood infections or exposure to dogs potentially infected with the cannine distemper virus and risk of multiple sclerosis by conducting a nested case-control study. In addition, we will examine the association between selected mutations of CYP-2D6-one of the cytochrome P450 enzymes-and risk of PD, and the potential interaction between CPY-2D6 mutations and cigarette smoking as risk factors for PD. The CYP-2D6 genotype will be determined using blood samples that have already been collected, or buccal smears that will be obtained as part of this grant from cases of PD for whom on blood samples are available. The proposed investigation is a highly cost-effective way for studying diet and MS and PD because it draws on a large amount of information already collected and processed, and because the cost of mailing and processing of the foollow-up questionnaires is provided by other sources (CA 55075, CA 40356, CA 50385). Reported cases of MS and PD will be confirmed by supplementary questionnaires sent to the patients and their physicians. Fatal events are identified by next-of-kin, postal service, or the National Death Index and confirmed by hospital records and other additional information. By the end of the follow-up, we project a total of 461 confirmed cases of MS and 380 confirmed cases of PD. We will have sufficient poser to evaluate a series of specific hypotheses with substantial public health implications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISEASE PROGRESSION AND OXIDATIVE STRESS IN ALS Principal Investigator & Institution: Xu, Zuoshang; Associate Professor; Pharmacology; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, MA 01655 Timing: Fiscal Year 2001; Project Start 01-APR-1996; Project End 31-JAN-2003 Summary: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes degeneration of motor neurons, leading to skeletal muscle atrophy, paralysis and death. Mutations in Cu/Zn superoxide dismutase (SOD1) are one cause of ALS. Transgenic mice that express mutated SOD1 develop ALS similar to human disease. To determine the mechanism by which mutant SOD1 causes motor neuron degeneration, we will test three hypothesis: 1) ALS caused by different SOD1 mutations undergo different clinical and pathological progression; 2) mitochondrial damage precedes the onset of muscle weakness and accumulation of this damage leads to a dysfunction and deletion of normal mitochondria in motor neurons, culminating the onset of ALS; 3) oxidative stress plays a role in triggering the onset of ALS. To test the first hypothesis, we will investigate the pathological evolution in correlation with clinical progression in mice expressing G85R mutation and compare the findings with G37R and G93A mutants. We will delineate and compare the sequence of pathological events leading to motor neuron death in these three lines. By this approach, we will determine the differences and common characteristics of ALS caused by different SOD1 mutations. The outcome of this study will provide guidance to further elucidation of the disease mechanism and help to improve prognosis and design therapies tailored to different

Studies 43

mutations. To test the second hypothesis, we will use electron microscopy to characterize the types of mitochondrial abnormality before and after onset of the disease. We will also determine the earliest time when mitochondrial abnormalities emerge and quantify the changes in the number of normal and abnormal mitochondria before and after the onset of the disease. To test the role of mitochondrial abnormality in triggering the onset of the disease, we will test whether energy supplementation by administering creatine delays the onset of the disease. To test the third hypothesis, we will measure the levels of oxidative markers at different disease stages to determine whether oxidative damage precedes or follows the onset of ALS. Further, we will test whether and how anti-oxidant treatment changes the course of disease progression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISSECTING THE MOLECULAR PATHOLOGY OF LAM DISEASE Principal Investigator & Institution: Noonan, Daniel J. Associate Professor; Molecular/Cellula/Biochemistry; University of Kentucky 109 Kinkead Hall Lexington, KY 40506 Timing: Fiscal Year 2002; Project Start 05-DEC-2001; Project End 30-NOV-2005 Summary: (provided by applicant): Lymphangioleiomyomatosis (LAM) is a rare lung disease limited principally to women of child bearing age and is characterized by an abnormal proliferation of smooth muscle cells in the pulmonary interstitium. The only viable treatment for the disease is lung transplantation. The limited available information on LAM demonstrates correlations with 2 metabolic phenomena, one being fluctuations in the female sex steroid hormone estrogen and the other being the genetic disease tuberous sclerosis. Recent work in our laboratory, and preliminary data presented in this proposal, for the first time offer a direct link between the activities of the gene mapping to the genetic locus for tuberous sclerosis (TSC2) with transcription events mediated by estrogen activation of its intracellular receptor (ER) and the intracellular signaling switch calmodulin (CaM). Our current working hypothesis is that LAM is an aberration in intracellular signaling that leads to inappropriate gene regulation of specific cell cycle control components. To establish the potential biological relevance of this hypothesis to the pathogenesis of LAM, the following specific aims will attempt to dissect the relationships between TSC, CaM and in the ER modulation of transcription and cell proliferation events. 1) Characterization of CaM-specific regulatory sequences in the TSC2 gene. 2) Characterization of Ca++/CaM signaling in TSC2/ER-mediated events. 3) Characterization of the role of calcium regulated phosphorylation events might play in TSC2-modulated steroid receptor-mediated transcription. 4) Characterization of TSC1?s role in the TSC2/calmodulin signaling pathway. 5) Characterization of links between TSC/CaM signaling and cell cycle control. The preliminary data presented in this grant provide a strong foundation for dissecting the molecular events associated with normal function of the TSC2 genes. The intriguing link among TSC2, ER and CaM for the first time offers a potential mechanism for cell proliferation events as observed with the loss of heterozygosity or deletion of the TSC genes. With this knowledge also comes potential avenues for drug development and interventions into this heretofore vaguely understood disease condition. It is truly believed that the results of these studies will provide critical insight into the pathology of LAM (and most likely tuberous sclerosis) as well as avenues for intervention into that pathology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

44 Sclerosis

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Project Title: SCLEROSIS

DNA

TOLERIZING

VACCINE

THERAPY

FOR

MULTIPLE

Principal Investigator & Institution: Garren, Hideki; Tolerion, Inc. 3400 W Bayshore Rd Palo Alto, CA 94303 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 14-MAR-2003 Summary: (provided by the applicant): This proposal is for preclinical development of a DNA tolerizing vaccine to treat multiple sclerosis (MS), a T cell-mediated autoimmune disease for which current therapies are marginally effective. DNA vaccines are a powerful tool to elicit immune responses, and were initially developed as protective vaccines against infection. More recently, DNA vaccines have proven an extremely effective method for treatment of autoimmune disease. DNA tolerizing vaccines encoding autoantigens specifically turn off pathogenic autoimmune responses, leaving the global immune system intact. The mechanism by which antigen-specific DNA therapy modulates disease is through deviation of autoreactive T lymphocytes from a disease-promoting Th1 phenotype to a disease-ameliorating Th2 phenotype. To further develop this technology, SunVax will optimize the DNA vaccine plasmid vector and determine the minimal dosing regimen for inducing immune tolerance, using the experimental autoimmune encephalomyelitis (EAE) animal model for MS. Once the optimal vector backbone is identified, SunVax will generate DNA tolerizing vaccine constructs encoding human myelin antigens. Upon meeting these primary milestones, Phase II of this SBIR will focus on developing molecules that enhance the effects of DNA tolerizing vaccines and completing the preclinical toxicity studies in animals necessary to file an investigational new drug (IND) application with the U.S. FDA. PROPOSED COMMERCIAL APPLICATION: The proposed studies are for the development of a DNA tolerizing vaccine for MS, which affects 350,000 people in the U.S. There is a $1B U.S. market for an effective therapy for MS, with currently available therapies having only marginal efficacy. Through these studies, Sun Vax will complete the animal model preclinical development studies needed to file an investigational new drug (IND) application with the U.S. FDA for the evaluation of a DNA tolerizing vaccine in a phase I clinical trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DYSREGULATION OF THE IMMUNE SYSTEM IN AUTOIMMUNITY Principal Investigator & Institution: Flavell, Richard A. Professor and Chairman; Immunobiology; Yale University 47 College Street, Suite 203 New Haven, CT 065208047 Timing: Fiscal Year 2001; Project Start 01-SEP-1994; Project End 29-SEP-2002 Summary: The goal of this program is to understand the regulation and dysregulation of the immune system in autoimmunity. The program involves collaborative interaction between members of three Departments, and is organized into four projects supported by three Core facilities. Expertise in the field of immunology, molecular biology, and biochemistry will focus on the vents that initiate and sustain autoimmune responses, and the regulatory processes. which contain autoimmunity. We will address the following questions. What are the requirements to initiate autoimmune responses? Are autoimmune responses regulated, and if so, by what mechanisms? Does immune regulation contain autoimmune responses under normal circumstances? Finally, do sustained autoimmune responses remain chronic because they diversity from a single initiating response to responses to other autoantigens from the same tissue? These questions will be addressed by collaborative interactions between the Principal Investigators of these projects, which are as follows: (1)R.A. Flavell- Using transgenic

Studies 45

mice expressing a T cell receptor specific for myelin basic protein (MPB) and gene targeted mice lacing L- selectin or E- and P-selectin, the role of selectins in the development of EAE will be determined. The requirement of selectins for the development of disease, as well as the mechanisms which underlie this requirement will be determined, focusing on the cell types which must express L-selectin, the role of selectins in the entry of leukocytes into the CNS and the potential role of selectins within the CNS. (2) C.A. Janeway Jr.- This project will investigate four aspects of the regulation of experimental allergic encephalomyelitis (EAE): Why are mice lacking B cells unable to fully resolve their disease; why does the inability to form cells with other receptors lead to spontaneous disease in mice transgenic for a TCR that recognizes myelin; why do mice cells with other receptors lead to spontaneous disease in mice transgenic for a TCR that recognizes myelin; why do mice with the same receptor who are heterozygous for gld get spontaneous disease; and what is the role of L- selectin in EAE, in collaboration with project 1. (3) M.J. Shlomchik- Transgenic mouse models will be used to study the regulation of B cells expressing a disease-related autoantibody, rheumatoid factor (RF), in normal and autoimmune mice. In contrast to some other autoantibody models, RF B cells from these transgenics are competent to initiate an immune response. Thus, studies will focus on how RF B cells are regulated after Ag stimulation in normal mice and propagated in autoimmune mice, and what prevents chronic autoimmunity in RF transgenic mice. (4) M.J. Mamula, PI- This project will examine the role of self-peptides in the initiation and perpetuation of both Band T cell autoimmunity in models of systemic lupus erythematosus (SLE) and multiple sclerosis (EAE). The role of B cells as autoantigen in models of systemic lupus erythematosus (SLE) and multiple sclerosis (EAE). The role of B cells as autoantigen presenting cells will be examined with relevance to mechanisms that lead to epitope spreading in autoimmunity. Finally, this work will study a novel post-translational peptide modification that arises naturally in cells and confers immunity to self peptides. These four projects will be supported by an administrative core to coordinate the project as a whole, a genetically modified mouse core to provide gene targeted and transgenic rodents essential to most of these studies, and a FACS core, to allow us to separate cells for analysis and to analyze cells in all of these projects. The program is coordinated by frequent meetings of the program faculty bringing together these diverse approaches to address a common goal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTOR MOLECULES IN DEMYELINATING DISEASE Principal Investigator & Institution: Cross, Dorothy A. Neurology; Washington University Lindell and Skinker Blvd St. Louis, MO 63130 Timing: Fiscal Year 2001; Project Start 05-DEC-1998; Project End 30-NOV-2001 Summary: Multiple sclerosis (MS) is a disease of unknown etiology for which experimental autoimmune encephalomyelitis (EAE) serves as a model. There is compelling evidence that peroxynitrite anion (PN) is present in the central nervous system (CNS) of laboratory animals with EAE and in MS lesions. PI's laboratory has evidence supporting the presence of high levels of PN in and near the inflammatory lesions of EAE, and in inflamed MS-affected human CNS. PI and others have shown that inhibiting PN inhibits EAE. PN is a strong oxidant with many detrimental effects, including the inhibition of mitochondrial electron transport, direct damage to proteins, lipid peroxidation which damages membranes, and DNA fragmentation. PN is generated by the rapid reaction of nitric oxide (NO) with superoxide, at a diffusionlimited rate. Many of toxic effects formerly attributed to excess NO are now realized to be due to PN. Furthermore, the breakdown product of PN, nitrogen dioxide, is also

46 Sclerosis

highly toxic to membranes. Ultrastructurally, it is clear that myelin membranes are a target of attack in MS, and oligodendroglia cells are lost from chronic MS lesions. Our hypothesis is that PN generation is a key component in the pathogenesis of inflammatory CNS demyelination by causing or increasing the destruction of oligodendroglia cells and/or myelin membranes, and enhancing inflammation. The proposed study will expand and confirm our findings of PN generation in MS and EAEaffected tissues. This proposal will also address the mechanisms by which PN may act in the pathogenesis of CNS inflammatory demyelination. We will examine the effects of PN on oligodendroglia, the cells that make CNS myelin, and on CNS myelin vesicles prepared from human myelin. We will determine what CNS proteins are altered by tyrosine nitration due to PN. Since there now have been identified pharmaceutic agents which can inhibit the production of PN, our findings from these studies may indicate an area with therapeutic potential for MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ELECTROPHYSIOLOGICAL AND GENETIC PREDICTORS IN AMYOTROPH Principal Investigator & Institution: Lomen-Hoerth, Catherine E. Neurology; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 05-JUL-1999; Project End 30-JUN-2004 Summary: With advances in clinical neurology and basic science research, the gap between these disciplines is narrowing. Researchers are needed to bridge this gap and apply basic science advances to clinical research and vice versa. The objective of this proposal is to produce a program combining didactic teaching, mentoring, and clinical research to allow Dr. Lomen-Hoerth to develop the skills necessary to study ALS from clinical, electrophysiological, and genetic perspectives. Among progressive motor neuron diseases, amyotrophic lateral sclerosis (ALS) is the most common affecting 1/100,000 people. ALS is a neurodegenerative disease that is inexorably progressive, with mean survival less than 4 years after diagnosis. ALS is characterized by progressive upper and lower motor neuron weakness, but survival is largely based on the degree of lower motor neuron involvement. This study will use a measure of the rate of motor neuron loss as a means of predicting prognosis. Additionally, this project will determine if relatives of sporadic ALS patients have a subclinical phenotype of ALS based on their number motor units and genetic analysis will determine if there is a heritability of the subclinical phenotype. ALS patients and age matched controls will be compared with electrophysiological studies to determine the amplitude of compound muscle action potentials, motor unit number estimates (MUNE) and fiber density of one hand muscle and one leg muscle. In ALS patients, the rate of motor unit loss will be measured and correlated with their survival. The heritability of the motor unit number will be determined by comparing the concordance of MUNE in monozygotic and dizygotic twins. The motor unit number will then be assessed in a population of siblings of sporadic cases of ALS to assess the heritability of a putative subclinical phenotype. DNA from ALS patients and their families will then be used to map susceptibility genes that are suspected to contribute to progression of sporadic ALS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ELECTROPORATION-MEDIATED GENE THERAPY WITH IFN-B FOR MS Principal Investigator & Institution: De Las Alas, Maida M.; Ichor Medical Systems 6310 Nancy Ridge Dr, Ste 107 San Diego, CA 92121

Studies 47

Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 30-NOV-2003 Summary: (provided by applicant): Ichor proposes to assess the basic feasibility of using its proprietary TriGrid electroporation (EP) system for in vivo intramuscular delivery of a plasmid encoding for interteron-beta (IFNb) into normal mice. This approach aims to improve the current route of administration of IFNb, an FDA approved recombinant protein drug for relapse-remitting multiple sclerosis. This improved administration method should reduce the number of treatments necessary for efficacy, reducing the cost for this lifetime therapy, and increasing patient compliance. A comprehensive-dose analysis of the magnitude and duration of lFNb expression from EP-mediated intramuscular delivery will be performed to confirm that this approach results in sufficient levels of protein production. Considering that current recombinant lFNb therapy is associated with minor toxicities, these studies also aim to identify and characterize toxicities associated with both the administration of EP and IFNb production from muscle tissue. The management of these toxicities with controlled dosing using TriGrid electroporation or a gene regulation system will be assessed, since current management of recombinant IFNb-induced toxicities entails control of protein dosing regimens. These findings will provide guidance for future Phase II studies in large animal disease models, and perhaps humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOTHELIAL CELLS AS GENE VEHICLES FOR MS THERAPY Principal Investigator & Institution: Liu, Xingluo; Oncoimmune, Ltd 1474 Bridgeton Dr Columbus, OH 43220 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 30-SEP-2003 Summary: (provided by the applicant): It is generally accepted that autoreactive T cells are involved in pathogenesis of multiple sclerosis (MS). We have shown that CD24 gene controls the effector function, but not the induction, of the autoreactive T cells in the mouse model of multiple sclerosis, the experimental autoimmune encephalomyelitis. We have also shown that injection of fusion protein comprising of the extracellular domain of the CD24 protein results in significant reduction in the clinical score of the EAE. More recently, we discovered that in bone marrow chimera mice, bone marrowderived cells could replace the vascular endothelial cells in the CNS. To explore the potential clinical application of these observations to the therapy of multiple sclerosis, we have established novel in vitro culture protocol to produce bone marrow-derived endothelial cells. We have found that they can migrate into the CNS after adoptive transfer and form neovasculature in the CNS. Moreover, we have produced lentiviral vector that can transduce the CD24Ig gene into the endothelial cells in vitro. In this proposal, we will test whether the endothelial cells expressing CD24Ig can be used for the therapy of EAE in mouse model. Specifically, we will address two questions: 1). Are mice reconstituted with endothelial cells expressing CD24Ig resistant to pathogenic autoreactive T cells in CNS? We will transduce bone marrow derived endothelial cells from C57BL/6 mice with CD24Ig gene and test whether injection of the CD24Igtransduced endothelial cells will result in resistance to autoreactive T cells. We will also compare the efficacy of CD24IgG to that of CD241gM that should have higher valences and therefore may have higher avidity for the potential CD24 ligands. 2). Can the CD24Ig-transduced endothelial cells provide therapeutic effect in mice with relapsing remitting EAE? We will transduce bone marrow derived endothelial cells from SJL mice with CD24Ig gene. We will inject the CD24Ig-transduced endothelial cells into SJL mice with ongoing EAE and test if these cells can prevent EAE relapse. Our proposed work will test the concept of using endothelial cells as a gene vehicle for the treatment of

48 Sclerosis

multiple sclerosis. If succeed, this will provide a new approach for therapy of organspecific autoimmune diseases in general and the multiple sclerosis in particular. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPILEPTOGENESIS IN A RAT MODEL OF TUBEROUS SCLEROSIS Principal Investigator & Institution: Emmi, Adriana; Neurological Surgery; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001; Project Start 24-SEP-2001; Project End 31-AUG-2004 Summary: (Applicant's abstract): This proposal, a response to the program announcement for exploratory (R21) grants in pediatric brain disorders, focuses on the issue of epileptogenesis in tuberous sclerosis. Tuberous sclerosis (TS) is an autosomal dominant disorder characterized by the formation of hamartomatous growths in multiple organ systems, including kidney, skin, and brain. Recent studies suggest a TS incidence of 1 in 6,000 live births. The most debilitating of the effects of TS are its nervous system manifestations, including epilepsy and mental retardation. It has been estimated that over 80% of TS patients have epilepsy, often occurring early in development as such difficult-to-control syndromes as infantile spasms. While insights into TS have been greatly advanced by our understanding of the underlying genes (TSC1 and TSC2), the connections between TS gene mutations and brain hamartomas (and particularly cortical tubers), and between tubers and seizure development, remain unclear. The absence of an animal model of TS with a CNS tuber and seizure phenotype has made it difficult to study these relationships. In this proposal, we exploit the Eker rat, a TSC2 +/- "carrier", to address two aspects of the tuber/epilepsy complex. First, we will examine the hypothesis that cytologically-abnormal cells characteristic of cortical tubers are a result of homozygous mutations at the TSC2 locus (TSC2 -/-); that is, loss of heterozygosity (LOH) is a critical feature of brain tuber formation, just as it is for tumors in other organs (e.g., kidney). TSC2 -/- cells will be obtained from embryonic CNS tissue (from +/- x +/- Eker crosses) and maintained in culture. Morphological and electrophysiological tools will be used to characterize these cells (vs. TSC2 +/- and +/+ cells). Differentiation of cultured TSC2 -/- neuroblasts will be examined under different culture conditions, their response to experimental challenge (e.g., irradiation, excitotoxicity) determined, and their effects on co-cultured tissue assessed. Second, to test the hypothesis that TSC -/- cells give rise to cortical tubers, cultured cells (containing a fluorescent marker gene) will be transplanted into normal rat brain. Morphological features (e.g., tuber formation, circuitry reorganization) of transplanted cortex, as well as its electrical excitability and the animal's seizure susceptibility, will be determined. These studies, while not yet probing the molecular mechanisms through which TSC2 mutations give rise to structural malformations in the developing animal, will address critical phenomenological cause-effect relationships that will serve as the basis for future mechanistic studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ESTROGEN DEFICIENCY AND RENAL DISEASE IN AGING WOMEN Principal Investigator & Institution: Striker, Liliane J. Professor; Medicine; University of Miami Box 016159 Miami, FL 33101 Timing: Fiscal Year 2001; Project Start 01-JUN-1999; Project End 31-MAY-2003 Summary: The incidence of endstage renal disease due to glomerulosclerosis rises with aging in women, especially in minority populations. Women are relatively protected

Studies 49

prior to menopause (F/M ratio =0.5), but after menopause this protection is lost (F/M ratio=1.0). Based on these data, we propose that estrogen deficiency after menopause is an important contributor to the development of progressive glomerulosclerosis, particularly in minority women. Glomerulosclerosis, defined as an excess deposition of extracellular matrix, is due to increased matrix synthesis and/or decreased degradation. Matrix metalloproteinases decrease deposition of matrix in vitro, and are linked to decreased glomerulosclerosis in vivo. We will use in vivo and in vitro mouse models of glomerulosclerosis, and human mesangial cell lines developed in our laboratory, as models of the kidney disease in majority (sclerosis-resistant) and minority (sclerosisprone) women. We recently found that mesangial cells, the major source of sclerotic tissue in glomeruli, express estrogen receptors and that estrogen increases matrix metalloproteinase-2 (MMP-2) activity. We have additional preliminary data showing that the MMP-2 response to estrogen supplementation is blunted in sclerosis-prone mice. These data linking matrix turnover and estrogen response lead us to propose that estrogen retards glomerulosclerosis due, in part, to its stimulatory effect on matrix metalloproteinase-2 activity. A corollary proposal is that appropriate estrogen replacement would decrease the incidence of endstage renal disease in postmenopausal women. These proposals will be tested by identifying and characterizing estrogen receptor subtypes (ERalpha and ERbeta) and receptor activity in mesangial cells from women and sclerosis-prone and sclerosis-resistant mice, using a reporter construct under the transcriptional control of an estrogen responsive element. Mesangial cell MMP expression will be studied under conditions of estrogen deficiency, supplementation and antiestrogen treatment. The response to estrogen of cis-acting elements in the MMP-2 promoter will be studied in mesangial cells using MMP-2 promoter constructs. In addition, glomerular lesions and glomerular MMPs and collagen mRNA levels will be studied in ovariectomized mice in the presence of estrogen deficiency or supplementation and antiestrogen treatment. These data will provide data as to whether estrogen retards the progression of glomerulosclerosis in postmenopausal women. It may also provide tools to evaluate replacement therapy by estrogen analogues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SCLEROSIS

ETIOLOGY

OF

NEUROLOGICAL

DISEASE

OF

MULTIPLE

Principal Investigator & Institution: Haines, Jonathan L. Director, Program in Human Genetics; Molecular Physiol & Biophysics; Vanderbilt University 3319 West End Ave. Nashville, TN 372036917 Timing: Fiscal Year 2001; Project Start 01-AUG-1995; Project End 31-MAY-2004 Summary: Multiple sclerosis (MS) is a chronic debilitating disorder characterized by demyelination of the central nervous system and is the second most common cause of acquired neurologic disability arising in early to mid adulthood. MS is an etiologically complex disorder with a strong but poorly understood genetic component. Four recent genomic screens each identified many potential genomic regions harboring MS genes. However, few of these regions overlapped across even two studies and none overlapped across all four. These results suggest that the genetics of MS are even more complex than previously thought. Even the major histocompatibility complex (MHC) on chromosome 6, which has been consistently associated with MS in studies of sporadic patients, was initially identified in only two of the four genomic screens (although all four have evidence upon follow-up). The MHC is likely to be the strongest genetic susceptibility in MS, yet accounts for as little as 20% and at most 50% of the overall genetic effect in MS.

50 Sclerosis

Although many additional biological candidate genes have been proposed and tested, the results have been inconsistent. The challenge now is to solve several problems previously inherent in these studies including small sample size, inadequate study design, and heterogeneity at both the genetic and clinical levels. To accept this challenge, we propose using a unified genetic approach to further dissect the genetic etiology of MS. We will attach the problem with a much larger sample seizure of multiplex families, an extensive dataset of MS singleton "triads", new genetic epidemiological techniques, and consider explicitly clinical and genetic heterogeneity. More specifically, we propose to: identify the probably genomic locations of susceptibility genes in MS using efficient, detailed genomic screening on a large set of multiplex families; to examine in detail these promising genomic regions; to use the transmission/disequilibrium test (TDT) to test locational candidate genes in these promising regions; to test for gene/gene interactions; and to use clinical and biological risk factor information on the families to test for genotype/phenotype correlations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXACERBATION OF EAE BY MURINE GAMMAHERPESVIRUS, MHV-68 Principal Investigator & Institution: Bost, Kenneth L. Belk Distinguished Professor; Biology; University of North Carolina Charlotte Office of Research Services Charlotte, NC 282230001 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2003 Summary: (adapted from applicant's abstract): For decades it has been suspected that some relatively common human virus might play a critical, but complex role in the pathogenesis of Multiple Sclerosis (multiple sclerosis3. A possible association between Epstein Barr Virus (EBV) and multiple sclerosis has been proposed, however this association is tenuous and not universally accepted. Essentially all multiple sclerosis patients demonstrate previous infection with EBV, but available data indicate that this virus hardly ever enters the central nervous system (CNS). It has been suggested that EBV infection might indirectly exacerbate multiple sclerosis, but studies which conclusively demonstrate such an indirect mechanism do not exist. In preliminary investigations, we have developed a rodent model to directly address whether EBV might augment multiple sclerosis. This model system takes advantage of the recently described murine gammaherpesvirus-68 (MHV-68), which induces disease, very similar to EBV infection in humans. Infection with MHV-68 followed by passive administration of myelin basic protein-specific T cells will be used to address whether an EBV-like infection can exacerbate Experimental Allergic Encephalomyelitis (EAE). The importance of replicating versus latent MHV-68 infection in the exacerbation of EAE will be addressed by quantifying clinical scores and markers for CNS inflammation. These initial studies will demonstrate for the first time a direct association of an EBVlike viral infection with the exacerbation of a model of multiple sclerosis. Mechanisms responsible for this exacerbation will also be investigated and will include: 1) a determination of whether MHV-68 can enter the CNS to augment inflammation; 2) a demonstration of possible molecular mimicry between viral epitopes and myelin basic protein (peptide 68-88)-specific T cell receptors; and 3) an evaluation of the MHV-68induced TH1 environment and its possible augmentation of the proliferation or activation of myelin basic protein (peptide 68-88)-specific Lymphocytes. Taken together, these studies will investigate mechanisms responsible for MHV-68 induced exacerbation of EAE using the first experimental model system appropriate for understanding the

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role of a neuroimmune event accompanied by a concomitant gammaherpesvirus infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXERCISE THERAPY FOR AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Miller, Robert F. Professor; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001 Summary: Exercise therapy in healthy sedentary adults improves limb strength by about 30%, increases aerobic capacity (VO2max) by about 15%, reduces depression and anxiety, and increases mood and self esteem. An increasing body of evidence indicates comparable benefit occurs in disease states that are relevant to ALS, such as post-polio syndrome - a disease of the lower motor neuron for which increased strength and aerobic capacity has been demonstrated - and multiple sclerosis - a disease of the upper motor neuron for which improved strength, aerobic capacity, mood, and quality of life has been shown. Neither the efficacy nor the safety of exercise therapy for ALS, or any of the other neurogenic diseases represented by the MDA, is known. The specific aims of this study are to determine if a supervised 4-month exercise training program can safely improve muscle strength, aerobic capacity, pulmonary function, mental health, and qualify of life in patients with ALS. The design is parallel, randomized, controlled, and blinded, and the sample size is 40 patients. If exercise increases muscle strength by the same mean magnitude in ALS as for healthy sedentary adults, it would represent a gain comparable to the expected mean decline in muscle strength over 9 months of the disease course. The possibility also exists that in ALS psychosocial benefits may be found from exercise which will surpass the physiological ones (strength and aerobic capacity). The recent data from multiple sclerosis (MS) is encouraging wherein exercise therapy had a significant impact in improving quality of life, strength, and endurance. Exercise therapy is an inexpensive, universally available, therapeutic modality. Improvement by exercise therapy of any of these measures without adverse effect would be expected to have a significant impact on clinical practice, not only for ALS, but also for other neurogenic diseases causing weakness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EXPLORATION OF THE GENETIC BASIS OF MULTIPLE SCLEROSIS Principal Investigator & Institution: De Jager, Philip L.; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The classic method of finding disease genes -linkage mapping - works well for rare, monogenic disorders. However, linkage scans have failed to find the genes for many common and genetically complex diseases such as multiple sclerosis (MS). While the state-of-the-art method of finding disease genes - the haplotype-based association study - has greater statistical power than linkage studies, it requires the genotyping of hundreds of thousands of markers. We hypothesize that an admixture scan can be used to screen for MS genes about 100 times more efficiently than a haplotype-based study. An admixture scan has the potential to rapidly identify disease regions for the subset of diseases with different prevalence rates in two populations. MS is an excellent candidate disease for an admixture scan. The risk for MS in AfricanAmericans may derive largely from high-risk European alleles; as a result, we can search for MS genes simply by looking for islands enriched in European ancestry in the

52 Sclerosis

genomes of African-American MS patients that are, for the most part, West African in origin. Aim 1: Building a high-resolution admixture map of the human genome. Admixture mapping has only become conceivable within the past six months, with the identification of large numbers of sites in the genome with known allele frequencies in different human populations. Our first Aim will be to generate a validated map of about 3,300 Single Nucleotide Polymorphisms (SNPs) spaced on average every 1.5 Mb of the genome. Aim 2: Carrying out a whole-genome admixture scan for multiple sclerosis. We will genotype the entire map in 1,500 African-American subjects with MS. 1) We will analyze the data using computer programs that calculate, at every point in the genome, the probability that the observed proportion of European ancestry is greater than the expected (background) value. 2) At loci where associations to disease are identified, we will triple the density of markers to refine the boundaries of the locus. Aim 3: Identifying the risk haplotypes. The admixture scan will demarcate regions that contain risk alleles for MS. A haplotype-based association study within the African-American study population will be necessary to identify the risk haplotvpe and eventually the risk allele. 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.; Massachusetts General Hospital 55 Fruit St Boston, MA 02114 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2003 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: GAIT DYNAMICS & FUNCTIONAL ASSESSMENT OF CHRONIC DISEASE Principal Investigator & Institution: Hausdorff, Jeffrey M.; Beth Israel Deaconess Medical Center St 1005 Boston, MA 02215 Timing: Fiscal Year 2001; Project Start 14-MAY-2001; Project End 30-APR-2006 Summary: Preliminary work suggests that measures based on gait dynamics may be useful in assisting in the functional assessment of chronic disease and the resulting disability. Approximately forty nine million Americans have a chronic disability. These disabilities often affect physical function and mobility, limit activities, reduce independence, and decrease quality of life. However, the absence of precise, quantitative and objective measures of function that can be administered in multiple settings (e.g., in the clinic) limits our ability to objectively monitor disease progression and assess the efficacy of new therapeutic interventions. The overall goal of the present application is to extend our preliminary findings to evaluate how measures of gait dynamics may be used in functional assessment of chronic disease. Because gait dynamics may serve as a sensitive and clinically relevant index of functional ability in the evaluation of intervention trials and may be useful in augmenting early diagnosis of chronic disease, we believe it is critical to understand its origins. A secondary goal of this project, therefore, is to quantitatively characterize the factors that contribute to altered gait dynamics. The third objective of this application is to develop practical measures of gait dynamics that can be used to augment clinical assessment of chronic disabling disease. In this project, we will study the relationship between chronic disease (i.e., knee osteoarthritis, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis), gait dynamics, and functional status and evaluate how gait dynamics change with disease progression and in response to therapeutic interventions, including exercise and deep brain stimulation. The results of the study will provide new insight into the physiology and adaptations of chronic disease, the efficacy of different therapeutic interventions, and may also provide a new method to augment functional assessment of chronic disability. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: GENDER DIFFERENCES IN MULTIPLE SCLEROSIS IMMUNE RESPONSE Principal Investigator & Institution: Pelfrey, Clara M.; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, OH 44195 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: (provided by applicant): Most autoimmune diseases are found with higher frequency in women. In fact, almost 80 percent of patients with autoimmune disease are women. This suggests that the autoimmune phenotype is related to gender-associated immunologic changes that could stem from sex hormone effects, genetic factors and/or neuroendocrine effects. Multiple sclerosis (MS) is a central nervous system (CNS) demyelinating disease of unknown etiology that is believed to be mediated by autoreactive T lymphocytes directed against CNS proteins including myelin basic protein (MBP) and proteolipid protein (PLP). MS is found 2 to 3 times more often in women than in men. Based on numerous similarities between MS and the animal model for MS, experimental autoimmune encephalomyelitis (EAE), it has been postulated that Th1-like T cells are involved in the pathogenesis of MS. What has also been learned from EAE is that production of pro-inflammatory cytokines such as IFNgamma and TNFalpha/beta are considered to be crucial for the initiation and amplification of

54 Sclerosis

inflammatory brain lesions and possibly also for direct myelin damage. In previous studies, we have shown a significant difference in the IFNgamma response to PLP peptides between MS patients and controls. In the current preliminary data, we present evidence to support gender differences in the cytokine response to PLP. Thus, we hypothesize that the increased incidence of MS in females is in part due to a genderrelated increase in Th1 cytokines in females as compared to males. Because upregulation of inflammatory cytokines generally requires expression of costimulatory molecules, some of which have been implicated in MS attacks, we also hypothesize that costimulatory molecules may shown differential gender expression. We propose to examine three inter-related immune effects that may underlie the higher incidence of Ms in females: (I) increased inflammatory (Th1) cytokine versus regulatory (Th2) cytokine secretion in females compared to males stimulated by proteins that are thought to be targets in MS; (II) the role of the cytokine IL-12 and costimulatory molecules in promoting gender differences; (III) the effect of sex hormones on cytokine secretion and on costimulation. Cytokines will be measured both at the single cell level using the n assay and in cell supernatants using ELISA. Cell surface molecules will be measured by flow cytometry. Ultimately, the goal of these studies is to improve current therapy for MS patients and allow development of new therapies that capitalize on the different immunological responses in women versus men. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE EXPRESSION ANALYSIS IN TUBEROUS SCLEROSIS Principal Investigator & Institution: Crino, Peter B. Professor; Neurology; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006 Summary: (provided by applicant): The tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder that affects the brain and results from mutations in one of two genes, TSC1, encoding hamartin, and TSC2, encoding tuberin. Neurological complications of TSC are the most disabling and include epilepsy in over 70-80% of TSC patients, as well as autism and mental retardation in half of TSC patients. These neuropsychiatric abnormalities in TSC result from the effects of cortical tubers, the characteristic brain lesions of TSC, on brain function. Tubers are developmental abnormalities of cerebral cortical cytoarchitecture (a form of cortical dysplasia) characterized histologically by disorganized cortical lamination and cells with aberrant morphologies. The prominent abnormal cell types in tubers are dysplastic neurons (DN), giant cells (GC), and abnormal astrocytes. Tubers are epileptogenic and seizures in TSC patients are often refractory to medical management despite anticonvulsant polytherapy. Surgical resection of tubers may be necessary to achieve adequate seizure control. The number of tubers present in TSC patients seems to correlate with the onset and severity of mental retardation and autism in TSC patients. The broad goal of this grant proposal is to investigate how hamartin and tuberin mutations contribute to tuber formation using 3 experimental paradigms. We will determine whether tubers form as a result of a "second hit" somatic mutation or haploinsufficency using a high resolution analysis of TSC1 and TSC2 genes in single microdissected GCs, DNs, and astrocytes. Second, we define the expression of five candidate gene and protein families that are pivotal in normal corticogenesis including cell adhesion molecules, transcription factors, growth factors, and cytoskeletal elements in single DNs, GCs, and astrocytes and then relate these changes in expression to the mutational state of these cell types. Third, the expression of the five candidate gene and protein families will be determined during distinct epochs of cortical developmental in 3 transgenic mouse strains in which tuberin

Studies 55

or hamartin have been completely or conditionally knocked out. These experiments provide a strategy to define the molecular mechanism of tuber formation as a direct consequence of TSC gene mutations and the downstream effects on gene expression within distinct populations of cells at defined developmental timepoints. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE EXPRESSION AND DIAGNOSIS OF AUTOIMMUNE DISEASE Principal Investigator & Institution: Aune, Thomas M. President; Arthrochip, Llc 117 Bromley Park Ln Franklin, TN 37069 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 14-FEB-2004 Summary: (provided by the applicant): Autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, and multiple sclerosis, are thought to arise from abnormalities of innate or adaptive immune responses. Autoimmune diseases are often difficult to diagnose, as the symptoms can be typical of other conditions and quite vague, such as musculoskeletal complaints and pain, headaches or dizziness. No available blood test can accurately exclude the possibility of an autoimmune disease in a subject with these symptoms. At best, a battery of tests and a period of observation are usually required to establish that a patient does in fact have an autoimmune disorder. Thus, a single test that could readily exclude the possibility of an autoimmune disease would allow physicians to focus their efforts on patients who have the greatest likelihood of serious disease. Using microarray technology, we have compared differences in gene expression in peripheral blood mononuclear cells among individuals with four distinct autoimmune diseases, normal control individuals before and after immunization, and individuals with other chronic diseases. Surprisingly, we find that each individual with autoimmune disease has a common gene expression signature that is independent of the specific autoimmune disease but is totally distinct from the normal immune response and is not observed in individuals with other chronic diseases. Based upon these observations, we have developed a simple test for excluding the possibility that a subject has an autoimmune disorder. The main advantage of this test is that it is a quicker and more accurate test than those currently available. This test has thus far predicted autoimmune patients from normal patients with 100 percent accuracy. The first goal of this proposal is to collect gene expression data from a sufficient number of individuals to design a test with optimal predictive power. The second goal is to validate the test by examining a cohort of individuals who do not yet carry a clear-cut diagnosis of an autoimmune disease. Long-term goals are to use results from microarray experiments to develop tests that have predictive value for the therapeutic management of individuals with autoimmune diseases. These include tests that classify diseases, predict severity, and predict the best therapeutic options. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE LINKAGE STUDY OF MULTIPLE SCLEROSIS SIBLING PAIRS Principal Investigator & Institution: Hauser, Stephen L. Chairman & Professor; Neurology; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 01-DEC-1988; Project End 30-NOV-2003 Summary: Multiple sclerosis (MS) is a disease characterized by inflammation and demyelination in central nervous system white matter. MS affects 250,000 American and is thus the most important cause of neurologic disability, excluding trauma, that arises in early to middle adult life. Indirect evidence suggests that the immune system plays a

56 Sclerosis

role in the pathogenesis of MS, and data from family and twin studies indicate that genetic factors are important determinants of MS susceptibility. This study will attempt to establish the identity of genes that influence susceptibility to MS by linkage analysis using the affected sibling pair (sibpair) method. During the initial funding period 70 families, each with 2 or more siblings affected with typical MS, have been identified, and it is expected that 150 families will be studied during the course of the project. Inheritance of germline T-cell receptor beta chain (TCRbeta) genes that are identical by descent (IBD) will be determined by segregation analysis of polymorphic markers within the TCRbeta complex. Similar studies will be undertaken for genes that encode other TCR chains and the major histocompatibility complex (MHC). Epistatic interactions, should they be present, between candidate genes will be assessed. Allelic variants of TCRbeta variable region genes inherited by MS patients will be studied by single strand conformation polymorphism analysis in order to assess the possibility that a relevant gene segment may be responsible for haplotype sharing by sibpairs. In addition, the T-cell repertoire to myelin basic protein and proteolipid protein will be identified in siblings who have inherited MHC and TCRbeta genes that are IBD; these studies will define whether the T-cell response to these myelin proteins correlates with inheritance of TCRbeta and MHC genes IBD or with the presence of MS. The collection of a large genetic repository of sibpair MS families should also prove useful as an available resource for other studies of the inherited basis of MS susceptibility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPEUTIC APPROACH FOR TOLERANCE INDUCTION Principal Investigator & Institution: Scott, David W. Head; American National Red Cross Rockville, MD 20855 Timing: Fiscal Year 2002; Project Start 01-MAY-1997; Project End 31-MAY-2007 Summary: (provided by applicant): T cells from multiple sclerosis patients have been shown to respond to a variety of CNS antigens, such as MBP, MOG and PLP. Modulation of these immune responses is a goal for therapeutic intervention in MS. The focus of our lab is to develop novel approaches for the induction of tolerance that can be applied to the prevention or reversal of undesirable immune responses, particularly in autoimmune diseases like MS. We have utilized immunoglobulin fusion proteins delivered via retroviral vectors for the induction of tolerance. This technology is based on the well-established tolerogenicity of immunoglobulin carriers, onto which we engineer multiple epitope-containing polypeptides in frame with this lgG scaffold. In this system, the transfected autologous donor cells presenting this fusion protein select the relevant epitopes for the respective MHC haplotypes. Our hypothesis is that the multiple epitopes so expressed via B-cell antigen presentation lead to immunologic tolerance via a FasL-dependent mechanism. Data in several experimental autoimmune models (uveitis, diabetes, EAE with MBP for multiple sclerosis) are promising in that significant clinical efficacy has been achieved. Since numerous antigens have been identified as potential targets in multiple sclerosis, it is important to extend our model system to these additional antigens in models of MS, and to understand the mechanisms of gene therapy for tolerance in order to achieve improved efficacy. Our goal is to induce tolerance to additional encephalitogenic antigens, such as MOG and PLP, in both unprimed and primed T cells. Moreover, we wish to apply this system in a model of relapsing MS, using PLP peptides. To establish the nature of the APC, we will track the transduced B-cell APC, using GFP constructs and PKH26 dye labeling, as well as modification of tolerance by CpG-containing oligonucleotides. Finally, we will use T cells from TCR transgenic mice to establish the mechanisms involved, including the

Studies 57

migration and fate of specific cells, role of FasL and involvement of suppression in this gene therapeutic approach for tolerance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR HEREDITARY TUMORS IN MODELS OF NF2 % TSC Principal Investigator & Institution: Breakefield, Xandra O. Professor; Massachusetts General Hospital 55 Fruit St Boston, MA 02114 Timing: Fiscal Year 2001; Project Start 23-JAN-1987; Project End 31-AUG-2006 Summary: (provided by applicant): Studies will be undertaken to develop modes of gene delivery to experimental neural tumors for therapeutic intervention. Neoplastic lesions associated with tuberous sclerosis (TSC) including subependymal glial nodules, giant cell astrocytomas and cortical hamartomas, are believed to represent the consequences of loss of tumor suppressor genes on growth of astrocytes, neuroprogenitor cells and mesenchymal elements. Tumor models in the TSC2 heterozygous and conditional knock-out mice have been chosen as they are genotypically similar to mutations seen in patient cells and derive spontaneously from endogenous cells. They include liver hemangiomas, renal cell carcinomas, cortical hamartomas, and potentially subependymal glial nodules. Gene delivery to these tumor cells will be explored using three types of hybrid amplicon vectors derived from herpes simplex virus type 1 (HSV): one bearing a tetracycline (tet)-regulatable transgene cassette; one bearing elements of adeno-associated virus (AAV) to promote chromosomal integration; and one with both Epstein Barr virus (EBV), elements to promote episomal retention, and retrovirus vector elements (RV), to convert ampliconinfected cells into retrovirus producer cells. Vectors will be delivered through the intravascular route, either directly or via endothelial carrier cells to vascularized tumor foci; by intrathecal injection for brain lesions; and by direct intratumoral injection to large tumor masses. The efficiency and longevity of gene delivery to tumors in vivo will be established using reporter genes. Effective delivery modalities will incorporate therapeutic transgenes for anti-angiogenic and apoptosis factors, and consequences to tumor growth and pathology will be evaluated. In parallel, we will incorporate additional elements into these vector systems to increase the fidelity of regulatable transgene expression and to facilitate gene delivery to slowly growing tumors, typically seen in patients. This will include, in the first case, use of a tetracycline-silencer element and elimination of the VP16 transactivating protein from virions to achieve a "full off? state in the absence of drug, and, in the second case, replacement of RV elements in the HSV/EBV vector with components of lentivirus (LV) vectors, which are able to integrate transgenes into both dividing and non-dividing cells. TSC2 +/-transgenic and TSC1 conditional knock-out animals will be provided by Dr. Kwiatkowski (Project 12); pathologic expertise by Dr. Louis (Core C); assistance with vector engineering by Dr. Sena-Esteves; and MRI analysis by Dr. Weissleder. This project is designed to develop a strategy for reducing bulk in slow growing, benign tumors using vectors safe enough for eventual human use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENES AND GENETIC MODELS IN MOTOR NEURON DISORDERS Principal Investigator & Institution: Siddique, Teepu; Professor; Northwestern University Office of Sponsored Programs Chicago, IL 60611 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 30-JUN-2008

Neurology;

58 Sclerosis

Summary: (provided by applicant): Familial amyotrophic lateral sclerosis (FALS), 'pure' hereditary spastic paraparesis (HSP) and primary lateral sclerosis (PLS) are genetically heterogeneous disorders caused by motor neuron degeneration. These disorders either affect, both the upper and lower motor neurons (FALS), or primarily the upper motor neuron (HSP and PLS). The long-term goal of my laboratory is to identify the genetic contribution to the pathogenesis of these disorders. Success in this goal will lead to the formulation of interventions based on disease mechanisms to prevent, postpone and treat these and related disorders. We now plan to build on the work we accomplished in the last five years as part of a program project (NS 21442). We fulfilled all the Specific Aims such that we identified the ALSIN gene, that cause both recessive FALS (ALS2) and recessive juvenile PLS (JPLS1), on chromosome 2q33, studied mutations in SPASTIN that cause HSP (SPG5), and identified new loci for dominant ALS (on the Xchromosome) and ALS/dementia on chromosome 9q21-q22. We will further expand our gene discovery effort in recessive ALS and recessive HSP develop genetic models of FALS, JPLS, and HSP, and interrogate the products of causative genes for their proteinprotein interactions to trace their signaling pathways. We plan to accomplish these goals by three main Specific Aims (1) Identify the genes for a more common form of recessive FALS (ALS5) on chromosome 15q15-q21 and a common form of recessive HSP (SPG5A) on chromosome 8q. (2) Develop genetic models of alsin for the JPLS and ALS phenotypes and of spastin for the HSP phenotype (SPG4). (3) Identify protein interactions of alsin. In the previous period we narrowed the loci for ALS5 and SPG5A. We will use high throughput sequencing and bioinformatic support to identify these genes, as we successfully did the case of the ALS2 gene. We will make knockout models for alsin and spastin, to study the pathology and pathogenesis of these disorders. Finally, the interacting partner proteins of alsin and subsequently of spastin will be interrogated by the two-hybrid systems and immunoprecipitation. Interaction will be confirmed by dual labeled confocal microscopy and FRET analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC AND MRI CORRELATES OF HUMORAL IMMUNITY TO MYELIN Principal Investigator & Institution: Genain, Claude P.; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): There is currently no paraclinical investigation that accurately predicts clinical course, prognosis, or pathological subtypes of multiple sclerosis (MS). A pathogenic role has been suggested, but not formally demonstrated for myelin-specific antibodies in MS, and genetic factors that control these autoantibodies are not characterized. We propose 1. That autoantibody responses against myelin are heterogeneous, and that antigen/epitope recognition influences pathogenicity 2. That the development of pathogenic humoral immunity in MS is controlled at least in part at the genomic level, and that comprehensive autoantibody profiling in MS families may define distinct clinical phenotypes influenced by single or multiple genetic factors. 3. That studies of anti-myelin antibodies at early stages of MS have prognostic value. First, using specific antibody assays and a unique repository of MS family samples assembled by the investigators of this project, we will perform an extensive evaluation of autoantibodies against 3 major autoantigens of myelin and with an investigation of clinical relevance in MS families, and will analyze full genome screen data using autoantibody profiles as trait loci. The relationship between autoantibody titers and clinical MS phenotype (especially optico/spinal forms, and progressive forms with

Studies 59

atrophy) will be evaluated. Second, we will correlate patterns of myelin autoantibodies with clinical and MRI outcomes in a 5 year prospective, longitudinal study of patients presenting with clinically isolated syndromes (CIS). Extensive analyses of antibody repertoires will be conducted, including specific detection of antibodies directed against conformational determinants of myelin oligodendrocyte glycoprotein (MOG), an exposed antigen of myelin that has been experimentally recognized as a target for demyelinating antibodies. Finally, we will directly evaluate the potential pathogenicity of anti-MOG antibody fractions purified from serum of CIS patients in vivo, using passive antibody transfer experiments in a primate MS model. These studies will provide new paraclinical markers for the subtyping and prognosis of MS, and will guide the implementation of antibody based therapies that are in development for CNS demyelinating disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC SUSCEPTIBILITY

BASIS

FOR

SEXUALLY

DIMORPHIC

EAE

Principal Investigator & Institution: Fillmore, Parley D. Cell and Structural Biology; University of Illinois Urbana-Champaign Henry Administration Bldg Champaign, IL 61820 Timing: Fiscal Year 2002; Project Start 22-MAY-2002; Project End 21-MAY-2008 Summary: Although it has been know for some time that multiple sclerosis (MS) is more frequently observed in women than in men (2-3:1), it is not known why. Current theories suggest that men may suffer a different type of MS and/or show more severity in their symptoms as compared to the milder relapsing-remitting disease frequently seen in females. It is thought that immune responses, such as responses to infectious agents and autoimmune reactivity, are sexually dimorphic. While these differences are likely influenced by sex steroids, current theories fail to account for the fact that hormone levels themselves are unlikely to vary widely between affected and nonaffected men, or affected and non- affected women. Instead, what is likely to be different is an individual's unique genetic profile of sexually responsive genes. Many immunologically significant genes are quite sensitive to the presence (or absence) of sexsteroids and sex-related soluble factors. Additionally, other genes that control the conversion of sex-steroids into immunologically more active forms could have significant influence on the clinical course of MS. This proposal uses genetic crosses of mice that differ in susceptibility to experimental autoimmune encephalomyelitis (EAE), the best-studied animal model of MS, to identify genes important in their ability to regulate the sexually dimorphic susceptibility see in MS and EAE. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC DETERMINANTS OF OXYGEN TOXICITY Principal Investigator & Institution: Culotta, Valeria C. Associate Professor; Environmental Health Sciences; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; 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

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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 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 LOCI PREDISPOSING TO MULTIPLE SCLEROSIS (MS) Principal Investigator & Institution: Peltonen, Leena; Professor & Chair; Human Genetics; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2006 Summary: (provided by the applicant): Multiple Sclerosis (MS) is a chronic neurological disease of the central nervous system characterized by multifocal inflammation, demyelination and axonal damage. The disease process shows inflammation resulting in multiple patches of demyelination in MRI analyses of CNS. MS shows a high-degree of individual variability in the severity and progress of the disease. The diagnosis of MS is still mainly based on the characteristic clinical symptoms. There are no specific laboratory tests for MS. However, changes in MRI and presence of oligoclonal IgG bands in the cerebrospinal fluid are used as supporting findings for the clinical diagnosis. In spite of extensive research, the basic molecular events in the initiation and progression of MS are still poorly understood. Most MS cases are sporadic, but family twin and adoption studies indicate a strong genetic component in the pathogenesis of the disease. As in most complex diseases, the genetic contribution, although important, is by no means the sole determinant, but environmental, so far unidentified, factors contribute to the pathogenesis. Due to the evident genetic contribution in MS, we hypothesize that distinct allelic variations predispose to MS. We further hypothesize that well-characterized, ethnically-homogenous populations provide advantages in identification of genetic variations predisposing to complex traits, such as MS. Thus, we aim to identify gene variants predisposing to MS. We will focus on genetic loci, which we have previously identified in a genome-wide scan and now restricted to a few megabases. Our strategy is to utilize the unique, ethnically homogenous population sample of Finnish MS families. More specifically, we aim to: 1) Restrict chromosomal loci linked to MS by monitoring for association and linkage disequilibrium, in MS alleles using multiple single nucleotide polymorphisms in the critical regions on chromosomes5 and -17; 2) monitor differential expression of genes located on the critical region of Chr.-5 and -17 using expression microarrays; and 3) sequence candidate genes selected

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in Aims 1 and 2 to detect allelic variants contributing to MS, and test these allelic variants in a study sample from more heterogeneous populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHENOTYPE

GENETIC

MODIFICATIONS

OF

TUBEROUS

SCLEROSIS

Principal Investigator & Institution: Govindarajan, Baskaran; Emory University 1784 North Decatur Road Atlanta, GA 30322 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2004 Summary: Tuberous sclerosis is an autosomal dominant disorder that causes morbidity and mortality due to seizures, mental retardation, hamartomas, and benign and malignant neoplasms. While two genes for TS have been cloned, hamartin (tsc1) and tuberin (tsc2), the mechanism behind the tissue specificity of hamartomas and neoplasms are poorly understood. In addition, no phenotype-genotype correlation has been established in TS. These tissues are not specific to TS, but exist in other autosomal dominant syndromes like neurofibromatosis, not only in which neoplasms occur, but also hamartomas which cause learning disabilities and hypertension. The bewildering array of disorders which occur in TS patients suggest that modifying genes regulate the TS phenotype. We will analyze the effect of a candidate modifying gene, HDAC9, on the phenotype of transgenic mice we have already generated which carry a specific modification in the tuberin gene and which develop hamartomas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICS OF JUVENILE AMYOTROPHIC LATERAL SCLEROSIS (JALS) Principal Investigator & Institution: Chance, Phillip F. Professor; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001 Summary: Chronic Juvenile Amyotrophic Lateral Sclerosis (JALS) combines the features of a spinal muscular atrophy syndrome with upper motor neuron dysfunction. We have identified a large pedigree in Southern Maryland segregating an autosomal dominant gene for this form of JALS. Over 75 persons in this family are affected with a peripheral neuropathy characterized by an age of onset in adolescence with slow progression, leading to severe neuromuscular impairment by the fourth and fifth decades. Altered or abnormal expression of a motor neuron-specific component or a more widely-expressed protein whose function is crucial to motor neuron function is suspected. The gene for this disorder does not map to known regions of other motor neuron syndromes including the Familial Amyotrophic Lateral Sclerosis (ALS1) locus on chromosome 21, the Juvenile Amyotrophic Lateral Sclerosis (ALS2) locus on chromosome 2 or to the Spinal Muscle Atrophy (SMA) locus on chromosome 5. We propose to investigate the molecular basis of the JALS gene in this pedigree by techniques of positional cloning, including linkage analysis, physical map construction and analysis of transcripts and candidate genes. Experiments aimed to characterize the patterns and distribution of expression of this gene at the transcriptional and protein revels are proposed through in situ hybridization analysis, construction of transgenic animals, protein/antibody production and analysis in a motor neuron cell culture system. Genetic analysis in this large JALS pedigree affords the opportunity to identify and characterize an important motor neuron component. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GOLGI APPARATUS IN AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Gonatas, Nicholas K. Professor of Neurology and Pathology; Pathology and Lab Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 30-APR-1998; Project End 31-MAR-2003 Summary: All proteins destined for fast axoplasmic transport are processed through the Golgi apparatus (GA) and an intact organelle is essential for neuronal function. Our laboratory was the first to identify the disruption of the GA in a high percentage of motor neurons in ALS and in both asymptomatic and symptomatic transgenic mice expressing the G93A mutation of the human Cu/Zn superoxide dismutase (SOD1) gene found in familial Amyotrophic Lateral Sclerosis. The fragmentation of the GA in ALS and G93A transgenes is identical to its dispersion in cells undergoing mitosis, and in cells treated with microtubule depolymerizing drugs as we discovered in 1964. We propose to evaluate the contribution of the GA in the pathogenesis of ALS using human tissues, animal models of motor neuronopathies, and in vitro (cell culture) systems. Specifically, the GA, the microtubules, and the proteins linking them with the GA will be examined by immunocytochemistry and morphometry of motor neurons of the spinal cord, cranial nerve nuclei and motor cortex in ALS (reviewer 2), in G93A transgenics, in transgenic mice overexpressing the human heavy neurofilament subunit, and in the wobbler mouse, a model of infantile spinal muscular atrophy (reviewer 1). All ALS spinal cord motor neurons with ubiquitin positive inclusions have a fragmented GA and a possible correlation with ubiquitin-positive Mallory bodies in hepatocytes will be examined (reviewer 2). Recent studies have proposed that the point mutations of the SOD1 protein cause neuronal degeneration by a gain of function mechanism. Pursuing this hypothesis the yeast-two hybrid system will be used to identify proteins that interact with the G93A mutant. The specificity of the interaction of the putative proteins with G93A will be examined by in vitro binding assays using CHO cells and postmitotic human neurons (NT2N) inducibly expressing the G93A mutant and the putative binding proteins by immunocytochemistry and immunoprecipitations with appropriate antibodies. In parallel experiments the GA will be investigated in cells expressing G93A after oxidative stress induced by H202, paraquat and peroxynitrite. The structure of the GA will be examined by light and ultrastructural immunocytochemistry and its function will be evaluated using as a marker the glycosylation, sialylation and immunolocalization of MG160, a Golgi membrane sialoglycoprotein identified, cloned and expressed in our laboratory. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GROWTH REGULATION DURING DROSOPHILA DEVELOPMENT Principal Investigator & Institution: Edgar, Bruce A. Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, WA 98109 Timing: Fiscal Year 2003; Project Start 01-AUG-1994; Project End 31-JUL-2007 Summary: (provided by applicant): This proposal is to continue ongoing studies of the cell growth control in Drosophila. We have three long-term objectives: 1) to define the cell-intrinsic mechanisms that control cell mass increase (growth); 2) to determine how cell cycle progression is coordinated with growth; and 3) to learn how patterned growth is regulated during organ morphogenesis. Four specific aims are proposed. In Aim 1 we characterize the molecular, cellular, and developmental functions of rheb, a conserved G-protein that appears to function in the insulin signaling/tuberous sclerosis (TSC)/target of rapamycin (TOR) pathway, which governs nutritionally regulated cell

Studies 63

growth. Under this aim we also ask whether the control of ribosomal RNA synthesis is used as a means of nutritional or developmental growth control. Aim 2 proposes two forward genetic screens. One screen will select for loss-of-function suppressors of rhebmediated growth, and should identify downstream effectors in the insulin/TSC/TOR pathway. The other screen is for genes that, when over-expressed, cause clonal overgrowth in the developing eye; this should isolate several classes of genes that promote cell proliferation. Aim 3 proposes molecular tests to determine how cellular growth regulates Cyclin E and E2F to drive G1/S transitions in the cell cycle. Aim 4 applies the yield of previous aims to the problem of development. We employ epistasis tests using known growth regulators, as well as gene expression profiling, to define growth-regulatory targets of the TGF-beta/BMP4 homolog, dpp, and the homeobox transcription factor, Ubx, which orchestrate patterned growth in the developing fly wing. We test the roles, in developmentally regulated growth, of dMyc, rRNA synthesis, components of the insulin/TOR signaling pathway, and others. The project as a whole makes extensive use of genetic epistasis tests, mosaic analysis, quantitative cytological assays of growth and proliferation, gene mapping, and gene expression profiling. This work will define new genes and mechanisms involved in growth control and should impact general paradigms in cell and developmental biology. It has relevance to medical conditions involving cell and tissue growth including cancer diagnosis and therapy, regeneration, wound healing, diabetes and other metabolic diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HLA CLASS II TRANSGENIC MICE AS EXPERIMENTAL MODEL OF MS Principal Investigator & Institution: David, Chella S. Professor of Immunology; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2001 Summary: Multiple sclerosis (MS) is a common inflammatory demyelinating disease of the central nervous system characterized by local infiltration of T cells and macrophages into the white matter. The etiology of MS remains unknown, but both genetic and environmental factors are important in the development of disease. Susceptibility to MS has been linked to certain MHC class II alleles, although analysis of their exact function remains complicated. In this proposal, we will investigate the contribution of different human MHC class II molecules in the pathogenesis of MS. To test this, e have generated transgenic mice expressing several HLA-DR and -DQ genes in mice where the endogenous class II genes have been knocked out. In addition, to further humanize our transgenic mice, we have replaced the mouse CD4 with human CD4 gene. Our objectives are: 1) To generate experimental models of MS via induction of experimental allergic encephalomyelitis (EAE) in the transgenic lines. This analysis will shed light into the role of HLA class II molecules in susceptibility/resistance of disease. 2) To analyze the role of HLA class II molecules in cytokine expression and T cell selection. 3) To examine processing and presentation of T cell epitopes derived from CNS autoantigens, restricted by the HLA class II molecules. The development of HLA class II restricted experimental models will aid towards understanding the exact role of HLA class II molecules in MS pathogenesis and in the formulation of immunotherapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IDENTIFYING A VIRAL CAUSE OF MULTIPLE SCLEROSIS Principal Investigator & Institution: Lipton, Howard L. Professor; Evanston Northwestern Healthcare 2650 Ridge Ave Evanston, IL 60201 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (Adapted from applicant's abstract): Myelin breakdown in multiple sclerosis (MS) is mediated by me helper T Iymphocyte (T cell) Th1 subset by a process analogous with that of the animal model, experimental autoimmune encephalomyelitis (EAE). Extensive efforts have failed to show dear differences in T cell reactivity to candidate autoantigen peptides of myelin basic protein (MBP) and proteolipid protein (PLP) in individuals with MS compared to healthy controls. This suggests that a different pathogenetic mechanism may be operative. Considerable circumstantial evidence supports a role for a viral infection in MS, although an MS-specific virus has not been identified. Thus, the immunopathologic changes could be caused by a persistent central nervous system (CNS) viral infection with the immune response directed at viral rather than self proteins, but still mediated by the helper T Iymphocyte (T cell) Th1 subset as in EAE. The hypothesis is that a novel virus persists in the CNS to to drive the MS immunopathology. The putative virus replicates continuously in the CNS, driving continuous disease activity that underlies relapsing-remitting MS Viral replication may be similar to that in Theiler's murine encephalomyelitis virus (TME\/) infection in mice or Visna virus infection in Icelandic sheep, relevant experimental viral models of MS. Since the putative MS virus may be noncultivatable, transmission attempts to animals and molecular approaches provide the best means of its detection. Two previous attempts to transmit MS to non-human primates in the 1960s to 1970s were not optimal by current standards, and therefore should not dissuade current attempts. This proposal stands in contrast to studies focused on incriminating a specific known pathogen as a cause of MS. We propose to transmit MS to non-human primates by inoculating pairs of 0.5-1.0 year-old chimpanzees and squirrel monkeys intracerebrally (ic) with MS CSF mononuclear inflammatory cells (24 hr collection) and also with acute post-mortem plaques if optimum material becomes available. White matter lesions (serial cranial MRls), and CSF pleocytosis (serial cisternal taps) will detect subclinical disease in the animals. Stereotaxic biopsy will confirm the nature of developing lesions and enable serial brain-to-brain passage to demonstrate a replicating agent and its characterization. We also propose to construct and express MS CSF cDNA libraries in gt-11 as another way of detecting such a virus without prior knowledge of its nature. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IFN BETA AND IMMUNOREGUALTION IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Karp, Christopher L. Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2004 Summary: (Adapted from the Investigator's abstract): Multiple sclerosis (MS) remains the major disabling neurological illness of young adults. The consensus that MS is a T cell mediated, organ specific autoimmune disease has led to the clinical use of various immunomodulatory therapies, systemic IFN beta being the best characterized and most utilized at present. Unfortunately, while IFN beta clearly has the potential to modify the clinical course of MS, the effect is partial and not curative. Furthermore, the relevant mechanism(s) of action of IFN beta in MS remain obscure, hindering both the search for more effective therapies as well as a better understanding of the immunopathogenesis. IL-12, a cytokine central to the generation of cell mediated immune responses, is critical

Studies 65

to the pathogenesis of experimental autoimmune encephalomyelitis, the primary experimental surrogate for MS. Further there is compelling evidence relating IL-12 production to disease activity and progression in MS itself. These investigators have found that IFN beta potently suppresses the production of IL-12 by human monocyte/macrophages. The central hypothesis underlying these studies is that a principal mechanism of action of therapeutic IFN beta in MS is the suppression of IL-12 production. The ultimate goal of this research is to use knowledge of the molecular mechanisms underlying IFN beta mediated alterations in IL-12 responses to devise novel therapeutic strategies for MS. The studies in this application aim to further characterize the effects of therapeutic IFN beta on in vivo and ex vivo IL-12 production and to characterize, in vitro, the molecular mechanisms responsible for IFN betamediated suppression of IL-12 production. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IL-6 IN AUTOIMMUNE ENCEPHALOMYELITIS Principal Investigator & Institution: Chen, Youhai H. Associate Professor; Pathology and Lab Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: Cytokines play pivotal roles in the development of autoimmune diseases. Cytokines are required for both activation and effector functions of inflammatory cells. The long-term goal of our research is to elucidate the mechanisms of cytokine action in autoimmune diseases. This proposal is based on our recent discovery that interleukin (IL)-6-deficient mice are completely resistant to experimental autoimmune encephalomyelitis (EAE), and are unable to develop a strong TH1 or TH2 type response to self- myelin antigens. The goal of this proposal is to elucidate the mechanisms of IL-6 action in animal models of multiple sclerosis. A major challenge to study the roles of cytokines in autoimmune diseases is that they are often produced by a variety of cell types that perform different functions. In the case of IL-6, it is produced not only by cells of the immune system that cause autoimmune inflammation, but also by cells of nonlymphoid tissues such as brain and spinal cord. While IL-6 may activate immune cells to induce autoimmune inflammation, it is also a potent neurotrophic factor that can prevent glia and neurons from inflammation-induced cell death. We hypothesize that IL-6 regulates autoimmune encephalomyelitis through two distinct pathways: 1) it promotes development of autoimmune inflammation by facilitating the activation, migration and effector functions of immune cells, and 2) it accelerates disease recovery by promoting growth and regeneration of neural cells, including oligodendrocytes. To test these hypotheses, we have developed four specific aims: I. The roles of IL-6 in the activation and differentiation of myelin-specific T cells in autoimmune encephalomyelitis. II. The roles of IL-6 in the formation of inflammatory lesions in autoimmune encephalomyelitis. III. The roles of IL-6 in apoptosis and disease recovery. IV. The roles of transcription factor NF-IL6 in autoimmune encephalomyelitis. These will be addressed by examining the consequences of IL-6 and NF-IL6 deficiency in various cell types using transgenic adoptive transfer and bone marrow chimeric models. Information generated from these studies may not only help elucidate the mechanisms of IL-6 action in EAE but also aid in developing novel strategies to treat autoimmune diseases such as multiple sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SCLEROSIS

IMAGING

TRYPTOPHAN

METABOLISM

IN

TUBEROUS

Principal Investigator & Institution: Chugani, Diane C. Associate Professor; Pediatrics; Wayne State University 656 W. Kirby Detroit, MI 48202 Timing: Fiscal Year 2001; Project Start 01-FEB-1999; Project End 31-JAN-2004 Summary: Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disorder, now known to result from mutations in at least two different genes, TSC1 and TSC2. These genetic defects result in tumorous growths in multiple organs, including the brain, skin, heart, and kidney. Although the neurological consequences of the brain lesions are diverse, two major problems are epilepsy (affecting more than 80 percent of TSC patients) and autism (affecting 17-61 percent of TSC patients). The central hypothesis of this proposal is that abnormalities tryptophan metabolism via the serotonergic and/or kynurenine pathways contribute to the pathophysiology of both epilepsy and autism in children with TSC. Brain tryptophan metabolism will be measured in vivo in children with TSC using the tracer alpha[C-11]methyl-L-tryptophan ([C-11]AMT) with positron emission tomography (PET). In addition, metabolites of the serotonin and kynurenine pathways will be measured in brain tissue resected for the control of intractable epilepsy. In TSC patients with epilepsy, our preliminary data using [C-11]AMT PET have demonstrated focal increases in [C-11]AMT uptake in the region of epileptogenic tubers, but not in nonepileptogenic tubers as correlated with scalp electroencephalogram (EEG). We propose to confirm and extend these findings in the present proposal. In non-TSC patients with autism, both focal and global alterations in serotonin synthesis have been reported by our group using [C-11]AMT PET. We propose to test whether the focal and global serotonin synthesis abnormalities measured previously in non- TSC autistic children are also found in autistic children with TSC and epilepsy. Four specific aims are to be addressed in this proposal: (1) To determine whether the presence of increased [C-11]AMT accumulation in and around cortical tubers in children with TSC indicate epileptogenicity. (2) To determine the underlying biochemical mechanism for the observed increase in [C-11]AMT uptake measured with PET in a subset of tubers in children with TSC. (3) To determine whether autistic children with TSC and epilepsy differ from non-autistic children with TSC and epilepsy with respect to changes in global brain serotonin synthesis capacity with age. (4) To determine whether autistic children with TSC and epilepsy differ from non-autistic children with TSC and epilepsy with regard to focal [C-11]AMT abnormalities in thalamus and cerebellum. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNE ABLATION/HEMATOPOIETIC STEM CELL SUPPORT IN PATIENTS WITH MALIGNANT MS Principal Investigator & Institution: Burt, Richard; Northwestern University Office of Sponsored Programs Chicago, IL 60611 Timing: Fiscal Year 2001 Summary: The molecular pathogenesis of multiple sclerosis (MS) has not been fully defined although T cell-mediated immune destruction of myelin is thought to be an important component. Despite some benefits of immune modulating or suppressive agents such as prednisone, cyclophosphamide, or B interferon, no standard therapy is curative. Beginning in the 1960's, human bone marrow transplantation (BMT) was successfully performed to provide immune deficient patients (e.g., Severe Combined Immunodeficiency and Wiskott Aldrich Syndrome) with a functional immune system.

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In simplistic terms, treatment of MS by means of BMT is designed to ablate an aberrant immune system and then, similar to the use of marrow transplants for immunodeficient patients, reconstitute a new immune system in the hopes of re-establishing tolerance to the relevant autoepitopes during thymic development of the donor T cells. This hypothesis is supported by animal experiments. In specific, Experimental Allergic Encephalomylitis (EAE) is an animal model for multiple sclerosis. Immune ablation and syngeneic marrow rescue in animals with EAE can prevent or ameliorate clinical symptoms and eliminate the effector lymphocytes responsible for EAE from the central nervous system. We propose to test the efficacy of complete immune ablation followed by hematopoietic stem cell support in patients with malignant MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNE RECOGNITION IN A PICORNAVIRUS MODEL OF MS Principal Investigator & Institution: Pease, Larry R. Associate Professor & Consultant; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2001 Summary: PROJECT 2 TITLE: Immune Recognition in a Picornavirus Model of Multiple Sclerosis The proposed studies examine the basis of the limited immune response against a persisting virus in the central nervous system (CNS). Mice infected intracranially with the DA-strain of Theiler's murine encephalitis virus (TMEV) clear the virus using T cell mediated immunity directed by the H-2D class I antigen-presenting molecules that are capable of recognizing the virus and eliminating the injection, yet fail to do so. By using transgenic mice, expressing chimeric class I genes generated by exchanging sequences between the K and D genes, the contribution of regulatory and coding features of the class I genes will be examined to assess the structural basis of the differential use of the class I molecules in the response against TMEV infection. Class I knockout mice will be used to investigate the functional importance of single native K or D antigen- presenting molecules in the development of neurological deficits in the TMEV model of multiple sclerosis. Chimeric transgenes will be intercrossed with the class I knockout MHC haplotype to investigate how differential regulation of single class I antigen presenting molecules will influence the pathology of disease. Recently, developments in our knowledge about the specificity of the anti-TMEV immune response, will permit us to specifically delete the immune response to the immunodominant viral peptide recognized by CD8+ T cells in H-2b mice. This approach will enable us to investigate the importance of the peptide dominant response in host resistance to persistent virus injection and the development of neurological deficits in persistently infected animals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNOGENETICS OF DEMYELINATION Principal Investigator & Institution: Rodriguez, Moses; Associate Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: The major goal of this program project is to investigate the immunogenetic basis of demyelination and neurological deficits. The experiments will utilize two excellent models of human multiple sclerosis, i.e. Theiler's virus infection and experimental autoimmune encephalomyelitis. The program project is under the direction of Dr. Moses Rodriguez Professor of Neurology and Immunology of the Mayo Medical School who has ha a long interest in the pathogenesis of demyelination and

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remyelination in human multiple sclerosis. Members of the Program Project (Drs. Chella S. David, Dr. Larry R. Pease, and Dr. Moses Rodriguez) are well established investigators and Professors of Immunology in the Mayo Medical School. This group has an impressive record of investigations on the immunogenetics in murine models of human disease. Project 1: (Dr. Rodriguez, Principal Investigator) will investigate transgenic expression of Theiler's virus genomes in mice. The experiments will also investigate the mechanisms of decreased demyelinating disease observed in human HLA transgenic mice and address the specificity of the pathogenic immune response important in development of functional neurological deficits following demyelination. Project 2: (Dr. Pease, Principal Investigator) will investigate the basis for H-2K vs. H-2D polarity of anti-TMEV lymphocyte responses in the central nervous system. Experiments will identify the importance of virus-specific CD8+ T cells in the resistance to persistence virus infection and in neuropathology. Project 3: (Dr. David, Principal Investigator) will investigate experimental autoimmune encephalomyelitis in HLA expressing HLA-DR or DQ haplotypes. Experiments will examine the presentation of putative autoantigens linked to MS by HLA-DR and DQ molecules. This Program Project focusing on the immunogenetic basis of demyelination by a group of highly interactive investigators is expected to provide new insights into the pathogenesis of myelin and neural injury in multiple sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOGENETICS OF RESISTANCE/SUSCEPTIBILITY TO TMEV INDUCED DEMYELINATION Principal Investigator & Institution: Kim, Byung S.; Northwestern University Office of Sponsored Programs Chicago, IL 60611 Timing: Fiscal Year 2001 Summary: Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in chronic inflammatory demyelination leading to clinical signs in susceptible mice. The TMEV system is considered to be one of the best animal models for studying human multiple sclerosis (MS) in light of the potential viral etiology and similarities in the progression of chronic demyelination. Extensive studies on the class II-restricted, CD4+ T cell response specific for TMEV, which appears to play an important role in the viral pathogenesis, have been reported. However, very little is known about the class Irestricted, CD8+ T cell response against TMEV, despite that this type of response is known to be the most efficient in protecting the host from viral infections. The resistance/susceptibility of mice to TMEV-induced demyelinating disease is controlled by the MHC, particularly by the H-2D locus coding for a class I molecule. Using beta2microglobulin (beta2M) deficient mice lacking class molecules, we have further demonstrated that the effect of the MHC may represent a protective (or regulatory) role for this virus-induced demyelinating disease. In addition, such a CD8+ T cell population appears to be involved in the resistance of some BALB/c substrains. Based on our preliminary results, we hypothesize that MHC class II-restricted Th1 population is responsible for the development of disease and class I (H-2D)-restricted CD8+ cells are responsible for protection from the disease. We propose here to examine the potential role of MHC class I-restricted cytotoxic T cells in the protection and/or pathogenesis of Theiler's virus-induced demyelinating disease as a model for human multiple sclerosis. The specific aims for the proposed studies include: 1) To generate stable target cells expressing viral antigens in conjunction with proper MHC class antigens by viral DNA transfection; 2) To assess the level of MHC class I-restricted T cells specific for viral antigens in resistant and susceptible mice during the course of demyelination; 3) To

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establish TMEV-specific, class I-restricted T cell clones and analyze their roles in TMEVIDD; and 4) To identify the viral epitopes involved in the cytotoxic T cell reactivity. We believe that our proposed studies will yield important information on the potential control mechanism(s) against virus-induced, immune-mediated demyelination, which is a relevant animal model for studying human MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOLOGICAL STUDIES IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Friedman, Jacqueline; Rockefeller University New York, NY 100216399 Timing: Fiscal Year 2001 Summary: Multiple sclerosis (MS) is a disease which significantly affects areas of the central nervous system required for normal neurological functioning. Pathological studies of patients have suggested a viral etiology for this disease, based on similarities to known viral illnesses and the pathological changes observed. Epidemiological studies also support the hypothesis of a viral cause of MS with reported outbreaks of the disease in areas such as the Faeroe Islands. We now believe that our laboratory at the Rockefeller University, as well as other research labs, have sufficient preliminary evidence to warrant a clinical trial in MS using an anti-herpes antibiotic, Valtrex, to determine if the ravages of this disease can be controlled. Specifically, we have demonstrated that the Human herpes type -6 (HHV-6) virus can be detected by immunological methods in post mortem brain specimens of MS patients (oligodendrocyte glial cells), but not in brain specimens from decedents with other diseases. In addition HHV-6 DNA has been detected in MS brain tissue by the PCR technique, but not in controls. Finally, MS patients have a high serum antibody response to the Herpes-6 virus. Valtrex is a drug inhibitory to the HHV-6 virus with a good safety profile and is FDA approved. The general plan of study is to enroll 60 patients into a two-year trial with half randomly assigned to receive the drug and the other half a placebo. The patients will be evaluated over the trial period by two neurologists, one of whom will not know which treatment the patients have been assigned, to assess disease progression and to evaluate disability, as measured in disability rating scales. In addition the frequency of attacks will be monitored and serial brain M.R.I. scans will be obtained to determine the number of brain lesions. Blood and spinal fluid will be periodically drawn to determine the immune response to the HHV-6 virus in the Valtrex study patients and in patients not in the drug trial, but followed at Rockefeller under the protocol "Immunological Studies in MS." Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNOMODULATION INTERFERON B

IN

MULTIPLE

SCLEROSIS

BY

Principal Investigator & Institution: Oksenberg, Jorge R. Associate Professor; Neurology; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Multiple sclerosis (MS) is a common inflammatory disorder of the CNS characterized by myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. Interferon beta (IFNa) has been shown to decrease clinical relapses, reduce brain MRI activity, and slow progression of disability. However, the effect of this treatment is partial, and a significant amount of patients are not responders. The overall goal of this proposal is to characterize the

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mechanisms involved in the response to IFNa therapy in MS. A Clinical Core has established and maintains a dataset of patients with relapsing remitting MS treated with IFNa. The Core has sequentially collected blood from study participants and store genomic DNA, total RNA, peripheral blood lymphocytes (PBMC) and sera for the studies proposed in this application. Stringent and well established primary and secondary clinical endpoints are available to investigate promising relationships between candidate immunological (specific aim 1, subcontract B), molecular (specific aim 2) and genetic (specific aim 3) surrogate markers and the clinical response to treatment. Based on the hypothesis that IFNa is a pleiotropic immunoregulatory reagent, a multi-analytical longitudinal strategy was designed to elucidate basic therapeutic mechanisms and identify the patients who will benefit the most from this mode of therapy. Specific Aim 1 is primarily concerned with the expression of cellular markers of activation following treatment. In Specific Aim 2, kinetic (real time)-PCR will be used to analyze transcriptional profiles in PBMC of IFNa treated patients. Finally, Specific Aim 3 is a pharmacogenomic study of potential gene-immunotherapy interactions. A comprehensive multi-analytical strategy was designed and is presented in this proposal to generate reliable working models for the understanding of the physiological mechanisms of IFNa administration in autoimmune demyelination. In addition to new insights into the fundamental biology of interferons, our results will potentially identify surrogate markers of activity, and define the molecular basis of interferon response heterogeneity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOPATHOGENESIS OF MULTIPLE SCLEROSIS Principal Investigator & Institution: Racke, Michael K. Associate Professor; Neurology; University of Texas Sw Med Ctr/Dallas Dallas, TX 753909105 Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 30-APR-2008 Summary: (provided by applicant): The studies which are outlined in this proposal represent a very exciting and ambitious plan to address the issues of the magnitude, fine specificity, and precise nature of the autoreactive T cell response in MS and further explore the potential contribution of clonally expanded CSF B cells to disease pathogenesis. Using highly innovative approaches we plan to characterize these responses at a single cell level and analyze the TCR usage and CSF B cell repertoire, specifically in the context of various therapeutic interventions. These studies will determine the effectiveness of immune reconstitution with respect to the response to myelin antigens and compare that with what happens to the immune response following more standard immune suppression using mitoxantrone. We will also be able to compare this information with the data we are generating on patients with RRMS receiving more standard immunomodulatory therapies. We anticipate that these studies will provide important information with regard to the immunopathogenesis of MS. Data from these studies will allow the PI to design clinical trials testing novel therapeutic agents for MS based on the translational studies. In addition, the proposed Award will allow the PI to concentrate his efforts on mentoring the next generation of clinician scientists focusing their efforts on multiple sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNOPATHOLOGY OF VIRUS INDUCED DEMYELINATION Principal Investigator & Institution: Dal Canto, Mauro C. Professor; Pathology; Northwestern University Office of Sponsored Programs Chicago, IL 60611

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Timing: Fiscal Year 2001; Project Start 01-MAY-1976; Project End 30-NOV-2002 Summary: (adapted from the applicant's abstract): Theiler's murine encephalomyelitis virus (TMEV)-induced de-myelinating disease (IDD) is believed to be one of the best viral models of multiple sclerosis (MS). TMEV-IDD has been shown to be genetically regulated by genes both in and outside the major histocompatibility complex (MHC). The best immunological parameter that correlates with susceptibility of a particular strain to this demyelinating disease is its ability to develop a delayed-type hypersensitivity (DTH) response to viral antigens. Both immunological parameters, such as the ability to develop a DTH response to virus, as well as factors regulated at target cell level may be responsible for differential susceptibility to TMEV-IDD in different murine strains. DTH responses are driven by CD4+ Tho cells which are negatively regulated by CD4+ The cells. These two different populations of helper lymphocytes secrete different cytokines that are important in the development of the inflammatory response. The main hypothesis of this proposal is that strains with different susceptibility TMEV-IDD may show different expression of these important cytokines in parallel with their susceptibility or resistance to TMEV-IDD. Since chronic DTH responses depend on the persistence of the eliciting antigen, Dr Dal Canto proposes also to study the ability of various CNS cells from murine strains with different susceptibility/resistance to TMEVIDD to become infected by TMEV, and will explore the ability by these cells to express a number of important soluble and surface molecules which are believed to be important in the development and progress of the inflammatory response in the CNS. This proposal is articulated into four Specific Aims. Studies will be both in vivo and in vitro. In a 1, the principal investigator proposes to explore the possible differential susceptibility to infection by astrocytes and oligodendrocytes from strains with different susceptibility to TMEV-IDD. Both survival of the cells and their most important luxury functions will be studied. In Aim 2, the principal investigator proposes to investigate the role of different sub-sets of inflammatory cells in lesion formation in a temporal fashion, and to focus particularly on the balance between Th1 and Th2 cells by studying their specific lymphokines. In addition, the role of astrocytes as immune-competent cells will be investigated. Aim 3 will be to manipulate the expression of IL-4, the most important cytokine for the differentiation of Th2 lymphocytes, to see whether the development and/or severity of TMEV-IDD can be controlled. Aim 4 will test the DTH hypothesis more directly by mutating the major DTH epitope of the virus. It is expected that disease will be either prevented or significantly reduced in its severity in mice infected with the mutated virus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOREGULATION OF THE TCR REPERTOIRE IN MULTIPLE SCLEROSIS / ANTI CD40L TRIAL Principal Investigator & Institution: Jiang, Hong; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2001 Summary: The overall aim of this grant is to study the immunopathogenesis of multiple sclerosis (MS) and to define immunoregulatory pathways that may control disease. In addition, we will use the opportunity presented by ongoing treatment of MS patients with IFN-beta and a planned clinical trial of a humanized monoclonal antibody to CD40L in MS to evaluate basic mechanisms of these therapeutic interventions in this disorder. Based on clinical evidence as well as data we have generated in EAE we hypothesize that there are four principal events in the development of MS: (1) genes including MHC alleles predisposing to MS establish a T-cell repertoire capable of

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recognizing self myelin related peptides intrinsic to the autoimmune process of MS: (2) myelin specific CD4+ T cell clones previous tolerant to autoantigen become activated and expand to change the T cell repertoire to reflect autoreactive CD4 T cells; (3) regulatory mechanisms, including the activation of TH1 and TH2 CD4+ T cell subsets as well as those involving regulatory CD8 T-cells fail, through processes, such as clonal deletion or changes in the cytokine milieu and (4) potentially myelin reactive TH1 CD4+ T-cells migrate to the CNS and induce tissue damage and disease. There will be two interactive aspects of this project. The first aspect will consist of three specific aims designed to study basic aspects of the immunopathogenesis and immunoregulation of human MS. These aims will: (1) determine if regulatory CD8+ T cells which specifically down-regulate MBP specific CD4+ T cells exist in the PBL or CSF of MS patients. (2) determine if the MBP specific CD4+ T cell TCRVB or functional repertoires are different at different disease stages and are modified by CD8+ T cells: (3) identify antigen activated CD4+ T cell clones in the CSF or MS patients, immortalize these clones and use libraries of T cell clones to determine antigen specificity. The second aspect of studies will consist of several specific aims directly concerned with the investigation of immunoregulatory mechanisms and TCRVB functional repertoires in patients being treated with IFN-beta or anti-CD40L. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPACT OF GENETIC, SOCIODEMOGRAPHIC & BEHAVIORAL FACTORS IN SYSTEMIC SCLEROSIS Principal Investigator & Institution: Fischbach, Michael; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, TX 78229 Timing: Fiscal Year 2001 Summary: Systemic sclerosis (SS) is an uncommon disease of uncertain etiology in which both genetic and environmental causes are postulated to play a role. However it is hypothesized that the disease is more aggressive in non-Caucasians who manifest a higher occurrence of organ involvement and a worse prognosis. The reasons for this may include genetic factors or organic or behavioral factors. At the three Texas medical centers, cohorts of Caucasians, African American, and Hispanics will be studied from early onset. The study will determine the HLA class II genotypes by DNA oligotyping and disease-associated alleles of other candidate genes found to be associated with SS; determine the sociodemographic parameters and behavioral features of the patients; determine pertinent clinical and laboratory parameters including disease manifestations; follow disease progression to outcomes; and examine the relative contributions and interactions of genetic, demographic, socioeconommic, cultural, familial, and initial clinical and laboratory features on the course and outcome of the disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INHIBITION OF MONOCYTE TGFB1-INDUCED SKIN FIBROSIS Principal Investigator & Institution: Gilliam, Anita C. Associate Professor; Dermatology; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 14-JUL-2000; Project End 30-JUN-2003 Summary: The candidate, Anita C. Gilliam, is a junior faculty member on tenure track in Dermatology at Case Western Reserve University (CWRU), where she is developing a research career in molecular mechanisms of autoimmune disease. The proposed work draws on her experience in molecular biology and cutaneous immunobiology, and requests support for a mentored Clinical Scientist Development Award to acquire new

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expertise in monocyte biology under the mentorship of Dr. Kevin D. Cooper (Dermatology). The research environment, resources, and opportunities for career development at CWRU are superb, with CWRU School of Medicine recently listed as one of the top 10 research institutions in the country, and the Department of Dermatology as the top US program in NIH funding. The candidate's immediate goals are to develop the animal model in the proposed work into a vehicle useful for testing of interventions in scleroderma; long term goals are to develop the science of cutaneous monocyte biology and gene transfer in autoimmune disease as an independently funded investigator in an outstanding research environment. The proposal involves the study of systemic sclerosis/scleroderma, a chronic autoimmune disease of unknown etiology characterized by altered humoral and cell-mediated immunity, and excessive deposition of collagen in viscerae and skin, which is thought to be driven by activated monocytes making TGFbeta. We have characterized a very promising murine model for scleroderma that recapitulates many important features of scleroderma. Hypothesis: Monocytes are critical effector cells in Scl GVHD. TGF -beta1 is a major fibrogenic cytokine driving skin fibrosis in mice with Scl GVHD; TGF-beta2 and TGF-beta3 play minor if any roles in this cutaneous fibrosis. Skin fibrosis can be inhibited by: 1) antibodies to TGF-beta, 2), and latency associated peptide (LAP), a naturally occurring antagonist for TGF-beta. Specific Aim 1: To investigate the mechanism and sequence of early critical events leading to skin fibrosis in animals with Scl GVHD to better understand the pathophysiology of fibrosing disease and to devise novel focused interventions. Establishing the critical parameters of monocyte influx into skin, production of fibrogenic TGFbeta, and upregulation of proalpha(I) collagen mRNA synthesis provides a foundation for in vivo focused interventions. Specific Aim II: To further characterize in vivo interventions that inhibit TGFbeta1 in Scl GVHD. We have shown in preliminary experiments that TGF-beta LAP and antibodies to TGF-beta inhibit skin fibrosis in animals with Scl GVHD. Further characterization of these observations have high relevance to our understanding of basic monocyte biology, to the TGFbeta-driven fibrosing process in the animal model and in the autoimmune disease scleroderma, and potentially to the treatment of scleroderma and human graft versus host disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INHIBITORS OF FATTY ACID AMIDE HYDROLASE (FAAH) Principal Investigator & Institution: Boger, Dale L. Professor; Scripps Research Institute 10550 N Torrey Pines Rd La Jolla, CA 920371000 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): The development of exceptionally potent inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid) and anandamide (an endogenous ligand for cannabinoid and vanilloid receptors), is detailed. With the help of an extensive set of collaborations that will provide not only the in vitro characterization of the inhibitors, but also their in vivo evaluation (animal pain, sleep, anxiety, and multiple sclerosis models) and characterization (PK properties, metabolism), the studies will clarify the role of endogenous oleamide and anandamide, establish the utility of FAAH as a therapeutic target, and potentially provide therapeutic agents for the treatment of sleep disorders, anxiety, epilepsy, pain, cancer, Parkinson's and Huntington's disease, stroke, and/or multiple sclerosis. Preliminary studies conducted over a period spanning 5 years have been extensive, providing the first class of exceptionally potent, competitive inhibitors of FAAH and defining key structural features that impact future inhibitor

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design. These studies have provided a set of a-ketoheterocycle FAAH inhibitors with Ki's that drop below 200 pM and that are l00-1000 times more potent than the corresponding trifluoromethyl ketones. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTELLIGIBILITY ASSESSMENT IN DYSARTHRIA Principal Investigator & Institution: Kent, Ray D. Professor; Waisman Ctr/Mr & Human Devlmt; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2001; Project Start 01-JUL-1985; Project End 31-DEC-2005 Summary: Dysarthria is a frequent result of several neurological disorders, including Parkinson disease, stroke, cerebellar pathologies, multiple sclerosis, and traumatic brain injury. Dysarthrias often lead to decreased speech intelligibility, but they also affect other dimensions of spoken language, including voice quality, prosody, and paralinguistic features. These have not been studied collectively in large numbers of individuals with dysarthria. This project uses a multiple-task protocol with both perceptual and acoustic measures to examine intelligibility, voice quality, prosody, and paralinguistic aspects in children and adults with acquired dysarthria. Several newly developed analyses will be used to provide quantitative data toward the construction of profiles of speech impairment and neurologic lesion. Included will be the first systematic replication of the original work that led to the contemporary classification of the dysarthrias. The data on dysarthria will be integrated with data on speech development and normal adult speech in a neural network model of speech production that is based on internal models of auditory and articulatory representations of speech. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INTERFERON-B AND COPOLYMER-I IN MULTIPLE SCLEROSIS. Principal Investigator & Institution: Dhib-Jalbut, Suhayl S. Professor; Neurology; University of Maryland Balt Prof School Baltimore, MD 21201 Timing: Fiscal Year 2001; Project Start 02-MAY-1999; Project End 30-APR-2004 Summary: Candidate: The applicant is an associate professor of Neurology at the university of Maryland and a staff neurologist at the Baltimore VA Medical Center. Current academic activities include clinical and basic research in multiple sclerosis (MS). Currently, there are two ongoing research projects in the applicant's laboratory: The first is a VA funded Merit Review Award through March, 2002 to examine mechanisms of virus persistence in human neurons, and the second is to examine the therapeutic mechanisms of 2 newly approved drugs for MS, IFNbeta and copolymer-1. During the past 6-years four postdoctoral fellows conducted research related to MS in the applicant's laboratory. Environment: The Maryland Center for MS is internationally recognized for clinical and basic research in MS. Clinical research at this center contributed to the FDA approval of 2 of the 3 currently marketed drugs for MS namely Betaseron and copolymer-1. More than 800 annual patient visits occur, and the center participates in several multisite clinical trials. The center is staffed by 5 full time MS specialists, 3 nurses, and 2 support staff. Research: The proposed research will focus on understanding the therapeutic mechanisms of Betaseron and copolymer-1 in MS. Supplies and partial technical support for this research is currently provided by Berlex and TEVA, the manufacturers of Betaseron and copolymer-1 respectively. Our specific aims include: 1. Examination of the modulatory effect of IFNbeta treatment on IL-12 in MS. IL-12 is a pro-inflammatory cytokine implicated in the pathogenesis of MS. Preliminary data indicate that IFNbeta has a cell-specific regulatory effect on IL-12 in

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peripheral blood mononuclear cells (PBMNC). We will examine the mechanism of this regulatory effect both in vitro and ex-vivo using PBMNC from MS patients pre- and post-treatment with IFNbeta. The findings will also be correlated with MRI disease activity. 2. Mechanisms of Copolymer-I therapy in MS. We will examine the immunologic effects of copolymer-1 in PBMNC obtained ex-vivo from MS patients treated with this drug. This includes induction of copolymer-1 specific regulatory cells, whether these cells cross react with myelin antigens and induce cytokine deviation, or whether copolymer-1 produces T-cell anergy. The proposed research could help identify components of the immunologic network in MS that are associated with response to treatment, and therefore help in the design of more effective future therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: KENNY HYPOCALCEMIA

CAFFEY

SYNDROME:

BONE

SCLEROSIS

AND

Principal Investigator & Institution: Diaz, George A. Human Genetics; Mount Sinai School of Medicine of Nyu of New York University New York, NY 10029 Timing: Fiscal Year 2001; Project Start 15-JUL-1999; Project End 03-JUN-2004 Summary: This application is designed to provide George A. Diaz, M.D., Ph.D. with a program of mentored patient-oriented research which will facilitate his development as an independent physician-scientist. Dr. Diaz has completed a residency in pediatrics and, upon completion of his fellowship in human genetics, will become an Assistant Professor of Human Genetics and Pediatrics at the Mount Sinai School of Medicine. During the course of his fellowship, he initiated positional cloning studies of an autosomal recessive skeletal dysplasia, the Kenny-Caffey Syndrome (KCS), using eight consanguineous Kuwaiti pedigrees. The principal manifestations KCS are short stature and hypocalcemia, but significant additional manifestations include eye abnormalities, developmental delay and immune deficits. Although KCS is a rare disease, its unique and protean manifestations suggest that identification of the disease gene will lead to novel insight into bone metabolism and calcium homeostasis as well as into the development of other affected organ systems, including the immune and central nervous systems. During the course of his fellowship, Dr. Diaz undertook a positional cloning project which required that he master linkage analysis and physical mapping. By homozygosity mapping, the KCS gene was successfully localized to chromosome Iq42-43, and the KCS critical region defined by haplotype analysis to an approximately 4 cM interval. To initiate physical mapping of the region, a YAC contig was constructed across the critical region by PcR content mapping using simple tandem repeats and sequence-tagged sites as markers. In order to identify the KCS gene and elucidate its function, further laboratory and clinical investigations are proposed. These studies will accomplish the following: l) the KCS critical region will be narrowed by development of new polymorphic markers and identification of new KCS families; 2) the natural history and phenotypic features of KCS will be further delineated to gain additional insight into the disease pathogenesis and the function of the KCS gene; 3) the physical mapping of the critical region will continue using PAC, BAC or cosmid clones; and 4) candidate genes in the KCS critical region will be evaluated, novel transcripts isolated by exon trapping and cDNA selection, and the disease gene will be identified by mutation analysis techniques. Dr. Diaz will be supported in his endeavors with protected research time, access to the General Research Clinical Center and institutional core facilities, and dedicated laboratory space. His development will be fostered by the serious commitment of his mentors to guide him in the proposed studies and in the responsible

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conduct of research, and by the outstanding research and intellectual environment at Mount Sinai. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LONG-ACTING BETA INTERFERON FOR MULTIPLE SCLEROSIS Principal Investigator & Institution: Cox, George N.; Bolder Biotechnology, Inc. 4056 Youngfield St Wheat Ridge, CO 800333862 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 30-SEP-2002 Summary: Beta-interferon is a fibroblast-derived cytokine that exhibits antiviral, antiproliferative and immunomodulatory effects on many cell types. Recombinant human beta-interferon has proven effective in treating Multiple Sclerosis and had worldwide sales of $850 million during 1998. We propose to create modified betainterferon proteins that can be administered less frequently, but with greater efficacy, than existing beta-interferon products. During Phase I we will identify sites in betainterferon that can be modified without affecting the protein's in vitro bioactivity. During Phase II, we will develop manufacturing processes to produce sufficient quantities of the modified beta-interferon proteins for testing in animal disease models. The improved characteristics of the novel beta-interferon proteins should reduce the amount of beta- interferon required per patient, enhance efficacy, reduce toxicity, improve patient compliance and quality of life and result in considerable cost savings to patients and healthcare providers. Beta- interferon is a member of a large family of structurally related growth factors and cytokines. Information gained from these studies will aid in creating long-acting versions of other members of this gene family for use in treating cancer, infectious disease and hematopoietic disorders. PROPOSED COMMERCIAL APPLICATIONS: Recombinant human beta-interferon is used to treat Multiple Sclerosis and had worldwide sales of $850 million in 1998. The modified betainterferon proteins under development will require less frequent dosing than existing beta-interferon products, resulting in significant cost savings to patients and healthcare providers. Additional expected benefits include improved drug efficacy and reduced toxicity, which will significantly enhance patient quality of life. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISM OF SELECTIVE TOXICITY OF SOD1 MUTANTS IN ALS Principal Investigator & Institution: Crow, John P. Anesthesiology; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001; Project Start 15-JUN-2001; Project End 31-MAY-2005 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,

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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 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 ABERRANT GLUTAMATE TRANSPORT IN ALS Principal Investigator & Institution: Rothstein, Jeffrey D. Professor; Neurology; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 01-MAY-1995; Project End 29-FEB-2004 Summary: (Applicant's abstract) Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by selective upper and lower motor neuron degeneration, the pathogenesis of which is unknown. About 60-70 percent of sporadic ALS patients have a 30-95 percent loss of the astroglial glutamate transporter EAAT2 (excitatory amino acid transporter 2) protein in motor cortex and spinal cord. Loss of EAAT2 leads to increased extracellular glutamate and excitotoxic neuronal degeneration. Preliminary studies document multiple abnormal EAAT2mRNAs, including intron-retention and exon-skipping, in the affected tissues of ALS pateints. The aberrant mRNAs were highly abundant and were only found in neuropathologically affected areas of ALS patients, but not in other brain regions. They were found in 65 percent of sporadic ALS patients, but were not found in nonneurologic disease or other diseased controls. They were also detectable in the cerebrospinal fluid of living ALS patients, early in the disease. In vitro expression studies suggest that proteins translated from these aberrant mRNAs may undergo rapid degradation and/or produce a dominant negative effect on normal EAAT2 resulting in loss of protein and activity. We propose a systematic approach to study the biology and relevance of aberrant EAAT2 mRNA and protein in ALS. The specific aims address: 1) Identification and characterization of aberrant EAAT2 mRNA species and proteins in ALS, including disease and tissue specificity, quantification. 2) Using in vitro expression systems we will investigate the biology of the aberrant RNA species to understand how they could account for the loss of EAAT2 in ALS by examining their transporter characteristics-Vmax, Km, conductance properties, stability and cellular trafficking. 3) Develop in vitro model systems to determine the processes that could be responsible for their formation in vivo, including excitotoxicity/oxidative stress, DNA repair, RNA processing proteins, and use astrocytes cultures from ALS patients to study their formation. Our preliminary work suggests that the loss of EAAT2 IN ALS is due to aberrant mRNA, and these aberrant mRNAs could result from RNA processing errors.

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Aberrant RNA processing could bed an important process in the pathophysiology of neurodegenerative disease and in excitotoxicity. The presence of these mRNA species in also cerebrospinal fluid may have diagnostic utility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF GLIAL PATHOGENESIS AND REGENERATION Principal Investigator & Institution: De Vellis, Jean; Professor; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 30-NOV-2006 Summary: Demyelinating diseases are devastating maladies that affect the stability and maintenance of the insulating membrane myelin, leading to damage of the nervous tissue and threatening the standard of life of the affected individual. For a long time, the adult CNS has been considered to be depleted of cells capable of remyelinating axons. However, growing evidence shows that oligodendrocytes (OLs), the CNS myelin forming cells, have some remyelinating capacity under the appropriate circumstances. As a result, new therapeutic strategies can be envisioned to repair demyelination. OLs are plastic cells and several extracellular signals have been shown to play key roles in timing the development of these cells in the CNS. For example, PDGF-AA, IGF-I, Tf, NT-3 and T3 have critical and supportive effects on the proliferation, survival and differentiation of OLs in vitro and in vivo. On the other hand, OLs are susceptible to dysfunction and consequently, myelin can be damaged. Many cytokines like IL-6, TNFa1FN-a and LT-a, which are produced in high levels in some autoimmune diseases, are particularly toxic to OLs. The effects of these molecules have been evaluated using in vitro cell cultures and explants and relatively few studies have approached the in vivo importance of these factors on glial development. In this grant, we propose to address a number of questions to study the in vivo physiological role of these factors and their relevance for therapeutic strategies. Recent studies suggest that PDGF-AA and IGF-I may be the best candidates to therapeutically treat CNS disorders where OLs are compromised. We propose to expand our studies to examine the therapeutic potential of other factors like bFGF, Tf and NT-3 and hormones like T3 and hydrocortisone in combination with PDGF-AA and IGF-I. We will test the hypothesis that remyelination can be controlled externally by providing an appropriate growth factor treatment to animals suffering from experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease Multiple Sclerosis (MS) and in animals where CNS myelin has been damaged by treatment with cuprizone. We will evaluate the benefits of modulating the critical and valuable information about the mechanisms that control oligodendrogenesis in the normal adult CNS and in pathological conditions and will be essential for future design or effective therapies to attempt the remyelination of adult CNS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF PODOCYTE INJURY Principal Investigator & Institution: Shankland, Stuart J. Assistant Professor; Medicine; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2006 Summary: Glomerular diseases remain a leading cause of kidney failure in the US. Injury to podocytes (visceral glomerular epithelial cell) in diabetic and membranous nephropathy, focal segmental glomerular sclerosis and minimal change disease, results in proteinuria, but if not adequately repaired, leads progressive glomerular sclerosis

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and reduced renal function. In order to perform a highly specialized function, podo are terminally differentiated in quiescent cells. Studies have shown that the apparent inability to proliferate and replace those podocytes lost by detachment/apoptosis, is central to the development of progressive glomerulosclerosis. Studies have shown that intraglomerular capillary pressure (Pgc) increases in most forms of progressive glomerular disease such as diabetic nephropathy. Increased Pgc, and the resultant mechanical stretch, is therefore considered a final common pathway to glomerulosclerosis. Although increased Pgc is associated with podo injury, the mechanisms are not known. In the first Specific Aim, we will apply mechanical stretch mouse podocytes in vitro to induce stress-tension injury. We will test the central hypothesis that stress-tension inhibits podo proliferation and induces hypertrophy. We will test the hypothesis that stretch increases the levels of CDK-inhibitors (p21, p27, p57), thereby inhibiting proliferation, and inducing hypertrophy. Specific null podo be used for study. We will also test the hypothesis that 3beta1 integrin and integrin-linked kinase mediate these growth effects (anti-proliferation, hypertrophy) and we will examine how specific signaling pathways (ERK1/2, Akt) mediate these events. In the second specific aim we will test the hypothesis that cyclin I and cyclin-dependent kinase (CDK) 5, recently identified cell cycle proteins, regulate podo proliferation and differentiation. Although podo do not typically proliferate following injury, podo dedifferentiate and re-enter the cell cycle in HIV nephropathy. Our exciting preliminary data shows that cyclin and CDK5 are constitutively expressed in podo. Utilizing mouse podocytes in culture, and CDK5 and cyclin I null mice, we will examine podo differentiation, proliferation and phenotype during development and in disease. Finally, we will also test the novel hypothesis that cyclin I regulates CDK5, and that CDK5 is the catalytic partner for cyclin I. Taken together, the overall goal is to show novel mechanisms underlying podo injury, so that ultimately, specific therapeutic strategies can be developed to reduce podo injury in the development of glomerular sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MHC PROTEINS AND HUMAN DISEASE Principal Investigator & Institution: Strominger, Jack L. Biochem and Molecular Biology; Harvard University Holyoke Center 727 Cambridge, MA 02138 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 30-JUN-2006 Summary: (provided by applicant): A great deal has been learned about the structure and function of human histocompatibility antigens in the past thirty years. Some details remain to be elucidated but, in addition, the information already obtained can be used to explore the relationship of these proteins to human diseases. The specific aims of this application are: 1. To develop murine models of pemphigus vulgaris employing human genes and to use these models to identify disease-related peptide epitopes bound to human Class 11 MHC proteins. 2. To examine the relationship between HLA-DP (a Class II MHC protein) and Hard Metal Diseases. 3. To examine the basis of the reactivity of a subset of HLA-B27 molecules (a class I MHC protein linked to ankylosing spondylitis) with an unusual monoclonal antibody MARB-4 and whether this subset might be related to the disease. 4. To examine the basis for the effectiveness of Copolymer 1 in the treatment of multiple sclerosis [genetically linked to the Class II MHC protein HLA-DR2 (DRB1*1501)] and to examine the possibility that more effective copolymers could be designed for the therapy of this disease, as well as for the therapy of the autoimmune disease (i.e. rheumatoid arthritis). 5. To utilize oligomerized T cell epitopes to study mouse models of, multiple sclerosis and pemphigus vulgaris, both of which are linked to specific alleles of Class II MHC genes.

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

Project Title: MICROGLIAL ACTIVATION BY SERUM FACTORS Principal Investigator & Institution: Moeller, Thomas; Neurology; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2006 Summary: (provided by applicant): Microglial cells are the resident immune cells of the central nervous system (CNS). They have been implicated in many acute and chronic neurological diseases, including trauma, stroke and multiple sclerosis. Upon CNS injury microglial cells are rapidly activated. Through the release of bioactive substances such as cytokines activated microglial cells can exert powerful toxic as well as protective effects on neurons. Until recently, research has mainly focused on microglial activation by cytokines. These potent peptides elicit a broad range of responses, including proliferation, motility and cytokine release itself. Nevertheless, before cytokines can activate microglia, they need to be induced, synthesized and released from neighboring cells. The reported rapid activation of microglia after CNS injury, leads to the question: Are there other, factors acting as microglial activators? One group of candidates is serum factors (SFs). SFs leak into the CNS parenchyma during insults associated with impairment of the blood-brain-barrier, such as trauma, stroke, and multiple sclerosis. Serum factors therefore could serve as immediate signals of injury and activate microglial cells without the need of intermediary, cytokine- producing "relay" cells. We hypothesize that serum factors (SF) represent a "short-cut" to microglial activation. Based on recently published reports and our preliminary findings, we propose to examine the effects of the serum factors thrombin, lysophosphatidic acid and sphingosine-1 -phospate on microglial Activation. Using molecular, immunological and imaging techniques the following issues will be addressed: 1. Determine the cellular consequences of microglial activation by SFs in vitro. 2. Determine the signal transduction mechanisms involved in SF-mediated microglial activation in vitro. 3. Determine the cellular consequences of microglial activation by SFs in a retina explant culture model in situ. In many pathological events SFs act immediately on microglial cells, long before first-phase cytokines could influence microglial behavior. Each of the receptors or signal transduction mechanisms identified may constitute a new target for therapeutic intervention in CNS injuries, which are accompanied by the break down of the blood-brain-barrier, such as trauma, multiple sclerosis or stroke. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MITOCHONDRIA IN AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Beal, Flint M.; Cornell University Ithaca, NY 14853 Timing: Fiscal Year 2003; Project Start 01-DEC-2002; Project End 30-NOV-2007 Summary: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which affects motor neurons of the spinal cord and cerebral cortex, leading to progressive paralysis and premature death. While the majority of the cases are sporadic and due to unknown causes, about 5-10% are familial (FALS), and of those approximately 25% are associated with mutations in the gene for Cu/Zn superoxide dismutase (SOD1). These mutations are the first identified cause of ALS, and their finding has allowed the development of a transgenic mouse model of the disease. Abnormal mitochondria and impaired mitochondrial respiratory chain function have been reported in motor neurons of patients with sporadic and ALS, as well as in the mouse models. A growing body of evidence suggests that impaired mitochondrial

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energy production and increased oxidative radical formation in the mitochondria and damage to the mitochondrial DNA (mtDNA) could be causally involved in motor neuron death in ALS. Indeed, several studies have postulated the involvement of mtDNA abnormalities in motor neuron degeneration. To define the role of mitochondrial alterations in the pathogenesis of ALS, we propose the following studies. 1) Analyze mitochondrial functions in brain and spinal cord in ALS transgenic mice at various stages of disease and in cultured cells expressing mutant human SOD1. Analyze the mtDNA from ALS transgenic mice in cybrids constructed with synaptosomes from brain and spinal cords. 2) Study the structural properties and the functional effects of SOD1 localized to mitochondria in transgenic animals and in cultured neuroblastoma cells expressing wild type and mutated h SOD1. 3) Analyze respiratory chain functions and mtDNA in individual motor neurons from ALS patients. We think that a better comprehension of the molecular basis of mitochondrial dysfunction in ALS will help us to understand the mechanisms responsible for the motor neuron loss and, in some cases may even identify the primary cause of the disease, with a potential impact on therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODELS OF DIABETIC NEPHROPATHY Principal Investigator & Institution: Heilig, Charles W. Assistant Professor; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: This portion of the proposed work will be performed at the Johns Hopkins School of Medicine in Dr. Charles Heilig's laboratory. The consortium proposes to create and study new transgenic mouse models of diabetes. One measure of the extent to which these mouse models reproduce and/or exacerbate a diabetic renal lesion, is the degree of glomerulosclerosis which develops. Dr. Heilig's laboratory will be responsible for morphometric measurements of pathologic changes in kidneys from transgenic and diabetic mice to be created in this proposed work. Dr. Heilig's laboratory will employ PAS and trichrome staining of formalin-fixed kidney sections from the mice, to measure percent mesangial sclerosis using computer-assisted microscopy with the Osteomeasure(R) software from Osteometrics, Inc. Glomerular and mesangial crosssectional areas are traced and calculated using this program. Freshly harvested mouse kidneys are sectioned sagittally and fixed in 10% buffered formalin prior to preparation of microscopic slides. Measurements of mesangial sclerosis will be performed on both PAS-stained sections (extracellular matrix) and Gomori-trichrome-stained sections (collagen). A minimum of 50 sequential glomeruli from each kidney will be used for quantitation of cross-sectional mesangial and glomerular areas, and for calculation of the percent mesangial sclerosis as the ratio of the two measurements x 100. The mean percent mesangial sclerosis in glomeruli will be determined for each kidney. Subsequently, the mean +/- SEM percent mesangial sclerosis in glomeruli will be determined for kidney samples in each experimental group, prior to statistical analysis for detection of significant intergroup differences. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR ASPECTS OF ANTIGEN PRESENTATION IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Ploegh, Hidde L. Professor; Dana-Farber Cancer Institute 44 Binney St Boston, MA 02115

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Timing: Fiscal Year 2001 Summary: Microglial cells are the antigen presenting cells of the central nervous system and are likely involved in the initiation of multiple sclerosis (MS). The present application will explore their cell-biological and biochemical be obtained from HLADR2 transgenic animals and used to characterize the antigen presentation capacity of such cells, using stimulation of appropriately restricted human T cells as a readout. Two antigens will be examined in detail: myelin basic protein (MBP) and myelin/oligodendrocytes glycoprotein (MOG). Preparations of MBP and MOG obtained by in vitro transcription/translation will serve as a source of native, radiolabeled antigen, the processing of which will be monitored using biochemical techniques. These experiments will be performed not only in DR2 transgenic mice, but also in DR2transgenics bred to homozygosity for mutations in the lysosomal proteases Cathepsin B, D, L or S. These enzymes are likely candidates for the proteolytic conversion of MBP and MOG into peptides that can bind to DR2. In this manner, the processing pathway of important autoantigens can be examined. The identification of the protease(s) essential for conversion of MBP and MOG into the offending DR2-peptide complex that initiates disease is a first step towards identification of inhibitors that could block these enzymes and thus be of therapeutic value in the treatment of ms. We shall characterize the trafficking of Class Ii molecules and antigen (MOG) in human microglia. The limited availability of this material necessarily implies a more restricted range of experiments, but the studies performed on DR2 transgenic murine microglia, the characterization of their functional properties and the assessment of the relevant proteases required for processing of MBP and MOG will allow a well-argued choice of experiments to validate the concepts elaborated for the murine model. The proposed experiments should not only uncover cell biological properties unique to microglia and essential for initiation of autoimmune T cell responses, but also point the way to new strategies for treatment of MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR BASIS OF LYMPHANGIOMYOMATOSIS Principal Investigator & Institution: Henske, Elizabeth P. Associate Professor; Fox Chase Cancer Center Philadelphia, PA 19111 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: Lymphangiomyomatosis (LAM) is a lung disease affecting women with a distinctive histologic pattern of diffuse smooth muscle proliferation and cystic degeneration of the lung interstitium. LAM can occur in the absence of systemic disease ("sporadic LAM") or in women with tuberous sclerosis ("TSC-associated LAM"). Tuberous sclerosis (TSC) is an autosomal dominant syndrome characterized by seizures, mental retardation, and tumors of the brain, kidney, heart, and skin. LAM affects about 5 percent of women with TSC. TSC is associated with mutations in two genes: TSC1, on chromosome 9q34, and TSC2, on chromosome 16p13. TSC1 and TSC2 appear to be tumor suppressor genes. TSC1 or TSC2 loss of heterozygosity has been demonstrated in several types of TSC tumors, including renal angiomyolipomas. One objective of this proposal is to investigate the genetic mechanisms leading to smooth muscle proliferation in LAM. We have found absence of tuberin immunoreactivity in some cases of both TSC-associated and sporadic LAM. This is consistent with the "two hit" tumor suppressor gene model. To understand whether LAM fits this model, we will analyze LAM cells for clonality and loss of heterozygosity. We will also determine whether a relationship exists between specific types of TSC1 or TSC2 mutations and the development of LAM. A genotype-phenotype correlation might explain the fact that

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only 5 percent of women with TSC get LAM. Another objective of this proposal is to determine the relationship between sporadic LAM and TSC. Renal angiomyolipomas, which are benign tumors consisting of fat, smooth muscle, and dysmorphic vessels, occur in 70 percent of patients with TSC and in 40 percent of women with sporadic LAM. We found chromosome 16p13 (TSC2) loss of heterozygosity in renal angiomyolipomas from 7 women with sporadic LAM. This suggests that some women with sporadic LAM have underlying TSC2 gene mutations. These mutations could be either germline or somatic. We anticipate that this project will elucidate the genetic mechanisms leading to LAM. The long-term goals of this work are to understand the roles of TSC1 and TSC2 in cellular pathways controlling normal smooth muscle growth and differentiation, and to determine how disruptions in these pathways lead to disease. This work may lead to new diagnostic and therapeutic strategies for women with LAM, and may also have relevance to other diseases involving smooth muscle growth, including pulmonary fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOTOR NEURON SURVIVAL IN AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Harris, Brent T. Neurobiology; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 30-JUN-2002 Summary: The ability to move our arms and legs depends on the integrity of our upper and lower motor neurons, which relay electrical signals from our brain to our muscles. When motor neurons die, as occurs after injury or in a variety of degenerative diseases that affect primarily infants and children (spinal muscular atrophies) or adults (amyotrophic lateral sclerosis (ALS)), irreversible paralysis ensues. In order to develop better ways to treat these clinical conditions, I propose to investigate the signaling mechanisms that normally promote motor neuron survival and how these pathways may go awry in disease. The Barres lab has developed methods to purify and culture defined types of CNS neurons including spinal motor neurons (SMNs). Using these methods, they recently discovered that elevation of cAMP alone is sufficient to strongly promote the survival of SMNs, even in the absence of peptide trophic factors. I will investigate the signaling pathways that enable cAMP to promote survival, specifically focusing on the hypothesis that the newly described B-raf signaling pathway is involved. Second, I will test the hypothesis that spinal motor neurons survive after axotomy because their cAMP levels become elevated, allowing them to survive in the absence of their usual peptide trophic inputs from muscle and Schwann cells. I will also study whether elevation of cAMP levels will prevent SMNs from dying in a transgenic mouse model of ALS. Lastly, I will devise a novel technique utilizing adenoviral vectors and immunopanning to purify and culture upper motor neurons in order to investigate the signals that promote their survival in vitro. By defining the signaling mechanisms involved in upper and lower motor neuron survival in culture and in animal models my goal is to develop new strategies to treat patients with spinal cord injuries and motor neuron diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MRI T2 SHORTENING ('BLACKT2') IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Bakshi, Rohit; Neurology; State University of New York at Buffalo 402 Crofts Hall Buffalo, NY 14260

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Timing: Fiscal Year 2001; Project Start 25-JAN-2001; Project End 31-DEC-2003 Summary: Dr. Bakshi is an assistant professor of neurology at Buffalo. During 1991 to 1996, he completed an internship at Massachusetts General Hospital, followed by neurology residency at UCLA and neuroimaging fellowship at Buffalo. His immediate goal is to.perform clinical-neuroimaging correlation research concentrating on multiple sclerosis (MS). His long- term career goal is to obtain the skills and experience necessary to develop into a funded independent clinical investigator using neuroimaging to study the pathophysiology of MS. The proposed three- year research training will provide skills for him in important aspects of patient-oriented research in MS. He will deepen his knowledge of biostatistics and epidemiology through formal coursework and supervision. He will learn a variety of computer-assisted MRI analysis methods under the teaching of Dr. Jack Simon that are critical in assessing MS. He will learn how to correlate these data with clinical and neuropathologic findings under the guidance of Dr. Lawrence Jacobs. Dr. Bakshi proposes to study MRI T2 shortening - "Black T2" (BT2) - as a surrogate marker of brain injury in MS. He will extend and attempt to confirm his preliminary observations that BT2 is present commonly in deep central gray matter as compared to normal controls by measuring tissue intensities and T2 relaxation times. He will determine if BT2 varies over time in parallel with other MRI changes (plaques/atrophy), clinical evolution, and therapeutic effects by analyzing 2-year longitudinal data of interferon-beta vs. placebo treated MS patients. To evaluate the hypothesis that BT2 represents pathologic iron deposition, Dr. Bakshi will examine autopsied MS brains in collaboration with Dr. Peter Ostrow for microscopic iron deposition. If the current study is fruitful, BT2 could become a useful laboratory marker of disease burden to assess the course of disease, select patients for therapies, or measure immunotherapeutic effects. In future studies, BT2 can be correlated with metabolism and MR spectroscopic evidence of neuronal injury in deep gray matter. If iron plays a pathophysiologic role in MS, this could offer a novel therapeutic opportunity. Alternatively, if iron accumulation is a disease epiphenomenon, then BT2 could be used as a noninvasive marker of brain degeneration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTIMODALITY NEUROIMAGING DATABASE SYSTEM Principal Investigator & Institution: Wong, Stephen T. Assistant Professor; Radiology; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 01-FEB-1998; Project End 31-JAN-2003 Summary: (Taken from application abstract): The past three decades have witnessed a remarkable growth of medical imaging modalities in patient care. Ironically, however, the field of medical imaging is threatened by its own success in that the sheer mass of information available is becoming unmanageable. The long-term objective of this application is to develop the next generation of medical image information systems. This five-year FIRST award project will focus on the design and implementation of a prototype neuroimaging database management system (NI-DBMS) for managing and indexing multimodality brain images, including MRI, PET, MR spectroscopy, and MEG. This new image DBMS intends to support flexible search and browsing of picture archiving and communication systems (PACS) image library, as well as clinical applications in epilepsy and multiple sclerosis. The hypothesis of this research is that different kinds of three-dimensional (3D) brain images and associated clinical data can be modeled, correlated, queried, and analyzed by computers on the World Wide Web (WWW) to aid neurologic education, practice, and research. The specific aims to investigate this hypothesis are: (I) design a new framework for multimodality

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neuroimage management; (ii) develop tools for extracting structural, functional, and temporal features of different brain images; (iii) investigate new content based search algorithms for epilepsy and multiple sclerosis imaging; (iv) develop a neuroimaging data model to allow access from the Web; and (v) evaluate system performance with well-defined experiments in epilepsy and multiple sclerosis imaging. The neuroimaging DBMS will be built on top of the large image archives in hospitals and will add values to the existing PACS with content-based information management and Web accessibility. The software product developed in this research will be generalizable and extensible so that it can be put into wide use by other medical centers and hospitals. Its open systems architecture will ensure image databases developed by the medical community will be sharable through the ubiquitous Web. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTIPLE SCLEROSIS EFFECTS ON COGNITIVE PROCESSES Principal Investigator & Institution: Kail, Robert V. Professor; Psychological Sciences; Purdue University West Lafayette West Lafayette, IN 479072040 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: (adapted from applicant's abstract): Individuals with multiple sclerosis (MS) often show performance deficits on a range of cognitive tasks, including abstract reasoning, and information processing speed. Furthermore, the cognitive deficits are greater for individuals in more advanced stages of MS. What is not clear from extant research is whether each of the cognitive impairments is a direct, unique consequence of MS. That is, does MS lead directly to diminished attention, memory, reasoning, and processing speed? Or does MS directly affect only one of these processes, which, in turn, leads to impairments in other cognitive skills? For example, perhaps MS affects only memory directly; the other cognitive consequences would be indirect, stemming from the direct effect of MS on memory. The aim of the proposed research is to determine the direct and indirect effects of MS on cognitive processes. 125 30-55 year old MS patients will be tested, along with 125 adults without MS who are matched by sex, age, and education. Each subject will be administered 15 primary instruments: 3 measures of MS symptoms, 3 measures of speed of information processing, 3 measures of short term memory, 3 measures of working memory, and 3 measures of reasoning ability. Structural equation modeling will then be used to compare models that posit different links between MS, processing speed, memory, and reasoning. Specifically, these analyses will be used to distinguish a model in which MS affects speed, memory, and reasoning directly from models in which MS affects some but not all of these cognitive processes. For example, preliminary results suggest that MS-related deficits in memory are due to deficits in processing speed. Consequently, one of the comparison models of interest is one that omits the direct link between MS and memory. These results will help to identify the impact of MS on cognition and thereby help to plan more effective cognitive rehabilitation programs for MS patients. If, for example, memory deficits are actually a byproduct of speed deficits, then rehabilitation should be directed at speed of processing; improved processing speed should also improve both memory and reasoning. The results of this project will help to identify the appropriate targets of rehabilitation efforts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MULTIPLE-SCLEROSIS: A CD40 LIGAND ANTAGONIST Principal Investigator & Institution: Kasper, Lloyd H. Professor; Medicine; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, NH 03755

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Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: Multiple sclerosis (MS) is a clinical neurological disease characterized by chronic inflammation, demyelination and gliosis of the central nervous system. It is the principal neurologic disease of individuals in early to middle adult life and afflicts as many as 350,000 people in this country. The available therapy for treating and preventing the progression of disease is limited. Recent evidence suggests that early therapeutic intervention may be important in decreasing disease activity. MS is mediated at least in part by T cells, macrophages and to a lesser extent B cells. Activation of T and B cells is dependent upon the interaction of the TCR/MHC as well as co-stimulatory molecules, including CD40-CD40L. CD40 and its ligand have been shown to play a critical role in the regulation of both humoral and cell-mediated immunity. Blockade of CD154 is effective in ameliorating the manifestations of several autoimmune diseases and thus has become an attractive therapeutic target. The interaction of CD40/CD40L has been demonstrated in both the experimental model of experimental allergic encephalomyelitis (EAE) as well as multiple sclerosis. In EAE, antibody blocking of CD40L prevents the progression of disease in both the monophasic and relapsing remitting experimental models. The overall objective of this clinical research trial is to determine whether antibody to CD40L can block the progression of enhancing lesions on MRI in those individuals with relapsing- remitting MS (primary outcome). Individuals (n=40) with clinically defined MS (EDSS 0-less than 3.5) will be evaluated for six months by monthly GdDTPA enhanced MRI scans and EDSS to determine disease progression. If eligible (greater than 2 new enhancing lesion 2mm or greater during the 6 month pretreatment phase), these individuals (n=20-24) will be treated with intravenous humanized anti-CD40L (IDEC-131). Patients will be treated for 6 months (total=8 infusions) with 5mg/kg antibody during which time they will continue to undergo monthly Gd enhanced MRI and EDSS evaluation(secondary outcome). We will determine the effect of therapy on MR spectroscopy metabolic, peaks for NAA, choline and creatine (absolute magnitude and ratios) in left and right hemispheric periventricular white matter voxels of interest (secondary outcome). Delay in cerebral atrophy will be evaluated by determining the change in parenchymal brain fraction. We will also develop a novel biological assay to determine efficacy of therapy(secondary outcome). MHCII-Ig fusion proteins that have an embedded MBP peptide will be used to identify MBP-reactive T cells in the peripheral blood of these patients. The polarity (Th1 and Th2) of the MBP-MHCII-Ig binding T cells will be determined as well as their activation status. The impact of in vivo anti-CD40L therapy on the frequency, phenotype and functional status of the MBP-MHCII-Ig binding T cells will be determined in vitro as well as T and B cell recall to tetanus toxoid. An additional secondary outcome will be to assess change in the cognitive impairment index in response to therapy. Neuropsychological variables sensitive to clinical trial outcomes in MS include measures of visual memory and mental flexibility. Follow up will be done with MRI and EDSS at 18 and 24 months after enrollment(secondary outcome). The study will will allow us to achieve a power of 85 percent (32 percent reduction in plaque burden). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MUTANT ANALYSIS OF TSC1 & TSC2 IN TSC RELATED DISORDERS Principal Investigator & Institution: Dabora, Sandra L.; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 26-SEP-2000; Project End 31-AUG-2004

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Summary: The goals of this proposal are to develop robust, sensitive, and high throughput methods for mutation analysis for the tumor suppressor syndrome, tuberous sclerosis complex (TSC). These methods will be immediately useful for clinical purposes but will also be valuable research tools for analysing the molecular pathology in TSC and related disorders. The technology developed during this project will be directly applicable to the study of genetic variation in other disorders as well. TSC is a familial tumor syndrome characterized by the development of benign tumors (hamartomas) in multiple organs. Although it is inherited in an autosomal dominant pattern, the majority of new cases (about 65 percent) are sporadic without antecedent family history. Penetrance is high but expression is variable with both severely and mildly affected individuals. Organs most frequently involved are the brain, skin, kidneys and heart. Neurologic morbidity from seizures, mental retardation and behavior disorders is common. Two disease genes, TSC1 and TSC2 have been identified recently. Unfortunately the development of a genetic test has been hindered by the large size of the two genes and the diversity of the mutation spectrum in TSC. The R21 portion of this grant focuses on the development and optimization of a series of 3 assays which will allow for high throughput comprehensive genetic analysis for TSC. The R33 portion of this proposal focuses on using comprehensive mutation analysis for TSC to collect genotype and clinical data on a large cohort of TSC patients. Comprehensive mutation detection methods will also be used to study the role of TSC1 and TSC2 in related disorders as well as in TSC lesions and related non-TSC tumors. There is currently much demand from TSC patients and families for comprehensive mutation analysis for family planning and prenatal diagnosis, diagnosis confirmation, and prognostic information. The proposed plan of study will address this issue as well as help elucidate the role of TSC1 and TSC2 in the molecular pathology of TSC lesions and non-TSC tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MUTATION SELECTION FOR IMMUNE RESPONSE TO MBP IN HAM/TSP Principal Investigator & Institution: Allegretta, Mark; Pathology; University of Vermont & St Agric College 340 Waterman Building Burlington, VT 05405 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2004 Summary: (provided by applicant): Human T-cell lymphotropic virus type I (HTLV-1) is a human retrovirus that infects approximately 10 million people worldwide. The majority of infected individuals remain healthy lifelong asymptomatic carriers (ACs); approximately 0.25% to 3% develop an inflammatory disease of the central nervous system termed HTLV-1- associated myelopathy/tropical spastic paraparesis (HAM/TSP), and another 2% to 3% develop an aggressive mature T-cell malignancy termed adult T-cell leukemia (ATL). The virus is endemic throughout Japan, with certain regions of the country having elevated prevalence rates. Because such a large number of people are carders of this potentially devastating virus, developing an effective measure to control the endemic cycle of HTLV-1 has been imperative. Since the clinical findings in HAM/TSP resemble the clinical picture of multiple sclerosis (MS), an understanding of the neuropathogenesis of a disease with a known viral etiology may provide insights into mechanisms of pathogenesis in an autoimmune disease of unknown etiology. This is particularly relevant since T cell receptor (TCR) sequences derived from spinal cord lesions from HAM/TSP patients show similarity to TCRs from myelin basic protein (MBP)-reactive T-cells, TCRs detected within the brain lesions of MS patients, and encephalitogenic T-cell clones from rodents with experimental

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autoimmune encephalomyelitis. We have observed similar TCR sequences from HAMFFSP patients using a method of isolating T cells that have undergone extensive in vivo cell division. The method involves detecting cells with mutations in a selectable reporter gene, and has been used to demonstrate the presence of in vivo activated T cells responsive to MBP in MS patients. The approach may be useful for addressing a variety of questions in human immunology. The goal of this proposal is to demonstrate that the reporter gene-selected T cells from HAM/TSP patients respond to MBP much like their counterparts derived from MS patients, indicating similar pathogenic mechanisms for the two diseases. The long-term goal of the project would be to broaden the applicability of this approach for the study of other human immune responses, particularly in autoimmune disease and cancer, where an understanding of detrimental and beneficial immune responses can ultimately translate into improved treatment options based on new immunotherapeutic approaches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MUTATIONAL ANALYSIS OF MOTONEURON SPECIFIC NMDA-R IN ALS Principal Investigator & Institution: Hayashi, Yasunori; Center for Learning and Memory; Massachusetts Institute of Technology Cambridge, MA 02139 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motoneurons. It affects 500,000 individuals worldwide annually and remains untreatable. To develop an effective treatment for ALS, a precise understanding of its pathogenesis is indispensable. One approach toward this goal involves identifying the gene(s) responsible for familial forms of ALS. Such an approach has uncovered mutations in the gene encoding Cu/Zn cytosolic superoxide dismutase (SOD1); these mutations only account for 20%-25% of familial cases. Despite intense efforts, the pathogenesis of the remainder of familial cases and all of sporadic cases are practically unknown. We have recently identified a new NMDA type glutamate receptor, NR3B. Interestingly, it is expressed almost exclusively in the motoneurons known to be affected in ALS and negatively regulates the function of NMDA receptor to limit Ca2+ influx. Because it is well documented that an overactivation of NMDA receptor causes the cell death associated with various neurological disorders, the identification of NR3B lead us to propose the "NR3B hypothesis" of the pathogenesis of ALS. This hypothesis proposes that defects in NR3B function may be neurotoxic in motoneurons through loss of the negative regulation of motoneuronal NMDA-mediated Ca2+ currents. Loss of NR3B function may increase the NMDA receptor current and Ca2+ influx in these cells, thereby predisposing motoneurons to excitotoxicity. This mechanism may cause ALS by itself or may predispose carrier to ALS when it is combined other genetic or epigenetic factors. In this proposal, we will test this NR3B hypothesis by genetic analysis of the NR3B gene in humans and modifications of NR3B gene dose in ALS mice. We will first analyzing DNA from ALS patients for mutations in the NR3B gene. We will first screen ALS families without a known genetic defect for genetic linkage to the NR3B gene (Aim 1). We will then perform mutational analysis of the full NR3B gene in linked cases and in a series of individuals with both familial and sporadic ALS, as well as controls (Aim 2). Thereafter (Aim 3) we will test the hypothesis that polymorphisms in the NR3B gene are associated with an increased risk of developing ALS or with some aspect of the clinical course of ALS (e.g. onset age, life span after onset, disease distribution). In related studies in mice, we will determine whether variations in the dose of the NR3B gene alter

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the phenotype of transgenic SOD1-G93A mice (Aim 4). In our view, this is a significant translational and explorative investigation that promises to relate a newly discovered, novel motoneuronal glutamate receptor subunit, NR3B, with a fatal human motor neuron disease; the findings have potential implications for the development of new approaches to therapy in ALS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MYELIN BASIC PROTEIN, TOLERANCE AND AUTOIMMUNE DISEASE Principal Investigator & Institution: Goverman, Joan M. Associate Professor; Molecular Biotechnology; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001; Project Start 01-DEC-1996; Project End 31-AUG-2005 Summary: (Adapted from the Applicant's Abstract): Multiple sclerosis (MS) is a neurodegenerative demyelinating, disease of unknown etiology. MS plaques contain both CD4+ and CD8+ T-cells and susceptibility is linked to immune response genes, suggesting that MS occurs when autoreactive T-cells enter the central nervous system (CNS) and attack cells expressing myelin antigens. Myelin basic protein (MBP) is one likely target: for these T-cells because it is an abundant protein in the myelin sheath. Auto‑reactive CD4+ T-cells specific for MBP have been extensively studied in an animal model of MS, experimental allergic encephalomyelitis (EAE). EAE is induced by activating CD4+ T-cells through immunization of animals with MBP. Although this model demonstrates that MBP‑specific T-cells are present in the periphery of healthy animals, the investigators have shown that the repertoire of MBP‑specific T-cells in the periphery is strongly shaped by induction of immune tolerance to MBP in vivo. Some MBP‑specific T-cells are more prevalent in the periphery because they escape tolerance while other MBP‑specific T-cells are tightly regulated by tolerance. The mechanisms that induce tolerance to MBP, and how these mechanisms influence autoimmune disease, are unknown and are the focus of this application. In Aim 1, they will use newly developed TCR transgenic mouse models specific for highly tolerogenic MHC class II‑associated epitopes of MBP to define tolerance mechanisms and their impact on disease susceptibility. In Aims 2 and 3, they will investigate a new area: tolerance and autoimmune potential of MBP‑specific CD8+ cytotoxic T-cells (CTLs). Our recent data show that MBP‑specific CTLs are generated in vivo and regulated by tolerance induction. In this proposal, they show that these MBP‑specific CTLs induce a novel CNS autoimmune disease that differs from EAE and demonstrates new parallels to symptoms of MS. They will investigate mechanisms of tolerance that operate on these CTLs as well as their effector mechanisms and target cells within the CNS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEUROFILAMENTS, SOD1 AND MOTOR NEURON DISEASES Principal Investigator & Institution: Cleveland, Don W. Professor; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, CA 92093 Timing: Fiscal Year 2001; Project Start 01-APR-1989; Project End 30-JUN-2001 Summary: Motor and sensory neurons of the periphery are among the largest cells, with volumes up to 5,000 times that typical for animal cells. Most of this volume is acquired just after stable synapse formation and concomitant with myelination, during which time the axons grow in diameter by more than an order of magnitude. One basic cell biological question is how is this volume expansion, a key component for conduction

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velocity, is mediated. Earlier efforts using classical and molecular genetics have demonstrated that incorporation into axons of an ordered array of neurofilaments is essential for radial growth. Using gene targeting and gene replacement, the principles through which neurofilaments structure axoplasm to support axonal volume will be determined. This will include a focus on identification of the interfilament crosslinkers that probably support growth through formation a deformable, three dimensional, space filling, structural array. Beyond this, multiple preceding lines of evidence, including use of transgenic mice expressing mutated neurofilament genes, has demonstrated that disorganization/damage to neurofilaments can itself provoke death of motor neurons that mimics most aspects of the most abundant human adult motor neuron disease, amyotrophic lateral sclerosis (ALS). With neurofilamentous pathology frequently reported in human ALS, a search will be undertaken for possible neurofilament mutations or variants as causes or contributors to human ALS. A parallel approach will search for covalent damage to neurofilaments and their associated components that may develop during ALS. A high through put screen will be conducted for agents that can provoke disassembly of neurofilaments. Lastly, for human ALS, a proportion of dominantly inherited disease arises from mutation in superoxide dismutase (SOD 1), but the mechanism through which mutation in this ubiquitously expressed protein provokes late onset, selective motor neuron killing has remained elusive. To this, transgenic mice that develop disease from expressing any of three SOD 1 mutants, as well as cell cultures from those mice, will be used to test how toxicity of the mutants is related to binding of the catalytic copper or zinc, whether toxicity is cell autonomous (that is, arises uniquely from damage directly within motor neurons) and how aggregation of mutant SOD 1, and compromise in protein folding and catabolism, contributes to toxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEURONAL INTERACTIONS IN EPILEPSY/DYSPLASIA Principal Investigator & Institution: Schwartzkroin, Philip A. Professor; Neurological Surgery; University of California Davis Sponsored Programs, 118 Everson Hall Davis, CA 95616 Timing: Fiscal Year 2001; Project Start 01-JAN-1983; Project End 31-AUG-2005 Summary: (Verbatim from the Applicant's Abstract) Cortical dysplasia is thought to arise from abnormalities in brain cell proliferation, migration, and/or differentiation. Advances in biomedical technology - medical genetics and brain imaging - have confirmed that a high proportion of early-onset epilepsies is associated with such structural abnormalities. Despite this high correlation, we still do not understand what features of dysplasia lead to epilepsy - the cause and effect relationship between structural and and functional abnormalities. To gain some insight into the epileptogenic components of dysplastic brain tissue, we propose to analyze animal models in which dysplastic abnormalities are or are not associated with seizure activity. We will test two general hypotheses. First, disruption of normal cortical organization (as seen in models of heterotopia) leads to epileptigenicity by virtue of subsequent reorganization. In such cases, we propose that heterotopic cell regions are rarely the site of seizures initiation, but serves to distribute epileptic discharge generated by surrounding brain regions. To test this hypothesis, we will characterize heterotopic dysplasia seen in the methylazoxymethanol (MAM) rat and in the p35 mouse knockout models of neuronal migration disorder. Second, we hypothesize that disruption of differentiation programs as seen in syndromes such as tuberous sclerosis gives rise to cells with aberrant electrical activity. properties that can trigger epileptic discharges. In such cases we

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propose that the ''tuber'' containing the aberrant cells serves as an initiator zone. We will explore this hypothesis in the Eker rat model of tuberous sclerosis (heterozygous mutation of the TSC2 gene). Finally, key characteristics obtained from animal model studies will be compared to morphological and electrophysiological properties of human cortical tissue resected from patients with cortical dysplasia and medicallyintractable epilepsy. By identifying the critical features that are essential for epileptic activity, we will be able to develop more effective treatments that target seizure-causing aberrations in brain structure and function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEURONAL-GLIAL INTERACTION IN THE PATHOGENESIS OF ALS Principal Investigator & Institution: Elliott, Jeffrey L. Neurology; University of Texas Sw Med Ctr/Dallas Dallas, TX 753909105 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2005 Summary: (Adapted from applicant's abstract): Because it is motor neurons that invariably die in amyotrophic lateral sclerosis (ALS), most attention has focused on these cells as the primary site where pathophysiologic injury is initiated. However, evidence from human autopsy studies and a transgenic mouse model of familial amyotrophic lateral sclerosis, suggests a potential role for glia in the pathogenesis of disease. To address the cell specific origin of mutant (m) Cu/Zn superoxide dismutase (SOD1) induced disease, we have generated lines of transgenic mice using glial or neuronal specific promoters which allow expression of MSOD1 restricted to either neuronal or glial population. These lines do not develop motor weakness, raising the possibility that disease expression requires both neuronal and glial dysfunction induced by mSOD1. To test this hypothesis, we will determine whether crossing glial and neuronal restricted transgenic lines expressing mSOD1 will reconstitute the disease process in mice and lead to motor neuron degeneration. We will also use a spinal cord organotypic slice model of motor neuron degeneration to address specific mechanisms underlying interactions in fALS, we will generate chimeric mice from wild type and conventional mSOD1 mice, as well as derive chimera from conventional mSOD1 mice and either glial or neuronal specific mSOD1 transgenic liens. These experiments will determine whether glial/neuronal dysfunction involves cell-cell autonomous processes and ascertain whether the disease can be rescued by normal functioning glia. Although the exact mechanism of mSOD1 toxicity is still unknown, recent evidence has supported a critical role for zinc and copper ions. Because neurons and glia both express a repertoire of genes related to zinc/copper binding including the metallothioneins (MTs), we predict that both cell types will manifest abnormal MT expression patterns. In addition, we hypothesize that targeted deletion of neuronal or glial MT genes will significantly accelerate mSOD1- induced disease. Overall, these experiments will test the hypothesis that both neuronal and astroglial dysfunction is required for manifestation of disease in a transgenic murine model of fALS. These results will provide critical insights into mechanisms underlying human motor neuron disease and have important implications for future therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NITRIC OXIDE, PLP ACYLATION & THE PATHOPHYSIOLOGY OF MS Principal Investigator & Institution: Bizzozero, Oscar A. Professor; Cell Biology and Physiology; University of New Mexico Albuquerque Controller's Office Albuquerque, NM 87131 Timing: Fiscal Year 2001; Project Start 01-DEC-1998; Project End 30-NOV-2003 Summary: Our long-term goal is to understand the molecular mechanisms that control the formation and maintenance of CNS myelin and the factors that lead to its breakdown in multiple sclerosis (MS). Although the production of nitric oxide (NO) and peroxynitrite by activated macrophages and microglial cells is considered responsible for the destruction of myelin and oligodendrocytes in MS, the molecular targets of these agents in myelin have not yet been identified. We hypothesize that both the structure and fatty acid acylation of the abundant myelin proteolipid protein (PLP) are affected by NO and peroxynitrites, and that this may lead to myelin instability. Our specific aims are: 1- To characterize the mechanism of fatty acylation of PLP using endogenously generated 18/O-labeled fatty acids. This recently developed isotopomeric technique measures not only the acylation rate but also the minimal amount of proteins that are modified. Brain white matter slices from rapidly myelinating rats will be incubated with [3H]palmitate and H2/18/O, in the presence of a variety of metabolic poisons and enzyme inhibitors to ascertain whether PLP acylation (a) needs ATP, (b) requires the formation acyl-CoA, (c) using primarily fatty acids synthesized de novo, and (d) is catalyzed by a separate protein fatty acyltransferase. 2- To assess the effects of nitric oxide and peroxynitrite on the fatty acylation of PLP. We will determine the effects of pathological concentrations of endogenously-generated NO, exogenously-produced NO and peroxynitrite on acylation on PLP and lipids using tissue slices and the double-label technique described above. In addition, a variety of metabolic and structural studies will be carried out to identify the mechanism(s) by which nitrogen and oxygen free radicals could alter protein acylation. 3- To determine whether or not the structure and fatty acylation of the various PLP species isolated from MS brains are normal. The major PLP, DM-20 and 16 KdA proteolipid present in myelin and non-myelin membranes prepared from control and MS brains will be isolated and subjected to a comprehensive chemical and mass-spectrometric analysis. The studies proposed in this application will provide direct information into the mechanisms of myelin destruction that takes place in MS, and at the same time, they will aid our understanding of the biology of PLP and its only post-translational modification. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NONPEPTIDE IMMUNOSUPPRESSION

ANTAGONISTS

OF

CCR-7

FOR

Principal Investigator & Institution: Alleva, David G.; Neurocrine Biosciences, Inc. 10555 Science Center Dr San Diego, CA 921211100 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JUL-2002 Summary: (provided by the applicant): Multiple sclerosis (MS) is a chronic autoimmune disease that afflicts roughly 300,000 Americans. The disease involves immune-mediated inflammation of the central nervous system (CNS) which leads to paralysis, bowel and bladder incontinence, and blindness. Neuro-inflammation in MS is mediated by inflammatory autoreactive T cells that recognize self-antigens from the CNS and require continual re-activated with antigen in secondary lymphoid organs (i.e., lymph nodes). Recently, it has been discovered that the two chemokines (i.e., small chemotactic

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cytokines), macrophage inflammatory protein (MIP)-3beta and secondary lymphoid organ chemokine (SLC), play a fundamental role in the migration of T cells and antigenpresenting cells (APCs), such as dendritic cells (DC), to secondary lymphoid organs. Expression of these chemokines is constitutive and limited to secondary lymphoid organs, and attracts T cells and mature DC (DC that have processed antigen) that express CC chemokine receptor 7 (CCR7), the G-protein coupled receptor (GPCR) for these two chemokines. Thus, our objective is to develop an orally-active small molecule antagonists of CCR7 that would prevent the migration of pathogenic T cells and DC to lymph nodes, which would be a powerful approach to suppressing T cell activation during the autoimmune process and, in turn, blocking end-stage inflammation. To accomplish this goal, our Specific Aims for this Phase I are (i) to synthesize focused combinatorial small molecule libraries based on lead antagonist compounds to identify high-affinity antagonists (Ki < 50 nM) for CCR7, (ii) to demonstrate that the high-affinity antagonists specifically interact with CCR7 on native-receptor expressing cells and selectively inhibit CCR7-mediated cellular responses (i.e., calcium mobilization and chemotaxis), (iii) to assess stability and toxicity of lead compounds in vitro and in vivo, and (iv) to assess whether lead compounds show in vivo efficacy in rodent models of MS and other autoimmune diseases. Indeed, a favorable out-come of these experiments would support the therapeutic potential of CCR7 antagonists in MS PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL APOPTOTIC PATHWAY ACTIVATED BY MISFOLDED PROTEINS Principal Investigator & Institution: Bredesen, Dale E. Director; Buck Institute for Age Research Novato, CA 94945 Timing: Fiscal Year 2003; Project Start 01-JAN-1997; Project End 30-JUN-2008 Summary: (provided by applicant): Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) and prion protein diseases all feature misfolded proteins and their aggregates, which appear to play a role in disease pathogenesis. However, the mechanism(s) and pathways by which misfolded proteins couple to the cell death program is poorly understood. We have recently found that misfolded proteins, which trigger endoplasmic reticulum stress (ER stress), induce a novel intrinsic apoptotic pathway that is independent of Apaf-1 and mitochondria (Rao et al., 2001; Rao et al., 2002a; Rao et al., 2002b). In order to define the molecular requirements of this pathway, we have developed a cell-free system of ER stress-induced apoptosis. In this system, microsomes isolated from cells lacking ER stress fail to activate cytosolic extracts, whereas microsomes isolated from cells undergoing ER stress activate caspases-3 and -9 in cytosolic extracts. Using a set of complementary approaches including protein purification procedures, 2D MALDITOF/nano-ESMS (two-dimensional matrix-assisted laser desorption ionization-time of flight/nanoelectrospray mass spectrometry), immunodepletion of candidate proteins, and an RNA interference (RNAi) approach, we have identified the initial candidate biochemical mediators of this novel apoptotic pathway, and here we propose to continue to identify the components of this ER stress-induced apoptotic pathway. Because an understanding of the relationship between the accumulation of misfolded proteins, cellular stress response, and cell death programs should facilitate the development of new therapeutic strategies for neurodegenerative disorders that feature misfolded proteins, we propose to integrate the findings from our cell work with an animal model of ALS, and address the following questions: (1) What are the proteins

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that mediate ER stress-induced cell death? (2) Within the set of relevant proteins that are differentially expressed, what are the crucial proteins for cell death induction? (3) Is there evidence of activation of the ER stress-induced apoptotic pathway in transgenic mice expressing mutant (vs. wild type) CuZnSOD? (4) Does recombinant mutant CuZnSOD protein induce normal organelles to initiate a specific cell death pathway? We believe that the results of the proposed experiments may offer insight into the pathogenesis of neurodegenerative disorders that feature misfolded proteins, and should enhance the usefulness of our system for development of therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL MHC CLASS II CONSTRUCTS FOR TREATMENT OF EAE Principal Investigator & Institution: Burrows, Gregory G. Associate Professor of Neurology; Neurology; Oregon Health & Science University Portland, OR 972393098 Timing: Fiscal Year 2001; Project Start 15-AUG-1999; Project End 31-JUL-2004 Summary: The interaction between the MHC/peptide-antigen complex and the T cell receptor (TCR) is essential for antigen-specific T cell activation. Antigen analogs can act as powerful and specific inhibitors of T cell activation and provide a rational approach to antigen-specific immuno-intervention in allergies and autoimmune diseases. Lewis rats immunized with myelin basic protein (MBP) or MBP peptides develop experimental autoimmune encephalomyelitis (EAE), a CD4+, Th1 cell-mediated demyelinating disease of the central nervous system (CNS) that is used as a model for the human disease multiple sclerosis (MS). In the Lewis rat model of EAE, T cells specific for MBP72-89 dominate the autoimmune response and TCR expression on the pathogenic T cells is well characterized. This model provides an excellent opportunity to test the hypothesis that regulating the context in which MHC/peptide interacts with TCR can be used to control antigen-directed T cell activation. We have recently developed a family of novel molecules derived from the rat MHC class II alpha-1 and beta-1 domains, with and without a genetically linked polypeptide epitope. Both the non-covalent and covalent beta1alpha1/MBP-72-89 constructs inhibited activation of pathogenic MBP-7289 reactive T cells and could be used to prevent and treat EAE. The potential of these molecules in the treatment of human autoimmune disease provides a strong rationale to further characterize the mechanism by which these molecules regulate CD4+ pathogenic T cells. We propose to 1) Characterize the beta1alpha1 molecules biochemically; 2) Determine the specificity of the beta1alpha1/peptide molecules by direct binding studies to define the interaction surface between the TCR and beta1alpha1/peptide molecules; 3) To characterize the in vitro effects of the beta1alpha1/peptide molecules and define the time-frame and context within which beta1alpha1/peptide treatment can alter the activation of effector cells in response to antigen stimulation; and 4) To characterize the in vivo effects of the beta1alpha1/peptide molecules, with the goal of defining the mechanism by which the beta1alpha1/peptide molecules block the induction of EAE in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOVEL OLIGODENDROCYTE PROTEIN--IMPLICATIONS FOR MS Principal Investigator & Institution: Shafit-Zagardo, Bridget; Pathology; Yeshiva University 500 W 185Th St New York, NY 10033 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-DEC-2002 Summary: Multiple Sclerosis (MS) is a paralyzing disease affecting young adults. While a number of experimental drugs are available to minimize the devastation of the

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disease's course the cause of MS is unknown. A central issue for the treatment of MS is whether oligodendrocytes or resident oligodendrocyte precursors have the potential to remyelinate axons following episodes of demyelination. We have identified a novel variant of human high molecular weight (HMW) microtubule-associated protein-2, designated MAP-2+13, and have generated monoclonal antibodies specific to this splice form. Immunocytochemistry with light and electron microcopy have demonstrated MAP-2+13 staining in human fetal oligodendrocytes during process extension and active myelination, and in numerous oligodendrocytes adjacent to a zone of demyelination in sections from MS lesions. MAP-2+13 is either minimally or not expressed in oligodendrocytes in the normal adult CNS. The hypothesis to best tested in this proposal is that MAP-2+13 is required for the elaboration of oligodendrocyte processes during myelination and that it can be used as a marker for myelinating and remyelinating oligodendrocytes. To determine whether MAP-2+13 expression parallels myelination within the developing CNS, a range of fetal ages will be examined by double-label immunofluorescence and Confocal microscopy, immunoblotting and electron microscopy. MAP-2+13 expression in MS lesions will be extensively examined to determine if the expression correlates with remyelination. Studies will correlate MAP2+13 expression with the type of lesion and will be compared with age-matched, non neurologic sections. Rat progenitor cells and primary oligodendrocyte cultures will permit the study of MAP-2+13 in a well characterized in vitro system. Analysis will include how changes in MAP-2+13 expression correlate with process outgrowth and oligodendrocyte maturation. These studies permit the examination of a newly identified MAP-2 form in oligodendrocytes and the potential to gain insight into the extension of processes during myelination and disease. Attempts to identify developmentally regulated genes and to understand the regulation involved in the extension of myelinating processes is beneficial for both our understanding of normal CNS development and for treating demyelinating diseases such as Multiple Sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OLFACTION IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Doty, Richard L. Director and Professor; Otorhinolaryngology Head & Neck Surgery; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 30-SEP-1996; Project End 30-NOV-2003 Summary: (Adapted from the Investigator's Abstract): Multiple sclerosis (MS) can lead to paralysis and death and affects millions of Americans, often in the prime of their lives. While it is well documented that MS alters vision, hearing, speech and balance, its influence on olfaction - a sense critical for determination of food flavor and protection from spoiled food, leaking natural gas, fire, and other environmental hazards - has been controversial. Indeed, a number of medical textbooks state that the sense of smell is spared in MS, erroneously assuming that the olfactory system is unmyelinated. In 1984, the principal investigator discovered that 23 percent of 31 MS patients scored below normal on the University of Pennsylvania Smell Identification Test (UPSIT). Last year, he reported a series of case studies demonstrating that olfactory dysfunction can be the presenting symptom of MS. In a pilot study of 14 MS patients, the principal investigator has shown a significant relationship between UPSIT scores and the number of plaques within brain regions related to olfactory function (i.e., the orbitofrontal cortex and inferior temporal lobe). No such relationship was observed within non-olfactory related brain regions. These novel findings suggest that the olfactory dysfunction associated with MS directly reflects the degree of neuropathological involvement of central

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olfactory structures. In the proposed study, the principal investigator will determine the degree to which a number of well-validated olfactory tests are altered in a large cohort of MS patients, including tests of odor detection, identification, discrimination, and memory. He will (1) characterize the olfactory dysfunction of MS on each side of the nose using both psychophysical and electrophysiological measures, (2) determine, using high resolution MRI, whether the test measures are correlated with the number/volume of plaques in olfactory-related structures, (3) establish if olfactory measures are related to the exacerbation or remission of the MS symptoms (including appearance or disappearance of plaques), (4) ascertain whether women are more susceptible than men to MS-related olfactory loss, and (5) establish whether the olfactory test measures are related to neuropsychological measures of cognitive function, with an emphasis on tests which measure orbitofrontal and inferior temporal lobe neural processing. Given the pilot findings of a close relationship between olfactory function and the number of MSrelated plaques within olfactory-related structures, the principal investigator expects that this research will explicate, for the first time, the pathogenesis of an olfactory dysfunction associated with a common neurological disorder. Importantly, this study will provide insight as to how different measures of olfactory function are related to pathological alterations within specific central nervous system structures, as well as information for the clinician to rationally counsel patients with MS-related deficits in this underappreciated primary sensory modality. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OPTIC NERVE DEMYELINATION STUDY USING MRI Principal Investigator & Institution: Fraser, Scott E. Director; None; California Institute of Technology Mail Code 201-15 Pasadena, CA 91125 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 29-SEP-2003 Summary: (Verbatim from the Applicant's Abstract) Although the symptomology of multiple sclerosis (MS) has been described for decades, an understanding of the mechanisms and causes of the disease are only now emerging. Early signatures of multiple sclerosis (MS) often involve degradation of visual acuity, sometimes resulting in episodes of double vision and even blindness. Visual evoked potentials (VEPs) are widely used to asses patients suspected have having MS because of their high sensitivity for detecting even clinically silent lesions of the visual pathway. Although increased VEP latency and broadened waveforms are taken to indicate lesions, little is known of the exact relationship (s) between the VEP and the sizes, locations or histories of lesions. Investigating such relationships would require some means to perform longitudinal histopathological studies of the optic nerve. The proposed experiments will draw upon recent advances in magnetic resonance imaging microscopy (uMRI) to perform longitudinal in vivo imaging studies of the optic nerve in mice. These uMRI methods are based on qualitative measurements of local water diffusion. Pilot experiments, in which the techniques have been applied to fixed spinal cords from nice demonstrate that the approach offers unprecedented sensitivity tot the trajectories and myelination of nerve tracks. The goal here is to harness the potential of these new uMRI methods to perform longitudinal, in vivo studies of the demyelination of the optic nerve and correlate these with the VEPs, performed on the same animals, as a functional assay for visual function. The studies will employ a strain of transgenic mice which experience spontaneous demyelination of the central nervous system (CNS), with episodic weakness and demyelination similar to MS, making it an appropriate model system for the technical developments and experiments proposed here. Quantitative MRI measurements of water diffusion will be performed hind-in-hind with theoretical modeling of the

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diffusion though neural tissues to develop a sensitive and high-resolution probe of myelination in vivo. By performing quantitative uMRI measurements on the same animal, and correlating these images with longitudinal measurements of the VEP and with conventional histopathalogical analyses of the same animal, the goal is to permits a one-to-one comparison between the anatomy, physiology and symptomology of a demyelinating disease, modeling and the longitudinal imaging studies described in this proposal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OXIDATIVE STRESS IN ALS/PDC Principal Investigator & Institution: Good, Paul F.; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, CA 92093 Timing: Fiscal Year 2001 Summary: There is now increasing evidence that neuronal damage in the-age-related neurodegenerative diseases is mediated by the mechanism of oxidative stress. Oxidative stress occurs when there is an overproduction of reactive oxygen species (ROS), an underactivity of cellular defense mechanisms, or both, leading to uncontrolled oxidation of critical biological molecules. The products of such oxidative attack on macromolecules include the formation of lipid hydroperoxides and aldehyde breakdown products, nitrotyrosine and carbonyl modifications of proteins, and DNA hydroxylation. Amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam displays many similarities to the age-related neurodegenerative diseases but with an earlier onset and much higher prevalence suggesting that ALS/PDC recapitulates the pathogenetic mechanism(s) of the age-related neurodegenerative diseases at an intense level. We have developed evidence of oxidative damage in ALS/PDC and the neurodegenerative diseases of aging, suggesting that the mechanism of oxidative stress participates in producing neuronal degeneration. In both ALS/PDC and Alzheimer's disease we have shown evidence of nitrated tyrosine residues localized to neurofibrillary tangles of the hippocampus and entorhinal cortex, and in both ALS/PDC and idiopathic Parkinson's disease we have demonstrated increased iron concentrations within dopaminergic neurons of the substantia nigra. In this project, we will further examine cases of ALS/PDC for evidence of oxidative damage. The end products of oxidative damage to cellular structures that we will investigate include lipid peroxidation (malondialdehyde), protein nitration (nitrotyrosine), protein oxidation (protein carbonyls) and DNA hydroxylation (8-OlIdG). We will also investigate the potential for oxidative stress to develop as a result of increased intraneuronal iron, decreased ferritin or a decrease in glutathione content. Low molecular weight iron, unprotected by storage in ferritin, can mediate the oxidation of macromolecules initiating lipid peroxidation, DNA hydroxylation or site specific protein oxidation. Protection against an increase in available iron, and therefore the production of ROS, is accomplished by increasing iron storage capacity in response to increases in intracellular free iron. Glutathione, the major defense against ROS produced in the brain, is oxidised by glutathione peroxidase reducing hydrogen peroxide to water. A decline of cellular glutathione content, implicated in Parkinson's disease, will cause a decrease in the removal of hydrogen peroxide and an increase in the potential for the generation of hydroxyl radicals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOGENESIS AND TREATMENT OF MULTIPLE SCLEROSIS Principal Investigator & Institution: Raine, Cedric S. Professor; Pathology; Yeshiva University 500 W 185Th St New York, NY 10033 Timing: Fiscal Year 2001; Project Start 01-JUN-1975; Project End 31-DEC-2004 Summary: Pathogenesis and treatment of multiple sclerosis-COMBINED ABSTRACTThis Program Project is to understand regulatory underlying inflammation in the central nervous system (CNS) as it relates to the human demyelinating disease, multiple sclerosis (MS). The approach seeks to abrogate CNS inflammation therapeutically and to up- regulate repair pathways pertinent to CNS remyelination While the etiology and pathogenesis of MS remain unknown, compelling evidence exists for immunemediation in the demyelinated MS plaque and from a number of investigators on animal models, it has been shown that blocking of inflammation in the CNS frequently leads to remyelination. The Program combines the efforts of three independent investigators with different but complimentary skills who have worked together on MS for several years and who propose projects that target different hypotheses on factors regulating CNS inflammation. The first project (Raine) will examine autoimmune demyelination in a mouse lacking the chemokine receptor, CCR2, a molecule necessary in monocyte trafficking to sites of inflammation; the expression of a novel growth factor, glial growth factor 2, a known potentiator of remyelination, and its receptor, within the CNS of animals with demyelinating disease and in MS lesions; and progenitor oligodendrocytes in MS lesions of different ages The next project (Brosnan) targets mutations in chemokine receptors, their role and effects upon CNS inflammatory pathways and their presence in MS, and molecules related to the NF kappaB signaling cascade during inflammation and in MS lesions. The final project (Berman) will apply an in vitro model of the human blood-brain barrier (BBB) to the roles of chemokines and chemokine receptors in leukocyte migration into the CNS; the effect of the regulatory cytokine, IFNbeta, a cytokine used to treat MS, upon molecular expression (cytokine, chemokine and adhesion molecule), and alterations in the molecular profile of a number of pro- inflammatory mediators during leukocyte transmigration. Each of the projects will incorporate examination of MS material and their combination under one Program will be mutually reinforcing. Since a major driving concept in this proposal is that down-regulation of pro- inflammatory pathways is a factor sine qua non for the upregulation of myelin repair genes and CNS remyelination in MS, this proposal may be of considerable therapeutic import for the MS patient. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOGENESIS OF MHV-INDUCED DEMYELINATION Principal Investigator & Institution: Dandekar, Ajai A. Microbiology; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2002; Project Start 19-DEC-2001; Project End 18-DEC-2005 Summary: (provided by applicant): C57B1/6 (B6) mice infected with mouse hepatitis virus, strain JHM (MHV) develop either an acute encephalitis or chronic demyelinating disease. This demyelinating disease is a model for the human disease multiple sclerosis. We are interested in the immunological mediators of demyelination in this model. In our model, a percentage of mice protected from the acute encephalitis by maternal antibody develop a demyelinating disease We have previously observed in this model of demyelination that roughly twenty percent of the lymphocytes infiltrating the CNS are B cells, although no serum antibody can be measured in these mice. Additionally, nude (athymic) mice develop a demyelinating disease in which some 70 percent of

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lymphocytes in the CNS are B cells. The function of these B cells has not been characterized. In order to investigate the role of these cells in demyelination, three specific aims will be pursued: 1) To characterize the nature of the B cell response in the MHV-infected CNS; 2) To investigate failure of antibody production in the chronic demyelinating disease; and 3) To determine the immunological effectors of MHV-JHM disease in nude mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS OF TSCE-RELATED TUMORS IN THE EKER RAT Principal Investigator & Institution: Yeung, Raymond; Associate Professor; Surgery; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-MAR-2003 Summary: Tuberous sclerosis is a clinical disorder whose manifestations include both benign and malignant diseases. The mechanism of their pathogenesis is not known but the identification of one of the genes responsible for this autosomal dominant syndrome, TSC2, has provided an avenue to investigate the molecular basis of this complex syndrome. TSC2 is a novel gene that encodes about 190kD membrane bound protein, known as tuberin, that has limited homology with the catalytic domain of rap1GAP. Although biochemical studies have demonstrated specific in vitro GTPase activating function for rap1a, how this GAP activity relates to its physiologic function and the pathways in which it causes cancer, development remains to be elucidated. Our approach to study these questions exploits the use of a unique animal model, the Eker rat, that carries a germline mutation of this gene. Although initially described as a model of hereditary cancer, closer examination revealed striking phenotypic parallels between the human disorder and the Eker rat. As such, it can serve as an animal model of tuberous sclerosis. Molecular, genetic and cell biologic analyses of our animal model have provided the strongest evidence to date that TSC2 behaves as a tumor suppressor gene. In this proposal, our aim is to elucidate the signaling pathway(s) that is relevant to tuberin tumor suppressor function and to understand the biochemical basis of TSC2related disorders. Specifically, the studies will propose 1) to identify and characterize proteins that interact with tuberin, 2) to analyze the function of these tuberin-binding proteins in the context of cellular transformation, and 3) to assess the role of TSC2-GAP function in tumorigenesis. Creating this network of information about tuberin and its interacting proteins will facilitate our long-term objective of identifying therapeutic targets that will benefit those who suffer from these devastating diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PDGF-A REMYELINATION

AND

FGF2:

IN

VIVO

ROLES

DURING

CNS

Principal Investigator & Institution: Armstrong, Regina C. Professor; Henry M. Jackson Fdn for the Adv Mil/Med Rockville, MD 20852 Timing: Fiscal Year 2001; Project Start 01-DEC-1999; Project End 30-NOV-2004 Summary: Growth factor interactions have been shown to regulate the generation of differentiated cells from progenitor cells during CNS development. Similar cellular and molecular interactions are required for repopulation of demyelinated lesions and remyelination in the adult CNS. The proposed studies will test the in vivo roles of platelet-derived growth factor (OPDGF-AA) and fibroblast growth factor 2 (FGF2) in promoting remyelination. In human demyelinating diseases, such as multiple sclerosis, remyelination can lead to recovery of neurologic function of intact axons. However, in

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multiple sclerosis, remyelination is often limited and so investigating mechanisms to improve remyelination is warranted. Two experimental models of demyelination in mice will be used: murine hepatitis virus A59 (MHV-A59) infection and ingestion of euprizone toxin. Each model produces extensive CNS demyelination followed by spontaneous remyelination. However, the mechanism of demyelination is distinctly different in each model and the lesion environment is distinctly different in each model. Growth factors that are required for remyelination in both models may be universally required for remyelination in murine CNS and may be likely to be required during remyelination in human CNS. In these spontaneously remyelinating models, growth factors that are required for remyelination must already be present at appropriate levels to accomplish successful remyelination. Indeed, we have already show increased expression of PDGF- A and FGF2 mRNA during remyelination after MHV-A59 infection. Thus, the activity of PDGF-AA and FGF2 will be impaired in vivo to test the requirement of these growth factors in mediating specific oligodendrocyte lineage cell responses involved in remyelination. PDGF-AA and FGF2 in vivo activity will be impaired, singly and in combination in each model of demyelination using genetic and pharmacologic tools. Specific in vivo oligodendrocyte lineage cell responses will be elucidated by qualitatively and quantitatively monitoring a) disease severity and time course, b) progenitor cell proliferation, migration, differentiation, and survival, and c) reactive glial cell populations. This detailed understanding of growth factor regulation of remyelination may provide the insight needed to aid in designing therapeutics to improve the capacity for remyelination in multiple sclerosis, and following demyelination associated with traumatic injuries or toxic insults. 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. Assistant Professor; Anesthesiology; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001; 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

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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 •

Project Title: PHASE I/II TRIAL ON THE USE OF IL12 ANTIBODY FOR THE TREATMENT OF MS Principal Investigator & Institution: Galetta, Steven; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001 Summary: The overall objective of this project is to assess a potentially valuable therapeutic approach in Multiple Sclerosis (MS), a chronic, progressive or relapsing disorder in which mor effective treatments are greatly needed. The hypothesis to be tested is that inhibiting the biologic effects of the cytokine Interleukin-12 (IL-12) by treatment with a recently developed humanized anti-IL-12 monoclonal antibody will interfere with the pathogenesis of MS. As a result, there would be a reduction in the relapse rate and progression of this disease. Specific Aims: a. Phase I trial of A/IL-12 Proposed is a one-year pilot trial )Phase I) of monthly infusions of a humanized anti-IL12 monoclonal antibody (hereafter called A/IL-12) in MS patients with histories of recent frequent (greater than or equal to 2 per year) clinical exacerbations. Specific aims include: i) Assess safety and tolerability hematologic, hepatic, dermatologic, renal, pulmonary, etc. ii) Assess effects on host defenses against infection cell mediated and humoral immunity. iii) Determine whether there is a beneficial effect on A/IL-12 on the frequency and severity of MS clinical relapses and disability progression. iv) Determine if A/IL-12 treated MS patients have an unexpected worsening of their clinical manifestations. b. Phase II- Trial of A-IL-12 for assessment of efficacy of A/IL-12 in reducing the relapses and progression of MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHASE IA SAFETY STUDY INTERFERON TAU IN MULTIPLE SCLEROSIS

OF

RECOMBINANT

OVINE

Principal Investigator & Institution: Olek, Michael J.; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001 Summary: The purpose of this study is to learn more about a possible new oral drug for multiple sclerosis, called ovine interferon tau. This is an investigator-initiated, industry sponsored clinical trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE II STUDY OF HU23F2G IN ACUTE EXCERBATIONS OF MULTIPLE SCLEROSIS Principal Investigator & Institution: Brooks, Benjamin R.; University of Wisconsin Madison 750 University Ave Madison, WI 53706

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Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE III TRIAL OF MINOCYCLINE IN ALS:I-CLINICAL CENTER Principal Investigator & Institution: Gordon, Paul H. Neurology; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2003; Project Start 25-AUG-2003; Project End 31-MAY-2007 Summary: (provided by the applicant): Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to death on average in 3 years (1). There is no cure or known treatment that significantly improves function. Loss of motor neurons in the brain and spinal cord of ALS patients causes the progressive symptoms. Motor nerve degeneration may result from a cascade of events including free radical toxicity, glutamate excitotoxicity and mitochondrial dysfunction (2-4), which lead to the activation of cell death pathways (5-9). Mitogen-Activated Protein (MAP) kinases, including p38, are up-regulated in response to cell stress, and promote pro-apoptotic and inflammatory mediators (10, 11). Caspase enzymes and inflammatory mediators regulate cell death pathways (12-14), and are activated in human and transgenic mousemodel ALS (15,16). Caspase enzyme inhibitors and anti-inflammatory agents have been shown to slow progression in the ALS model (6,7,17,18). Minocycline, FDA approved for treatment of infection, has high central nervous system penetration when taken orally, inhibits p38 MAP kinase, prevents activation of caspase-1, caspase-3 and inflammatory mediators (19,20), and delays disease progression in animal models of neurodegenerative disorders, including Huntington disease (19), Parkinson disease (21) and ALS (22) (Serge Przedborski, personal communication). It is well-tolerated as an oral treatment for outpatients. The objective of this clinical trial is to determine whether 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

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Project Title: PHYTOESTROGENS AS AN ALTERNATIVE TREATMENT FOR MS Principal Investigator & Institution: Bebo, Bruce F. Assistant Professor; None; Oregon Health & Science University Portland, OR 972393098 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-JAN-2007

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Summary: (provided by applicant): Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. MS attacks occur less frequently during pregnancy, which is likely due to the increased production of steroidal sex hormones. Similarly, the severity of experimental autoimmune encephalomyelitis (EAE), an MSlike disease in mice, is also diminished during pregnancy. In mice, steroidal estrogens can inhibit anti-myelin helper T-lymphocyte responses and suppress EAE. In some women with MS, steroidal estrogens can decrease the number of demyelinating lesions in the CNS. Nevertheless, steroidal estrogens have a limited therapeutic potential because their long-term use increases the risk for hormone-related cancers. Consequently, the development of non-steroidal estrogens that reduce the severity of MS, while minimizing risks, is highly desirable. One class of non-steroidal estrogens that may have the capacity to suppress MS is phytoestrogens. Phytoestrogens are plantderived compounds that are structurally similar to steroidal estrogens. Unlike steroidal estrogens, however, they have a higher affinity for estrogen receptor-beta (ER-beta) than for estrogen receptor-alpha (ER-alpha). Because of the distinct tissue distribution of these two receptors, phytoestrogens have potent estrogen-agonist activity in bone and cardiovascular tissues, yet lack activity in breast and uterine tissues. In addition, phytoestrogens may regulate immune cell function, based on our recent discovery that ER-beta is expressed by immune cells. The therapeutic potential of phytoestrogens in MS, has yet to be studied. Isoflavones derived from soybeans are a rich source of phytoestrogens. Genistein, daidzein, and glycitein are the major isoflavones derived from soy. Our preliminary experiments found that the severity of EAE was diminished in mice treated either with a soy isoflavone preparation or genistein, and that this suppression occurred in the absence of injury to the reproductive system. In addition, soy isoflavone-treated mice had a reduced capacity to respond to myelin antigens and to produce TNF-alpha, a cytokine that is essential to the pathogenesis of EAE and MS. These data support our hypotheses that soy isoflavones reduce the severity of EAE by an ER-beta dependent pathway, which diminishes the capability of helper T lymphocytes to proliferate and secrete TNF-alpha, and results in the suppression of inflammation and demyelination in the CNS. The main objectives of this proposal are: (1) To identify the soy-isoflavones with the greatest ability to suppress EAE, (2) To determine whether soy isoflavone-mediated inhibition of TNF-alpha and suppression of EAE are dependent on signaling through ER-beta, (3) To determine which immune cells express ER-beta and whether transcription of immunologically relevant genes is regulated by soy isoflavones. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PILOT--BRAIN PLASTICITY/DISABILITY IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Cramer, Steven C. Assistant Professor; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001 Summary: MS (MS) is an important cause of adult disability. Early in the disease course, damage occurs in the brain without disability. As a, many studies have found only a weak correlation between clinical disability and the volume of disease burden on brain MRI. At early stages, therefore, the brain may compensate for damage and stave off disability. These compensatory events have received little attention in MS and are the focus of the proposed pilot studies. Functional imaging studies have provided insights into multiple diseases. In some cases, functional imaging shows changes much between than findings with anatomical studies. Functional MRI (fMRI) is a method for studying brain activation with excellent temporal and spatial resolution. By performing a motor

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or cognitive task over a course of several minutes, brain areas activated can be identified with great anatomical precision. The proposed project will first develop fMRI paradigms over three domains (cognitive, motor and somatosensory) that are relevant to MS disability and that show low intra-subject variability across time. It will work with the Functional Neuroimaging Core (Core D) of RehabNet- West to test and refine these paradigms, as well as the quantitative interpretation of fMRI data. In the second phase of the project the refined paradigms will be used with MS subjects studied sequentially to determine the correlation of changes in fMRI activation, some of which may be indicative of functional brain plasticity, and disability. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SCLEROSIS

PPAR-GAMMA

IMMUNE

REGULATION

AND

MULTIPLE

Principal Investigator & Institution: Drew, Paul D. Assistant Professor; Anatomy; University of Arkansas Med Scis Ltl Rock 4301 W Markham St Little Rock, AR 72205 Timing: Fiscal Year 2003; Project Start 15-DEC-2002; Project End 30-NOV-2006 Summary: (provided by applicant): The long-term goal of this project is to determine the mechanisms by which the peroxisome proliferator-activated receptor (PPAR)-gamma modulates inflammatory diseases of the central nervous system (CNS), including multiple sclerosis (MS). The critical role of PPAR-gamma in glucose and lipid metabolism is well established. Recently, however, PPAR-gamma was also demonstrated to be a potent inhibitor of macrophage activation. Our studies indicated that PPAR-gamma ligands inhibited the activation of microglia in response to interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, cytokines that may contribute to the pathology associated with MS. In addition, PPAR-gamma is expressed by T cells and affects T-cell proliferation. PPAR-gamma ligands also indirectly affect T-cell function by inhibiting the production of T-cell active chemokines by endothelial cells. Importantly, PPAR-gamma ligands have recently been demonstrated to ameliorate a variety of inflammatory conditions, including arthritis, atherosclerosis, and inflammatory bowel disease. We have recently demonstrated that a PPAR-gamma ligand blocks the development of experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Collectively, these studies suggest that PPAR-gamma ligands may be efficacious in the treatment of MS. The mechanisms by which PPAR-gamma ligands modulate susceptibility to MS have not been elucidated. MS is believed to be initiated by autoreactive T cells. Activated microglia also contribute to MS development through production of a variety of molecules that may affect the viability of myelin-producing oligodendrocytes, and are capable of altering T-cell phenotype. The hypothesis of the proposed studies is that PPAR-gamma agonists (1) inhibit the activation of microglia resulting in protection of oligodendrocytes, (2) inhibit microglial production of chemokine and chemokine receptors believed to contribute to the movement of immune cells into the CNS in MS patients, (3) affect T-cell phenotype and apoptosis, and (4) inhibit the development of EAE. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREGNANCY AND THE MODULATION OF MULTIPLE SCLEROSIS Principal Investigator & Institution: Langer-Gould, Annette; Neurology & Neurological Scis; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2007

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Summary: (provided by the applicant): It is well known that disease activity is significantly reduced during late pregnancy in women with multiple sclerosis (MS). This disease-modifying effect is far more powerful than any existing treatments for MS. There are no studies of pregnant women with MS to investigate the underlying mechanisms responsible for this effect. Based on our studies of the disease-modifying effect of pregnancy in the animal model of MS, experimental allergic encephalomyelitis, we hypothesize that there is a circulating factor present during late pregnancy that suppresses activation of memory CD4+ T cells and accounts for the disease amelioration in pregnant women with MS. We will test this hypothesis first by characterizing the state of T cell activation in MS patients during pregnancy and for 1-year postpartum using 11-color FACS analysis of peripheral blood mononuclear cells. Secondly, we will determine if the changes in antigen-specific memory T cell activation are different in women with MS as compared with healthy pregnant women (n = 20). This will address the important question of whether an underlying defect in pregnancy-related hormonal regulation of the immune system is key in the pathogenesis of MS. Finally, we will test (in vitro) the effect of human pregnancy sera on alterations in Th1-like memory T cells and compare this with the ex vivo measurements of memory T cell function during pregnancy in women with MS. To address these aims, we will enroll pregnant women with MS (n = 50) and healthy pregnant women (n = 20). Clinical information will be collected prospectively by the participants? neurologist and from medical records and interviewer-administered questionnaires in early pregnancy, late pregnancy, and at 2, 4, 6 and 12 months postpartum. Statistical analyses of the data will examine the association between the immunologic measures and clinical disease activity while examining (and controlling for) other important factors, such as disease subtype, age, treatment history, and disease duration. The search for the pregnancy-related factor or hormone responsible for the protective effect of pregnancy in MS may potentially lead to the development of novel treatments for MS and other Th1-driven autoimmune diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROCESSED SPECTROMETRY

ANTIGEN

CHARACTERIZATION

BY

MASS

Principal Investigator & Institution: Hunt, Donald F. Chemistry; University of Virginia Charlottesville Box 400195 Charlottesville, VA 22904 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: (adapted from applicant's abstract) Research to continue the development of instrumentation and methods for the sequence analysis of peptide antigens presented to the immune system in association with class I and class II molecules of the major histocompatibility complex is proposed. Routine detection and characterization of disease associated antigens present at the attomole level in a mixture of 10,000 self peptides is the expected outcome. Identification of disease associated antigens is an important first step in the development of vaccines or other immune system modulators that are effective against bacterial and viral infections, cancer, autoimmune disorders and tissue transplant rejection. Multistage chromatography in conjunction with our recently developed, automated peak parking technology plus nanoliter/min, high performance liquid chromatography and high performance capillary electrophoresis interfaced to an ion trap mass spectrometer via an electrospray ionization source will be employed to achieve this goal. Specific aims of the proposed research include the following: (1) to identify melanoma specific antigens presented by the class I molecules, HLA A2.1, A1 and A3, and the class II molecule, DR4, (2) to identify minor histocompatibility antigens associated with graft-vs-host disease and tissue transplant

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rejection, (3) to identify peptides derived from myelin basic protein as well as cross reactive self peptides that are presented by the multiple sclerosis associated class II molecule, DR15Dw2, and recognized by T-cell clones derived from multiple sclerosis patients, (4) to identify peptides presented by the class I molecule, B27, that are unique to individuals diagnosed with ankylosing spondylitis (5) to identify peptides presented by the class I molecule, A2.1, that are unique to individuals diagnosed as having chronic lymphocytic leukemia, (6) to identify and characterize peptides presented by HLA-A2.1, that have been post translationally modified by either phosphorylation or glycosylation, (7) to identify class II peptides presented by the HLA-DR4Dw4 molecule in the presence and absence of the chaperone molecule, HLA-DM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROGRESSION OF NUCLEAR DENSITY OVER A 10-YEAR INTERVAL Principal Investigator & Institution: Klein, Barbara E. Professor; Ophthalmology and Visual Sci; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Nuclear sclerosis, and its clinically important manifestation as nuclear cataract, is a common age-related ocular problem. In Beaver Dam, Wisconsin, nuclear cataract was the most common cataract type to precede lens extraction While older age and female gender are associated with increased risk, other factors have been found and still other, hypothesized to also be associated with risk, some positively and others negatively. Many current epidemiologic studies of nuclear sclerosis use slit lamp photographs to document severity and compare these with photographic standards to assign severity levels. The resultant grades, while in general ordered as to severity, are variable regarding repeat masked gradings by the same and by different graders. Thus, effects of risk or protective factor, which may be small to moderate, may be missed. We have developed a semi-automated scheme for measuring nuclear density, a reflection of nuclear sclerosis, from previously collected photographs. The method reflects current manual grading schemes in ordering severity, but is highly reproducible. We propose to apply these methods to slit lamp photographs taken three times over a ten-year interval in the large cohort participating in the Beaver Dam Eye Study. This will permit quantitation of nuclear sclerosis in a more reliable manner and on a finer scale than with current manual grading. We propose to examine relationships between previously hypothesized risk and protective factors for prevalent severity of nuclear sclerosis at baseline and for its progression, and to estimate the association of nuclear density with measures of visual function. The advantages of developing and testing these procedures in the Beaver Dam Eye Study are that (1) the data are from a free-living, unselected population in which the spectrum nuclear sclerosis is likely to represent that in other similar communities and (2) the photographs are in hand and thus the project is economical. The approach described will be important in clinical trials that are ongoing, others that have been completed, and still others that are planned by the National Eye Institute and other groups in which finding small to moderate affects will be enhanced by more reliable measures of disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROINFLAMMATORY ENZYMES IN AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Przedborski, Serge E. Professor; Neurology; Columbia University Health Sciences New York, NY 10032

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Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2005 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 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: PROTECTION OF HOST TISSUES FROM FDURD TOXICITY Principal Investigator & Institution: Maybaum, Jonathan; Professor; Pharmacology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-JAN-2003 Summary: (Applicant's Abstract) The therapeutic selectivity of a chemotherapeutic regimen is defined by its relative effect on tumor cells vs. critical host tissues. Although most strategies for improving selectivity have been directed towards increasing the host toxic effects of drugs in tumor cells, selective protection of host tissues from these drugs should also enhance therapeutic effect, by increasing the intensity of treatment that can be tolerated by the host. When FdUrd is administered to humans by extended hepatic arterial infusion for the treatment of intrahepatic neoplasms, the dose-limiting toxicity is biliary sclerosis (also called sclerosing cholangitis). Several lines of evidence suggest that this sclerosis is caused by the direct injury of biliary epithelium due to druginduced inhibition of thymidylate synthase (TS). If this mechanism is correct, then we would expect the following hypothesis to be true: Expression of TS in biliary epithelial cells will attenuate or prevent FdUrd-induced biliary sclerosis. The overall objective of

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this project is to test this hypothesis, by evaluating the ability of an adenoviral vector for TS expression to prevent biliary toxicity in animal models when administered by retrograde biliary infusion. If the hypothesis is correct, the applicant plans to apply his studies to humans, where protection of the biliary tree should permit the administration of FdUrd treatments that are significantly more intense than can ordinarily be tolerated, and where it has been demonstrated that even a modest intensification of FdUrd treatment can have significant therapeutic benefit. These studies will proceed in three phases: first he will produce an adenoviral vector for expression of TS and characterize it in cell culture systems. Next he will characterize the ability of the vector to transduce and protect biliary epithelial cells in rats, which represent the most practical and economical animal model for initial studies on the properties of this vector in vivo. Finally he will test the therapeutic efficacy of transduction with TS adenovirus in a canine model, which is the only model that is currently known to closely mimic the toxic syndrome seen in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PSYCHOSOCIAL INTERVENTIONS FOR SCLERODERMA Principal Investigator & Institution: Haythornthwaite, Jennifer A. Associate Professor; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: (adapted from investigator's abstract): Systemic sclerosis (scleroderma: SSc) is a rare, disfiguring connective tissue disease characterized by inflammation vascular injury, and fibrosis. Despite the significant physical disability, pain, disfigurement, negative prognosis, and lack of a cure associated with SSc, no psychosocial interventions have been developed and tested to guide these individuals in managing the daily challenges of living with a chronic illness and improving the quality of their lives. The proposed research will examine the efficacy of two psychological interventions designed to target important areas of daily living: pain, depression, and distress about disfigurement (Specific Aim #1). Individual differences in treatment outcome will be examined by determining whether clinical depression predicts the effects of professionally guide self-help materials (Specific Aim #2). Since psychological interventions requiring a trained professional can be costly and are often not available to the majority of patients, professional involvement in the proposed interventions will be minimal. Two hundred and one patients with systemic sclerosis who report symptoms of pain, depression, or distress about disfigurement will be recruited and randomized to one of three interventions: individual cognitive-behavioral therapy, self-help cognitivebehavioral intervention facilitated by a Psychologist, or a disease/health education intervention. Measures of pain, functioning, distress about disfigurement, and mood will be collected at baseline and following the 8-week intervention period by an individual blind to intervention assignment. Both the cognitive-behavioral self-help materials and the educational materials (8 written chapters and audiotapes) will be designed for home use but will be supplemented by individual sessions (2) and telephone contacts (2) with the professional. Patients will be followed for one year after completing the active intervention phase (Specific Aim #3). It is hypothesized that the therapist administered CB intervention and the self-help CB intervention will result in greater declines in pain, depression, and distress about disfigurement both at the end of the active intervention and at one year follow-up as compared to the disease/health educational intervention. Depression is expected to reduce the efficacy of the CB selfhelp intervention. These findings will increase our understanding of the quality of life of

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individuals with scleroderma and determine whether self-help interventions can be used effectively to manage pain, depression, and distress about disfigurement. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: QUANTITATIVE MR IMAGING AND PROTON SPECTROSCOPY IN MS Principal Investigator & Institution: Grossman, Robert I. Louis Marx Professor and Chairman; Radiology; New York University School of Medicine 550 1St Ave New York, NY 10016 Timing: Fiscal Year 2001; Project Start 19-AUG-1991; Project End 30-JUN-2003 Summary: The central hypothesis of this proposal is that neuronal death (reflected primarily by gray matter volume loss) resulting from demyelination and inflammationinduced axonotomy (rather than myelin loss per se) is the primary factor in induction and progression of physical and neurocognitive disability in patients with multiple sclerosis (MS). We will detect and measure neuronal loss in our well- characterized cohort of MS patients over a 5 year period using magnetic resonance imaging and proton magnetic resonance spectroscopy (1H MRS). In Specific Aim 1 MS lesions will be assessed by measuring T2 and T1- enhanced lesion volumes and magnetization transfer ratio histogram parameters (MTRHP) in patients with relapsing-remitting and secondary progressive disease. This data will be correlated with total brain parenchymal volume and will be used to characterize the effect of MS lesion on the gray and white matter volumetric components of brain parenchyma. The brain volumetric measurements will be compared to clinical measures of disability including Kurtzke Expanded Disability Status Scale (EDSS) and a specific battery of neuropsychological tests. Specific Aim 2 includes quantitation of N-acetylaspartate over the whole brain (WBNAA), a reproducible measure of viable neuron number based upon 1H MRS, and comparison of the results to age-matched controls over a duration of 5 years. Specific Aim 3 is to examine the correlations between the volumetric and clinical measurements in Specific Aim 1 and WBNAA in Specific Aim 2. The techniques that we have developed and validated, which include computerized quantitation of brain parenchyma and the gray and white matter components of parenchyma, analysis of the MTR histogram, and measurement of WBNAA will be utilized to estimate neuronal loss. Additionally we will determine the course of neuronal change over a 5 year duration, and will correlate the markers of neuronal loss with clinical measures of disability. This approach will, for the first time, provide important new data on the full extent of neuronal loss in patients with MS. We feel that these studies will ultimately lead to a more thorough understanding of the natural history of neurodegeneration in MS, and to a more rational design of outcome measures, and patient stratification in MS treatment trials. In addition, these studies will provide a basis for analysis of both primary and secondary central nervous system (CNS) neurodegeneration in other common and devastating disorders such as AIDS dementia complex, Alzheimer's disease and traumatic brain injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: QUANTITATIVE MR OF NORMAL APPEARING WHITE MATTER IN MS Principal Investigator & Institution: Atlas, Scott W. Radiology; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2001; Project Start 25-FEB-2000; Project End 31-JAN-2003

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Summary: (Adapted from applicant's abstract): The overall goal of this research is to test the feasibility of identifying and characterizing brain parenchymal disease invisible to conventional MRI that differentiates secondary-progressive (SP) from relapsingremitting (RR) multiple sclerosis (MS) patients using diffusion and MT MRI and MRS. We will: Aim 1. Quantify structural brain parenchymal disease burden in the normalappearing white matter for relapsing-remitting (RR) and secondary-progressive (SP) multiple sclerosis (MS) patients using quantitative whole-brain diffusion MRI and magnetization transfer (MT) MRI. We will test the hypothesis that SPMS patients harbor disease in normal-appearing white matter that is characterized by quantitatively abnormal diffusion and MT, as defined by normal controls, whereas RRMS patients have abnormal normal-appearing white matter on MT but may retain normal diffusion by histogram analysis. Aim 2. Characterize differences in whole-brain disease in normal-appearing white matter of RRMS and SPMS patients, as shown by diffusion and MT histogram analysis, using metabolite maps and quantitative metabolite analysis by whole-brain MR spectroscopy (MRS). Since axonal loss is thought to represent the histopathologic indicator of irreversible disease and the cause of morbidity in MS, we predict that total cerebral N-acetyl aspartate (NAA), the putative neuronal marker, will be abnormal in the normal-appearing white matter of MS patients with irreversible disease. We will test the hypotheses that: a) clinical disability correlates to NAA levels only in those patients with abnormal diffusion. This study will exploit new MR pulse sequences in a combined approach and apply them quantitatively to evaluate total brain normal-appearing white matter, in isolation, in MS patients. The future extension of this exploratory work will be a large scale, longitudinal study in which we will test that abnormalities in normal-appearing white matter on diffusion MR in RRMS predict progression to SPMS, and perfusion changes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RAPAMYCIN ANGIOMYOLIPOMAS

FOR

THE

TREATMENT

OF

RENAL

Principal Investigator & Institution: Bissler, John J.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Targeted molecular therapy is the ultimate objective for the management of neoplasia, but only a few examples exist in practice, due in large part to the complexity of genetic events that result in unregulated cell growth. Tuberous sclerosis is an inherited cancer syndrome associated with the formation of hamartomas in multiple organs, including angiomyolipomas in the kidney, caused by wellcharacterized inactivating mutations at genetic loci that encode the interacting proteins, tuberin or hamartin. Elegant studies have recently elucidated the pivotal role of the tuberin/hamartin complex in the checkpoint control of the Akt signaling pathway that regulates cell growth and division. Rapamycin, an FDA immunosuppressive approved drug used to prevent renal transplant rejection, mimics the function of the tuberin/hamartin complex by binding to a protein downstream of Akt called mammalian target of rapamycin (mTOR) and inhibiting the phosphorylation of more distal elements that control cell cycle and protein translation. Rapamycin has been shown to specifically inhibit the growth of tuberin and hamartin deficient cells from humans, rodents and flies, and to produce tumor regression in rats and mice. The consensus opinion of the recent Tuberous Sclerosis Complex Research conference in Chantilly, Virginia was that the preclinical evidence for the use of rapamycin in TSC was sufficiently compelling to warrant a human trial. The objective of the current study

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is to determine if rapamycin reduces the volume of angiomyolipomas. This goal will be accomplished by treatment of thirty patients with angiomyolipomas, either in the setting of tuberous sclerosis, or a related disease associated with mutations in tuberous sclerosis genes called sporadic lymphangioleiomyomatosis, with dose-adjusted rapamycin for a period of one year. The size, number, volume and tissue composition of renal angiomyolipomas will be monitored by MRI scans of the kidney, performed prior to treatment, at two months, four months, and every six months. Other manifestations of TSC, including brain, skin and lung lesions, will also be monitored with appropriate clinical, functional and imaging techniques. The minimal rapamycin dose that produces an effect, defined as a greater than 10% decrease in angiomyolipoma volume, will be titrated beginning with doses that result in subimmunosuppressive serum levels to those that produce levels in the low to modestly immunosuppressive range. Toxicities, as defined by the NCI common toxicities criteria, will be carefully monitored, reported, and expeditiously addressed. Successful completion of the aim of this study will help to establish tuberous sclerosis as a valuable model for targeted molecular therapy for neoplasia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHENOTYPE

RECEPTOR-MEDIATED

EFFECTS

ON

OLIGODENDROCYTE

Principal Investigator & Institution: Greene, Mark I. Professor; Pathology and Lab Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2008 Summary: Receptor-mediated effects on oligodendrocyte phenotype and disease. The objectives of this ongoing continuation are to define the paired interactions of the erbB family and TNF family of receptors that influence the development and differentiation of oligodendrocytes (OL). TNF family members are thought relevant to OL death in multiple sclerosis (MS), and we hypothesize that their activity influences the function of erbB receptor members on OL cells. We will use a variety of approaches to determine the biochemical basis of the paired relationship of these receptor families and how they guide maturation driven by erbB ligands in vitro and in vivo. In the course of the efforts we hope to identify signaling pathways that are most relevant to mitotic growth of OL precursors and those that lead to maturation to functional OL cells. Attempts will be made to correlate differentiation of OL with cyclin dependent kinase inhibitor accumulation. Efforts to modify TNF activity in vivo by macromolecular therapy alone have been unsuccessful. We have developed a novel class of secondary structure exocyclic peptides and cystine knot mimetics that may limit TNF receptor signaling in a way beneficial to MS therapy, especially if coupled to erbB growth factor receptor activation. This new class of secondary structural exocyclics and cystine knot forms designed from the TNF receptor structure will be used in vivo in attempts to modify the immunologically driven oligodendrocyte death seen in the experimental allergic encephalomyelitis (EAE) model. Extensive collaborations with Dr. Rostami, Dr. Pleasure, and Dr. Chen will be important during the course of these studies. Basic principles resolved by these studies may have relevance to multiple sclerosis therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF CELL AND ORGAN SIZE IN VIVO Principal Investigator & Institution: Hariharan, Iswar K. Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, MA 02114

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Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: The eventual size reached by an animal is determined both by the total number of cells as well as the size of individual cells. Total cell number is determined by cell proliferation and cell death. Recent years have witnessed substantial progress our understanding of the regulation of these two processes. In contrast, the mechanisms that regulate the size of individual cells are not well understood. The experiments detailed in this proposal are aimed at understanding the mechanisms that regulate cell size in vivo. A genetic screen using FLP-recombinase induced mitotic recombination in the Drosophila eye was used to identify mutations that resulted in increased cell size. The mutations isolated to date map to six different genetic loci. One of the loci corresponds to the gigas gene which has been characterized by others and results in large polyploid cells. The gigas gene is the Drosophila homologue of the TSC2 gene which is mutated in approximately 70 percent of patients with tuberous sclerosis. One of the loci identified in the screen, rocky has a phenotype that is extremely similar to that of gigas and maps to the location of the TSC1 gene which is mutated in 30 percent of patients with tuberous sclerosis. Another mutation, which increases cell size without altering ploidy, maps to the vicinity of PTEN gene which is mutated in a number of different human cancers. Another, expanded, appears to act in a non-autonomous manner. Two others have not yet been mapped. Specific Aim 1 of this proposal describes the completion of a comprehensive genetic screen to identify mutations that lead to an increase in cell size. Mutations will be sorted into complementation groups and the genes will be mapped. Specific Aim 2 describes a detailed phenotypic analysis of gigas, rocky, wolf and expanded. Experiments will address the precise mechanism by which these mutations increase cell size. In each case the effect of the mutation on ploidy, growth and cycle regulation will be determined and the role of the gene will be studied in the context of known regulators of cell size. Specific Aim 3 describes a general strategy for characterizing the phenotype of the remaining mutations and those that will be identified as the screen moves to completion. An approach to cloning the genes is also described. Analysis of the mutations identified in the screen will contribute to our understanding of cell size regulation in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF IMMUNE RESPONSES IN THE CNS Principal Investigator & Institution: Brosnan, Celia F. Professor; Yeshiva University 500 W 185Th St New York, NY 10033 Timing: Fiscal Year 2001; Project Start 01-JAN-2001; Project End 31-DEC-2001 Summary: Project 2: Regulation of immune responses in the central nervous system Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (NS) that is thought to be mediated by an autoimmune tack directed against CNS myelin. Although the etiology and pathogenesis of MS is unknown, disease expression is considered to reflect a loss of tolerance for self-reactive lymphocytes. The pathways involved in regulation of immune responses remain rather poorly understood, but in MS may reflect an imbalance between pro- and anti- inflammatory activities. In the coming granting period we propose to dissect out the contribution of some of the regulatory pathways involved as they relate to CNS inflammation. Two major areas of research will be investigated. The first will address the potential contribution of altered chemokine receptor expression to the generation of a highly polarized immune response. We have identified two previously undocumented point mutations in the chemokine receptors CCR3 and CCR1b in the SJL mice. We will investigate how these mutations affect the functional properties of different subsets of

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leukocytes, alter susceptibility to experimental allergic encephalomyelitis (the animal model for MS), and determine whether similar mutations are present in patients with MS. The second area is directed at determining regulatory pathways involved in NFkappaB activation that result in differential regulation of genes dependent upon NFkappaB for transcription. In preliminary studies we have shown that signaling via purinergic receptors modulates NF-kappaB expression by specifically targeting activation of IkappaBbeta, proving us with a tool to dissect out potential mechanisms involved in the regulation of stimulus-specific and cell-type specific responses. The hypothesis to be tested is that the inflammatory response is regulated at many different levels, resulting in a response that shows factor-specific, cell-type specific, and speciesspecific regulatory events, even though common initiating pathways are activated. To test the hypothesis we propose: 1) to define the contribution of mutations in chemokine receptors to the establishment of an immune response that is biased towards a Th1 response. 2) to assess whether patients with MS demonstrate point mutations in these chemokine receptors and show altered migratory responses to specific ligands. 3) to determine the regulatory pathways involved in NF-kappaB activation that may lead to differential activation of specific components of the inflammatory cascade. 4) to investigate whether the functional activity of NF-kappaB is regulated by species-specific and/or the stimulus-specific signals. 5) to study MS plaques And animals with EAE for expressing of members of the NF-kappaB signaling cascade, and relate this expression to lesion activity. The overall objective of this proposal is to identify novel targets for specific therapies directed at inhibiting the induction and/or persistence of an inflammatory cascade within the CNS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF LEUKOCYTE TRAFFICKING AT THE BBB Principal Investigator & Institution: Berman, Joan; Yeshiva University 500 W 185Th St New York, NY 10033 Timing: Fiscal Year 2001 Summary: Project 3: Regulation of leukocyte trafficking at the BBB: Perivascular accumulation of mononuclear cells within the white matter of the central nervous system (CNS) is a pathologic hallmark of multiple sclerosis (MS). The mechanisms involved in the selective infiltration of the CNS by circulating T cells and monocytes during the pathogenesis of MS are not completely understood. This process is dependent on expression of chemokines and their receptors, which direct leukocyte migration t9o specific sites within the vasculature, and adhesion molecules, which mediate selective leukocyte adhesion to endothelium resulting in subsequent extravasation into perivascular regions. The hypothesis to be tested is that the kinetic and region expression of chemokines, their receptors, adhesion molecules and matrix metalloproteinases (MMP's) by endothelial cells (EC) and astrocytes, components of the specialized vessels of the CNS, a swell as by T cells, monocytes and cells specific to the CNS are critical to the type of tissue mononuclear cell accumulation. Subsets of leukocytes express different chemokine receptors and adhesion proteins And transmigrate in response to specific chemoattractants. The timing and sequence of chemokine and adhesion molecule expression within the CNS may have a direct effect on the inflammatory profile and phenotype characteristic of the developing MS lesion. In the previous granting period, a tissue culture model of the human BBB was developed. The model enabled analysis of mechanisms involved in transmigration of mononuclear cells (PBMC) as they relate to the CNS-specific inflammation that occurs in MS. The major findings of these studies are: monocyte and T cell transmigration across

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co-cultures is chemokine and adhesion molecule dependent; astrocyte-derived factors significantly regulate transmigration; astrocyte-derived MCP-1 is a potent inducer of monocyte but not T cell migration; T cells transmigrate in response to IFN-gammainducer factors; treatment of T cells and monocytes with IFN-beta, an approved therapy for MS, inhibits their transmigration in the BBB model; and chemokine expression in human microglia and astrocytes is induced by TH-1-like cytokines. These novel findings form the basis for the experiments in this proposal. Specifically, the Aims are to: 1. Examine the effects of chemokines and adhesion molecules on T cell and monocyte trafficking across the BBB model. The role of the IFN- gamma induced chemokines, IP10 and MIG, in transmigration will be assayed. SDF-1 will also be tested as it may facilitate the influx of unactivated as well as activated T cells into the CNS. The cytokine, chemokine and chemokine receptor profiles of cells subsequent to transmigration will be assayed. 2. Characterize the mechanisms by which IFN-beta inhibits transmigration across the BBB model. 3. Analyze the mechanisms by which PBMC and gamma/delta T cell clones from MS patients transmigrate across co-cultures. 4. Determine the regulation of expression of MIG, IP-1-, SDF-1 and their receptors, CXC43 and CXCR4, in astrocytes and microglia. 5. Determine the expression in vivo of SDF-1, MIG and IP-10 and their receptors, as well as of MMP's in tissues from MS lesions of different ages. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REHABILITATION OF COGNITIVE SYMPTOMS IN MS Principal Investigator & Institution: Deluca, John; Director of Neuroscience Research; Kessler Medical Rehab Res & Educ Corp Research & Education Corp. West Orange, NJ 07052 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-MAY-2003 Summary: (Adapted from the Investigator's Abstract): In March 1993, the National Advisory Board on Medical Rehabilitation Research identified "the development of cognitive rehabilitation strategies" in persons with neurological disorders as a high priority research area (HPRA). The present proposal is designed to study the precise mechanism responsible for impaired working memory performance in patients with multiple sclerosis (MS), and to more closely test a rehabilitation strategy previously found by our laboratory to improve working memory in this population. It has long been recognized that persons with MS have deficits in working memory (defined as the ability to simultaneously store and manipulate information in short-term storage). However, preliminary work from our laboratory has shown that, when given enough time to process information, MS subjects perform as well as healthy controls (HCs) on the most commonly used working memory task, the Paced Auditory Serial Addition Test (PASAT). This suggests that persons with MS may not be impaired with regard to working memory at all! Rather, their working memory deficits appear to be primarily attributable to impaired information processing speed. What is still not known, however, is whether increased time for information processing improves MS accuracy on working memory tasks: a) other than the PASAT and b) with varied levels of working memory difficulty. The OVERALL OBJECTIVE of this project is to determine whether increasing the amount of information processing time improves working memory accuracy in MS subjects across tasks with different levels of difficulty. The SPECIFIC AIMS of this project are to: I ) examine the hypothesis that working memory impairment among MS subjects is due to speed of information processing and not accuracy of performance; 2) examine the hypothesis that MS subjects, when given more time to process information, will perform as accurately as HCs on working memory tasks; And 3) extend our initial pilot study by using working memory tasks at various

Studies 115

levels of difficulty, thereby increasing the generalizability of our preliminary findings. To investigate these hypotheses, 80 subjects (40 MS and 40 HC) will be administered a variant of the PASAT (also known as the l-back) as well as a more difficult derivative, known as the 2back. In both the 1- and 2-back tasks, accuracy of performance will be controlled at 50 percent correct (by using a computer algorithm utilizing a "method of limits" procedure). This then allows for the quantification of the amount of information processing time required for each subject to achieve accuracy performance of 50 percent correct. To address our aim of increasing the generalizability of our pilot data, we will assess the impact of increased information processing time on performance accuracy on a different working memory task. To achieve this, all subjects will be administered the Salthouse working memory task at 4 levels of task difficulty and with three different amounts of time for information processing (12 different permutations in all). By performing these experiments, we will be able to determine whether increased information processing time is the key cognitive element responsible for deficient working memory performance in patients with MS. Results of this project will have significant implications for the treatment of memory disorders in persons with MS. If our hypotheses are supported, then our data will lay the foundation for intervention strategies geared toward increasing information processing efficiency to improve memory performance in everyday life. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESOLUTION OF GLOMERULOSCLEROSIS Principal Investigator & Institution: Fogo, Agnes B. Professor; Pathology; Vanderbilt University 3319 West End Ave. Nashville, TN 372036917 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: Our previous work indicates that angiotensin induces expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of fibrinolysis and matrix degradation, in vitro and in vivo. A causal link between angiotensin and PAI-1 and sclerosis is supported by our in vivo demonstration that inhibition of angiotensin II (AII) selectively decreases expression of PAI-1, and that high doses of either a type 1 AII receptor antagonist, or angiotensin I converting enzyme inhibitor (ACEI) can even lead to resolution of existing, biopsy-proven sclerosis in the rat in the 5/6 nephrectomy model of progressive glomerulosclerosis. Based on these data, we hypothesize that inhibition of angiotensin II and PAI-1, by promoting matrix degradation and modulating cell growth/differentiation, is pivotal in resolution of sclerosis. The available mutant mice strains have so far not been utilized to examine mechanisms of progression of renal disease because of a lack of success in applying established models of progressive renal disease in the mouse. We now have in hand a model of progressive glomerulosclerosis in the mouse, which will be applied to the newly available mutant mice strains deficient for or overexpressing components of the plasmin/plasminogen activator system, that provide a unique opportunity to study mechanisms of resolution of sclerosis. We also have available a specific inhibitor of PAI-1, which will allow additional, time specific inhibition of PAI-1 and determination of its contribution to sclerosis and its reversal in vivo. We will use in vivo models together with in vitro experiments to examine the interactions of the renin angiotensin system and the plasmin/plasminogen activator system in sclerosis and its resolution. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF OXIDATIVE DAMAGE TO PROTEIN IN AGING Principal Investigator & Institution: Binninger, David M. Associate Professor; Florida Atlantic University Boca Raton, FL 33431 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): This proposal is being submitted as an application for an AREA award that would allow the Principal Investigator to initiate a new research program related to aging and neurodegenerative diseases. As by-products of cellular respiration, a variety of oxygen reactive compounds are formed that can be highly damaging to most types of cellular macromolecules. Several degenerative disorders commonly associated with aging, including Alzheimer's and amyotrophic lateral sclerosis, are thought to involve oxidative damage. Studies using fruit flies (Drosophila melanogaster) indicate that the motor neurons are the most sensitive tissue for oxidative damage. Superoxide dismutases (SODs) are cellular enzymes that initiate a series of reactions that ultimately convert highly reactive superoxide radical to water. Flies having a mutation in the SOD1 gene exhibit hypersensitivity to oxidizing agents and have dramatically shortened life spans. However, genetically engineered flies that express the SOD1 gene at above normal levels actually have extended life spans - nearly 40% longer than normal flies. Thus, there appear to be oxidation-sensitive macromolecules within the motor neurons that play a central role in the aging process. Minimizing the oxidative environment of the neurons actually slows the aging process. SOD reacts with a wide variety of compounds and thus, it is unlikely that we could identify these putative target molecules within the motor neurons. In contrast, peptide methionine sulfoxide reductases (Msr) specifically act on methionine sulfoxide residues in proteins. Here we propose experiments that test our overarching hypothesis that the expression of two Msr genes directly affects the life span of the organism and its resistance to oxidative stress. When methionine residues within critical neuronal proteins are oxidized, biological function is compromised and the aging process accelerates. Data from the experiments in this proposal will be used to develop an R01 grant application to identify these target proteins. Identification of these critical proteins would be a major contribution to our understanding of aging and lend insight into therapeutic approaches for neurodegenerative diseases such Alzheimer's and amyotrophic lateral sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF PLATELETS AND T CELLS IN REMYELINATION IN M.S. Principal Investigator & Institution: Burns, James B. Professor; Neurology; University of Utah 200 S University St Salt Lake City, UT 84112 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2006 Summary: (provided by applicant): The basic objective of the proposed research is characterization of factors that may contribute to remyelination in M.S. The novel aspect of the proposal is that we will emphasize the potential role of platelets in remyelination associated with multiple sclerosis. Other investigators have suggested that T cells and other components of the "standard" immune system promote remyelination and neuroprotection through neurotrophins. We will not ignore this possibility in our research. However, initially, the proposed research will emphasize the possible role of platelets in remyelination. The role of platelets in remyelination is an area of research that has not been a topic for investigation in the past. For this reason the current proposal is submitted as a developmental grant. In multiple sclerosis, it is well established that in some lesions there is remyelination that is likely to be responsible for

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some of the recovery that can occur after some multiple sclerosis attacks. In the long term, areas that have been severely demyelinated probably do not permit a return of function unless remyelination occurs. A major impetus for this project includes recent publications that have emphasized the presence of oligodendrocytes in some areas that remain demyelinated. Also, many of the oligodendrocytes express receptors for known growth factors. Platelets are known to release the neurotrophins that bind these receptors. These growth factors promote the proliferation and differentiation of oligodendrocytes into mature cells. Other investigations in vitro and in vivo with human material has suggested that T cells may be an important source of neurotrophins, especially BDNF. By contrast, our preliminary data investigating BDNF indicates that platelets are a major source of BDNF. The specific aims of this proposal will include extending our preliminary studies, reviewed below, to include additional control subjects as well. We will further characterize production of additional neurotrophins by other components of the peripheral blood mononuclear cells with initial emphasis on platelets. In addition we will extend our preliminary study examining the presence of platelets in multiple sclerosis lesions. We plan to examine active and chronic lesions including the simultaneous localization of specific neurotrophins with various PBMC cell types and platelets. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF SOD INSTABILITY IN ALS MOTOR NEURON TOXICITY Principal Investigator & Institution: Hayward, Lawrence J. Neurology; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, MA 01655 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) is an age-dependent degenerative disorder of motor neurons characterized by progressive weakness and death within five years after the onset of symptoms. A subset of familial ALS is caused by mutations in Cu/Zn superoxide dismutase (SOD1) that render this antioxidant enzyme toxic by an unknown mechanism. Expression of mutant SOD1 in man or mice causes selective degeneration of motor neurons in the brain and spinal cord. The long-term objectives of this study are to understand how mutant SOD1 kills neurons and to identify novel pathways of cell death that may be relevant to ALS. Aim 1 of this project is to define important biophysical and biochemical characteristics that distinguish mutant from wild type SOD1. Recent studies in our lab indicate that mutant SOD1 enzymes all share an increased tendency to unfold or to lose metal ions when stressed by denaturing influences. Experiments will be performed to (1) define conditions that preferentially destabilize mutant but not normal SOD1, (2) identify factors that alter the dynamics of the SOD1 monomer-dimer equilibrium as measured by analytical ultracentrifugation, and (3) map regions of the protein that are susceptible to proteolytic cleavage or partial unfolding. In Aim 2, the affinities and thermodynamics of metal binding to SOD1 as a function of pH or denaturant will be measured using a novel calorimetric approach. Conditions that alter Cu ion reactivity in mutant SOD1 will also be defined. Aim 3 will employ cell culture models to test hypotheses of mutant SOD1 toxicity that are consistent with the physicochemical findings from Aims 1 and 2. Initial investigations will test whether early lysosomal dysfunction occurs in response to specific stresses in mutant SOD1 -bearing neuroblastoma cells or in organotypic spinal cord slice cultures. Future results from Aims 1 and 2 may favor alternative hypotheses of mutant SOD1 toxicity to test in these cellular models and may suggest new therapeutic approaches to evaluate in ALS mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: S6K AND MTOR AS TARGETS FOR TUBEROUS SCLEROSIS Principal Investigator & Institution: Guan, Kun-Liang; Oncoimmune Ltd 1275 Kinnear Rd Columbus, OH 43210

Associate

Professor;

Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2004 Summary: (provided by applicant): Tuberous sclerosis (TSC) is a common autosomal dominant genetic disorder occurring in approximately 1/6000 of the population. TSC is characterized by the development of hamartomas in a wide range of human tissues. Common clinic symptoms include seizures, mental retardation, kidney failure, facial angiofibromas, and cardial rhabdomyomas. Mutation in either TSC1 or TSC2 gene is responsible for TSC. Recent genetic studies have indicated that TSC I/TSC2 are involved in cell growth control and function as tumor suppressors. The TSC1 and TSC2 proteins form a physical and functional complex in the cell. The long-tern objectives of this project are to identify critical cellular targets, which mediate the physiological functions of TSC I/TSC2 and to verify potential drug targets for TSC. The specific aims of this proposal are: 1. To demonstrate that TSC1 and TSC2 function through the mammalian target of rapamycin (mTOR); 2. To validate S6K as a key downstream effector of TSC1/ TSC2. Biochemical, molecular and cell biological approaches will be used to accomplish these specific aims. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SAFETY/TOLERABILITY OF CGP 77116 IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Guarnaccia, Joseph B.; Yale University 47 College Street, Suite 203 New Haven, CT 065208047 Timing: Fiscal Year 2001 Summary: This study will evaluate and compare safety, tolerability, and effect on cranial MRI of three dose levels of CGP77116 versus placebo in patients with relapsingremitting multiple sclerosis. The purpose of the study is to assess whether CGP77116 modifies inflammatory disease activity as measured by MRI and to facilitate dose selection for future studies in relapsing-remitting multiple sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SEARCH FOR BIOMARKERS IN HUMAN ALS PERIPHERAL BLOOD Principal Investigator & Institution: Dangond, Fernando; Assistant Professor; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2003 Summary: (provided by applicant): The applicant is a neuroimmunologist with molecular biology and functional genomics experience, and an interest in immune cellactivation mechanisms. His training in neuroimmunology and functional genomics was completed at the Brigham and Women's Hospital (BWH), Boston, MA. He also holds an appointment as an Assistant Professor of Neurology at Harvard Medical School. His interest is now focused on the application of DNA microarrays to establish markers of disease activity in peripheral blood and tissues. The scientific goal of this proposal is to explore the gene expression profile of immune cells in amyotrophic lateral sclerosis. Our hypothesis is that ALS is a complex neurodegenerative disease with a prominent immune component, and understanding of the role that the immune system plays in the disease may lead to new therapies. The Specific Aims are: 1) To perform genechip experiments of peripheral blood mononuclear cells of patients with ALS, other neurological diseases, and normal controls; 2) perform confirmatory northern blots,

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FACS analysis and TaqMan assays to identify patterns of gene expression that may indicate a) immune system dysfunction, or b) other metabolic changes that may give clues to ALS pathogenesis, and 3) perform comparative analysis of our results in peripheral blood with our other DNA microarray data (currently ongoing) of gene expression in ALS spinal cords and brains, for posting in a web site for public use. The applicant's training in functional genomics, molecular biology and cell immunology will allow him to further explore the critical role of genes whose regulation is altered in ALS. The R21 RFA Award will provide the necessary support for accomplishing these aims. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SERIAL MAGNETIC RESONANCE IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Narayana, Ponnada A. Professor; Radiology; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, TX 77225 Timing: Fiscal Year 2001; Project Start 01-APR-1993; Project End 31-MAR-2004 Summary: Magnetic resonance imaging (MRI) is the most sensitive radiologic modality in visualizing multiple sclerosis (MS) plaques. However, the monotonous appearance of many lesions limits the usefulness of a single MRI in distinguishing active lesions from inactive ones. The proposed longitudinal studies are designed to utilize state-of-the-art volumetric image analysis and image-guided in vivo proton magnetic resonance spectroscopy (MRS) in combination with the paramagnetic contrast agent gadolinium diethylentriaminepentaacetic acid (GdDTPA) for distinguishing different stages of MRIdefined and clinically correlated disease activity. Volumetric image analysis performed on dual echo thin slices (3 mm) with no interslice gap will allow quantitation of total lesion burden as well as volumes of individual plaques independent of small unavoidable errors in repositioning the patients on serial scans. The number and degree of enhancement of plaques will also be quantified using the image analysis. Multivoxel proton MRS will be performed at short-echo times to visualize lipids and other membrane breakdown products from the plaque-containing as well as adjacent-tissue with a volume resolution on the order of 2 cc. MRS data will be quantitatively analyzed to critically assess the role of lipids, N-acetyl aspartate (NAA) and other MR-visible neurochemicals in the characterization of MS plaques. Linked GdDTPA MRI and MRS should allow us to determine the MRS-defined changes in the neurochemicals in relation to acute changes in regional vascular permeability. Computed Relaxation images should allow the detection of plaques even when they are too small to be resolved on MRI or prior to GdDTPA enhancement. Many of the patients will be scanned at intervals of four weeks up to a period of six months. Magnetic resonance results will be correlated with clinical status. These multi-pronged MA studies should allow us to characterize and follow the evolution of MS plaques and improve our understanding of the pathophysiology of MS. A further significance of these studies is that they may enable us to follow objectively and quantitatively the efficacy of drugs in the treatment of MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRESS EFFECTS ON AN ANIMAL MODEL OF AUTOIMMUNE DISEASE Principal Investigator & Institution: Welsh, C Jane. Veterinary Anatomy & Public Health; Texas A&M University System College Station, TX 778433578 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006

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Summary: (provided by applicant): Physical and psychosocial stressors have been shown to compromise immune function. An individual's response to a stressor is manifested in physiological, hormonal, behavioral, and immunological changes. These stress-induced responses are initiated by the hypothalamus and translated into action by the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system. Products from these two systems (e.g., corticoid hormones and catecholamines) are able to modulate the activity of various immune effector cells directly. Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS), affecting approximately 1/2000 of the US population. The etiology of this disease is unknown, although viral infection in early adulthood is suspected as an initiating event followed by autoimmune-mediated demyelination. In common with other autoimmune diseases, stressful life events may precipitate both the onset and clinical relapses in MS patients. The current proposal examines the effect of stress on the pathogenesis of an animal model of multiple sclerosis, Theiler's virus-induced demyelination (TVID). Persistent infection of the CNS with Theiler's virus results in primary inflammatory demyelination which has proved to be an excellent model of MS. Current research indicates that chronic restraint stress during early infection with Theiler's virus results in high levels of glucocorticoids, immunosuppression, reduced immune cell infiltration into the CNS and consequently reduced viral clearance and increased mortality. This proposal seeks to determine the effect of stress on the ability of the host to mount an anti-viral immune response within the CNS and the effect of stress on the ability of a virus to establish a persistent infection in the CNS. Preliminary results also indicate that restraint stress during the later demyelinating phase of Theiler's virus infection modulates the clinical signs of disease. This phenomenon will be further investigated in order to determine how stress impacts on the immune system and subsequently alters the demyelinating disease process. The current application proposes to use the restraint stress paradigm to identify the neuroimmune mechanisms that underlie susceptibility to virus-induced demyelinating disease. Clarifying how environmental stressors influence an individual's vulnerability to autoimmune disease may increase our understanding of diseases such as multiple sclerosis and thus lead to the development of therapeutic regimens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: T CELL RECOGNITION OF MYELIN IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Hafler, David A. Professor; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 24-DEC-1990; Project End 30-NOV-2003 Summary: Multiple sclerosis (MS) is hypothesized to be an autoimmune disease where the activation of myelin-reactive T cells, possibly by cross-reactive antigens, mediates the initial inflammatory insult leading to the recruitment of effector inflammatory cells. While there are no differences in the frequency of MBP and PLP reactive T cells in MS patients as compared to controls using limiting dilution analysis (LDA), it has become clear that there are both functional differences in the myelin reactive T cells of MS patients and differences in their regulation. We recently developed methods to directly measure the frequency of clonally expanded and activated antigen specific and invariant T cells ex vivo without in vitro manipulations. This analysis uses PCR to measure the number of T cells expressing particular TCR alpha/beta chains. In contrast to frequencies of T cells recognizing the immunodominant MBPp85-99 epitope in MS patients of approximately 1:10/5 as measured by LDA, we found T cell frequencies as high as 1:300 in the same subjects by PCR analysis: This grant will focus on three major

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issues. First, we will investigate whether the clonal expansion we observed for MBPp8599 reactive T cells is also observed for T cells recognizing other immunodominant regions of MBP and PLP. This is critical to known in the development of antigen specific immunotherapies. As autoreactive T cells are present in the circulation of normal individuals, it has also become clear that other populations of T cells exist which may regulate the activation of autoreactive T cells, including a recently described subset of T cells expressing the invariant Valpha24JalphaQ sequences. We recently demonstrated that the Valpha24JalphaQ T cells are reduced ion frequency and are Th1 like (lacking IL4 secretion) in diabetic twins as compared to non-diabetic twins. As the same methods can be used to quantify the frequency of Valpha24JalphaQ in patients with MS. The third aim of the grant will focus on the loss of IL-4 producing CD4+/B7.1+ cells, we recently observed in patients with MS. Using the PCR/TCR technology to identify antigen reactive T cells, we will explore the hypothesis that MS patients have a loss of myelin reactive T cells in the ex vivo IL-4 producing population, while in normal subjects IL-4 producing T cells are autoreactive. These experiments will provide insights that may be important for the design of antigen specific immunotherapies for patients with multiple sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TCR RECOGNITION OF MHC CLASS II PEPTIDE COMPEXES IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Wucherpfennig, Kai W. Associate Professor; DanaFarber Cancer Institute 44 Binney St Boston, MA 02115 Timing: Fiscal Year 2001 Summary: T cell receptor sequence analysis indicates that myelin specific T cells are expanded in multiple sclerosis (MS) patients, but adequate techniques for the enumerization of antigen-specific T cells in relationship to the disease process are not available. We hypothesize that the frequency of T cells specific for myelin-derived peptides has been greatly underestimated by limiting dilution techniques. Analysis of antigen-specific CD4+ T cells with sensitive techniques will have important implications for understanding the pathogenesis of MS and for developing adequate tools for immune monitoring. The analysis of CD8+ T cells in viral infections has been revolutionized by the creation of tetrameric forms of MHC class I/peptide complexes. Massive expansion of antigen-specific CD8+ T cells has been documented in both acute and chronic viral infections. The introduction of this technology led to the realization that the frequency of antigen specific CD8+ T cells in viral infections had been greatly underestimated. The generation of tetrameric forms of human MHC class II molecules may have a major impact on the investigation of human autoimmune disease. An expression system for soluble HLA-DR2 was previously developed for crystallization of HLA-DR2 with a bound peptide form human myelin basic protein. Based on this expression system, tetramers of HLA-DR2/peptide complexes have been generated with fluorescently labeled streptavidin. These molecules will be used to determine the frequency, activation state and cytokine profile of antigen specific T cells in the cerebrospinal fluid and blood of MS patients with the HLA-DR2 haplotype. The tetramer approach will also be used to generate multivalent TCRs using cDNAs derived from myelin specific T cell clones. MS plaque tissue will be stained with these multivalent TCRs to examine surface expression of HLA-DR2-bound myelin peptides by antigen presenting cells in the target organ. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE EFFECTS OF BBIC ON MULTIPLE SCLEROSIS Principal Investigator & Institution: Ware, Jeffrey H.; Protomed, Inc. 225 E Deerpath, Ste 250 Lake Forest, IL 60045 Timing: Fiscal Year 2001; Project Start 15-SEP-2001; Project End 31-AUG-2004 Summary: (Adapted from the Applicant's Abstract) The goal of the proposed studies in this SBIR Program is to develop a protease inhibitor-containing product which can be developed commercially as an anti-inflammatory agent to be utilized in the treatment of Multiple Sclerosis (MS). In Phase I, we propose a feasibility study to investigate whether Bowman-Birk Inhibitor Concentrate (BBIC), a drug containing high levels of the Bowman-Birk protease inhibitor (BBI) can affect indicators of neuroinflammatory disease in rats with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE will be induced in rats by immunization with guinea pig myelin basic protein. We propose two experiments. The first will be a pilot study to determine a dose of BBIC which can affect the clinical symptoms of rats with EAE. The second study will be a larger experiment designed to 1) show the effect of BBIC on these symptoms with statistical significance, 2) confirm this effect histopathologically, and 3) attempt to show correlation of these symptoms with serum levels of soluble vascular cell adhesion molecule, a protein marker of inflammation. BBIC will be administered orally in both studies. We plan to move to a pilot human study in Phase II. PROPOSED COMMERCIAL APPLICATION: Should clinical trials indicate a beneficial effect, we plan to market BBIC tablets for use as a therapeutic agent in the treatment of Multiple Sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE ELECTROPHYSIOLOGY OF MOTOR NEURON DISEASES Principal Investigator & Institution: Bromberg, Mark B. Professor; Neurology; University of Utah 200 S University St Salt Lake City, UT 84112 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2003 Summary: (provided by applicant): Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders of unknown etiology. They have in common death of lower motor neurons (LMN) causing muscle weakness, and both disorders are fatal. Mechanisms of LMN death differ for SMA and ALS. In SMA, LMN death may occur over a limited period of time. Unanswered is whether there is late or continued LMN loss. Recent genetic studies in SMA indicate a relationship between survival motor neuron gene (SMN2) copy number and SMA type. Unanswered is the relationship between copy number and LMN number. In ALS, no single mechanism of LMN death explains known features, and a cascade of events ultimately leading to LMN death is likely. Unanswered in ALS is the natural pattern of progression of LMN loss from muscle to muscle. Although muscle weakness is the clinical manifestation of LMN loss for both disorders, the rate of loss of strength does not accurately reflect the rate of loss of LMNs. The discrepancy is due to the compensatory effects of reinnervation of denervated fibers by collateral sprouting from surviving motor nerve terminals. Similarly, routine electrophysiologic tests do not accurately measure LMN loss. Unanswered for both disorders is the dynamics of the compensatory process that determines the clinical state and level of function. Motor unit number estimation (MUNE) is a special electrophysiologic test that can directly assess the number of LMNs innervating a muscle. There are no data on the natural course of LMN loss for SMA, and little data for ALS. We propose to develop and refine MUNE and other electrophysiologic techniques to study, and follow the course of LMN loss and

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associated compensatory changes. For SMA, we will adapt MUNE techniques to study infants and children. For older SMA and ALS, we will refine MUNE techniques to optimize data collection. For SMA, we will correlate LMN loss with clinical type and SMN2 copy number. We will begin, in the two years of the grant-performing serial studies, to assess whether there is continued LMN loss. For ALS, we will determine and compare the rate and pattern of LMN loss in distal and proximal muscles. In older SMA and ALS, we will assess relationships between LMN loss and measures of collateral reinnervation and strength. We anticipate that MUNE and other electrophysiologic techniques will have direct applicability to the design of clinical trials for SMA and ALS, because these techniques can be used as informative end-point measures. To facilitate the use of MUNE in clinical trials, we will develop and refine the techniques in a form that can be used in any clinical center participating in trials. Currently, most MUNE techniques rely on proprietary software. We will develop software for use on PC-based computer systems, making them available to all laboratories. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE MECHANISMS OF AUTOIMMUNE RESPONSE INITIATION IN MS Principal Investigator & Institution: Markovic-Plese, Silva; Neurology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS) affecting primarily young adults in their most productive age, and therefore causing a significant disability. While its etiology remains elusive, most evidence supports the autoimmune pathogenesis of the disease. According to this hypothesis, the activation of autoreactive T-cells is a central event in the development of autoimmune response in MS. The objective of this proposal is to examine molecular events involved in the initiation of autoimmune response in MS. Recent studies have reported an unexpectedly high degree of T-cell receptor (TCR) degeneracy and molecular mimicry as a frequent phenomenon that might play a role in the initiation of autoimmune response in MS. MHC DR2-biased combinatorial peptide libraries are developed as a tool to characterize degenerate Tcells. As auto-antigens are predominantly weak TCR ligands, we propose that myelinreactive T-cells may be over-represented among the cells with a degenerate TCR. Myelin basic protein (MBP)-specific T-cells exhibit decreased CD28 co-stimulatory requirements in MS patients when compared to healthy controls. We hypothesize that dysregulation of co-stimulatory pathways play a role in the initial activation, prolonged survival, and the expansion of autoreactive cells in MS. Co-stimulation-independent activation might be particularly relevant for the autoantigen recognition within the CNS, as local inflammatory environment enhances autoantigen presentation even in the absence of co-stimulatory molecules on the resident antigen presenting cells. We plan to achieve our objective by pursuing the following Specific Aims: 1) Determine the frequency and TCR repertoire of T-cell clonotypes with a high degree of TCR flexibility. 2) Define costimulation requirements for the activation and growth characteristics of T-cells with flexible TCR in RR MS patients and OND controls. 3) Identify mechanisms by which the inflammatory environment induces the autoreactive T-cell activation. The information provided by these studies may yield important insights into the physiologic and pathologic role of the autoreactive T cells, and characterize structurally and functionally the specific targets for the new therapies of MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE REGULATION OF SP3 EXPRESSION IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Moran, Kelly M. Microbiology and Immunology; Georgetown University Washington, DC 20057 Timing: Fiscal Year 2001; Project Start 01-SEP-2001 Summary: (provided by applicant): Multiple Sclerosis (MS) is a presumed autoimmune disease of the central nervous system (CNS). Although etiology is unknown, it is thought to be incited by an environmental factor in a genetically susceptible host. Patients with MS tend to be immune hyper-responders, with enhanced T cell and /or B cell responses to a variety of antigens of host and infectious origin. This suggests an element of immune dysregulation in the pathogenesis of the disease. It has been demonstrated that specificity protein 3 (Sp3), a bifunctional transcription factor, is not expressed in the immune cells of patients with MS. Sp3 plays a role in the expression of various immune molecules such as anti-inflammatory cytokines and adhesion molecules. Hence, the lack of Sp3 expression could be a source of immune dysregulation in MS. Determining what surpresses the expression of Sp3 in MS immune cells will be accomplished by sequencing 5? flanking regions of the Sp3 gene, determining regulatory regions, and characterizing factors that bind to these regions in both MS and non-MS PBMCs. Ascertaining how Sp3 is surpressed in MS immune cells has potential etiological significance as well as therapeutic significance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE ROLE OF SOD MISFOLDING/AGGREGATION IN FAMILIAL ALS Principal Investigator & Institution: Colon, Wilfredo; Assistant Professor; Chemistry; Rensselaer Polytechnic Institute 110 Eighth Street Troy, NY 12180 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2005 Summary: (provided by the applicant): The long-term goal of this application is to understand the mechanism by which over 90 missense mutations in human Cu / Zn superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (FALS), a fatal degenerative disease of the motor neuron system. SOD1 protects the cell against free radical damage by catalyzing the dismutation of superoxide radicals into hydrogen peroxide and molecular oxygen. It was originally believed that a decrease in SOD1 activity was the cause of SOD-related FALS; there is now overwhelming evidence that a gain in an unknown pathological function of mutant SOD1 causes the disease. While the age of disease onset (about47 years) varies little with mutation, disease duration after onset is often mutant-dependent, ranging from 1 to 20 years. The proposed research will test the hypothesis that the pathological function of SOD1 mutants is intimately related to an abnormal SOD1 conformation that is prone to aggregation. The stability, denaturation mechanism, copper and zinc affinity, and the radical-generating ability of the holo, apo, zinc-deficient and copper-deficient states of wild type and selected SOD1 mutants will be investigated. The metal content and the radical-generating activity of aggregated SOD1 will also be studied. Fluorescence, UV / Vis, and circular dichroism spectroscopy will be used to monitor conformational changes in SOD1. The stability, morphology, and association rate of SOD1 aggregates will be studied by various techniques, including polyacrylamide gel electrophoresis, UV / Vis spectroscopy, and electron microscopy. One of the main purposes of the proposed research is to determine the biochemical/biophysical effects of PALS-related SOD1 mutations, and to establish a correlation between these effects and the severity of FALS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THIRD INT'L CONFERENCE ON REACTIVE NITROGEN SPECIES Principal Investigator & Institution: Beckman, Joseph S. Professor; Anesthesiology; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001; Project Start 20-MAY-2001; Project End 30-APR-2002 Summary: (provided by applicant): We request support principally to fund travel awards for young investigators to attend and present at the Third International Conference on Reactive Nitrogen Species and Peroxynitrite in Biology and Medicine. This is the only meeting focusing entirely upon the physiological and pathological effects of peroxynitrite and other reactive nitrogen species derived from nitric oxide in biological systems. Peroxynitrite is a powerful oxidant formed by the reaction of nitric oxide with superoxide and is implicated in amyotrophic lateral sclerosis, Parkinson's disease, inflammation and vascular disease. The conference will bring together chemists, biologists and physicians to unravel the complex biological chemistry and physiological actions of these reactive intermediates. NIH currently funds 145 applications on peroxynitrite alone, investigating its roles in neurodegenerative diseases, respiratory distress, cardiovascular disorders, cancer and other disorders. Over half of the participants at the two previous meetings were post docs and graduate students, several of whom are now becoming established investigators in the field. The two previous meetings have helped shaped current research on peroxynitrite and resolve fundamental issues about the chemistry of these reactive intermediates. Scavengers of peroxynitrite, first described at the first two meetings, have now been shown to be effective in animal models of multiple sclerosis and amyotrophic lateral sclerosis. The third international meeting will be held at the Asilomar Conference Center near Monterey, CA. The format will be similar to a Gordon conference with morning oral presentations followed by group discussions in the evening. The objectives are to exchange information and engage in discussions across the disciplines of chemistry, biology and medicine of peroxynitrite and other reactive nitrogen species. The meeting is an important focal point for the great diversity of scientific disciplines and talents working with peroxynitrite and other reactive nitrogen species and provides an important opportunity to attract young investigators to the field. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TISSUE INJURY AND INFLAMMATION IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Ransohoff, Richard M. Professor; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, OH 44195 Timing: Fiscal Year 2001; Project Start 01-DEC-1999; Project End 30-NOV-2004 Summary: Multiple sclerosis (MS) is the leading cause of neurological non- traumatic disability for young adults in Norther America. This revised Program Project application is based on the hypothesis that the inflammatory destructive process in MS patients is active from disease onset and that progressive neurologic disability is a late complication of accumulated, irreversible tissue injury. The program consists of three related projects and one core. Project 1: Chemokines and chemokine receptors in multiple sclerosis (RM Ransohoff, PI) will address the hypothesis that specific chemokines and receptors are significantly involved in central nervous system (CNS) inflammation during MS. To define molecular targets for therapy, we will focus on chemokines and receptors expressed by T cells and mononuclear phagocytes in MS. PROJECT 2: Axonal pathology in multiple sclerosis (BD Trapp) is based on the hypothesis that axonal pathology is a primary contributor to neurological deficits in MS patients and should be considered as a therapeutic target. Axonal pathology will be

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characterized in spinal cords of patients dying from MS; in rats subjected to spinal cord transection and in mice with experimental autoimmune encephalomyelitis (EAE). Data will be correlated with biochemical measures of N-acetyl aspartate of N-acetyl aspartate, a reflection of axonal injury. In aim 4, oligodendrocyte progenitors in MS brain will be characterized, because chronic deprivation of the trophic support of myelin is responsible in part for anatomic interruption of axons in MS lesions. Project 3: Monitoring brain atrophy during the course of multiple sclerosis (RA Rudick) will test the hypothesis that brain atrophy will be a practical, sensitive and relevant surrogate marker of the underlying disease process. Recent studies indicate that brain atrophy can be measured from the early stages of MS in relapsing-remitting patients. Project 3 will address the rate and temporal pattern of brain atrophy in MS patients, and will establish relationships between brain atrophy and clinical disability in MS patients. The relation between brain atrophy on MRI and various additional MRI lesion types will be established, and we will perform MR/pathological correlations from scans performed at the time of autopsy during our tissue acquisition protocol. Core: Tissue acquisition, biostatistics, administration (RA Rudick) will establish, maintain and distribute for projects a unique resource of MS autopsy tissue, histological and post- mortem imaging data. This core will provide data analysis/management and administrative support for projects. This research program will directly impact monitoring and treatment of MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSGENIC AND KNOCKOUT MODELS OF ADPKD Principal Investigator & Institution: Harris, Peter C. Professor of Medicine; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR-2007 Summary: We have previously developed transgenic lines that express the human autosomal dominant polycystic kidney disease gene, PKD1, from a large genomic fragment (TPK). The transgene rescues the lethal phenotype of Pkd1-/- mice, but the TPK animals often develop renal and hepatic cystic disease. These results indicated that the level of PKD1 protein, polycystin-1, may be important for maintaining normal renal architecture. The first part of this proposal is to clarify these findings by generating PKD1 transgenic lines with a smaller genomic insert containing PKD1, but not a transcriptionally active copy of the adjacent tuberous sclerosis gene, TSC2, as was present in the original TPK animals. These transgenic mice will clarify the importance of the TSC2 gene for normal expression of PKD1. Furthermore, they will show whether overexpressing just polycystin-1 is sufficient to cause a cystic phenotype. Subsequently, transgenic animals will be prepared with precisely defined copy numbers of functional PKD1. The phenotypic consequences and rescue potential of animals with different levels of PKD1 expression will be compared. The expression pattern, stability, phenotypic consequences and rescue potential of mutant PKD1 genes, with truncating, or motif specific in-frame or missense mutations, will also be assessed. These experiments will test the dominant negative potential of truncated polycystin-1 molecules. Furthermore, by examining the phenotypes associated with Pkd1-/- mice rescued, or partially rescued, by transgenes with motif specific mutations, the role of individual polycystin-1 domains will be elucidated. The second part of the proposal will test the function(s) of polycystin-1 during neonatal and adult life by creating conditional knockouts of Pkd1. The endogenous murine Pkd1 will be modified by insertion of LoxP sites flanking exon 1. Recombination to generate a null, Pkd1dell, allele will be induced by the addition of doxycycline after crossing with a transgenic mouse containing a Cre recombinase gene under the control of the Tet-On system. Cre expression will be

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activated for short periods during neonatal or adult life to examine the fate of null polycystin-1 cells in a viable animal. Cre recombination will further be directed to specific organs and/or tissues by placing the Tet-On system under the control of a tissue specific promoter, such as Ksp-cadherin, that is only expressed in the kidney. This system will allow temporal and spatial control of Pkd1 inactivation and allow the postdevelopmental role of polycystin-1 to be investigated in different organs and cell types. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSGENIC STUDIES OF AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Deng, Han-Xiang; Neurology; Northwestern University Office of Sponsored Programs Chicago, IL 60611 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (Adapted from applicant's abstract): The goal of this project is to investigate the pathogenic mechanisms underlying the neurodegeneration of amyotrophic lateral sclerosis (ALS) using transgenic mouse models. Our application has two immediate Aims: The first one is to replace the two free cysteine residues in mutant human SOD 1 protein to test the role of free -SH groups in the formation of intracellular aggregates noted in ALS. The second aim is to define the smallest fragment of SOD 1 that would still cause ALS in transgenic mice. AIM 1: About 20 percent of the familial ALS cases are caused by mutations in Cu/Zn superoxide dismutase gene (SOD 1). Transgenic mice that over express mutant SOD 1 develop an ALS-like phenotype and motor neuron degeneration. A common feature in the pathology of both human SOD1-linked ALS and the ALS (SOD1) mouse models is the presence of the SOD 1-inimunoreactive inclusions or aggregates in neurons of the brain and spinal cord. These inclusions/aggregates are thought to be important elements in motor neuron death in ALS. To test the hypothesis that these inclusions/aggregates may be formed by disulfide bonds through interaction of free -SH groups of one or both free cysteines in SOD 1, we propose to develop new transgenic mouse model that over expresses a mutated SOD 1 (C6A/C1 1 1S/G93A). In this transgenic mouse model, two free cysteines in human SOD1 are replaced by an alanine and a serine. Absence of inclusions/aggregates will indicate a role for free cysteines; Absence of disease as well as inclusions/aggregates may indicate a causative role of the free cysteines (-SH groups). AIM 2: We recently made a new transgenic mouse model that over expresses a truncation mutation in SOD 1 (L126Z). These mice developed a typical ALS-like phenotype and pathology. These results provide the experimental evidence that only a part of the SOD1 polypeptide, rather than entire SOD1 protein, is sufficient to produce the neuronal toxicity and cause motor neuron degeneration. We plan to define the minimum fragment of SOD 1 essential for toxicity so that further studies into the pathogenesis of ALS may be facilitated. To achieve this goal we propose to develop additional transgenic mouse lines that over express successively smaller fragments of SOD 1 polypeptide to determine the smallest segment of SOD 1 that causes ALS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TREATMENT OF AUTOIMMUNE DISEASE BY COSTIMULATORY SIGNAL* Principal Investigator & Institution: Khoury, Samia J. Associate Professor of Neurology; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2003; Project Start 28-SEP-1999; Project End 31-MAR-2008

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Summary: (provided by applicant): There have been tremendous advances in the field of autoimmunity in the last 20 years, and our understanding of the mechanisms underlying autoimmune disease has grown exponentially. True tolerance is likely to arise not from improved immunosuppression, but from improved understanding of the normal mechanisms that generate and maintain self-tolerance, and the ability to manipulate these mechanisms for the prevention and treatment of autoimmune diseases. The mechanisms of autoimmunity that underlie many diseases are similar, and an integrated multi-specialty approach for evaluating new and emerging therapies would provide the opportunity to integrate knowledge from the various specialties. We have chosen to study therapy of autoimmune disease by blocking co-stimulatory signals with CTLA4Ig and by blocking T cell activation with rapamycin. This strategy has two advantages. First, these are antigen non-specific steps in T cell activation and immune responses. This means that tolerance can be achieved without needing to know the identity of the antigen. Second, restricted delivery of signal two and alteration in cytokine production and profiles are probably involved in normal mechanisms of selftolerance. Third, by inhibiting T cell activation with rapamycin in addition to costimulatory signal blockade, we may be able to induce long term tolerance by allowing the occurrence of activation induced cell death. The human diseases that our program will focus on are multiple sclerosis (MS), autoimmune diabetes (IDDM), and psoriasis. All are organ specific diseases where T cells appear to be essential in initiating the immune response and lead to the particular disease pathology. Project #1 is the clinical trials project, in which we propose a clinical trial of CTLA4Ig in diabetes, a clinical trial of CTLA4Ig + rapamycin in early MS and describe the available patients and facilities for a potential psoriasis trial. The goals of project #2 are to investigate the role of NK T cells in human diabetes. Project #3 will take a direct approach by cloning T cells and NK T cells from the pancreas and pancreatic lymph nodes of patients with diabetes. The approach of treating autoimmune diseases by preventing T cell activation is timely and has a high likelihood of success. There is a body of evidence including clinical trials supporting the use of CTLA4Ig in autoimmune disease, and also evidence for the synergistic role of rapamycin. The data obtained from the clinical trials and the critical information from the basic science projects will be valuable in getting us closer to our goal of tolerance induction for autoimmune disease. PROJECT 1: Treatment of Autoimmune disease by costimulatory signal blockade (Khoury, Samia) PROJECT 1 (provided by applicant): The ultimate goal of immunotherapy in autoimmune diseases is to find immunologically specific, relatively non-toxic forms of therapy. Our understanding of the immunopathogenesis of T cell mediated autoimmune diseases implicates T cell activation as an important step in their pathogenesis. The CD28-B7 pathway of T cell costimulation plays a role in the pathogenesis of many T cell mediated autoimmune diseases as demonstrated by disease prevention after blocking this pathway in animal models. In experimental autoimmune encephalomyelitis (EAE) the animal model of MS, CTLA4Ig prevent disease and inhibits relapses. In a model of spontaneous diabetes (the NOD mouse) CTLA4Ig prevents the onset of diabetes. CTLA4Ig has shown effectiveness in a phase I clinical trial of psoriasis and more recently in clinical trials of rheumatoid arthritis. It is currently in clinical trials for multiple sclerosis (MS). It is likely that to achieve tolerance in autoimmune disease, one must target more than one pathway of immune activation. Data obtained from animal models of transplantation suggest that a combination of costimulatory signal blockade and rapamycin can induce long term tolerance. Thus, our primary objective in this project is to study the safety and efficacy of CTLA4Ig treatment in patients with new onset type I diabetes, and the safety and efficacy of CTLA4Ig + rapamycin in patients with the earliest manifestations of multiple sclerosis. The outcome measures for the diabetes trial are safety, metabolic and immune effects of CTLA4Ig therapy. For the MS

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trial, we will compare the safety and efficacy of CTLA4Ig, rapamycin, and CTLA4Ig+rapamycin, to placebo in patients with clinically isolated syndrome of demyelination. The outcome measures are safety and the development of MS by McDonald criteria. Our group also has the interest and patient populations to participate in clinical trials of psoriasis. The Dermatology Clinical Investigations Unit (DCIU) of Massachusetts General Hospital is an established clinical trials unit with extensive experience. Current and past investigations include five trials of systemic medications in psoriasis similar to those we anticipate studying in trials associated with the ACE. In summary, this proposal encompasses three autoimmune diseases: MS, type I diabetes, and psoriasis. We are submitting clinical trial proposals for MS and diabetes with a particular focus on T cell activation pathways. We believe that the interactions among investigators from different clinical specialties will foster new ideas and crossfertilization leading to better treatment for autoimmune diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TREATMENT OF EAE USING GENETICALLY MODIFIED CTL Principal Investigator & Institution: Geiger, Terrence L. Medical Director; St. Jude Children's Research Hospital Memphis, TN 381052794 Timing: Fiscal Year 2001; Project Start 01-JUL-1997; Project End 30-JUN-2002 Summary: Autoreactive T lymphocytes (ATL) are critical regulatory and effector cells for multiple sclerosis and other autoimmune diseases. Eradication of these ATL may ameliorate or cure such diseases. Therapies capable of selectively targeting ATL are not available clinically. This proposal describes the development of a novel therapy that uses genetically modified cytolytic T lymphocytes (GM-CTL) to selectively eliminate ATL. The GM- CTL will be transfected with a chimeric receptor capable of both recognizing ATL and activating the GM-CTL. This receptor will consist of: a class II major histocompatibility complex (MHC) alpha and beta chains, b. covalently linked antigenic peptide, and c. the activation domain of the T cell receptor zeta chain. The ALT T-cell receptor will specifically interact with the NHC- peptide complex of the chimeric receptor. This interaction will activate the GM-cTL, which in turn will kill the ATL. By using GM-CTL to selectively eliminate ATL it should be possible to modulate or abrogate ongoing autoimmune disease. This will be tested using a well characterized murine model for multiple sclerosis and post-vaccination encephalomyelitis, experimental allergic encephalomyelitis (EAE). Chimeric construct design will be optimized using in vitro assays of GM-CTL activity. GM-CTL will then be adoptively transferred into mice prior to, concurrent with, or following the induction of EAE. Pathologic and clinical measures of outcome will be assessed. These experiments will thus provide the initial studies assessing the usefulness of GM- CTL in treating autoimmune neurologic disease. It will establish a precedent for the analogous use of GM-CTL as a therapy for human autoimmune disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TREATMENT OF MULTIPLE SCLEROSIS MODEL WITH RNA PADLOCKS Principal Investigator & Institution: Johnston, Brian H.; Somagenics, Inc. 2161 Delaware Ave Santa Cruz, CA 95060 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2004 Summary: (provided by the applicant): The goal of this proposal is to test the hypothesis that RNA lassos(TM) that block the translation of TNF-alpha can decrease the clinical

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signs and tissue damage in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. RNA lassos are antisense RNAs containing an enzymatic feature that causes them to become topologically linked to a target mRNA upon hybridization. In previous work, we identified a lead lasso directed against TNF-alpha that effectively inhibits TNF-alpha secretion in a macrophage cell line and in mice. Initial experiments will compare several strategies, including electroporation, cationic lipids, and viruses, to optimize the delivery of RNA antisense lassos into myelin basic protein (MBP)-specific T cell lines. Those targeted cells will then receive stimulation to determine the effect of RNA lassos on TNF-alpha production. If the RNA lassos effectively decrease TNF-alpha, the cells will be injected into naive recipients to determine whether TNF-alpha RNA lassos decrease the severity of EAE. In addition, we will test whether in vivo administration of RNA lassos blocks the onset or ameliorates the severity of EAE. If TNF turns out not to be the best target, we will test lassos against interferon gamma. An acute toxicity study will also be performed. Commercial potential: A demonstration of efficacy in preclinical studies would lead to a clinical trail of RNA lassos alone and/or in combination with a currently approved therapeutic (e.g. Betaseron, Avonex, Copaxone). This technology may also have potential commercial applications in other conditions in which TNF-alpha contributes to inflammation and pathology, including rheumatoid arthritis and type-1 diabetes. If we demonstrate effective delivery of RNA lassos to T cells, it may also be possible to deliver lassos that block HIV gene expression and interfere with viral replication. The ultimate product would be lasso drugs for treatment of autoimmunity, an estimated market of over $6 billion per year Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TUBEROUS SCLEROSIS--MUTATIONS AND MURINE MODELS Principal Investigator & Institution: Kwiatkowski, David J. Associate Professor; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 20-JAN-1994; Project End 31-JAN-2002 Summary: (Adapted from investigator's abstract): Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting 1 in 6,000 births, that is characterized by benign tumors (hamartomas and hamartias) in multiple organ systems. Its major clinical manifestations are due to brain involvement -- seizures, mental retardation and autism and related disorders, each of which occur in about half of TSC patients. The existence of two genes (TSC1 and TSC2) causing this disorder was established by familiar genetic linkage studies. TSC2 was identified 4 years ago, and has weak GTPase activating protein (GAP) activity for two members of the Ras family of GTPases, rap1 and rab5. In the previous application, the PI proposed to identify the TSC1 gene by positional cloning. This is now accomplished by a collaborative effort by several laboratories. There are three specific aims in the competitive renewal application: 1) A detailed mutational analysis will be performed for both the TSC1 and TSC2 loci; 2) Development of murine models of TSC; and 3)Analysis of the function of TSC1 and TSC2 proteins, hamartin and tuberin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: USE OF NOVEL COX-2 INHIBITORS IN NEUROLOGICAL DISORDERS Principal Investigator & Institution: Bell, Stanley C.; Onconova Therapeutics, Inc. 993 Lenox Dr, Ste 200 Lawrenceville, NJ 08648

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Timing: Fiscal Year 2003; Project Start 03-MAR-2003; Project End 29-FEB-2004 Summary: (provided by applicant): Up-regulation of COX-2 has also been reported to occur in human brains following a lethal cerebral ischemic insult and selective inhibition of COX-2 has been demonstrated to be neuroprotective in animal models. In addition, there has been a voluminous literature that suggests that cyclooxygenase-2 (COX-2) may contribute to neuronal injury in various neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's and Alzheimer's disease. Indeed, numerous studies on the long-term use of NSAID's have demonstrated the improvement or a decrease in the potential of Alzheimer's disease (AD). The decrease in undesirable GI side effects of selective COX-2 has stimulated long-term clinical evaluation studies of current marketed COX-2 inhibitor for AD. We have developed a novel chemotype (Onconova compounds ON 09** Series) with potent and selective COX-2 inhibitory activity. In collaboration with Dr. Sandra Hewett at the University Connecticut Health Center, these compounds are now being applied for various indications including prevention of cancer, inflammation and CNS injury. The specific aims are as follows: Short term; 6 months - Employing the mini library of COX-2 inhibitors created around the new chemotype identified by Onconova, we will evaluate whether inhibition of COX-2 by these drugs in Dr. Hewett's CNS model will be neuroprotective. Specifically, studies will be undertaken to determine the therapeutic potential of these novel COX-2 compounds against NMDA-induced neuronal injury (excitotoxicity) in mixed cortical cell cultures as excitotoxicity has been implicated in the pathogenesis of brain injury triggered by hypoxic-ischemia insults as well as AD. Based on these results, we will employ Structure Activity Relationship (SAR) to prepare additional novel COX-2 compounds for evaluation. We will establish a SAR pattern of activity with our novel series of compounds. Intermediate term - Effective demonstration of neuroprotection in the in vitro model will aid in the identification of interesting and active compounds for in vivo animal studies of neuronal injury associated with over-activation of glutamate receptors, including AD and stroke. Following the identification of a lead compound, production of large quantities of the compound for these studies will be undertaken. Long term - A candidate that successfully completes Phase 1 will be further developed. The later studies for Phase 2 and Phase 3 evaluations will be carried out internally or with a commercial partner, based on the needs of the company. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VASCULOPATHY, APOPTOSIS AND AUTOIMMUNITY Principal Investigator & Institution: Ahearn, Joseph M. Associate Professor; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001; Project Start 27-SEP-1999; Project End 31-AUG-2004 Summary: This proposal is focused upon the molecular mechanism by which vasculopathy leads to fibrotic and autoimmune manifestations of systemic sclerosis. Autoantibodies generated by patients with systemic sclerosis are uniquely targeted to nucleolar proteins such as DNA topoisomerase I (topo-I). It has been demonstrated that topo-I is a substrate for protease(s) specific to the apoptotic process, resulting in novel cleavage fragments that may reveal cryptic epitopes to which the host has not previously been tolerized. It has also been recently demonstrated that several of the autoantigens targeted in diffuse scleroderma are uniquely susceptible to cleavage by metal-catalyzed oxidation reactions similar to what may occur during ischemiareperfusion in the presence of appropriate metals. This process may also reveal immunocryptic epitopes and provides a molecular explanation for why certain proteins are uniquely targeted by the immune response in systemic sclerosis. However, it is well

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known that a cryptic epitope alone is not sufficient to generate autoreactivity, which also requires the participation of a molecular adjuvant, and uptake of the potential autoantigen by an antigen presenting cell (APC) with costimulatory capacity. The central hypothesis of this proposal is that chronic ischemia-reperfusion injury in patients with systemic sclerosis not only generates immunocryptic epitopes within nucleolar autoantigens of cutaneous origin, but it also generates complement ligands that provide the molecular adjuvant required to break immune tolerance. The specific aims of this proposal are to: 1) Determine the capacity of apoptotic blebs bearing complement ligands to modulate the cytokine expression and costimulatory capacity of antigen presenting cells, 2) characterize the immune responses to self antigen- containing apoptotic blebs, and 3) examine the role of complement ligand C3d during induction of autoreactive T and B cell responses to topo I in vitro. Although systemic sclerosis is the focus of this proposal, the data generated by these studies should provide insight into our understanding of vasculopathic and autoimmune processes in general. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIRAL AND CELLULAR DETEMINANTS INVOLVED IN CNS DISEASE Principal Investigator & Institution: Fujinami, Robert S. Professor; Neurology; University of Utah 200 S University St Salt Lake City, UT 84112 Timing: Fiscal Year 2001; Project Start 01-AUG-1995; Project End 31-JUL-2005 Summary: (Adapted from the Investigator's abstract): Theiler's murine encephalomyelitis virus (TMBV) infection of mice is a relevant animal model for the human demyelinating disease multiple sclerosis (MS). TMEV belongs to the Picornaviridae family and are in the Cardiovirus genus. These viruses are small positive-sense single-stranded RNA viruses. Infection of mice with the DA strain of TMEV causes an acute polioencephalomyelitis where mice survive and later develop a central nervous system (CNS) inflammatory demyelinating disease. Once clinical signs (weight loss, spastic paralysis and gait disturbances) develop in these mice, there is disease progression without relapses or remissions. This mirrors the progressive forms of MS. Many reports have described the need for CD8+ and CD4+ T cells as well as antibodies in the pathogenesis of TMEV induced demyelinating disease. CD8+ T cells have been reported to be responsible for viral clearance and protection from the chronic demyelinating disease in resistant mice. Similarly, CD4+ T cells have been described to be responsible for the inflammatory CNS demyelination in infected susceptible mice. Recently, CD8+ T cells have also been shown to influence demyelination in DA virus infected mice. We have evidence that another cell type may also participate in TMEV infection and demyelinating disease. This new cell type has cytotoxic activity on uninfected syngenic target cells but not allogenic target cells. In preliminary studies, the cell is CD3+, CD8+ and B22O+ and can cause inflammation in the CNS. These cells are induced by TMEV infection but not vaccinia virus infection of susceptible SJL/J. The goals of this application are to: 1) further characterize the phenotype of the autoreactive killer cells; 2) determine how these cells contribute to disease and define the mechanism of killing; 3) study the induction of the killer cells; and 4) define the determinant(s) in VP1 necessary for the induction of the autoreactive cells. These findings are novel and may help explain differences between various reports stating that CD4+ or CD8+ T cells are exclusively involved in demyelination and viral clearance, respectively. The studies not only are important to viral pathogenesis but also the pathogenesis of autoimmune disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VIRAL CHEMOKINE RECEPTORS: TRANSPLANT VASCULAR SCLEROSIS Principal Investigator & Institution: Orloff, Susan L. Surgery; Oregon Health & Science University Portland, OR 972393098 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-JAN-2004 Summary: The long term goal of this project is to identify mechanisms involved with human cytomegalovirus (HCMV) acceleration of transplant vascular sclerosis. The primary cause of graft loss of all vascularized organ transplants is due to a vascular lesion associated with chronic rejection. This form of vasculopathy referred to as TVS is characterized by concentric neointimal smooth muscle cell proliferation that results in vessel occlusion and ultimately graft failure. To date the only therapy available to treat severe TVS is retransplantation. Clinical studies in transplant recipients have demonstrated a direct link between HCMV and the acceleration of TVS. Based on these findings, we have developed a rat model of heart and small bowel transplantation in which CMV infection accelerates the time and severity of TVS. While the exact mechanism through which CMV mediates this process is unknown, recent work from our group suggests that CMV may contribute to TVS through induction of smooth muscle cell (SMC) migration towards sites of chemokine production through expression of a virally encoded chemokine receptor (US28). We have also observed that Rat and Murine CMV also induce SMC migration through their respective viral chemokine receptors R33 and M33, which are functional homologues of HCMV US28. We hypothesize that the mechanism of CMV-accelerated TVS involves the expression of virally encoded chemokine receptors leading to intimal SMC migration, which results in the characteristic vascular lesions of TVS. Therefore, we will utilize our in vitro and in vivo models to extend our observations and determine the role of virally encoded chemokine receptors in the development of TVS in three specific aims. First, using a rat cardiac transplant model of chronic rejection, we will determine the effects of virus on the kinetics of disease progression of TVS and the extent of viral expression in tissues as well as the cell types involved in the process. We will also determine the host factors such as chemokines and cytokines, and the contribution of R33 involved at various stages of the development of RCMV-induced TVS. Secondly, we will characterize the R33 domains involved in signaling which induce SMC migration and the ligands, which serve as agonists or antagonists to induced cellular movement. In the last specific, we will generate recombinant RCMV which contain mutations in domains involved in signaling to understand their contribution to TVS in the rat cardiac transplant model. Lastly, antagonists of R33 induced SMC migration in vitro will be tested for their ability to block TVS in the in vivo rat model. These studies will provide a valuable animal model to understand the role of CMV in the acceleration of TVS. In addition completion of these studies will form the basis for novel and rational design of therapeutic strategies to enhance long-term graft survival in HCMV infected transplant recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VISUAL DYSFUNCTION AND QUALITY OF LIFE IN MS Principal Investigator & Institution: Balcer, Laura J. Neurology; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 03-SEP-2001; Project End 31-AUG-2004 Summary: Visual impairment is a leading cause of symptoms in patients with multiple sclerosis (MS). Despite the importance of vision to disability and health-related quality of life (HRQOL) in MS, the measurement of visual function in MS trials has been limited

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to measures of Snellen visual acuity. The extent to which vision has been affected by new therapies for MS is not known, and has been difficult to assess using traditional measures of neurologic impairment. The visual profile of MS has not been examined, and the relation of visual function to overall neurologic impairment and to vision- and disease-specific HRQOL in patients with MS has not been determined in a large, heterogeneous cohort. This proposal will accomplish the following specific aims: 1. Define the visual profile of MS in a large cohort (400 patients), and determine which measures best identify visual dysfunction in patients with MS. The vision tests which best distinguish MS patients from an age-matched control group will be identified from among five candidate measures using analysis of variance (ANOVA), receiver operating characteristic curve (ROC) area analysis, and discriminant function analysis. Visual function measures will include visual acuity, contrast letter acuity, contrast sensitivity, color vision, and visual field. The relation of vision scores to overall neurologic impairment (Expanded Disability Status Scale, MS Functional Composite scores) will also be examined using linear regression and correlation techniques. 2. Determine the relation of visual function to vision- and disease-specific HRQOL in patients with MS. Linear regression and correlation techniques will be used to determine the relation of vision scores to vision- and disease-specific HRQOL scores, using the Multiple Sclerosis Quality of Life Inventory (MSQLI) and the 25Item National Eye Institute Visual Function Questionnaire (VFQ-25). The proposed research will contribute significantly to our understanding of visual dysfunction in MS, its relation to neurologic function, and its impact on vision- and disease-specific HRQOL. Results from this project will also advance outcomes assessment for MS research and clinical trials, allowing for more efficient monitoring and development of MS therapies. This proposal will provide a crucial foundation for future studies of vision in MS that will involve longitudinal assessment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VITAMIN D REGULATION OF TYPE-2 HELPER T CELL RESPONSES Principal Investigator & Institution: Cantorna, Margherita T. Nutritional Sciences; Pennsylvania State University-Univ Park 201 Old Main University Park, PA 16802 Timing: Fiscal Year 2001; Project Start 05-JAN-2001; Project End 31-DEC-2004 Summary: The objective of this proposal is to define molecular and cellular targets of vitamin D in the immune system. There is a large body of anecdotal data to suggest that there is a link between vitamin D status and the human autoimmune disease multiple sclerosis. Experimentally, vitamin D deficiency exacerbates experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Furthermore supplementation of mice with vitamin D can suppress and prevent symptoms of EAE. Two targets of vitamin D in the immune system have been identified the interleukin (IL)-4. secreting type-2 helper T (Th2) cells and transforming growth factor (TGF)-beta1 (two cytokines shown to be protective in EAE) secreting cells. The hypotheses to be tested are: 1. Vitamin D status regulates Th cell differentiation. 2. Vitamin D treatment of EAE results because of the induction of Th2 cells. 3. Vitamin D induction of Th2 cells and protection from EAE depends on TGF-beta1 synthesis. 4. Vitamin D negatively regulates Th1 effector cells. Th cell differentiation and function will be measured as a function of increasing vitamin D both in vitro and in vivo in Th cells from T cell receptor transgenic mice. T cells from vitamin D treated mice will be isolated and tested for their ability to transfer protection from EAE. TGF-beta1 will be neutralized in vitro and in vivo to determine if vitamin D functions via the transcriptional upregulation of TGFbeta1. Similarly, TGF-beta1 supplementation will be done and compared to vitamin D

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treatment for the mechanisms by which they suppress EAE. Th2 cell deficient mice will be used as a source of Th1 effector cells and vitamin D will be tested as a direct regulator of Th1 function. A better understanding of how vitamin D effectively blocks EAE is necessary for proper nutritional counseling and optimal treatment of multiple sclerosis patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: X-RAY STUDIES OF SOD IN AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Hart, P. John. Associate Professor; Biochemistry; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, TX 78229 Timing: Fiscal Year 2001; Project Start 05-MAY-2000; Project End 30-APR-2005 Summary: Eucaryotic copper-zinc superoxide dismutases (CuZnSODs) are 32 kDa homodimeric metalloproteins that catalyze the conversion of superoxide radical to molecular oxygen and hydrogen peroxide. The enzyme is particularly abundant in spinal tissue and red blood cells in mammals. Approximately 60 different single site mutations in human CuZnSOD have individually been linked to an inherited (familial) form of amyotrophic lateral sclerosis (FALS or Lou Gehrig's disease). The disease is characterized by progressive paralysis resulting from motor neuron degeneration and death. Trangenic mouse, neuronal cell culture, and in-vitro studies suggest strongly that a copper-mediated toxic gain of function instead of a loss of superoxide disproportionation activity is responsible for disease onset in individuals heterozygous for any one of the FALS CuZnSOD mutations. Many of these human FALS mutants have been prepared in the laboratory and have been found to have aberrant metal binding properties relative to wild type CuZnSOD. The new properties of the FALS mutant proteins will likely be linked to the gain of the toxin function involved in FALS causation. A recently discovered class of molecules termed "copper chaperones for SOD" (CCS) are responsible for sequestering reactive copper ion from the cellular environment and inserting it correctly into newly translated SOD apoprotein. Because the toxic gain of function of FALS mutant SODs appears to be copper-mediated, a search for inhibitors of the copper chaperone may represent a novel therapeutic avenue for FALS. The primary objectives of this proposal are to generate three-dimensional, atomic resolution structural information on the human and yeast FALS mutants and mutant protein analogs, their respective copper chaperones, and their complexes via the wellestablished tools of X-ray diffraction and analytical ultracentrifugation. Specifically, we shall: (1) compare and contrast the FALS structures with normal human CuZnSOD and yeast FALS mutant analog structures. (2) use X- radiation from synchroton sources tuned to copper and zinc absorption edges to determine the location and amount of these ions in the metal binding sites of remetallated and as-isolated FALS CuZnSODs, (3) illuminate the postulated interaction of peroxynitrite with normal and FALS mutant CuZnSOD proteins by determining their structures when exposed to peroxynitrite, (4) determine and analyze the structures of several species of CCS molecules alone and in complex with wild type and FALS mutant CuZnSODs, and elucidate the solution properties of these molecules and their complexes under different conditions using contemporary analytical ultracentrifugation methods. These studies will not only promote understanding of the molecular causes of FALS, but also will provide fundamental information on copper ion homeostasis and trafficking at the level of protein- protein interactions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “sclerosis” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for sclerosis in the PubMed Central database: •

[beta]-Arrestin and Arrestin are Recognized by Autoantibodies in Sera From Multiple Sclerosis Patients. by Ohguro H, Chiba S, Igarashi Y, Matsumoto H, Akino T, Palczewski K. 1993 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46275

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[gamma] Interferon Activates a Previously Undescribed Ca2+ Influx in T Lymphocytes From Patients With Multiple Sclerosis. by Martino G, Clementi E, Brambilla E, Moiola L, Comi G, Meldolesi J, Grimaldi LM. 1994 May 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43881

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[gamma][delta] T-Cell Receptor Repertoire in Acute Multiple Sclerosis Lesions. by Wucherpfennig KW, Newcombe J, Li H, Keddy C, Cuzner ML. 1992 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49128

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1,25-Dihydroxyvitamin D3 Reversibly Blocks the Progression of Relapsing Encephalomyelitis, a Model of Multiple Sclerosis. by Cantorna MT, Hayes CE, DeLuca HF. 1996 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38839

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A Gain-Of-Function of an Amyotrophic Lateral Sclerosis-Associated Cu,ZnSuperoxide Dismutase Mutant: An Enhancement of Free Radical Formation Due to a decrease in Km for Hydrogen Peroxide. by Yim MB, Kang J, Yim H, Kwak H, Chock PB, Stadtman ER. 1996 Jun 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39125

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A New Cell Enzyme-Linked Immunosorbent Assay Demonstrates Gamma Interferon Suppression by Beta Interferon in Multiple Sclerosis. by Bakhiet M, Ozenci V, Withagen C, Mustafa M, Fredrikson S, Link H. 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=103733

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Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

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A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain. by Shields DC, Schaecher KE, Saido TC, Banik NL. 1999 Sep 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18060

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Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant. by Williamson TL, Bruijn LI, Zhu Q, Anderson KL, Anderson SD, Julien JP, Cleveland DW. 1998 Aug 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21390

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Activation of the Inducible Form of Nitric Oxide Synthase in the Brains of Patients with Multiple Sclerosis. by Bagasra O, Michaels FH, Zheng YM, Bobroski LE, Spitsin SV, Fu ZF, Tawadros R, Koprowski H. 1995 Dec 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40292

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Advanced Glycation End Products Induce Glomerular Sclerosis and Albuminuria in Normal Rats. by Vlassara H, Striker LJ, Teichberg S, Fuh H, Li YM, Steffes M. 1994 Nov 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45300

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Alterations in levels of CD28-/CD8+ suppressor cell precursor and CD45RO+/CD4+ memory T lymphocytes in the peripheral blood of multiple sclerosis patients. by Crucian B, Dunne P, Friedman H, Ragsdale R, Pross S, Widen R. 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170139

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Alterations in peripheral blood mononuclear cell cytokine production in response to phytohemagglutinin in multiple sclerosis patients. by Crucian B, Dunne P, Friedman H, Ragsdale R, Pross S, Widen R. 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170236

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Altered decorin expression of systemic sclerosis by UVA1 (340 --400 nm) phototherapy: Immunohistochemical analysis of 3 cases. by Sawada H, Isogai Z, Morita A. 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153525

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Amyotrophic lateral sclerosis: A proposed mechanism. by Okado-Matsumoto A, Fridovich I. 2002 Jun 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124414

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Amyotrophic Lateral Sclerosis: Human Challenge for Neuroscience. by Rowland LP. 1995 Feb 28; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=file&artid=42496&blobname=[PNASPDFPath]/1995/92-05/pdf/pq001251.pdf

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An examination of the Apo-1/Fas promoter Mva I polymorphism in Japanese patients with multiple sclerosis. by Niino M, Kikuchi S, Fukazawa T, Miyagishi R, Yabe I, Tashiro K. 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122076

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Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers. by Distler O, del Rosso A, Giacomelli R, Cipriani

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P, Conforti ML, Guiducci S, Gay RE, Michel BA, Bruhlmann P, Muller-Ladner U, Gay S, Matucci-Cerinic M. 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153841 •

Antibody Responses to Acinetobacter spp. and Pseudomonas aeruginosa in Multiple Sclerosis: Prospects for Diagnosis Using the Myelin-Acinetobacter-Neurofilament Antibody Index. by Hughes LE, Bonell S, Natt RS, Wilson C, Tiwana H, Ebringer A, Cunningham P, Chamoun V, Thompson EJ, Croker J, Vowles J. 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96247

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Anti-DNA antibodies are a major component of the intrathecal B cell response in multiple sclerosis. by Williamson RA, Burgoon MP, Owens GP, Ghausi O, Leclerc E, Firme L, Carlson S, Corboy J, Parren PW, Sanna PP, Gilden DH, Burton DR. 2001 Feb 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29336

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Anti-Endothelial Cell Antibodies in Systemic Sclerosis. by Renaudineau Y, Revelen R, Levy Y, Salojin K, Gilburg B, Shoenfeld Y, Youinou P. 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95679

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Caspase-1 and -3 are sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. by Pasinelli P, Houseweart MK, Brown RH Jr, Cleveland DW. 2000 Dec 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17673

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Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosisassociated mutations in copper-zinc superoxide dismutase. by Pasinelli P, Borchelt DR, Houseweart MK, Cleveland DW, Brown RH Jr. 1998 Dec 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28118

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CCR5 + and CXCR3 + T cells are increased in multiple sclerosis and their ligands MIP-1[alpha] and IP-10 are expressed in demyelinating brain lesions. by Balashov KE, Rottman JB, Weiner HL, Hancock WW. 1999 Jun 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22009

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CD4 + and CD8 + T Cells Make Discrete Contributions to Demyelination and Neurologic Disease in a Viral Model of Multiple Sclerosis. by Murray PD, Pavelko KD, Leibowitz J, Lin X, Rodriguez M. 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=109956

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CD40-CD40 Ligand Interactions in Experimental Allergic Encephalomyelitis and Multiple Sclerosis. by Gerritse K, Laman JD, Noelle RJ, Aruffo A, Ledbetter JA, Boersma WJ, Claassen E. 1996 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39826

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Chaperone-facilitated copper binding is a property common to several classes of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants. by Corson LB, Strain JJ, Culotta VC, Cleveland DW. 1998 May 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27707

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Characterization of Three Yeast Copper-Zinc Superoxide Dismutase Mutants Analogous to those Coded for in Familial Amyotrophic Lateral Sclerosis. by Nishida CR, Gralla EB, Valentine JS. 1994 Oct 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44926

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Chemokine Expression in the Central Nervous System of Mice with a Viral Disease Resembling Multiple Sclerosis: Roles of CD4 + and CD8 + T Cells and Viral Persistence. by Ransohoff RM, Wei T, Pavelko KD, Lee JC, Murray PD, Rodriguez M. 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=153814

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Chromosomal Localization of Glutamate Receptor Genes: Relationship to Familial Amyotrophic Lateral Sclerosis and Other Neurological Disorders of Mice and Humans. by Gregor P, Reeves RH, Jabs EW, Yang X, Dackowski W, Rochelle JM, Brown RH Jr, Haines JL, O'Hara BF, Uhl GR, Seldin MF. 1993 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46235

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Clonal Expansions of Activated [gamma]/[delta] T Cells in Recent-Onset Multiple Sclerosis. by Shimonkevitz R, Colburn C, Burnham JA, Murray RS, Kotzin BL. 1993 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45782

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Colocalization of Lymphocytes Bearing [gamma][delta] T-Cell Receptor and Heat Shock Protein hsp65+ Oligodendrocytes in Multiple Sclerosis. by Selmaj K, Brosnan CF, Raine CS. 1991 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52103

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Comparative Study of the Presence of Chlamydia pneumoniae in Cerebrospinal Fluid of Patients with Clinically Definite and Monosymptomatic Multiple Sclerosis. by Sriram S, Yao SY, Stratton C, Calabresi P, Mitchell W, Ikejima H, Yamamoto Y. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130123

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Cost of managing an episode of relapse in multiple sclerosis in the United States. by O'Brien JA, Ward AJ, Patrick AR, Caro J. 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=201004

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Cytotoxicity of Immunoglobulins from Amyotrophic Lateral Sclerosis Patients on a Hybrid Motoneuron Cell Line. by Smith RG, Alexianu ME, Crawford G, Nyormoi O, Stefani E, Appel SH. 1994 Apr 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43583

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Detection of altered T helper 1 and T helper 2 cytokine production by peripheral blood mononuclear cells in patients with multiple sclerosis utilizing intracellular cytokine detection by flow cytometry and surface marker analysis. by Crucian B, Dunne P, Friedman H, Ragsdale R, Pross S, Widen R. 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170359

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Detection of Antibodies Directed against Human Herpesvirus 6 U94/REP in Sera of Patients Affected by Multiple Sclerosis. by Caselli E, Boni M, Bracci A, Rotola A, Cermelli C, Castellazzi M, Di Luca D, Cassai E. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=139661

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Detection of JC Virus in Cerebrospinal Fluid (CSF) Samples from Patients with Progressive Multifocal Leukoencephalopathy but Not in CSF Samples from Patients with Herpes Simplex Encephalitis, Enteroviral Meningitis, or Multiple Sclerosis. by Bogdanovic G, Priftakis P, Hammarin AL, Soderstrom M, Samuelson A, LewensohnFuchs I, Dalianis T. 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104707

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Detection of Viral DNA and Immune Responses to the Human Herpesvirus 6 101Kilodalton Virion Protein in Patients with Multiple Sclerosis and in Controls. by Tejada-Simon MV, Zang YC, Hong J, Rivera VM, Killian JM, Zhang JZ. 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=136216

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Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant. by Bruijn LI, Beal MF, Becher MW, Schulz JB, Wong PC, Price DL, Cleveland DW. 1997 Jul 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23869

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Embryonic neuronal markers in tuberous sclerosis: Single-cell molecular pathology. by Crino PB, Trojanowski JQ, Dichter MA, Eberwine J. 1996 Nov 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19509

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Expansion of a Recurrent V[beta]5.3+ T-Cell Population in Newly Diagnosed and Untreated HLA-DR2 Multiple Sclerosis Patients. by Musette P, Bequet D, Delarbre C, Gachelin G, Kourilsky P, Dormont D. 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38014

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Expression of calbindin-D28K in Motoneuron Hybrid Cells after Retroviral Infection with calbindin-D28K cDNA Prevents Amyotrophic Lateral Sclerosis igG-Mediated Cytotoxicity. by Ho B, Alexianu ME, Colom LV, Mohamed AH, Serrano F, Appel SH. 1996 Jun 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39107

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Expression of Urokinase Plasminogen Activator Receptor on Monocytes from Patients with Relapsing-Remitting Multiple Sclerosis: Effect of Glatiramer Acetate (Copolymer 1). by Balabanov R, Lisak D, Beaumont T, Lisak RP, Dore-Duffy P. 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96249

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Fine Specificity of the Antibody Response to Myelin Basic Protein in the Central Nervous System in Multiple Sclerosis: The Minimal B-Cell Epitope and a Model of Its Features. by Warren KG, Catz I, Steinman L. 1995 Nov 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40571

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Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). by Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, Erickson J, Kulik J, DeVito L, Psaltis G, DeGennaro LJ, Cleveland DW, Rothstein JD. 2002 Feb 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122237

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Formation of high molecular weight complexes of mutant Cu,Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis. by Johnston JA, Dalton MJ, Gurney ME, Kopito RR. 2000 Nov 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18805

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Fragmentation of the Golgi Apparatus of Motor Neurons in Amyotrophic Lateral Sclerosis Revealed by Organelle-Specific Antibodies. by Mourelatos Z, Adler H, Hirano A, Donnenfeld H, Gonatas JO, Gonatas NK. 1990 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54116

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Geographical and seasonal correlation of multiple sclerosis to sporadic schizophrenia. by Fritzsche M. 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149400

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Glatiramer acetate (Copaxone) therapy induces CD8 + T cell responses in patients with multiple sclerosis. by Karandikar NJ, Crawford MP, Yan X, Ratts RB, Brenchley JM, Ambrozak DR, Lovett-Racke AE, Frohman EM, Stastny P, Douek DC, Koup RA, Racke MK. 2002 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150895

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Heterogeneity of T-Cell Receptor [alpha]-Chain Complementarity-Determining Region 3 in Myelin Basic Protein-Specific T Cells Increases with Severity of Multiple Sclerosis. by Utz U, Brooks JA, McFarland HF, Martin R, Biddison WE. 1994 Jun 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44037

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Histometric data obtained by in vivo confocal laser scanning microscopy in patients with systemic sclerosis. by Sauermann K, Gambichler T, Jaspers S, Radenhausen M, Rapp S, Reich S, Altmeyer P, Clemann S, Teichmann S, Ennen J, Hoffmann K. 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122067

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Human CCS gene: genomic organization and exclusion as a candidate for amyotrophic lateral sclerosis (ALS). by Silahtaroglu AN, Brondum-Nielsen K, Gredal O, Werdelin L, Panas M, Petersen MB, Tommerup N, Tumer Z. 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107843

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Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. by Warrington AE, Asakura K, Bieber AJ, Ciric B, Van Keulen V, Kaveri SV, Kyle RA, Pease LR, Rodriguez M. 2000 Jun 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18751

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Identification of Peptides Specific for Cerebrospinal Fluid Antibodies in Multiple Sclerosis by Using Phage Libraries. by Cortese I, Tafi R, Grimaldi LM, Martino G, Nicosia A, Cortese R. 1996 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38284

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IgG from Amyotrophic Lateral Sclerosis Patients Increases Current Through P-Type Calcium Channels in Mammalian Cerebellar Purkinje Cells and in Isolated Channel

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Protein in Lipid Bilayer. by Llinas R, Sugimori M, Cherksey BD, Smith RG, Delbono O, Stefani E, Appel S. 1993 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48060 •

Immunoglobulins from Animal Models of Motor Neuron Disease and from Human Amyotrophic Lateral Sclerosis Patients Passively Transfer Physiological Abnormalities to the Neuromuscular Junction. by Apel SH, Engelhardt JI, Garcia J, Stefani E. 1991 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50869

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Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R( +)WIN55,212. by Croxford JL, Miller SD. 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152941

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Inactivation of the cyclin-dependent kinase inhibitor p27 upon loss of the tuberous sclerosis complex gene-2. by Soucek T, Yeung RS, Hengstschlager M. 1998 Dec 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28099

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Increased interleukin 12 production in progressive multiple sclerosis: Induction by activated CD4 + T cells via CD40 ligand. by Balashov KE, Smith DR, Khoury SJ, Hafler DA, Weiner HL. 1997 Jan 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19559

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Increased Levels of Alternatively Spliced Interleukin 4 (IL-4[delta]2) Transcripts in Peripheral Blood Mononuclear Cells from Patients with Systemic Sclerosis. by Sakkas LI, Tourtellotte C, Berney S, Myers AR, Platsoucas CD. 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95750

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Inducible Nitric Oxide Synthase and Nitrotyrosine Are Found in Monocytes/Macrophages and/or Astrocytes in Acute, but Not in Chronic, Multiple Sclerosis. by Oleszak EL, Zaczynska E, Bhattacharjee M, Butunoi C, Legido A, Katsetos CD. 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95596

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Interleukin 4 in Systemic Sclerosis: Not Just an Increase. by Atamas SP, White B. 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95749

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Is Chlamydia pneumoniae Present in Brain Lesions of Patients with Multiple Sclerosis? by Hammerschlag MR, Ke Z, Lu F, Roblin P, Boman J, Kalman B. 2000 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87583

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Laryngeal dysfunction in Amyotrophic Lateral Sclerosis: a review and case report. by Watts CR, Vanryckeghem M. 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60006

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Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development. by Rennebeck G, Kleymenova EV, Anderson R, Yeung RS, Artzt K, Walker CL. 1998 Dec 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28095

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Mobility impairments and use of preventive services in women with multiple sclerosis: observational study. by Cheng E, Myers L, Wolf S, Shatin D, Cui XP, Ellison G, Belin T, Vickrey B. 2001 Oct 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58661

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Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis. by Chilcott J, McCabe C, Tappenden P, O'Hagan A, Cooper NJ, Abrams K, Claxton K. 2003 Mar 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150460

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Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. by Perron H, Garson JA, Bedin F, Beseme F, Paranhos-Baccala G, Komurian-Pradel F, Mallet F, Tuke PW, Voisset C, Blond JL, Lalande B, Seigneurin JM, Mandrand B, Sclerosis TC. 1997 Jul 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23865

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Multiple sclerosis: Comparison of copolymer-1- reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells. by Neuhaus O, Farina C, Yassouridis A, Wiendl H, Then Bergh F, Dose T, Wekerle H, Hohlfeld R. 2000 Jun 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16566

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Mutations Associated with Amyotrophic Lateral Sclerosis Convert Superoxide Dismutase from an Antiapoptotic Gene to a Proapoptotic Gene: Studies in Yeast and Neural Cells. by Rabizadeh S, Gralla EB, Borchelt DR, Gwinn R, Valentine JS, Sisodia S, Wong P, Lee M, Hahn H, Bredesen DE. 1995 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42351

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Mutations in Copper-Zinc Superoxide Dismutase that Cause Amyotrophic Lateral Sclerosis Alter the Zinc Binding Site and the Redox Behavior of the Protein. by Lyons TJ, Liu H, Goto JJ, Nersissian A, Roe JA, Graden JA, Cafe C, Ellerby LM, Bredesen DE, Gralla EB, Valentine JS. 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=37974

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Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. by Carsillo T, Astrinidis A, Henske EP. 2000 May 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18562

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Myelin Autoreactivity in Multiple Sclerosis: Recognition of Myelin Basic Protein in the Context of HLA-DR2 Products by T Lymphocytes of Multiple- Sclerosis Patients and Healthy Donors. by Pette M, Fujita K, Wilkinson D, Altmann DM, Trowsdale J, Giegerich G, Hinkkanen A, Epplen JT, Kappos L, Wekerle H. 1990 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54873

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Oral tolerance with Copolymer 1 for the treatment of multiple sclerosis. by Weiner HL. 1999 Mar 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34268

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Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. by van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Simmons R, Taylor BV, Butzkueven H, Kilpatrick T. 2003 Aug 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=169645

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Plaque-Associated Expression of Human Herpesvirus 6 in Multiple Sclerosis. by Challoner PB, Smith KT, Parker JD, MacLeod DL, Coulter SN, Rose TM, Schultz ER, Bennett JL, Garber RL, Chang M, Schad PA, Stewart PM, Nowinski RC, Brown JP, Burmer GC. 1995 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41355

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Population based cost utility study of interferon beta-1b in secondary progressive multiple sclerosis. by Forbes RB, Lees A, Waugh N, Swingler RJ. 1999 Dec 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28295

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Predisposition to Renal Carcinoma in the Eker Rat is Determined by Germ-Line Mutation of the Tuberous Sclerosis 2 (TSC2) Gene. by Yeung RS, Xiao G, Jin F, Lee W, Testa JR, Knudson AG. 1994 Nov 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45241

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Preferential T-Cell Receptor [beta]-Chain Variable Gene Use in Myelin Basic ProteinReactive T-Cell Clones from Patients with Multiple Sclerosis. by Kotzin BL, Karuturi S, Chou YK, Lafferty J, Forrester JM, Better M, Nedwin GE, Offner H, Vandenbark AA. 1991 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52672

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Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: Implications for the treatment of multiple sclerosis. by Hooper DC, Bagasra O, Marini JC, Zborek A, Ohnishi ST, Kean R, Champion JM, Sarker AB, Bobroski L, Farber JL, Akaike T, Maeda H, Koprowski H. 1997 Mar 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20122

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Programmed cell death in amyotrophic lateral sclerosis. by Guegan C, Przedborski S. 2003 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151885

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PTPRC (CD45) is not associated with multiple sclerosis in a large cohort of German patients. by Miterski B, Sindern E, Haupts M, Schimrigk S, Epplen JT. 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116441

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Reexamination of the mechanism of hydroxyl radical adducts formed from the reaction between familial amyotrophic lateral sclerosis-associated Cu,Zn superoxide dismutase mutants and H2O2. by Singh RJ, Karoui H, Gunther MR, Beckman JS, Mason RP, Kalyanaraman B. 1998 Jun 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22595

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Restricted T-Cell Receptor V[beta] Gene Usage by Myelin Basic Protein-Specific TCell Clones in Multiple Sclerosis: Predominant Genes Vary in Individuals. by BenNun A, Liblau RS, Cohen L, Lehmann D, Tournier-Lasserve E, Rosenzweig A, Jingwu Z, Raus JC, Bach M. 1991 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51253

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Selective blockade of T lymphocyte K + channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. by Beeton C, Wulff H, Barbaria J, Clot-Faybesse O, Pennington M, Bernard D, Cahalan MD, Chandy KG, Beraud E. 2001 Nov 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61146

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Self reported stressful life events and exacerbations in multiple sclerosis: prospective study. by Buljevac D, Hop WC, Reedeker W, Janssens AC, van der Meche FG, van Doorn PA, Hintzen RQ. 2003 Sep 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=196389

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Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. by Black JA, Dib-Hajj S, Baker D, Newcombe J, Cuzner ML, Waxman SG. 2000 Oct 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17246

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Similar Humoral and Cellular Immunological Reactivities to Human Herpesvirus 6 in Patients with Multiple Sclerosis and Controls. by Enbom M, Wang FZ, Fredrikson S, Martin C, Dahl H, Linde A. 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95725

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Superoxide Dismutase 1 with Mutations Linked to Familial Amyotrophic Lateral Sclerosis Possesses Significant Activity. by Borchelt DR, Lee MK, Slunt HS, Guarnieri M, Xu Z, Wong PC, Brown RH Jr, Price DL, Sisodia SS, Cleveland DW. 1994 Aug 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44592

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Suppression of Tumorigenicity by the Wild-Type Tuberous Sclerosis 2 (Tsc2) Gene and its C-Terminal Region. by Jin F, Wienecke R, Xiao G, Maize JC, DeClue JE, Yeung RS. 1996 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38611

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Synaptic sprouting increases the uptake capacities of motoneurons in amyotrophic lateral sclerosis mice. by Millecamps S, Nicolle D, Ceballos-Picot I, Mallet J, Barkats M. 2001 Jun 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34711

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The Gene Encoding the Glutamate Receptor Subunit GluR5 is Located on Human Chromosome 21q21.1-22.1 in the Vicinity of the Gene for Familial Amyotrophic Lateral Sclerosis. by Eubanks JH, Puranam RS, Kleckner NW, Bettler B, Heinemann SF, McNamara JO. 1993 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45623

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The inhibitory effects of camptothecin, a topoisomerase I inhibitor, on collagen synthesis in fibroblasts from patients with systemic sclerosis. by CzuwaraLadykowska J, Makiela B, Smith EA, Trojanowska M, Rudnicka L. 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64844

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The neuregulin, glial growth factor 2, diminishes autoimmune demyelination and enhances remyelination in a chronic relapsing model for multiple sclerosis. by Cannella B, Hoban CJ, Gao YL, Garcia-Arenas R, Lawson D, Marchionni M, Gwynne D, Raine CS. 1998 Aug 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21468

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The neuroprotective agent SR 57746A abrogates experimental autoimmune encephalomyelitis and impairs associated blood --brain barrier disruption: Implications for multiple sclerosis treatment. by Bourrie B, Bribes E, Esclangon M, Garcia L, Marchand J, Thomas C, Maffrand JP, Casellas P. 1999 Oct 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23131

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The role of immunophilins in mutant superoxide dismutase-1linked familial amyotrophic lateral sclerosis. by Lee JP, Palfrey HC, Bindokas VP, Ghadge GD, Ma L, Miller RJ, Roos RP. 1999 Mar 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15928

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The Treatment of Chronic Progressive Multiple Sclerosis with Cladribine. by Beutler E, Sipe JC, Romine JS, Koziol JA, McMillan R, Zyroff J. 1996 Feb 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40008

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Transfer of Multiple Sclerosis into Severe Combined Immunodeficiency Mice by Mononuclear Cells from Cerebrospinal Fluid of the Patients. by Saeki Y, Mima T, Sakoda S, Fujimura H, Arita N, Nomura T, Kishimoto T. 1992 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49457

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Transgenic Mice Carrying a Human Mutant Superoxide Dismutase Transgene Develop Neuronal Cytoskeletal Pathology Resembling Human Amyotrophic Lateral Sclerosis Lesions. by Tu P, Raju P, Robinson KA, Gurney ME, Trojanowski JQ, Lee VM. 1996 Apr 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39778

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Transgenic Mice Expressing an Altered Murine Superoxide Dismutase Gene Provide an Animal Model of Amyotrophic Lateral Sclerosis. by Ripps ME, Huntley GW, Hof PR, Morrison JH, Gordon JW. 1995 Jan 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42685

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Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. by Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. 2002 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129715

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Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. by Hooper DC, Spitsin S, Kean RB, Champion JM, Dickson GM, Chaudhry I, Koprowski H. 1998 Jan 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18479

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Von Willebrand factor propeptide as a marker of disease activity in systemic sclerosis (scleroderma). by Scheja A, Akesson A, Geborek P, Wildt M, Wollheim CB, Wollheim FA, Vischer UM. 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30710

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Worsening of symptoms of multiple sclerosis associated with carbamazepine. by Ramsaransing G, Zwanikken C, De Keyser J. 2000 Apr 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27354

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 6

PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction

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The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with sclerosis, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “sclerosis” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for sclerosis (hyperlinks lead to article summaries): •

A case of multiple sclerosis associated with rheumatoid arthritis and positive anticardiolipin antibodies. Author(s): Mpofu S, Moots RJ. Source: Annals of the Rheumatic Diseases. 2003 April; 62(4): 376. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12634248&dopt=Abstract

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A clustering of conjugal amyotrophic lateral sclerosis in southeastern France. Author(s): Corcia P, Jafari-Schluep HF, Lardillier D, Mazyad H, Giraud P, Clavelou P, Pouget J, Camu W. Source: Archives of Neurology. 2003 April; 60(4): 553-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12707069&dopt=Abstract

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A comparison of the biologic activity of two recombinant IFN-beta preparations used in the treatment of relapsing-remitting multiple sclerosis. Author(s): Antonetti F, Finocchiaro O, Mascia M, Terlizzese MG, Jaber A. Source: Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research. 2002 December; 22(12): 11814. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12581490&dopt=Abstract

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A comparison of the mechanisms of action of interferon beta and glatiramer acetate in the treatment of multiple sclerosis. Author(s): Zhang J, Hutton G, Zang Y. Source: Clinical Therapeutics. 2002 December; 24(12): 1998-2021. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12581542&dopt=Abstract

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A double-blind randomized clinical trial in amyotrophic lateral sclerosis using lamotrigine: effects on CSF glutamate, aspartate, branched-chain amino acid levels and clinical parameters. Author(s): Ryberg H, Askmark H, Persson LI. Source: Acta Neurologica Scandinavica. 2003 July; 108(1): 1-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807386&dopt=Abstract

with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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A function of myelin is to protect axons from subsequent injury: implications for deficits in multiple sclerosis. Author(s): Rodriguez M. Source: Brain; a Journal of Neurology. 2003 April; 126(Pt 4): 751-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615635&dopt=Abstract

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A mitochondrial component of neurodegeneration in multiple sclerosis. Author(s): Kalman B, Leist TP. Source: Neuromolecular Medicine. 2003; 3(3): 147-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12835510&dopt=Abstract

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A new approach for evaluating antigen-specific T cell responses to myelin antigens during the course of multiple sclerosis. Author(s): Arbour N, Holz A, Sipe JC, Naniche D, Romine JS, Zyroff J, Oldstone MB. Source: Journal of Neuroimmunology. 2003 April; 137(1-2): 197-209. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667664&dopt=Abstract

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A new familial amyotrophic lateral sclerosis locus on chromosome 16q12.1-16q12.2. Author(s): Abalkhail H, Mitchell J, Habgood J, Orrell R, de Belleroche J. Source: American Journal of Human Genetics. 2003 August; 73(2): 383-9. Epub 2003 June 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12830400&dopt=Abstract

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A new paraclinical CSF marker for hypoxia-like tissue damage in multiple sclerosis lesions. Author(s): Lassmann H, Reindl M, Rauschka H, Berger J, Aboul-Enein F, Berger T, Zurbriggen A, Lutterotti A, Bruck W, Weber JR, Ullrich R, Schmidbauer M, Jellinger K, Vandevelde M. Source: Brain; a Journal of Neurology. 2003 June; 126(Pt 6): 1347-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12764056&dopt=Abstract

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A new view of the cortex, new insights into multiple sclerosis. Author(s): Wegner C, Matthews PM. Source: Brain; a Journal of Neurology. 2003 August; 126(Pt 8): 1719-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860746&dopt=Abstract

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A null mutation in the CNTF gene is not associated with early onset of multiple sclerosis. Author(s): Hoffmann V, Hardt C. Source: Archives of Neurology. 2002 December; 59(12): 1974; Author Reply 1974-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12470191&dopt=Abstract

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A pilot study of the relationship between multiple sclerosis and the physical environment in northwest Ireland. Author(s): Gilmore M, Grennan E. Source: Environmental Geochemistry and Health. 2003 March; 25(1): 157-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901091&dopt=Abstract

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A population-based study of IL4 polymorphisms in multiple sclerosis. Author(s): Kantarci OH, Schaefer-Klein JL, Hebrink DD, Achenbach SJ, Atkinson EJ, McMurray CT, Weinshenker BG. Source: Journal of Neuroimmunology. 2003 April; 137(1-2): 134-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667657&dopt=Abstract

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A randomised controlled trial comparing rehabilitation against standard therapy in multiple sclerosis patients receiving intravenous steroid treatment. Author(s): Craig J, Young CA, Ennis M, Baker G, Boggild M. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 September; 74(9): 1225-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12933923&dopt=Abstract

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A randomized clinical trial of a wellness intervention for women with multiple sclerosis. Author(s): Stuifbergen AK, Becker H, Blozis S, Timmerman G, Kullberg V. Source: Archives of Physical Medicine and Rehabilitation. 2003 April; 84(4): 467-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12690582&dopt=Abstract

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A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Author(s): Groeneveld GJ, Veldink JH, van der Tweel I, Kalmijn S, Beijer C, de Visser M, Wokke JH, Franssen H, van den Berg LH. Source: Annals of Neurology. 2003 April; 53(4): 437-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12666111&dopt=Abstract

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A review of the psychosocial aspect of multiple sclerosis. Author(s): Williamson K. Source: British Journal of Community Nursing. 2000 March; 5(3): 132-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12589242&dopt=Abstract

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A role for hypertrophic astrocytes and astrocyte precursors in a case of rapidly progressive multiple sclerosis. Author(s): Morcos Y, Lee SM, Levin MC. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 33241. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926837&dopt=Abstract

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A screening for superoxide dismutase-1 D90A mutation in Italian patients with sporadic amyotrophic lateral sclerosis. Author(s): Mancuso M, Filosto M, Naini A, Rocchi A, Del Corona A, Sartucci F, Siciliano G, Murri L. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. 2002 December; 3(4): 215-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710511&dopt=Abstract

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A study comparing patients with amyotrophic lateral sclerosis and their caregivers on measures of quality of life, depression, and their attitudes toward treatment options. Author(s): Trail M, Nelson ND, Van JN, Appel SH, Lai EC. Source: Journal of the Neurological Sciences. 2003 May 15; 209(1-2): 79-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12686407&dopt=Abstract

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A woman with multiple sclerosis and pink saliva. Author(s): van de Beek MT, Taal W, Veldkamp RF, Vecht CJ. Source: Lancet. Neurology. 2003 April; 2(4): 254-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849214&dopt=Abstract

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A4T mutation in the SOD1 gene causing familial amyotrophic lateral sclerosis. Author(s): Aksoy H, Dean G, Elian M, Deng HX, Deng G, Juneja T, Storey E, McKinlay Gardner RJ, Jacob RL, Laing NG, Siddique T. Source: Neuroepidemiology. 2003 July-August; 22(4): 235-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12792143&dopt=Abstract

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Abnormal response to glutamate of T lymphocytes from multiple sclerosis patients. Author(s): Lombardi G, Miglio G, Canonico PL, Naldi P, Comi C, Monaco F. Source: Neuroscience Letters. 2003 April 3; 340(1): 5-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12648745&dopt=Abstract

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Accuracy of death certificates for motor neuron disease and multiple sclerosis in the province of Palermo in southern Italy. Author(s): Ragonese P, Salemi G, Aridon P, Conte S, Cuccia G, Lupo I, Savettieri G. Source: Neuroepidemiology. 2002 May-June; 21(3): 148-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12006778&dopt=Abstract

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Acute myelogenous leukemia following mitoxantrone treatment for multiple sclerosis. Author(s): Mogenet I, Simiand-Erdociain E, Canonge JM, Pris J. Source: The Annals of Pharmacotherapy. 2003 May; 37(5): 747-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708958&dopt=Abstract

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Adhesion molecules and matrix metalloproteinases in Multiple Sclerosis: effects induced by Interferon-beta. Author(s): Avolio C, Giuliani F, Liuzzi GM, Ruggieri M, Paolicelli D, Riccio P, Livrea P, Trojano M. Source: Brain Research Bulletin. 2003 August 15; 61(3): 357-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12909305&dopt=Abstract

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Adult Hallervorden-Spatz syndrome simulating amyotrophic lateral sclerosis. Author(s): Vasconcelos OM, Harter DH, Duffy C, McDonough B, Seidman JG, Seidman CE, Campbell WW. Source: Muscle & Nerve. 2003 July; 28(1): 118-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811783&dopt=Abstract

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Age-related brain parenchymal fraction is significantly decreased in young multiple sclerosis patients: a quantitative MRI study. Author(s): Kassubek J, Tumani H, Ecker D, Kurt A, Ludolph AC, Juengling FD. Source: Neuroreport. 2003 March 3; 14(3): 427-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12634497&dopt=Abstract

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Alfacalcidol treatment in multiple sclerosis. Author(s): Achiron A, Barak Y, Miron S, Izhak Y, Faibel M, Edelstein S. Source: Clinical Neuropharmacology. 2003 March-April; 26(2): 53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12671521&dopt=Abstract

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Alpha-D-mannosidase properties in serum of patients with amyotrophic lateral sclerosis. Author(s): Orlacchio A, Bernardi G, Orlacchio A, Emiliani C. Source: Journal of Neurology. 2001 December; 248(12): 1090-2. Erratum In: J Neurol 2002 April; 249(4): 494-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12013588&dopt=Abstract

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Alterations in G(1) to S phase cell-cycle regulators during amyotrophic lateral sclerosis. Author(s): Ranganathan S, Bowser R. Source: American Journal of Pathology. 2003 March; 162(3): 823-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598317&dopt=Abstract

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Altered CD8+ T cell responses to selected Epstein-Barr virus immunodominant epitopes in patients with multiple sclerosis. Author(s): Hollsberg P, Hansen HJ, Haahr S. Source: Clinical and Experimental Immunology. 2003 April; 132(1): 137-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12653848&dopt=Abstract

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Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis. Author(s): Geurts JJ, Wolswijk G, Bo L, van der Valk P, Polman CH, Troost D, Aronica E. Source: Brain; a Journal of Neurology. 2003 August; 126(Pt 8): 1755-66. Epub 2003 June 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12805104&dopt=Abstract

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Amantadine for fatigue in multiple sclerosis. Author(s): Taus C, Giuliani G, Pucci E, D'Amico R, Solari A. Source: Cochrane Database Syst Rev. 2003; (2): Cd002818. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804439&dopt=Abstract

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Aminopyridines for symptomatic treatment in multiple sclerosis. Author(s): Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C. Source: Cochrane Database Syst Rev. 2003; (2): Cd001330. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804404&dopt=Abstract

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Amyotrophic lateral sclerosis associated with pregnancy: report of four new cases and review of the literature. Author(s): Chio A, Calvo A, Di Vito N, Vercellino M, Ghiglione P, Terreni A, Mutani R, Mora G. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. 2003 April; 4(1): 45-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12745618&dopt=Abstract

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Amyotrophic lateral sclerosis with IgM antibody against gangliosides GM2 and GD2. Author(s): Mizutani K, Oka N, Kusunoki S, Kaji R, Kanda M, Akiguchi I, Shibasaki H. Source: Intern Med. 2003 March; 42(3): 277-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12705795&dopt=Abstract

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Amyotrophic lateral sclerosis, lead, and genetic susceptibility: polymorphisms in the delta-aminolevulinic acid dehydratase and vitamin D receptor genes. Author(s): Kamel F, Umbach DM, Lehman TA, Park LP, Munsat TL, Shefner JM, Sandler DP, Hu H, Taylor JA. Source: Environmental Health Perspectives. 2003 August; 111(10): 1335-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12896855&dopt=Abstract

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Amyotrophic lateral sclerosis: from disease mechanisms to therapies. Author(s): Bruijn LI. Source: Biotechniques. 2002 May; 32(5): 1112, 1114, 1116 Passim. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12019785&dopt=Abstract

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An evidence-based medicine approach to the evaluation of the role of exogenous risk factors in sporadic amyotrophic lateral sclerosis. Author(s): Armon C. Source: Neuroepidemiology. 2003 July-August; 22(4): 217-28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12792141&dopt=Abstract

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An outcome study of riluzole in amyotrophic lateral sclerosis--a population-based study in Ireland, 1996-2000. Author(s): Traynor BJ, Alexander M, Corr B, Frost E, Hardiman O. Source: Journal of Neurology. 2003 April; 250(4): 473-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700914&dopt=Abstract

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Analyses of nursing home residents with multiple sclerosis and depression using the Minimum Data Set. Author(s): Buchanan RJ, Wang S, Tai-Seale M, Ju H. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 171-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708813&dopt=Abstract

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Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Author(s): Feghali-Bostwick C, Medsger TA Jr, Wright TM. Source: Arthritis and Rheumatism. 2003 July; 48(7): 1956-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12847690&dopt=Abstract

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Analysis of transmural trends in myocardial integrated backscatter in patients with progressive systemic sclerosis. Author(s): Hirooka K, Naito J, Koretsune Y, Irino H, Abe H, Ichikawa M, Yasuoka Y, Yamamoto H, Hashimoto K, Chin W, Kusuoka H, Inoue M, Hori M. Source: Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2003 April; 16(4): 340-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12712016&dopt=Abstract

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Anesthetic management of a patient with tuberous sclerosis presenting for renal transplantation. Author(s): Papaioannou EG, Staikou CV, Lambadarioui A, Karavokyros IG, Tsinari K. Source: Journal of Anesthesia. 2003; 17(3): 193-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12911208&dopt=Abstract

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Antibodies against a human endogenous retrovirus and the preponderance of env splice variants in multiple sclerosis patients. Author(s): Christensen T, Sorensen PD, Hansen HJ, Moller-Larsen A. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 615. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617261&dopt=Abstract

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Antibodies against myelin oligodendrocyte glycoprotein in the cerebrospinal fluid of multiple sclerosis patients. Author(s): Markovic M, Trajkovic V, Drulovic J, Mesaros S, Stojsavljevic N, Dujmovic I, Mostarica Stojkovic M. Source: Journal of the Neurological Sciences. 2003 July 15; 211(1-2): 67-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767500&dopt=Abstract

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Antibodies to myelin basic protein, myelin oligodendrocytes peptides, alpha-betacrystallin, lymphocyte activation and cytokine production in patients with multiple sclerosis. Author(s): Vojdani A, Vojdani E, Cooper E. Source: Journal of Internal Medicine. 2003 October; 254(4): 363-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974875&dopt=Abstract

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Antibodies to sulfatide in cerebrospinal fluid of patients with multiple sclerosis. Author(s): Ilyas AA, Chen ZW, Cook SD. Source: Journal of Neuroimmunology. 2003 June; 139(1-2): 76-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799023&dopt=Abstract

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Antibody response to myelin oligodendrocyte glycoprotein and myelin basic protein depend on familial background and are partially associated with human leukocyte antigen alleles in multiplex families and sporadic multiple sclerosis. Author(s): Lutterotti A, Reindl M, Gassner C, Poustka K, Schanda K, Deisenhammer F, Berger T. Source: Journal of Neuroimmunology. 2002 October; 131(1-2): 201-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458053&dopt=Abstract

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Anti-c-Mpl (thrombopoietin receptor) autoantibody-induced amegakaryocytic thrombocytopenia in a patient with systemic sclerosis. Author(s): Katsumata Y, Suzuki T, Kuwana M, Hattori Y, Akizuki S, Sugiura H, Matsuoka Y. Source: Arthritis and Rheumatism. 2003 June; 48(6): 1647-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12794833&dopt=Abstract

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Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. Author(s): Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, Dilitz E, Deisenhammer F, Reindl M. Source: The New England Journal of Medicine. 2003 July 10; 349(2): 139-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853586&dopt=Abstract

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Anti-myelin oligodendrocyte glycoprotein B-cell responses in multiple sclerosis. Author(s): Kennel De March A, De Bouwerie M, Kolopp-Sarda MN, Faure GC, Bene MC, Bernard CC. Source: Journal of Neuroimmunology. 2003 February; 135(1-2): 117-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12576231&dopt=Abstract

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Antineutrophil cytoplasmic antibodies a “Red Flag” in patients with systemic sclerosis. Author(s): Casari S, Haeney M, Farrand S, Herrick A. Source: The Journal of Rheumatology. 2002 December; 29(12): 2666-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12465176&dopt=Abstract

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Anxiety and depression influence the relation between disability status and quality of life in multiple sclerosis. Author(s): Janssens AC, van Doorn PA, de Boer JB, Kalkers NF, van der Meche FG, Passchier J, Hintzen RQ. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 397403. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926846&dopt=Abstract

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Apparent diffusion coefficient value of the hippocampus in patients with hippocampal sclerosis and in healthy volunteers. Author(s): Yoo SY, Chang KH, Song IC, Han MH, Kwon BJ, Lee SH, Yu IK, Chun CK. Source: Ajnr. American Journal of Neuroradiology. 2002 May; 23(5): 809-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12006282&dopt=Abstract

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Approach to discriminate subgroups in multiple sclerosis with cerebrospinal fluid (CSF) basic inflammation indices and TNF-alpha, IL-1beta, IL-6, IL-8. Author(s): Kleine TO, Zwerenz P, Graser C, Zofel P. Source: Brain Research Bulletin. 2003 August 15; 61(3): 327-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12909303&dopt=Abstract

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Are amyotrophic lateral sclerosis patients cognitively normal? Author(s): Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B. Source: Neurology. 2003 April 8; 60(7): 1094-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682312&dopt=Abstract

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Ascorbic acid does not improve endothelium-dependent flow-mediated dilatation of the brachial artery in patients with Raynaud's phenomenon secondary to systemic sclerosis. Author(s): Mavrikakis ME, Lekakis JP, Papamichael CM, Stamatelopoulos KS, Kostopoulos ChC, Stamatelopoulos SF. Source: Int J Vitam Nutr Res. 2003 February; 73(1): 3-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12690904&dopt=Abstract

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Association between cardiac tumors and tuberous sclerosis in the fetus and neonate. Author(s): Tworetzky W, McElhinney DB, Margossian R, Moon-Grady AJ, Sallee D, Goldmuntz E, van der Velde ME, Silverman NH, Allan LD. Source: The American Journal of Cardiology. 2003 August 15; 92(4): 487-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12914889&dopt=Abstract

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Association of common variation in glutathione S-transferase genes with premature development of cardiovascular disease in patients with systemic sclerosis. Author(s): Palmer CN, Young V, Ho M, Doney A, Belch JJ. Source: Arthritis and Rheumatism. 2003 March; 48(3): 854-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12632442&dopt=Abstract

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Association of HLA-B12 with multiple sclerosis in India. Author(s): Wadia NH, Trikannad VS, Krishnaswamy PR. Source: Tissue Antigens. 1980 January; 15(1): 90-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12735339&dopt=Abstract

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Asymptomatic visual loss in multiple sclerosis. Author(s): Lycke J, Tollesson PO, Frisen L. Source: Journal of Neurology. 2001 December; 248(12): 1079-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12013586&dopt=Abstract

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Autoantibodies to RNA-polymerases in Italian patients with systemic sclerosis. Author(s): Bardoni A, Rossi P, Salvini R, Bobbio-Pallavicini F, Caporali R, Montecucco C. Source: Clin Exp Rheumatol. 2003 May-June; 21(3): 301-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846047&dopt=Abstract

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Autoantibody to DNA binding protein B as a novel serologic marker in systemic sclerosis. Author(s): Jeoung DI, Bong Lee E, Lee S, Lim Y, Lee DY, Kim J, Kim HY, Wook Song Y. Source: Biochemical and Biophysical Research Communications. 2002 December 13; 299(4): 549-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12459173&dopt=Abstract

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Autoimmune neutropenia associated with multiple sclerosis. Author(s): Kozuka T, Kojima K, Kaneda K, Takenaka K, Manabe Y, Hirata Y, Okuma S, Toki H, Tanimoto M. Source: Intern Med. 2003 January; 42(1): 102-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12583629&dopt=Abstract

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Autoimmune optic neuropathy with anticardiolipin antibody mimicking multiple sclerosis in a child. Author(s): Frohman L, Turbin R, Bielory L, Wolansky L, Lambert WC, Cook S. Source: American Journal of Ophthalmology. 2003 August; 136(2): 358-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12888064&dopt=Abstract

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Automatic “pipeline” analysis of 3-D MRI data for clinical trials: application to multiple sclerosis. Author(s): Zijdenbos AP, Forghani R, Evans AC. Source: Ieee Transactions on Medical Imaging. 2002 October; 21(10): 1280-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12585710&dopt=Abstract

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Axonal injury in multiple sclerosis. Author(s): Rammohan KW. Source: Curr Neurol Neurosci Rep. 2003 May; 3(3): 231-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12691628&dopt=Abstract

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Bacterial infection as a cause of multiple sclerosis. Author(s): Wolfson C, Talbot P. Source: Lancet. 2002 August 3; 360(9330): 352-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12241771&dopt=Abstract

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Bactericidal/permeability-increasing protein and cathepsin G are the major antigenic targets of antineutrophil cytoplasmic autoantibodies in systemic sclerosis. Author(s): Khanna D, Aggarwal A, Bhakuni DS, Dayal R, Misra R. Source: The Journal of Rheumatology. 2003 June; 30(6): 1248-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12784398&dopt=Abstract

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Balo's concentric sclerosis. Evolution of active demyelination demonstrated by serial contrast-enhanced MRI. Author(s): Kastrup O, Stude P, Limmroth V. Source: Journal of Neurology. 2002 July; 249(7): 811-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12140661&dopt=Abstract

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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. 2002 September; 3(3): 137-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495575&dopt=Abstract

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Baseline T cell reactivity in multiple sclerosis is correlated to efficacy of interferonbeta. Author(s): Killestein J, Hintzen RQ, Uitdehaag BM, Baars PA, Roos MT, van Lier RA, Polman CH. Source: Journal of Neuroimmunology. 2002 December; 133(1-2): 217-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12446026&dopt=Abstract

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Bayesian approach to searching for susceptibility genes: Gc2 and EsD1 alleles and multiple sclerosis. Author(s): Di Bacco M, Luiselli D, Manca ML, Siciliano G. Source: Coll Antropol. 2002 June; 26(1): 77-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12137326&dopt=Abstract

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Beauty and the beast. The nitric oxide paradox in systemic sclerosis. Author(s): Matucci Cerinic M, Kahaleh MB. Source: Rheumatology (Oxford, England). 2002 August; 41(8): 843-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12154200&dopt=Abstract

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Behavioral phenotypes in four mental retardation syndromes: fetal alcohol syndrome, Prader-Willi syndrome, fragile X syndrome, and tuberosis sclerosis. Author(s): Steinhausen HC, Von Gontard A, Spohr HL, Hauffa BP, Eiholzer U, Backes M, Willms J, Malin Z. Source: American Journal of Medical Genetics. 2002 September 1; 111(4): 381-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12210296&dopt=Abstract

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Beliefs, perceptions, and practices related to osteoporosis risk reduction among women with multiple sclerosis. Author(s): Sharts-Hopko NC, Sullivan MP. Source: Rehabilitation Nursing : the Official Journal of the Association of Rehabilitation Nurses. 2002 November-December; 27(6): 232-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12432671&dopt=Abstract

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Benchmarking best practice in relapse management of multiple sclerosis. Author(s): Embrey N, Lowndes C. Source: Nursing Standard : Official Newspaper of the Royal College of Nursing. 2003 February 12-18; 17(22): 38-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12619406&dopt=Abstract

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Best cases from the AFIP: angiomyolipomas in tuberous sclerosis. Author(s): Logue LG, Acker RE, Sienko AE. Source: Radiographics : a Review Publication of the Radiological Society of North America, Inc. 2003 January-February; 23(1): 241-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12533658&dopt=Abstract

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Beta endorphin concentrations in PBMC of patients with different clinical phenotypes of multiple sclerosis. Author(s): Gironi M, Furlan R, Rovaris M, Comi G, Filippi M, Panerai AE, Sacerdote P. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 April; 74(4): 495-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640071&dopt=Abstract

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Beta-Interferon treatment does not always slow the progression of axonal injury in multiple sclerosis. Author(s): Parry A, Corkill R, Blamire AM, Palace J, Narayanan S, Arnold D, Styles P, Matthews PM. Source: Journal of Neurology. 2003 February; 250(2): 171-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574947&dopt=Abstract

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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: Current Drug Targets. Cns and Neurological Disorders. 2003 April; 2(2): 95-107. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12769802&dopt=Abstract

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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. 2003 July; 62(7): 791-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901704&dopt=Abstract

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Biochemical markers of damage of the central nervous system in multiple sclerosis. Author(s): Bartosik-Psujek H, Stelmasiak Z. Source: Ann Univ Mariae Curie Sklodowska [med]. 2001; 56: 389-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11977345&dopt=Abstract

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Birth cohort effects in multiple sclerosis. Author(s): Jin YP, De Pedro-Cuesta J, Lopez-Abente G, Link H. Source: Annals of Epidemiology. 2003 April; 13(4): 252-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12684191&dopt=Abstract

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Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies. Author(s): DasGupta R, Fowler CJ. Source: Drugs. 2003; 63(2): 153-66. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12515563&dopt=Abstract

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Blood cholesterol and MRI activity in first clinical episode suggestive of multiple sclerosis. Author(s): Giubilei F, Antonini G, Di Legge S, Sormani MP, Pantano P, Antonini R, Sepe-Monti M, Caramia F, Pozzilli C. Source: Acta Neurologica Scandinavica. 2002 August; 106(2): 109-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12100371&dopt=Abstract

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Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Author(s): Cerinic MM, Valentini G, Sorano GG, D'Angelo S, Cuomo G, Fenu L, Generini S, Cinotti S, Morfini M, Pignone A, Guiducci S, Del Rosso A, Kalfin R, Das D, Marongiu F. Source: Seminars in Arthritis and Rheumatism. 2003 April; 32(5): 285-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701039&dopt=Abstract

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Body composition in ambulatory women with multiple sclerosis. Author(s): Lambert CP, Lee Archer R, Evans WJ. Source: Archives of Physical Medicine and Rehabilitation. 2002 November; 83(11): 155961. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12422325&dopt=Abstract

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Brachial plexopathy associated with systemic sclerosis. Author(s): Allanore Y, Zuber M, Kahan A. Source: Clinical Rheumatology. 2002 September; 21(5): 401-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12223990&dopt=Abstract

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Brain atrophy in multiple sclerosis: impact of lesions and of damage of whole brain tissue. Author(s): Kalkers NF, Vrenken H, Uitdehaag BM, Polman CH, Barkhof F. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 October; 8(5): 4104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12356208&dopt=Abstract

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Brain calcifications in systemic sclerosis. Author(s): Gusbi O, Bernardini GL. Source: Archives of Neurology. 2002 October; 59(10): 1642-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12374504&dopt=Abstract

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Brain damage when multiple sclerosis is diagnosed clinically. Author(s): Lassmann H. Source: Lancet. 2003 April 19; 361(9366): 1317-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711464&dopt=Abstract

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Brain functional involvement by perfusion SPECT in systemic sclerosis and Behcet's disease. Author(s): Nobili F, Cutolo M, Sulli A, Vitali P, Vignola S, Rodriguez G. Source: Annals of the New York Academy of Sciences. 2002 June; 966: 409-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12114298&dopt=Abstract

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Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis. Author(s): Chard DT, Griffin CM, McLean MA, Kapeller P, Kapoor R, Thompson AJ, Miller DH. Source: Brain; a Journal of Neurology. 2002 October; 125(Pt 10): 2342-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12244090&dopt=Abstract

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Brain metabolite profiles of T1-hypointense lesions in relapsing-remitting multiple sclerosis. Author(s): Li BS, Regal J, Soher BJ, Mannon LJ, Grossman RI, Gonen O. Source: Ajnr. American Journal of Neuroradiology. 2003 January; 24(1): 68-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12533329&dopt=Abstract

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Brain MRI lesion load quantification in multiple sclerosis: a comparison between automated multispectral and semi-automated thresholding computer-assisted techniques. Author(s): Achiron A, Gicquel S, Miron S, Faibel M. Source: Magnetic Resonance Imaging. 2002 December; 20(10): 713-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591567&dopt=Abstract

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Brain tissue volume changes in relapsing-remitting multiple sclerosis: correlation with lesion load. Author(s): Quarantelli M, Ciarmiello A, Morra VB, Orefice G, Larobina M, Lanzillo R, Schiavone V, Salvatore E, Alfano B, Brunetti A. Source: Neuroimage. 2003 February; 18(2): 360-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12595189&dopt=Abstract

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Brain-derived neurotrophic factor in patients with multiple sclerosis. Author(s): Sarchielli P, Greco L, Stipa A, Floridi A, Gallai V. Source: Journal of Neuroimmunology. 2002 November; 132(1-2): 180-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12417449&dopt=Abstract

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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. 2002 March; 22(6): 473-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11976981&dopt=Abstract

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Can the repetition effect maximize learning in multiple sclerosis? Author(s): Chiaravalloti ND, Demaree H, Gaudino EA, DeLuca J. Source: Clinical Rehabilitation. 2003 February; 17(1): 58-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617380&dopt=Abstract

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Cannabinoids on trial for multiple sclerosis. Author(s): Zajicek J. Source: Lancet. Neurology. 2002 July; 1(3): 147. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849481&dopt=Abstract

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Cardiac autonomic dysfunction precedes the development of fibrosis in patients with systemic sclerosis. Author(s): Cozzolino D, Naclerio C, Iengo R, D'Angelo S, Cuomo G, Valentini G. Source: Rheumatology (Oxford, England). 2002 May; 41(5): 586-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12011386&dopt=Abstract

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Cardiac rhabdomyoma and tuberous sclerosis: prenatal diagnosis and follow-up. Author(s): Das BB, Sharma J. Source: Indian J Pediatr. 2003 January; 70(1): 87-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12619958&dopt=Abstract

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Caspase inhibitors protect against neuronal apoptosis induced by cerebrospinal fluid from multiple sclerosis patients. Author(s): Cid C, Alvarez-Cermeno JC, Regidor I, Plaza J, Salinas M, Alcazar A. Source: Journal of Neuroimmunology. 2003 March; 136(1-2): 119-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12620650&dopt=Abstract

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Causes of death and poor survival prognostic factors in thai patients with systemic sclerosis. Author(s): Ruangjutipopan S, Kasitanon N, Louthrenoo W, Sukitawut W, Wichainun R. Source: J Med Assoc Thai. 2002 November; 85(11): 1204-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546318&dopt=Abstract

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CD34+ selected autologous peripheral blood stem cell transplantation for multiple sclerosis: report of toxicity and treatment results at one year of follow-up in 15 patients. Author(s): Carreras E, Saiz A, Marin P, Martinez C, Rovira M, Villamor N, Aymerich M, Lozano M, Fernandez-Aviles F, Urbano-Izpizua A, Montserrat E, Graus F. Source: Haematologica. 2003 March; 88(3): 306-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12651270&dopt=Abstract

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CD83-positive dendritic cells are present in occasional perivascular cuffs in multiple sclerosis lesions. Author(s): Plumb J, Armstrong MA, Duddy M, Mirakhur M, McQuaid S. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 142-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708809&dopt=Abstract

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cDNA microarray analysis in multiple sclerosis lesions: detection of genes associated with disease activity. Author(s): Mycko MP, Papoian R, Boschert U, Raine CS, Selmaj KW. Source: Brain; a Journal of Neurology. 2003 May; 126(Pt 5): 1048-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12690045&dopt=Abstract

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Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. Author(s): Nguyen MD, Boudreau M, Kriz J, Couillard-Despres S, Kaplan DR, Julien JP. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2003 March 15; 23(6): 2131-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12657672&dopt=Abstract

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Cell transplantation, myelin repair, and multiple sclerosis. Author(s): Halfpenny C, Benn T, Scolding N. Source: Lancet. Neurology. 2002 May; 1(1): 31-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849543&dopt=Abstract

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Cellular compartmentalization of phosphorylated eIF2alpha and neuronal NOS in human temporal lobe epilepsy with hippocampal sclerosis. Author(s): Petrov T, Rafols JA, Alousi SS, Kupsky WJ, Johnson R, Shah J, Shah A, Watson C. Source: Journal of the Neurological Sciences. 2003 May 15; 209(1-2): 31-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12686399&dopt=Abstract

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Cellular microchimerism as a lifelong physiologic status in parous women: an immunologic basis for its amplification in patients with systemic sclerosis. Author(s): Burastero SE, Galbiati S, Vassallo A, Sabbadini MG, Bellone M, Marchionni L, Smid M, Ferrero E, Ferrari A, Ferrari M, Cremonesi L. Source: Arthritis and Rheumatism. 2003 April; 48(4): 1109-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687555&dopt=Abstract

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Cerebral atrophy and disability in relapsing-remitting and secondary progressive multiple sclerosis over four years. Author(s): Turner B, Lin X, Calmon G, Roberts N, Blumhardt LD. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 217. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617263&dopt=Abstract

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Cerebral blood flow and oxygen metabolism in patients with progressive dementia and amyotrophic lateral sclerosis. Author(s): Tanaka M, Ichiba T, Kondo S, Hirai S, Okamoto K. Source: Neurological Research. 2003 June; 25(4): 351-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870260&dopt=Abstract

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Cerebral venous thrombosis in four patients with multiple sclerosis. Author(s): Vandenberghe N, Debouverie M, Anxionnat R, Clavelou P, Bouly S, Weber M. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2003 January; 10(1): 63-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12534995&dopt=Abstract

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Changes in motor cortex inhibition over time in patients with amyotrophic lateral sclerosis. Author(s): Zanette G, Tamburin S, Manganotti P, Refatti N, Forgione A, Rizzuto N. Source: Journal of Neurology. 2002 December; 249(12): 1723-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12529797&dopt=Abstract

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Changes in the expression and localization of the paranodal protein Caspr on axons in chronic multiple sclerosis. Author(s): Wolswijk G, Balesar R. Source: Brain; a Journal of Neurology. 2003 July; 126(Pt 7): 1638-49. Epub 2003 April 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12805111&dopt=Abstract

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Characteristics of diadochokinesis in multiple sclerosis and Parkinson's disease. Author(s): Tjaden K, Watling E. Source: Folia Phoniatrica Et Logopaedica : Official Organ of the International Association of Logopedics and Phoniatrics (Ialp). 2003 September-October; 55(5): 241-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12931058&dopt=Abstract

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Chemokines in experimental autoimmune encephalomyelitis and multiple sclerosis. Author(s): Babcock A, Owens T. Source: Advances in Experimental Medicine and Biology. 2003; 520: 120-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12613576&dopt=Abstract

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Childhood and juvenile onset multiple sclerosis: clinical and paraclinical features. Author(s): Ozakbas S, Idiman E, Baklan B, Yulug B. Source: Brain & Development. 2003 June; 25(4): 233-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767452&dopt=Abstract

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Chlamydia pneumoniae and multiple sclerosis: the latest etiologic candidate. Author(s): Bashir K, Kaslow RA. Source: Epidemiology (Cambridge, Mass.). 2003 March; 14(2): 133-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12606874&dopt=Abstract

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Chromosome 19q13 and multiple sclerosis susceptibility in Finland: a linkage and two-stage association study. Author(s): Reunanen K, Finnila S, Laaksonen M, Sumelahti ML, Wikstrom J, Pastinen T, Kuokkanen S, Saarela J, Uimari P, Ruutiainen J, Ilonen J, Peltonen L, Tienari PJ. Source: Journal of Neuroimmunology. 2002 May; 126(1-2): 134-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12020965&dopt=Abstract

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Ciliary neurotrophic factor genotype does not influence clinical phenotype in amyotrophic lateral sclerosis. Author(s): Al-Chalabi A, Scheffler MD, Smith BN, Parton MJ, Cudkowicz ME, Andersen PM, Hayden DL, Hansen VK, Turner MR, Shaw CE, Leigh PN, Brown RH Jr. Source: Annals of Neurology. 2003 July; 54(1): 130-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12838531&dopt=Abstract

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Clinical exacerbation of multiple sclerosis following radiotherapy. Author(s): Murphy CB, Hashimoto SA, Graeb D, Thiessen BA. Source: Archives of Neurology. 2003 February; 60(2): 273-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12580715&dopt=Abstract

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Clinical features of patients with systemic sclerosis accompanied by rheumatoid arthritis. Author(s): Jinnin M, Ihn H, Yamane K, Asano Y, Yazawa N, Tamaki K. Source: Clin Exp Rheumatol. 2003 January-February; 21(1): 91-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12673896&dopt=Abstract

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Clinical presentation of primary progressive multiple sclerosis 10 years after the incidental finding of typical magnetic resonance imaging brain lesions: the subclinical stage of primary progressive multiple sclerosis may last 10 years. Author(s): McDonnell GV, Cabrera-Gomez J, Calne DB, Li DK, Oger J. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 204-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708816&dopt=Abstract

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Clinically definite multiple sclerosis after radiological Schilder-like onset. Author(s): Sastre-Garriga J, Rovira A, Rio J, Tintore M, Grive E, Montalban X. Source: Journal of Neurology. 2003 July; 250(7): 871-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883933&dopt=Abstract

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Clinic-based needs assessment of individuals with multiple sclerosis and significant others: implications for program planning--psychological needs. Author(s): Benbow CL, Koopman WJ. Source: Rehabilitation Nursing : the Official Journal of the Association of Rehabilitation Nurses. 2003 July-August; 28(4): 109-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875143&dopt=Abstract

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Clinics in diagnostic imaging (78). Cardiac rhabdomyoma in tuberous sclerosis. Author(s): Visrutaratna P, Sivasomboon C, Oranratanachai K. Source: Singapore Med J. 2002 October; 43(10): 541-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12587712&dopt=Abstract

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Coefficient D(av) is more sensitive than fractional anisotropy in monitoring progression of irreversible tissue damage in focal nonactive multiple sclerosis lesions. Author(s): Castriota-Scanderbeg A, Fasano F, Hagberg G, Nocentini U, Filippi M, Caltagirone C. Source: Ajnr. American Journal of Neuroradiology. 2003 April; 24(4): 663-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12695200&dopt=Abstract

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Cognitive dysfunction in multiple sclerosis: a review of recent developments. Author(s): Bobholz JA, Rao SM. Source: Current Opinion in Neurology. 2003 June; 16(3): 283-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858063&dopt=Abstract

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Cognitive impairment in multiple sclerosis does not affect reliability and validity of self-report health measures. Author(s): Gold SM, Schulz H, Monch A, Schulz KH, Heesen C. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 40410. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926847&dopt=Abstract

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Cognitive presentation of multiple sclerosis: evidence for a cortical variant. Author(s): Zarei M, Chandran S, Compston A, Hodges J. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 July; 74(7): 872-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810770&dopt=Abstract

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Comparability of perceptual analysis of speech characteristics in Australian and Swedish speakers with multiple sclerosis. Author(s): Hartelius L, Theodoros D, Cahill L, Lillvik M. Source: Folia Phoniatrica Et Logopaedica : Official Organ of the International Association of Logopedics and Phoniatrics (Ialp). 2003 July-August; 55(4): 177-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12802090&dopt=Abstract

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Complementarity-determining region 3 spectratyping analysis of the TCR repertoire in multiple sclerosis. Author(s): Matsumoto Y, Yoon WK, Jee Y, Fujihara K, Misu T, Sato S, Nakashima I, Itoyama Y. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 May 1; 170(9): 4846-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12707368&dopt=Abstract

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Comprehension of affective prosody in multiple sclerosis. Author(s): Beatty WW, Orbelo DM, Sorocco KH, Ross ED. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 148-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708810&dopt=Abstract

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Conflicts of interest: experiences of close relatives of patients suffering from amyotrophic lateral sclerosis. Author(s): Bolmsjo I, Hermern G. Source: Nursing Ethics. 2003 March; 10(2): 186-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12659489&dopt=Abstract

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Continuation of caregiving among partners who give total care to spouses with multiple sclerosis. Author(s): Boeije HR, Duijnstee MS, Grypdonck MH. Source: Health & Social Care in the Community. 2003 May; 11(3): 242-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823429&dopt=Abstract

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Conversion to multiple sclerosis after a clinically isolated syndrome of the brainstem: cranial magnetic resonance imaging, cerebrospinal fluid and neurophysiological findings. Author(s): Sastre-Garriga J, Tintore M, Rovira A, Grive E, Pericot I, Comabella M, Thompson AJ, Montalban X. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 3943. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617267&dopt=Abstract

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Correlation of mollicutes and their viruses with multiple sclerosis and other demyelinating diseases. Author(s): Brown JS Jr. Source: Medical Hypotheses. 2003 February; 60(2): 298-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12606251&dopt=Abstract

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Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Author(s): Hu PQ, Fertig N, Medsger TA Jr, Wright TM. Source: Arthritis and Rheumatism. 2003 May; 48(5): 1363-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746909&dopt=Abstract

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Correlation of serum IL-13 and IL-5 levels with clinical response to Glatiramer acetate in patients with multiple sclerosis. Author(s): Wiesemann E, Klatt J, Wenzel C, Heidenreich F, Windhagen A. Source: Clinical and Experimental Immunology. 2003 September; 133(3): 454-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12930374&dopt=Abstract

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Correlation of sexual dysfunction and brain magnetic resonance imaging in multiple sclerosis. Author(s): Zorzon M, Zivadinov R, Locatelli L, Stival B, Nasuelli D, Bratina A, Bosco A, Tommasi MA, Pozzi Mucelli RS, Ukmar M, Cazzato G. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 10810. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617277&dopt=Abstract

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Cortical silent period and motor evoked potentials in patients with multiple sclerosis. Author(s): Tataroglu C, Genc A, Idiman E, Cakmur R, Idiman F. Source: Clinical Neurology and Neurosurgery. 2003 April; 105(2): 105-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12691802&dopt=Abstract

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Corticomotoneuronal connections in primary lateral sclerosis (PLS). Author(s): Weber M, Stewart H, Hirota N, Eisen A. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. 2002 December; 3(4): 190-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710508&dopt=Abstract

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Costs of thalamic deep brain stimulation for movement disorders in patients with multiple sclerosis. Author(s): Hooper J, Whittle IR. Source: British Journal of Neurosurgery. 2003 February; 17(1): 40-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12779200&dopt=Abstract

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Crohn's associated NOD2 gene variants are not involved in determining susceptibility to multiple sclerosis. Author(s): Sawcer S, Maranian M, Hensiek A, Roxburgh R, Gray J, Compston A. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 August; 74(8): 1157. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876263&dopt=Abstract

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Cross-bridge mechanisms of muscle weakness in multiple sclerosis. Author(s): Garner DJ, Widrick JJ. Source: Muscle & Nerve. 2003 April; 27(4): 456-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12661047&dopt=Abstract

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Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis. Author(s): Tejada-Simon MV, Zang YC, Hong J, Rivera VM, Zhang JZ. Source: Annals of Neurology. 2003 February; 53(2): 189-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12557285&dopt=Abstract

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CTLA4 dimorphisms and the multiple sclerosis phenotype. Author(s): Masterman T, Ligers A, Zhang Z, Hellgren D, Salter H, Anvret M, Hillert J. Source: Journal of Neuroimmunology. 2002 October; 131(1-2): 208-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458054&dopt=Abstract

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CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls. Author(s): Oliveira EM, Bar-Or A, Waliszewska AI, Cai G, Anderson DE, Krieger JI, Hafler DA. Source: Journal of Autoimmunity. 2003 February; 20(1): 71-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604314&dopt=Abstract

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CTLA4 exon 1 dimorphism is associated with primary progressive multiple sclerosis. Author(s): Maurer M, Ponath A, Kruse N, Rieckmann P. Source: Journal of Neuroimmunology. 2002 October; 131(1-2): 213-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458055&dopt=Abstract

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Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro. Author(s): Stathopulos PB, Rumfeldt JA, Scholz GA, Irani RA, Frey HE, Hallewell RA, Lepock JR, Meiering EM. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 June 10; 100(12): 7021-6. Epub 2003 May 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12773627&dopt=Abstract

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Current aspects of pathogenesis and therapy of multiple sclerosis. Author(s): Kolar OJ, Han W, Huler KK, Muckway MA. Source: Suppl Clin Neurophysiol. 2000; 53: 424-32. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12741030&dopt=Abstract

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Current disease-modifying therapies in multiple sclerosis. Author(s): Kieseier BC, Hartung HP. Source: Seminars in Neurology. 2003 June; 23(2): 133-46. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894379&dopt=Abstract

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Cyclophosphamide is effective in stabilizing rapidly deteriorating secondary progressive multiple sclerosis. Author(s): Perini P, Gallo P. Source: Journal of Neurology. 2003 July; 250(7): 834-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883926&dopt=Abstract

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Cyclophosphamide pulse regimen in the treatment of alveolitis in systemic sclerosis. Author(s): Mittal G, Udwadia Z, Joshi VR. Source: The Journal of Rheumatology. 2003 May; 30(5): 1121-2; Author Reply 1122. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12734923&dopt=Abstract

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Cytokines in the pathogenesis and therapy of autoimmune encephalomyelitis and multiple sclerosis. Author(s): Willenborg DO, Staykova MA. Source: Advances in Experimental Medicine and Biology. 2003; 520: 96-119. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12613575&dopt=Abstract

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D90A-SOD1 mediated amyotrophic lateral sclerosis: a single founder for all cases with evidence for a Cis-acting disease modifier in the recessive haplotype. Author(s): Parton MJ, Broom W, Andersen PM, Al-Chalabi A, Nigel Leigh P, Powell JF, Shaw CE; D90A SOD1 ALS Consortium. Source: Human Mutation. 2002 December; 20(6): 473. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12442272&dopt=Abstract

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Death due to pulmonary tuberculosis in progressive systemic sclerosis. Author(s): Manz B, Noack-Wiemers F, Mittag M, Haustein UF, Nenoff P. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 2002 November; 16(6): 647-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12482061&dopt=Abstract

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Decompressive aspiration in myelinoclastic diffuse sclerosis or Schilder disease. Case report. Author(s): Nejat F, Eftekhar B. Source: Journal of Neurosurgery. 2002 December; 97(6): 1447-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12507147&dopt=Abstract

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Decrease in heart ventricular ejection fraction during multiple sclerosis. Author(s): Olindo S, Guillon B, Helias J, Phillibert B, Magne C, Feve JR. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2002 May; 9(3): 287-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11985637&dopt=Abstract

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Decreased amplitudes in multiple sclerosis patients with normal visual acuity: a VEP study. Author(s): Diem R, Tschirne A, Bahr M. Source: Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. 2003 January; 10(1): 67-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12464525&dopt=Abstract

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Decreased frequency of the tumor necrosis factor alpha -308 allele in Serbian patients with multiple sclerosis. Author(s): Drulovic J, Popadic D, Mesaros S, Dujmovic I, Cvetkovic I, Miljkovic D, Stojsavljevic N, Pravica V, Pekmezovic T, Bogdanovic G, Jarebinski M, Mostarica Stojkovic M. Source: European Neurology. 2003; 50(1): 25-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824709&dopt=Abstract

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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. 2003 April 15; 208(1-2): 67-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12639727&dopt=Abstract

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Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients. Author(s): Rejdak K, Bartosik-Psujek H, Dobosz B, Kocki T, Grieb P, Giovannoni G, Turski WA, Stelmasiak Z. Source: Neuroscience Letters. 2002 October 4; 331(1): 63-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12359324&dopt=Abstract

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Decreased levels of the brain specific 24S-hydroxycholesterol and cholesterol precursors in serum of multiple sclerosis patients. Author(s): Teunissen CE, Dijkstra CD, Polman CH, Hoogervorst EL, von Bergmann K, Lutjohann D. Source: Neuroscience Letters. 2003 August 28; 347(3): 159-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875910&dopt=Abstract

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Degeneration of corticospinal and bulbospinal systems in the superoxide dismutase 1(G93A G1H) transgenic mouse model of familial amyotrophic lateral sclerosis. Author(s): Zang DW, Cheema SS. Source: Neuroscience Letters. 2002 October 31; 332(2): 99-102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12384220&dopt=Abstract

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Denervation is not a primary cause of prion protein down-regulation occurring in the spinal cord of a transgenic model of amyotrophic lateral sclerosis. Author(s): Dupuis L, Rene F, Di Scala F, Gonzalez De Aguilar JL, De Tapia M, Loeffler JP. Source: Annals of the New York Academy of Sciences. 2002 November; 973: 116-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12485846&dopt=Abstract

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Depression and cognitive impairment in disability-free early multiple sclerosis. Author(s): Haase CG, Tinnefeld M, Lienemann M, Ganz RE, Faustmann PM. Source: Behavioural Neurology. 2003; 14(1-2): 39-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12719637&dopt=Abstract

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Depression in multiple sclerosis associated with interferon beta-1a (Rebif). Author(s): Pandya R, Patten S. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2002 September; 47(7): 686. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12355685&dopt=Abstract

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Depression is a treatable cause of suffering among multiple sclerosis patients and can result in suicide. Author(s): Bourdette D. Source: Neurology. 2002 September 10; 59(5): E6-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12221194&dopt=Abstract

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Depression, fatigue, and health-related quality of life among people with advanced multiple sclerosis: results from an exploratory telerehabilitation study. Author(s): Egner A, Phillips VL, Vora R, Wiggers E. Source: Neurorehabilitation. 2003; 18(2): 125-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867675&dopt=Abstract

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Depression-like changes of the sleep-EEG during high dose corticosteroid treatment in patients with multiple sclerosis. Author(s): Antonijevic IA, Steiger A. Source: Psychoneuroendocrinology. 2003 August; 28(6): 780-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12812864&dopt=Abstract

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Depressive symptoms and MRI changes in multiple sclerosis. Author(s): Zorzon M, Zivadinov R, Nasuelli D, Ukmar M, Bratina A, Tommasi MA, Mucelli RP, Brnabic-Razmilic O, Grop A, Bonfigli L, Cazzato G. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2002 September; 9(5): 491-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12220380&dopt=Abstract

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Depressive symptoms and severity of illness in multiple sclerosis: epidemiologic study of a large community sample. Author(s): Chwastiak L, Ehde DM, Gibbons LE, Sullivan M, Bowen JD, Kraft GH. Source: The American Journal of Psychiatry. 2002 November; 159(11): 1862-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12411220&dopt=Abstract

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Deriving summary indices of health status from the Amyotrophic Lateral Sclerosis Assessment Questionnaires (ALSAQ-40 and ALSAQ-5). Author(s): Jenkinson C, Norquist JM, Fitzpatrick R. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 February; 74(2): 2425. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531959&dopt=Abstract

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Designing peptide mimetics for the treatment of multiple sclerosis. Author(s): Matsoukas J, Apostolopoulos V, Mavromoustakos T. Source: Mini Reviews in Medicinal Chemistry. 2001 September; 1(3): 273-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12369974&dopt=Abstract

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Detection of antibodies directed against human herpesvirus 6 U94/REP in sera of patients affected by multiple sclerosis. Author(s): Caselli E, Boni M, Bracci A, Rotola A, Cermelli C, Castellazzi M, Di Luca D, Cassai E. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 4131-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409386&dopt=Abstract

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Detection of early impairment of coronary flow reserve in patients with systemic sclerosis. Author(s): Montisci R, Vacca A, Garau P, Colonna P, Ruscazio M, Passiu G, Iliceto S, Mathieu A. Source: Annals of the Rheumatic Diseases. 2003 September; 62(9): 890-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12922965&dopt=Abstract

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Detection of N epsilon-(carboxymethyl)lysine (CML) and non-CML advanced glycation end-products in the anterior horn of amyotrophic lateral sclerosis spinal cord. Author(s): Kikuchi S, Shinpo K, Ogata A, Tsuji S, Takeuchi M, Makita Z, Tashiro K. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. 2002 June; 3(2): 63-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12215227&dopt=Abstract

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Detection of the 14-3-3 protein in the cerebrospinal fluid of Japanese multiple sclerosis patients presenting with severe myelitis. Author(s): Satoh J, Yukitake M, Kurohara K, Takashima H, Kuroda Y. Source: Journal of the Neurological Sciences. 2003 August 15; 212(1-2): 11-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809994&dopt=Abstract

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Detection of visual field defects in patients after anterior temporal lobectomy for mesial temporal sclerosis-establishing eligibility to drive. Author(s): Pathak-Ray V, Ray A, Walters R, Hatfield R. Source: Eye (London, England). 2002 November; 16(6): 744-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12439670&dopt=Abstract

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Developing clinical outcome measures in multiple sclerosis: an evolving process. Author(s): Thompson AJ. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 October; 8(5): 3578. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12356199&dopt=Abstract

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Development and validation of a self-efficacy measure for people with multiple sclerosis: the Multiple Sclerosis Self-efficacy Scale. Author(s): Rigby SA, Domenech C, Thornton EW, Tedman S, Young CA. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 7381. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617272&dopt=Abstract

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Development of a CENP-A/CENP-B-specific immune response in a patient with systemic sclerosis. Author(s): Mahler M, Mierau R, Genth E, Bluthner M. Source: Arthritis and Rheumatism. 2002 July; 46(7): 1866-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12124871&dopt=Abstract

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Development of case definitions for acute encephalopathy, encephalitis, and multiple sclerosis reports to the vaccine: Adverse Event Reporting System. Author(s): Ball R, Halsey N, Braun MM, Moulton LH, Gale AD, Rammohan K, Wiznitzer M, Johnson R, Salive ME; VAERS Working Group. Source: Journal of Clinical Epidemiology. 2002 August; 55(8): 819-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12384197&dopt=Abstract

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Differences in autoantibody response to Th/To between systemic sclerosis and other autoimmune diseases. Author(s): Kuwana M, Kimura K, Hirakata M, Kawakami Y, Ikeda Y. Source: Annals of the Rheumatic Diseases. 2002 September; 61(9): 842-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12176814&dopt=Abstract

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Different mechanisms contribute to motor cortex hyperexcitability in amyotrophic lateral sclerosis. Author(s): Zanette G, Tamburin S, Manganotti P, Refatti N, Forgione A, Rizzuto N. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2002 November; 113(11): 1688-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12417221&dopt=Abstract

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Differential diagnosis and management of fatigue in multiple sclerosis: considerations for the nurse. Author(s): Costello K, Harris C. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 2003 June; 35(3): 139-48. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12830661&dopt=Abstract

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Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory. Author(s): Bertolotto A, Malucchi S, Sala A, Orefice G, Carrieri PB, Capobianco M, Milano E, Melis F, Giordana MT. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 August; 73(2): 148-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12122172&dopt=Abstract

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Differentially expressed genes in sporadic amyotrophic lateral sclerosis spinal cords-screening by molecular indexing and subsequent cDNA microarray analysis. Author(s): Ishigaki S, Niwa J, Ando Y, Yoshihara T, Sawada K, Doyu M, Yamamoto M, Kato K, Yotsumoto Y, Sobue G. Source: Febs Letters. 2002 November 6; 531(2): 354-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12417341&dopt=Abstract

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Differentiation of multiple sclerosis plaques, subacute cerebral ischaemic infarcts, focal vasogenic oedema and lesions of subcortical arteriosclerotic encephalopathy using magnetisation transfer measurements. Author(s): Reidel MA, Stippich C, Heiland S, Storch-Hagenlocher B, Jansen O, Hahnel S. Source: Neuroradiology. 2003 May; 45(5): 289-94. Epub 2003 April 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700877&dopt=Abstract

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Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability. Author(s): De Stefano N, Narayanan S, Francis SJ, Smith S, Mortilla M, Tartaglia MC, Bartolozzi ML, Guidi L, Federico A, Arnold DL. Source: Archives of Neurology. 2002 October; 59(10): 1565-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12374493&dopt=Abstract

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Diffusion imaging in multiple sclerosis. Author(s): Bammer R, Fazekas F. Source: Neuroimaging Clin N Am. 2002 February; 12(1): 71-106. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11998254&dopt=Abstract

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Diffusion MR imaging of giant cell tumors in tuberous sclerosis. Author(s): Sener RN. Source: Journal of Computer Assisted Tomography. 2003 May-June; 27(3): 431-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12794612&dopt=Abstract

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Diffusion tensor imaging detects corticospinal tract involvement at multiple levels in amyotrophic lateral sclerosis. Author(s): Toosy AT, Werring DJ, Orrell RW, Howard RS, King MD, Barker GJ, Miller DH, Thompson AJ. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 September; 74(9): 1250-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12933929&dopt=Abstract

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Digital necrosis related to carboplatin and gemcitabine therapy in systemic sclerosis. Author(s): Clowse ME, Wigley FM. Source: The Journal of Rheumatology. 2003 June; 30(6): 1341-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12784412&dopt=Abstract

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Discordant effect of IFN-beta1a therapy on anti-IFN antibodies and thyroid disease development in patients with multiple sclerosis. Author(s): Monzani F, Meucci G, Caraccio N, Saviozzi M, Casolaro A, Moscato G, Lombardo F, Mosti S, Scagnolari C, Bruschi F, Antonelli G, Ferrannini E, Murri L. Source: Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research. 2002 July; 22(7): 773-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12184915&dopt=Abstract

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Disease modifying therapies in multiple sclerosis. Author(s): Khatri BO, McQuillen MP. Source: Neurology. 2002 August 13; 59(3): 472; Author Reply 472-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12184316&dopt=Abstract

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Disease modifying therapies in multiple sclerosis. Author(s): Fox RJ, Fisher E, Rudick R. Source: Neurology. 2002 August 13; 59(3): 471-2; Author Reply 472-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12177396&dopt=Abstract

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Disease progression in a transgenic model of familial amyotrophic lateral sclerosis is dependent on both neuronal and non-neuronal zinc binding proteins. Author(s): Puttaparthi K, Gitomer WL, Krishnan U, Son M, Rajendran B, Elliott JL. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2002 October 15; 22(20): 8790-6. Erratum In: J Neurosci. 2003 January 15; 23(2): 1A. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12388585&dopt=Abstract

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Disease-modifying therapies in multiple sclerosis: an update on recent and ongoing trials and future strategies. Author(s): Wiendl H, Kieseier BC. Source: Expert Opinion on Investigational Drugs. 2003 April; 12(4): 689-712. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12665424&dopt=Abstract

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Disease-modifying therapy in relapsing--remitting multiple sclerosis: efficacy is paramount. Author(s): Cristiano E. Source: Int J Clin Pract Suppl. 2002 September; (131): 3-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12564806&dopt=Abstract

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Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: evidence for a protective role of acetylcarnitine. Author(s): Calabrese V, Scapagnini G, Ravagna A, Bella R, Butterfield DA, Calvani M, Pennisi G, Giuffrida Stella AM. Source: Neurochemical Research. 2003 September; 28(9): 1321-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12938853&dopt=Abstract

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Dissociating perceptual and conceptual implicit memory in multiple sclerosis patients. Author(s): Blum D, Yonelinas AP, Luks T, Newitt D, Oh J, Lu Y, Nelson S, Goodkin D, Pelletier D. Source: Brain and Cognition. 2002 October; 50(1): 51-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372351&dopt=Abstract

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Dissociation between neurodegeneration and caspase-11-mediated activation of caspase-1 and caspase-3 in a mouse model of amyotrophic lateral sclerosis. Author(s): Kang SJ, Sanchez I, Jing N, Yuan J. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2003 July 2; 23(13): 5455-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843244&dopt=Abstract

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Distinct immune profiles characterize patients with diffuse or limited systemic sclerosis. Author(s): Ingegnoli F, Trabattoni D, Saresella M, Fantini F, Clerici M. Source: Clinical Immunology (Orlando, Fla.). 2003 July; 108(1): 21-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865067&dopt=Abstract

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Disturbed function and plasticity in multiple sclerosis as gleaned from functional magnetic resonance imaging. Author(s): Filippi M, Rocca MA. Source: Current Opinion in Neurology. 2003 June; 16(3): 275-82. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858062&dopt=Abstract

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Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis. Author(s): Zamvil SS, Steinman L. Source: Neuron. 2003 June 5; 38(5): 685-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797954&dopt=Abstract

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DNA base-excision repair enzyme apurinic/apyrimidinic endonuclease/redox factor-1 is increased and competent in the brain and spinal cord of individuals with amyotrophic lateral sclerosis. Author(s): Shaikh AY, Martin LJ. Source: Neuromolecular Medicine. 2002; 2(1): 47-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12230304&dopt=Abstract

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Do myelin-directed antibodies predict multiple sclerosis? Author(s): Antel JP, Bar-Or A. Source: The New England Journal of Medicine. 2003 July 10; 349(2): 107-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853581&dopt=Abstract

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Dorfin localizes to the ubiquitylated inclusions in Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and amyotrophic lateral sclerosis. Author(s): Hishikawa N, Niwa J, Doyu M, Ito T, Ishigaki S, Hashizume Y, Sobue G. Source: American Journal of Pathology. 2003 August; 163(2): 609-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875980&dopt=Abstract

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Doublecortin immunoreactivity in giant cells of tuberous sclerosis and focal cortical dysplasia. Author(s): Mizuguchi M, Yamanouchi H, Becker LE, Itoh M, Takashima S. Source: Acta Neuropathologica. 2002 October; 104(4): 418-24. Epub 2002 June 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12200630&dopt=Abstract

180 Sclerosis

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Drug therapy for amyotrophic lateral sclerosis: Where are we now? Author(s): Carter GT, Krivickas LS, Weydt P, Weiss MD, Miller RG. Source: Idrugs. 2003 February; 6(2): 147-53. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12789618&dopt=Abstract

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Dual benefit from intramuscular interferon-beta treatment in a patient with multiple sclerosis and chronic hepatitis-C virus infection. Author(s): Tan FU, Cetinkaya H, Erden E, Ulkatan S, Aydin N. Source: Hepatogastroenterology. 2002 November-December; 49(48): 1686-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12397766&dopt=Abstract

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Dynamic properties of the G93A mutant of copper-zinc superoxide dismutase as detected by NMR spectroscopy: implications for the pathology of familial amyotrophic lateral sclerosis. Author(s): Shipp EL, Cantini F, Bertini I, Valentine JS, Banci L. Source: Biochemistry. 2003 February 25; 42(7): 1890-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12590575&dopt=Abstract

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Dynamics of immune cell trafficking in interferon-beta treated multiple sclerosis patients. Author(s): Hartrich L, Weinstock-Guttman B, Hall D, Badgett D, Baier M, Patrick K, Feichter J, Hong J, Ramanathan M. Source: Journal of Neuroimmunology. 2003 June; 139(1-2): 84-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799025&dopt=Abstract

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Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Author(s): Confavreux C, Vukusic S, Adeleine P. Source: Brain; a Journal of Neurology. 2003 April; 126(Pt 4): 770-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615637&dopt=Abstract

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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. 2003 May; 74(5): 683-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700323&dopt=Abstract

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Early use of interferon beta patients with multiple sclerosis. Author(s): Bosley EB, Capildeo R. Source: Int J Clin Pract Suppl. 2002 September; (131): 17-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12564808&dopt=Abstract

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Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996-2000. Author(s): Traynor BJ, Alexander M, Corr B, Frost E, Hardiman O. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 September; 74(9): 1258-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12933930&dopt=Abstract

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Effect of combined IFNbeta-1a and glatiramer acetate therapy on GA-specific T-cell responses in multiple sclerosis. Author(s): Dhib-Jalbut S, Chen M, Henschel K, Ford D, Costello K, Panitch H. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 December; 8(6): 485-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474988&dopt=Abstract

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Effect of N-acetyl-L-cysteine on peroxynitrite and superoxide anion production of lung alveolar macrophages in systemic sclerosis. Author(s): Failli P, Palmieri L, D'Alfonso C, Giovannelli L, Generini S, Rosso AD, Pignone A, Stanflin N, Orsi S, Zilletti L, Matucci-Cerinic M. Source: Nitric Oxide : Biology and Chemistry / Official Journal of the Nitric Oxide Society. 2002 December; 7(4): 277-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12446176&dopt=Abstract

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Effects of a short outpatient rehabilitation treatment on disability of multiple sclerosis patients--a randomised controlled trial. Author(s): Patti F, Ciancio MR, Cacopardo M, Reggio E, Fiorilla T, Palermo F, Reggio A, Thompson AJ. Source: Journal of Neurology. 2003 July; 250(7): 861-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883930&dopt=Abstract

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Effects of an energy conservation course on fatigue impact for persons with progressive multiple sclerosis. Author(s): Vanage SM, Gilbertson KK, Mathiowetz V. Source: Am J Occup Ther. 2003 May-June; 57(3): 315-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12785670&dopt=Abstract

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Effects of combination therapy of beta-interferon 1a and prednisone on serum immunologic markers in patients with multiple sclerosis. Author(s): Salama HH, Kolar OJ, Zang YC, Zhang J. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 2831. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617264&dopt=Abstract

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Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: meta-analysis of three double-blind, randomized, placebo-controlled clinical trials. Author(s): Boneschi FM, Rovaris M, Johnson KP, Miller A, Wolinsky JS, Ladkani D, Shifroni G, Comi G, Filippi M. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 34955. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926839&dopt=Abstract

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Effects of mitoxantrone on multiple sclerosis patients' lymphocyte subpopulations and production of immunoglobulin, TNF-alpha and IL-10. Author(s): Gbadamosi J, Buhmann C, Tessmer W, Moench A, Haag F, Heesen C. Source: European Neurology. 2003; 49(3): 137-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12646755&dopt=Abstract

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Effects of oral cyclophosphamide and prednisolone therapy on the endothelial functions and clinical findings in patients with early diffuse systemic sclerosis. Author(s): Apras S, Ertenli I, Ozbalkan Z, Kiraz S, Ozturk MA, Haznedaroglu IC, Cobankara V, Pay S, Calguneri M. Source: Arthritis and Rheumatism. 2003 August; 48(8): 2256-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12905480&dopt=Abstract

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Effects of pregnancy on the renal and pulmonary manifestations in women with tuberous sclerosis complex. Author(s): Mitchell AL, Parisi MA, Sybert VP. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2003 May-June; 5(3): 154-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12792422&dopt=Abstract

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Efficacy and safety of repeated intrathecal triamcinolone acetonide application in progressive multiple sclerosis patients. Author(s): Hoffmann V, Schimrigk S, Islamova S, Hellwig K, Lukas C, Brune N, Pohlau D, Przuntek H, Muller T. Source: Journal of the Neurological Sciences. 2003 July 15; 211(1-2): 81-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767502&dopt=Abstract

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Electrophysiological evidence for a defect in the processing of temporal sound patterns in multiple sclerosis. Author(s): Jones SJ, Sprague L, Vaz Pato M. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 November; 73(5): 561-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12397152&dopt=Abstract

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Elevated exhalation of hydrogen peroxide in patients with systemic sclerosis. Author(s): Luczynska M, Szkudlarek U, Dziankowska-Bartkowiak B, Waszczykowska E, Kasielski M, Sysa-Jedrzejowska A, Nowak D. Source: European Journal of Clinical Investigation. 2003 March; 33(3): 274-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12641548&dopt=Abstract

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Elevated levels of neurotrophins in human biceps brachii tissue of amyotrophic lateral sclerosis. Author(s): Kust BM, Copray JC, Brouwer N, Troost D, Boddeke HW. Source: Experimental Neurology. 2002 October; 177(2): 419-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12429188&dopt=Abstract

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Elevated osteopontin levels in active relapsing-remitting multiple sclerosis. Author(s): Vogt MH, Lopatinskaya L, Smits M, Polman CH, Nagelkerken L. Source: Annals of Neurology. 2003 June; 53(6): 819-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783433&dopt=Abstract

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Elevated suicide risk among patients with multiple sclerosis in Sweden. Author(s): Fredrikson S, Cheng Q, Jiang GX, Wasserman D. Source: Neuroepidemiology. 2003 March-April; 22(2): 146-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12629281&dopt=Abstract

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Endocrine and cytokine responses to acute psychological stress in multiple sclerosis. Author(s): Heesen C, Schulz H, Schmidt M, Gold S, Tessmer W, Schulz KH. Source: Brain, Behavior, and Immunity. 2002 June; 16(3): 282-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12009688&dopt=Abstract

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Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis. Author(s): Ilzecka J, Kocki T, Stelmasiak Z, Turski WA. Source: Acta Neurologica Scandinavica. 2003 June; 107(6): 412-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757473&dopt=Abstract

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Endothelial-dependent vasodilation is impaired in patients with systemic sclerosis, as assessed by low dose iontophoresis. Author(s): Anderson ME, Moore TL, Hollis S, Clark S, Jayson MI, Herrick AL. Source: Clin Exp Rheumatol. 2003 May-June; 21(3): 403. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846066&dopt=Abstract

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Endothelin-I receptor antagonist for the treatment of pulmonary arterial hypertension in systemic sclerosis. Author(s): Varga J. Source: Curr Rheumatol Rep. 2003 April; 5(2): 145-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628045&dopt=Abstract

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Environmental exposure to trace elements and risk of amyotrophic lateral sclerosis: a population-based case-control study. Author(s): Bergomi M, Vinceti M, Nacci G, Pietrini V, Bratter P, Alber D, Ferrari A, Vescovi L, Guidetti D, Sola P, Malagu S, Aramini C, Vivoli G. Source: Environmental Research. 2002 June; 89(2): 116-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12123644&dopt=Abstract

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Epidemiological and clinical patterns of western pacific amyotrophic lateral sclerosis (ALS) in Guam and sporadic ALS in Rochester, Minnesota, U.S.A. and Hokkaido, Japan: a comparative study. Author(s): Okumura H. Source: Hokkaido Igaku Zasshi. 2003 May; 78(3): 187-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12795170&dopt=Abstract

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Epidemiological data of multiple sclerosis in the province of Evros, Greece. Author(s): Piperidou HN, Heliopoulos IN, Maltezos ES, Milonas IA. Source: European Neurology. 2003; 49(1): 8-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12464712&dopt=Abstract

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Epidemiology and multiple sclerosis. Author(s): Kurtzke JF. Source: Revista De Neurologia. 2002 December 16-31; 35(12): 1177. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12587573&dopt=Abstract

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Epilepsia partialis continua as a first symptom of multiple sclerosis: electrophysiological study of one case. Author(s): Striano P, Striano S, Carrieri PB, Boccella P. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 199203. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708815&dopt=Abstract

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Epilepsy and multiple sclerosis. Author(s): Poser CM, Brinar VV. Source: Epilepsy & Behavior : E&B. 2003 February; 4(1): 6-12. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12609222&dopt=Abstract

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Epilepsy surgery in tuberous sclerosis: multistage procedures with bilateral or multilobar foci. Author(s): Romanelli P, Najjar S, Weiner HL, Devinsky O. Source: Journal of Child Neurology. 2002 September; 17(9): 689-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12503646&dopt=Abstract

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Epilepsy surgery outcome in children with focal epilepsy due to tuberous sclerosis complex. Author(s): Karenfort M, Kruse B, Freitag H, Pannek H, Tuxhorn I. Source: Neuropediatrics. 2002 October; 33(5): 255-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12536368&dopt=Abstract

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Epileptic seizures, cranial neuralgias and paroxysmal symptoms in remitting and progressive multiple sclerosis. Author(s): Eriksson M, Ben-Menachem E, Andersen O. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 December; 8(6): 495-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474990&dopt=Abstract

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Epitope spreading and molecular mimicry as triggers of autoimmunity in the Theiler's virus-induced demyelinating disease model of multiple sclerosis. Author(s): Croxford JL, Olson JK, Miller SD. Source: Autoimmunity Reviews. 2002 October; 1(5): 251-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848977&dopt=Abstract

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Epstein-barr virus and risk of multiple sclerosis. Author(s): Tenser RB. Source: Jama : the Journal of the American Medical Association. 2003 July 9; 290(2): 1923; Author Reply 193. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12851269&dopt=Abstract

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Epstein-Barr virus and risk of multiple sclerosis. Author(s): Lily O. Source: Jama : the Journal of the American Medical Association. 2003 July 9; 290(2): 192; Author Reply 193. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12851268&dopt=Abstract

186 Sclerosis

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Erythrocyte zinc, copper, and copper/zinc superoxide dismutase and risk of sporadic amyotrophic lateral sclerosis: a population-based case-control study. Author(s): Vinceti M, Bergomi M, Nacci G, Pietrini V, Ferrari A, Fortini K, Guidetti D, Sola P, Rocchi E, Mancia D, Vivoli G. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. 2002 December; 3(4): 208-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710510&dopt=Abstract

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Ethnicity and race and systemic sclerosis: how it affects susceptibility, severity, antibody genetics, and clinical manifestations. Author(s): Reveille JD. Source: Curr Rheumatol Rep. 2003 April; 5(2): 160-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628048&dopt=Abstract

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European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. III. Assessment of the construct validity of the preliminary activity criteria. Author(s): Valentini G, Bencivelli W, Bombardieri S, D'Angelo S, Della Rossa A, Silman AJ, Black CM, Czirjak L, Nielsen H, Vlachoyiannopoulos PG. Source: Annals of the Rheumatic Diseases. 2003 September; 62(9): 901-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12922968&dopt=Abstract

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European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. IV. Assessment of skin thickening by modified Rodnan skin score. Author(s): Valentini G, D'Angelo S, Della Rossa A, Bencivelli W, Bombardieri S. Source: Annals of the Rheumatic Diseases. 2003 September; 62(9): 904-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12922969&dopt=Abstract

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Evaluation of functional disability using the health assessment questionnaire in Japanese patients with systemic sclerosis. Author(s): Kuwana M, Sato S, Kikuchi K, Kawaguchi Y, Fujisaku A, Misaki Y, Hatamochi A, Kondo H, Takehara K. Source: The Journal of Rheumatology. 2003 June; 30(6): 1253-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12784399&dopt=Abstract

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Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Author(s): Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, Montanari E, Zaffaroni M; Independent Comparison of Interferon (INCOMIN) Trial Study Group. Source: Lancet. 2002 April 27; 359(9316): 1453-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11988242&dopt=Abstract

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Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis. Author(s): Rocca MA, Mezzapesa DM, Falini A, Ghezzi A, Martinelli V, Scotti G, Comi G, Filippi M. Source: Neuroimage. 2003 April; 18(4): 847-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725761&dopt=Abstract

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Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Author(s): Filippi M, Bozzali M, Rovaris M, Gonen O, Kesavadas C, Ghezzi A, Martinelli V, Grossman RI, Scotti G, Comi G, Falini A. Source: Brain; a Journal of Neurology. 2003 February; 126(Pt 2): 433-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12538409&dopt=Abstract

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Evidence of Wallerian degeneration in normal appearing white matter in the early stages of relapsing-remitting multiple sclerosis: a HMRS study. Author(s): Casanova B, Martinez-Bisbal MC, Valero C, Celda B, Marti-Bonmati L, Pascual A, Landente L, Coret F. Source: Journal of Neurology. 2003 January; 250(1): 22-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527988&dopt=Abstract

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Evidence-based measurement in multiple sclerosis: the psychometric properties of the physical and psychological dimensions of three quality of life rating scales. Author(s): Riazi A, Hobart JC, Lamping DL, Fitzpatrick R, Thompson AJ. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 411-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926848&dopt=Abstract

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Evolution of T1 black holes in patients with multiple sclerosis imaged monthly for 4 years. Author(s): Bagnato F, Jeffries N, Richert ND, Stone RD, Ohayon JM, McFarland HF, Frank JA. Source: Brain; a Journal of Neurology. 2003 August; 126(Pt 8): 1782-9. Epub 2003 June 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821527&dopt=Abstract

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Excitatory amino acids and multiple sclerosis: evidence from cerebrospinal fluid. Author(s): Sarchielli P, Greco L, Floridi A, Floridi A, Gallai V. Source: Archives of Neurology. 2003 August; 60(8): 1082-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925363&dopt=Abstract

188 Sclerosis

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Expectations of wheelchair-dependency in recently diagnosed patients with multiple sclerosis and their partners. Author(s): Janssens AC, de Boer JB, van Doorn PA, van ver Ploeg HM, van ver Meche FG, Passchier J, Hintzen RQ. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2003 May; 10(3): 287-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12752403&dopt=Abstract

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Expression of beta2 adrenoreceptors on peripheral blood mononuclear cells in patients with primary and secondary progressive multiple sclerosis: a longitudinal six month study. Author(s): Zoukos Y, Thomaides TN, Kidd D, Cuzner ML, Thompson A. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 February; 74(2): 197202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531948&dopt=Abstract

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Expression of CD5 on B lymphocytes correlates with disease activity in patients with multiple sclerosis. Author(s): Seidi OA, Semra YK, Sharief MK. Source: Journal of Neuroimmunology. 2002 December; 133(1-2): 205-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12446024&dopt=Abstract

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Expression of chemokine receptor CXCR3 on cerebrospinal fluid T-cells is related to active MRI lesion appearance in patients with relapsing-remitting multiple sclerosis. Author(s): Sindern E, Patzold T, Ossege LM, Gisevius A, Malin JP. Source: Journal of Neuroimmunology. 2002 October; 131(1-2): 186-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458051&dopt=Abstract

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Expression of hepatocyte growth factor and c-Met in the anterior horn cells of the spinal cord in the patients with amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS and familial ALS with superoxide dismutase 1 gene mutation. Author(s): Kato S, Funakoshi H, Nakamura T, Kato M, Nakano I, Hirano A, Ohama E. Source: Acta Neuropathologica. 2003 August; 106(2): 112-20. Epub 2003 April 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12707786&dopt=Abstract

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Expression of macrophage migration inhibitory factor in diffuse systemic sclerosis. Author(s): Selvi E, Tripodi SA, Catenaccio M, Lorenzini S, Chindamo D, Manganelli S, Romagnoli R, Ietta F, Paulesu L, Miracco C, Cintorino M, Marcolongo R. Source: Annals of the Rheumatic Diseases. 2003 May; 62(5): 460-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12695161&dopt=Abstract

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Expression profiling identifies responder and non-responder phenotypes to interferon-beta in multiple sclerosis. Author(s): Sturzebecher S, Wandinger KP, Rosenwald A, Sathyamoorthy M, Tzou A, Mattar P, Frank JA, Staudt L, Martin R, McFarland HF. Source: Brain; a Journal of Neurology. 2003 June; 126(Pt 6): 1419-29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12764062&dopt=Abstract

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Expression ratios of the Bcl-2 family proteins and disease activity in multiple sclerosis. Author(s): Sharief MK, Matthews H, Noori MA. Source: Journal of Neuroimmunology. 2003 January; 134(1-2): 158-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12507784&dopt=Abstract

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Extracellular potentials of human motor myelinated nerve fibers in normal case and in amyotrophic lateral sclerosis. Author(s): Stephanova DI, Daskalova M. Source: Electromyogr Clin Neurophysiol. 2002 October-November; 42(7): 443-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12395619&dopt=Abstract

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Extraocular blood flow and endothelin-1 plasma levels in patients with multiple sclerosis. Author(s): Pache M, Kaiser HJ, Akhalbedashvili N, Lienert C, Dubler B, Kappos L, Flammer J. Source: European Neurology. 2003; 49(3): 164-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12646761&dopt=Abstract

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Factors predicting outcome of surgery for intractable epilepsy with pathologically verified mesial temporal sclerosis. Author(s): Hardy SG, Miller JW, Holmes MD, Born DE, Ojemann GA, Dodrill CB, Hallam DK. Source: Epilepsia. 2003 April; 44(4): 565-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12681006&dopt=Abstract

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Factors that contribute to quality of life outcomes prioritised by people with multiple sclerosis. Author(s): Somerset M, Peters TJ, Sharp DJ, Campbell R. Source: Quality of Life Research : an International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation. 2003 February; 12(1): 21-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12625515&dopt=Abstract

190 Sclerosis

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Factors that predict health-related quality of life in patients with relapsing-remitting multiple sclerosis. Author(s): Miller DM, Rudick RA, Baier M, Cutter G, Doughtery DS, WeinstockGuttman B, Mass MK, Fisher E, Simonian N. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 1-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617260&dopt=Abstract

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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. 2003; 41(2): 59-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899197&dopt=Abstract

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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. 2003 February 21; 278(8): 5984-92. Epub 2002 November 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458194&dopt=Abstract

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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. 2002 December; 3(4): 244-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710516&dopt=Abstract

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Familial multiple sclerosis: case study of three affected siblings. Author(s): Bencsik K, Rajda C, Seres E, Voros E, Janaky M, Dibo G, Jardanhazy T, Vecsei L. Source: Acta Neurologica Scandinavica. 2002 December; 106(6): 392-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12460148&dopt=Abstract

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Fas expression on T cells and sFas in relapsing-remitting multiple sclerosis. Author(s): Bilinska M, Frydecka I, Podemski R, Gruszka E. Source: Acta Neurologica Scandinavica. 2003 June; 107(6): 387-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757469&dopt=Abstract

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Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters. Author(s): Flachenecker P, Kumpfel T, Kallmann B, Gottschalk M, Grauer O, Rieckmann P, Trenkwalder C, Toyka KV. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 December; 8(6): 523-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474995&dopt=Abstract

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Fatigue in multiple sclerosis: current understanding and future directions. Author(s): Schwid SR, Covington M, Segal BM, Goodman AD. Source: Journal of Rehabilitation Research and Development. 2002 March-April; 39(2): 211-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12051465&dopt=Abstract

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Fatigue in multiple sclerosis: definition, pathophysiology and treatment. Author(s): Krupp LB. Source: Cns Drugs. 2003; 17(4): 225-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12665396&dopt=Abstract

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Fatigue in multiple sclerosis: reciprocal relationships with physical disabilities and depression. Author(s): Schreurs KM, de Ridder DT, Bensing JM. Source: Journal of Psychosomatic Research. 2002 September; 53(3): 775-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12217451&dopt=Abstract

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Febrile seizures and mesial temporal sclerosis: No association in a long-term followup study. Author(s): Tarkka R, Paakko E, Pyhtinen J, Uhari M, Rantala H. Source: Neurology. 2003 January 28; 60(2): 215-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12552033&dopt=Abstract

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Fifteen cases of encapsulating peritoneal sclerosis related to peritoneal dialysis: a single-center experience in Japan. Author(s): Yamamoto H, Nakayama M, yamamoto R, Otsuka Y, Takahashi H, Kato N, Hayakawa H, Hasegawa T, Ikeda M, Yokoyama K, Kawaguchi Y, Mukai H, Hosoya T. Source: Adv Perit Dial. 2002; 18: 135-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12402605&dopt=Abstract

192 Sclerosis

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Fine mapping of a multiple sclerosis locus to 2.5 Mb on chromosome 17q22-q24. Author(s): Saarela J, Schoenberg Fejzo M, Chen D, Finnila S, Parkkonen M, Kuokkanen S, Sobel E, Tienari PJ, Sumelahti ML, Wikstrom J, Elovaara I, Koivisto K, Pirttila T, Reunanen M, Palotie A, Peltonen L. Source: Human Molecular Genetics. 2002 September 15; 11(19): 2257-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12217954&dopt=Abstract

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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.). 2002 September 15; 45(4): 245-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12125045&dopt=Abstract

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Fluency in multiple sclerosis: which measure is best? Author(s): Beatty WW. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 May; 8(3): 261-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12120700&dopt=Abstract

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Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis. Author(s): Becker AJ, Urbach H, Scheffler B, Baden T, Normann S, Lahl R, Pannek HW, Tuxhorn I, Elger CE, Schramm J, Wiestler OD, Blumcke I. Source: Annals of Neurology. 2002 July; 52(1): 29-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12112044&dopt=Abstract

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Focal segmental glomerular sclerosis in two patients with Addison's disease: any more than fortuitous development of glomerular disease? Author(s): Arrizabalaga P, Bergada E, Sole M, Halperin I, Botey A. Source: American Journal of Nephrology. 2002 July-August; 22(4): 389-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12169875&dopt=Abstract

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Focal thinning of the cerebral cortex in multiple sclerosis. Author(s): Sailer M, Fischl B, Salat D, Tempelmann C, Schonfeld MA, Busa E, Bodammer N, Heinze HJ, Dale A. Source: Brain; a Journal of Neurology. 2003 August; 126(Pt 8): 1734-44. Epub 2003 June 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12805100&dopt=Abstract

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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. 2003 March 22; 361(9362): 1007-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12660059&dopt=Abstract

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Free intra-abdominal gas associated with octreotide use: intestinal perforation or benign pneumoperitoneum associated with underlying systemic sclerosis? Author(s): Yarze JC, Chase MP. Source: The American Journal of Gastroenterology. 2002 July; 97(7): 1844-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12135052&dopt=Abstract

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Frequencies of the G-protein beta3 subunit C825T polymorphism and the delta 32 mutation of the chemokine receptor-5 in patients with multiple sclerosis. Author(s): Haase CG, Schmidt S, Faustmann PM. Source: Neuroscience Letters. 2002 September 27; 330(3): 293-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12270649&dopt=Abstract

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Frequency of functional interleukin-10 promoter polymorphism is different between relapse-onset and primary progressive multiple sclerosis. Author(s): de Jong BA, Westendorp RG, Eskdale J, Uitdehaag BM, Huizinga TW. Source: Human Immunology. 2002 April; 63(4): 281-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12039409&dopt=Abstract

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From swelling to sclerosis: acute change in mesial hippocampus after prolonged febrile seizure. Author(s): Sokol DK, Demyer WE, Edwards-Brown M, Sanders S, Garg B. Source: Seizure : the Journal of the British Epilepsy Association. 2003 June; 12(4): 237-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12763472&dopt=Abstract

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Frontal fluency and memory functioning among multiple sclerosis patients in Hong Kong. Author(s): Tong BS, Yip JT, Lee TM, Li LS. Source: Brain Injury : [bi]. 2002 November; 16(11): 987-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12443548&dopt=Abstract

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Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis. Author(s): Sato S, Hayakawa I, Hasegawa M, Fujimoto M, Takehara K. Source: The Journal of Investigative Dermatology. 2003 April; 120(4): 542-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12648215&dopt=Abstract

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Functional brain reorganization for hand movement in patients with multiple sclerosis: defining distinct effects of injury and disability. Author(s): Reddy H, Narayanan S, Woolrich M, Mitsumori T, Lapierre Y, Arnold DL, Matthews PM. Source: Brain; a Journal of Neurology. 2002 December; 125(Pt 12): 2646-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12429592&dopt=Abstract

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Functional cortical changes in patients with multiple sclerosis and nonspecific findings on conventional magnetic resonance imaging scans of the brain. Author(s): Rocca MA, Pagani E, Ghezzi A, Falini A, Zaffaroni M, Colombo B, Scotti G, Comi G, Filippi M. Source: Neuroimage. 2003 July; 19(3): 826-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12880811&dopt=Abstract

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Functional properties of myelin oligodendrocyte glycoprotein-reactive T cells in multiple sclerosis patients and controls. Author(s): Van der Aa A, Hellings N, Bernard CC, Raus J, Stinissen P. Source: Journal of Neuroimmunology. 2003 April; 137(1-2): 164-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667661&dopt=Abstract

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Functional tyrosine kinase inhibitor profiling: a generally applicable method points to a novel role of platelet-derived growth factor receptor-beta in tuberous sclerosis. Author(s): Arbiser JL, Govindarajan B, Bai X, Onda H, Kazlauskas A, Lim SD, Amin MB, Claesson-Welsh L. Source: American Journal of Pathology. 2002 September; 161(3): 781-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12213705&dopt=Abstract

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Functions of the stratum corneum in systemic sclerosis as distinct from hypertrophic scar and keloid functions. Author(s): Sogabe Y, Akimoto S, Abe M, Ishikawa O, Takagi Y, Imokawa G. Source: Journal of Dermatological Science. 2002 May; 29(1): 49-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12007721&dopt=Abstract

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Future immunotherapies in multiple sclerosis. Author(s): Blevins G, Martin R. Source: Seminars in Neurology. 2003 June; 23(2): 147-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894380&dopt=Abstract

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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. 2002 September; 3(3): 131-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495574&dopt=Abstract

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GABA(A) receptor active steroids are altered in epilepsy patients with tuberous sclerosis. Author(s): di Michele F, Verdecchia M, Dorofeeva M, Costamagna L, Bernardi G, Curatolo P, Romeo E. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 May; 74(5): 667-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700317&dopt=Abstract

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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. 2003 March; 24(3): 476-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12637300&dopt=Abstract

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Gadolinium-enhanced magnetic resonance imaging predicts response to methylprednisolone in multiple sclerosis. Author(s): Sellebjerg F, Jensen CV, Larsson HB, Frederiksen JL. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 1027. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617276&dopt=Abstract

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Gamma knife radiosurgery for treatment of trigeminal neuralgia in multiple sclerosis patients. Author(s): Huang E, Teh BS, Zeck O, Woo SY, Lu HH, Chiu JK, Butler EB, Gormley WB, Carpenter LS. Source: Stereotactic and Functional Neurosurgery. 2002; 79(1): 44-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12677104&dopt=Abstract

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Gamma knife radiosurgery for trigeminal neuralgia associated with multiple sclerosis. Author(s): Rogers CL, Shetter AG, Ponce FA, Fiedler JA, Smith KA, Speiser BL. Source: Journal of Neurosurgery. 2002 December; 97(5 Suppl): 529-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12507090&dopt=Abstract

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gamma/delta T cells in multiple sclerosis: chemokine and chemokine receptor expression. Author(s): Murzenok PP, Matusevicius D, Freedman MS. Source: Clinical Immunology (Orlando, Fla.). 2002 June; 103(3 Pt 1): 309-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12173306&dopt=Abstract

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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. 1999 December; 1(1): 15-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12365061&dopt=Abstract

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Gelatinase B, PECAM-1 and MCP-3 gene polymorphisms in Belgian multiple sclerosis. Author(s): Nelissen I, Dubois B, Goris A, Ronsse I, Carton H, Opdenakker G. Source: Journal of the Neurological Sciences. 2002 August 15; 200(1-2): 43-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12127674&dopt=Abstract

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Gender analyses of nursing home residents with multiple sclerosis. Author(s): Buchanan RJ, Wang S, Ju H. Source: J Gend Specif Med. 2003; 6(2): 35-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814001&dopt=Abstract

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Gender prevalence in childhood multiple sclerosis and myasthenia gravis. Author(s): Haliloglu G, Anlar B, Aysun S, Topcu M, Topaloglu H, Turanli G, Yalnizoglu D. Source: Journal of Child Neurology. 2002 May; 17(5): 390-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12150589&dopt=Abstract

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Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Author(s): Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, LangerGould A, Strober S, Cannella B, Allard J, Klonowski P, Austin A, Lad N, Kaminski N, Galli SJ, Oksenberg JR, Raine CS, Heller R, Steinman L. Source: Nature Medicine. 2002 May; 8(5): 500-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11984595&dopt=Abstract

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Genetic aspects of multiple sclerosis. Author(s): Oksenberg JR, Barcellos LF, Hauser SL. Source: Seminars in Neurology. 1999; 19(3): 281-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12194384&dopt=Abstract

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Genetic epidemiology: systemic sclerosis. Author(s): Herrick AL, Worthington J. Source: Arthritis Research. 2002; 4(3): 165-8. Epub 2002 January 16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12010566&dopt=Abstract

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Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients. Author(s): Alizadeh M, Babron MC, Birebent B, Matsuda F, Quelvennec E, Liblau R, Cournu-Rebeix I, Momigliano-Richiardi P, Sequeiros J, Yaouanq J, Genin E, Vasilescu A, Bougerie H, Trojano M, Martins Silva B, Maciel P, Clerget-Darpoux F, Clanet M, Edan G, Fontaine B, Semana G. Source: Annals of Neurology. 2003 July; 54(1): 119-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12838528&dopt=Abstract

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Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients. Author(s): Niino M, Kikuchi S, Fukazawa T, Yabe I, Tashiro K. Source: Journal of Neuroimmunology. 2003 March; 136(1-2): 125-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12620651&dopt=Abstract

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Genetic programs and responses of neural stem/progenitor cells during demyelination: potential insights into repair mechanisms in multiple sclerosis. Author(s): Imitola J, Snyder EY, Khoury SJ. Source: Physiological Genomics. 2003 August 15; 14(3): 171-97. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923300&dopt=Abstract

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Genetics of multiple sclerosis: determinants of autoimmunity and neurodegeneration. Author(s): Kalman B, Albert RH, Leist TP. Source: Autoimmunity. 2002 July; 35(4): 225-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12482189&dopt=Abstract

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Genetics of multiple sclerosis: linkage and association studies. Author(s): Giordano M, D'Alfonso S, Momigliano-Richiardi P. Source: American Journal of Pharmacogenomics : Genomics-Related Research in Drug Development and Clinical Practice. 2002; 2(1): 37-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12083953&dopt=Abstract

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Genome-wide association study for regions of systemic sclerosis susceptibility in a Choctaw Indian population with high disease prevalence. Author(s): Zhou X, Tan FK, Wang N, Xiong M, Maghidman S, Reveille JD, Milewicz DM, Chakraborty R, Arnett FC. Source: Arthritis and Rheumatism. 2003 September; 48(9): 2585-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13130478&dopt=Abstract

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Genome-wide linkage screen of a consanguineous multiple sclerosis kinship. Author(s): Modin H, Masterman T, Thorlacius T, Stefansson M, Jonasdottir A, Stefansson K, Hillert J, Gulcher J. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 128-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708807&dopt=Abstract

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Geographic and temporal distribution of mortality rates for multiple sclerosis in Canada, 1965-1994. Author(s): Warren S, Warren KG, Svenson LW, Schopflocher DP, Jones A. Source: Neuroepidemiology. 2003 January-February; 22(1): 75-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12566957&dopt=Abstract

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Glatiramer acetate (Copaxone) therapy for multiple sclerosis. Author(s): Dhib-Jalbut S. Source: Pharmacology & Therapeutics. 2003 May; 98(2): 245-55. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725872&dopt=Abstract

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Glatiramer acetate treatment in patients with childhood and juvenile onset multiple sclerosis. Author(s): Kornek B, Bernert G, Balassy C, Geldner J, Prayer D, Feucht M. Source: Neuropediatrics. 2003 June; 34(3): 120-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12910434&dopt=Abstract

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Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis. Author(s): Simpson D, Noble S, Perry C. Source: Cns Drugs. 2002; 16(12): 825-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12421116&dopt=Abstract

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Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Author(s): Ziemssen T, Kumpfel T, Klinkert WE, Neuhaus O, Hohlfeld R. Source: Brain; a Journal of Neurology. 2002 November; 125(Pt 11): 2381-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12390966&dopt=Abstract

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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. 2003 March; 25(2): 195-200. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12635522&dopt=Abstract

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Glioma and multiple sclerosis: case report. Author(s): Werneck LC, Scola RH, Arruda WO, Torres LF. Source: Arquivos De Neuro-Psiquiatria. 2002 June; 60(2-B): 469-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12131952&dopt=Abstract

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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. 2003 January 1; 23(1): 43-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12514200&dopt=Abstract

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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. 2003 May; 17(8): 938-40. Epub 2003 March 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12626432&dopt=Abstract

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Growth dynamics of meningiomas in patients with multiple sclerosis treated with interferon: report of two cases. Author(s): Batay F, Al-Mefty O. Source: Acta Neurochirurgica. 2002 April; 144(4): 365-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12021883&dopt=Abstract

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Guidelines for using quantitative magnetization transfer magnetic resonance imaging for monitoring treatment of multiple sclerosis. Author(s): Horsfield MA, Barker GJ, Barkhof F, Miller DH, Thompson AJ, Filippi M. Source: Journal of Magnetic Resonance Imaging : Jmri. 2003 April; 17(4): 389-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12655577&dopt=Abstract

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Health-related quality of life and depression in an Italian sample of multiple sclerosis patients. Author(s): Patti F, Cacopardo M, Palermo F, Ciancio MR, Lopes R, Restivo D, Reggio A. Source: Journal of the Neurological Sciences. 2003 July 15; 211(1-2): 55-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767498&dopt=Abstract

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Health-related quality of life and its relationship to cognitive and emotional functioning in multiple sclerosis patients. Author(s): Benito-Leon J, Morales JM, Rivera-Navarro J. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2002 September; 9(5): 497-502. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12220381&dopt=Abstract

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Heart structure and function in systemic sclerosis. Author(s): Plazak W, Zabinska-Plazak E, Wojas-Pelc A, Podolec P, Olszowska M, Tracz W, Bogdaszewska-Czabanowska J. Source: Eur J Dermatol. 2002 May-June; 12(3): 257-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11978567&dopt=Abstract

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Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. Author(s): Fassas A, Passweg JR, Anagnostopoulos A, Kazis A, Kozak T, Havrdova E, Carreras E, Graus F, Kashyap A, Openshaw H, Schipperus M, Deconinck E, Mancardi G, Marmont A, Hansz J, Rabusin M, Zuazu Nagore FJ, Besalduch J, Dentamaro T, Fouillard L, Hertenstein B, La Nasa G, Musso M, Papineschi F, Rowe JM, Saccardi R, Steck A, Kappos L, Gratwohl A, Tyndall A, Samijn J, Samign J; Autoimmune Disease Working Party of the EBMT (European Group for Blood and Marrow Transplantation). Source: Journal of Neurology. 2002 August; 249(8): 1088-97. Erratum In: J Neurol. 2002 November; 249(11): 1619. J Neurol. 2002 October; 249(10): 1482. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12195460&dopt=Abstract

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Hematopoietic stem cell transplantation for multiple sclerosis: current status and future challenges. Author(s): Muraro PA, Cassiani Ingoni R, Martin R. Source: Current Opinion in Neurology. 2003 June; 16(3): 299-305. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858065&dopt=Abstract

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Hemimegalencephaly in tuberous sclerosis complex. Author(s): Galluzzi P, Cerase A, Strambi M, Buoni S, Fois A, Venturi C. Source: Journal of Child Neurology. 2002 September; 17(9): 677-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12503644&dopt=Abstract

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Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Author(s): Kawut SM, Taichman DB, Archer-Chicko CL, Palevsky HI, Kimmel SE. Source: Chest. 2003 February; 123(2): 344-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12576350&dopt=Abstract

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Hemophagocytosis associated with MPO-ANCA positive vasculitis in systemic sclerosis. Author(s): Kumakura S, Ishikura H, Kondo M, Murakawa Y, Kobayashi S. Source: Clin Exp Rheumatol. 2002 May-June; 20(3): 411-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12102482&dopt=Abstract

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Hemoptysis as the first symptom of limited cutaneous systemic sclerosis. Author(s): Pasalidou E, Tzavara V, Vondetsianos Ch, Boki K. Source: Clin Exp Rheumatol. 2003 January-February; 21(1): 140. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12673910&dopt=Abstract

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Hemorrhagic angiomyolipoma and tuberous sclerosis complex: a case report. Author(s): Mirchandani GR, Kempton JE, Dainiak C, Kraus ML. Source: Conn Med. 2002 August; 66(8): 451-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12407954&dopt=Abstract

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Hepatitis B vaccine and risk of multiple sclerosis. Author(s): DeStefano F, Verstraeten T, Chen RT. Source: Expert Rev Vaccines. 2002 December; 1(4): 461-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901584&dopt=Abstract

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Heterogeneity of pathogenesis in multiple sclerosis: implications for promotion of remyelination. Author(s): Paz Soldan MM, Rodriguez M. Source: The Journal of Infectious Diseases. 2002 December 1; 186 Suppl 2: S248-53. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12424705&dopt=Abstract

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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. 2003 July; 28(1): 109-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811781&dopt=Abstract

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HHV-6 DNAaemia in patients with multiple sclerosis in Kuwait. Author(s): Al-Shammari S, Nelson RF, Voevodin A. Source: Acta Neurologica Scandinavica. 2003 February; 107(2): 122-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12580862&dopt=Abstract

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High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial. Author(s): Beck RW, Trobe JD, Moke PS, Gal RL, Xing D, Bhatti MT, Brodsky MC, Buckley EG, Chrousos GA, Corbett J, Eggenberger E, Goodwin JA, Katz B, Kaufman DI, Keltner JL, Kupersmith MJ, Miller NR, Nazarian S, Orengo-Nania S, Savino PJ, Shults WT, Smith CH, Wall M; Optic Neuritis Study Group. Source: Archives of Ophthalmology. 2003 July; 121(7): 944-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860795&dopt=Abstract

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High frequency of human herpesvirus 6 DNA in multiple sclerosis plaques isolated by laser microdissection. Author(s): Cermelli C, Berti R, Soldan SS, Mayne M, D'ambrosia JM, Ludwin SK, Jacobson S. Source: The Journal of Infectious Diseases. 2003 May 1; 187(9): 1377-87. Epub 2003 April 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12717618&dopt=Abstract

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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. 2002 September; 9(5): 525-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12383408&dopt=Abstract

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High incidence of encapsulating peritoneal sclerosis in pediatric patients on peritoneal dialysis longer than 10 years. Author(s): Hoshii S, Honda M. Source: Perit Dial Int. 2002 November-December; 22(6): 730-1. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12556080&dopt=Abstract

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High prevalence of polymorphisms of angiotensin-converting enzyme (I/D) and endothelial nitric oxide synthase (Glu298Asp) in patients with systemic sclerosis. Author(s): Fatini C, Gensini F, Sticchi E, Battaglini B, Angotti C, Conforti ML, Generini S, Pignone A, Abbate R, Matucci-Cerinic M. Source: The American Journal of Medicine. 2002 May; 112(7): 540-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12015245&dopt=Abstract

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High-dose cyclophosphamide in multiple sclerosis patients undergoing autologous stem cell transplantation. Author(s): McGuire TR, Gwilt P, Manouvilov K, Healey K, Ursick MM, Nash RA, Pavletic SZ. Source: International Immunopharmacology. 2003 February; 3(2): 279-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12586609&dopt=Abstract

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High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes. Author(s): McSweeney PA, Nash RA, Sullivan KM, Storek J, Crofford LJ, Dansey R, Mayes MD, McDonagh KT, Nelson JL, Gooley TA, Holmberg LA, Chen CS, Wener MH, Ryan K, Sunderhaus J, Russell K, Rambharose J, Storb R, Furst DE. Source: Blood. 2002 September 1; 100(5): 1602-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12176878&dopt=Abstract

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High-dose intravenous immunoglobulin treatment of multiple sclerosis. Author(s): Durelli L, Isoardo G. Source: Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2002 April; 23 Suppl 1: S39-48. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032586&dopt=Abstract

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High-dose methylprednisolone therapy in multiple sclerosis increases serum uric acid levels. Author(s): Toncev G, Milicic B, Toncev S, Samardzic G. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 May; 40(5): 505-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12113297&dopt=Abstract

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Hippocampal deformation-based shape analysis in epilepsy and unilateral mesial temporal sclerosis. Author(s): Hogan RE, Bucholz RD, Joshi S. Source: Epilepsia. 2003 June; 44(6): 800-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790893&dopt=Abstract

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Hippocampal sclerosis and other hippocampal abnormalities in the early identification of candidates for epilepsy surgery. Author(s): Semah F, Lamy C, Demeret S. Source: Archives of Neurology. 2002 June; 59(6): 1042-3; Author Reply 1043. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12056946&dopt=Abstract

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Hippocampal sclerosis dementia with tauopathy. Author(s): Beach TG, Sue L, Scott S, Layne K, Newell A, Walker D, Baker M, Sahara N, Yen SH, Hutton M, Caselli R, Adler C, Connor D, Sabbagh M. Source: Brain Pathology (Zurich, Switzerland). 2003 July; 13(3): 263-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12946017&dopt=Abstract

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Hippocampal sclerosis in a case of Alzheimer's disease-like dementia with late onset intractable epilepsy. Author(s): Josephs KA, Wai DF, Parisi JE. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2003 May; 10(3): 333-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12752417&dopt=Abstract

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Hippocampal sclerosis is a progressive disorder: a longitudinal volumetric MRI study. Author(s): Fuerst D, Shah J, Shah A, Watson C. Source: Annals of Neurology. 2003 March; 53(3): 413-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12601713&dopt=Abstract

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Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Author(s): Bouros D, Wells AU, Nicholson AG, Colby TV, Polychronopoulos V, Pantelidis P, Haslam PL, Vassilakis DA, Black CM, du Bois RM. Source: American Journal of Respiratory and Critical Care Medicine. 2002 June 15; 165(12): 1581-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12070056&dopt=Abstract

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Hit-Hit and hit-Run: viruses in the playing field of multiple sclerosis. Author(s): Scarisbrick IA, Rodriguez M. Source: Curr Neurol Neurosci Rep. 2003 May; 3(3): 265-71. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12760396&dopt=Abstract

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HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Author(s): Barcellos LF, Oksenberg JR, Begovich AB, Martin ER, Schmidt S, Vittinghoff E, Goodin DS, Pelletier D, Lincoln RR, Bucher P, Swerdlin A, Pericak-Vance MA, Haines JL, Hauser SL; Multiple Sclerosis Genetics Group. Source: American Journal of Human Genetics. 2003 March; 72(3): 710-6. Epub 2003 January 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12557126&dopt=Abstract

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HLA-patterns in patients with multiple sclerosis and type I diabetes mellitus: evidence for possible mutual exclusion of both diseases. Author(s): Lobnig BM, Chantelau E, Vidgren G, Van Landeghem AA, Kinnunen L, Tuomilehto-Wolf E. Source: Diabetes & Metabolism. 2002 June; 28(3): 217-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12149602&dopt=Abstract

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Home based management in multiple sclerosis: results of a randomised controlled trial. Author(s): Pozzilli C, Brunetti M, Amicosante AM, Gasperini C, Ristori G, Palmisano L, Battaglia M. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 September; 73(3): 250-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12185154&dopt=Abstract

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Hopelessness ratings in relapsing-remitting and secondary progressive multiple sclerosis. Author(s): Patten SB, Metz LM. Source: International Journal of Psychiatry in Medicine. 2002; 32(2): 155-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12269596&dopt=Abstract

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Horizontal monocular saccadic failure: an unusual clinically isolated syndrome progressing to multiple sclerosis. Author(s): Frohman EM, Frohman TC. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 558. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617269&dopt=Abstract

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How do multiple sclerosis patients in Lanarkshire rate health professionals and hospitals? Author(s): Scrimgeour EM, Barnes JA. Source: Health Bull (Edinb). 2001 May; 59(3): 155-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12664754&dopt=Abstract

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How promising is hematopoetic stem cell transplantation in multiple sclerosis? Author(s): Hohlfeld R. Source: Journal of Neurology. 2002 September; 249(9): 1147-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12242531&dopt=Abstract

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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]. 2002 April 19; 3(1): 5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11991808&dopt=Abstract

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Human herpes virus 6 and multiple sclerosis. Author(s): Moore FG, Wolfson C. Source: Acta Neurologica Scandinavica. 2002 August; 106(2): 63-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12100366&dopt=Abstract

206 Sclerosis

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Human herpesvirus 6 and Chlamydia pneumoniae as etiologic agents in multiple sclerosis - a critical review. Author(s): Swanborg RH, Whittum-Hudson JA, Hudson AP. Source: Microbes and Infection / Institut Pasteur. 2002 November; 4(13): 1327-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12443897&dopt=Abstract

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Human herpesvirus 6 and multiple sclerosis: a study of T cell cross-reactivity to viral and myelin basic protein antigens. Author(s): Cirone M, Cuomo L, Zompetta C, Ruggieri S, Frati L, Faggioni A, Ragona G. Source: Journal of Medical Virology. 2002 October; 68(2): 268-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12210418&dopt=Abstract

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Human herpesvirus 6 and multiple sclerosis: the continuing conundrum. Author(s): Tyler KL. Source: The Journal of Infectious Diseases. 2003 May 1; 187(9): 1360-4. Epub 2003 April 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12717616&dopt=Abstract

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Human herpesvirus 6 genome and antigen in acute multiple sclerosis lesions. Author(s): Goodman AD, Mock DJ, Powers JM, Baker JV, Blumberg BM. Source: The Journal of Infectious Diseases. 2003 May 1; 187(9): 1365-76. Epub 2003 April 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12717617&dopt=Abstract

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Human herpesvirus 6 in serum and spinal fluid of patients with multiple sclerosis? Author(s): Beck R, Wiendl H, Jahn G, Melms A, Neipel F. Source: Archives of Neurology. 2003 April; 60(4): 639; Author Reply 639-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12707085&dopt=Abstract

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Hyperbaric oxygen therapy, multiple sclerosis, and unapproved indications: taking a stand. Author(s): Jacoby IJ. Source: Undersea & Hyperbaric Medicine : Journal of the Undersea and Hyperbaric Medical Society, Inc. 2001 Fall; 28(3): 113-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12067145&dopt=Abstract

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Hypointensity in T2-weighted images of the basal ganglia in solvent-exposed patients with multiple sclerosis: clinical, MRI and CSF characteristics. Author(s): Landtblom AM, Thuomas KA, Sjodqvist L, Flodin U, Nyland FH, Soderfeldt B. Source: Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2003 April; 24(1): 2-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12754650&dopt=Abstract

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Hypothalamic-pituitary-adrenal axis function and cytokine production in multiple sclerosis with or without interferon-beta treatment. Author(s): Limone P, Ferrero B, Calvelli P, Del Rizzo P, Rota E, Berardi C, Barberis AM, Isaia GC, Durelli L. Source: Acta Neurologica Scandinavica. 2002 May; 105(5): 372-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11982488&dopt=Abstract

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Hypothesis: pathogenesis of systemic sclerosis. Author(s): Takehara K. Source: The Journal of Rheumatology. 2003 April; 30(4): 755-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12672195&dopt=Abstract

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Hypoxia-like tissue injury as a component of multiple sclerosis lesions. Author(s): Lassmann H. Source: Journal of the Neurological Sciences. 2003 February 15; 206(2): 187-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559509&dopt=Abstract

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Identification of an IL1A gene segment that determines aberrant constitutive expression of interleukin-1 alpha in systemic sclerosis. Author(s): Kawaguchi Y, Hara M, Kamatani N, Wright TM. Source: Arthritis and Rheumatism. 2003 January; 48(1): 193-202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12528119&dopt=Abstract

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Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Author(s): Sapp PC, Hosler BA, McKenna-Yasek D, Chin W, Gann A, Genise H, Gorenstein J, Huang M, Sailer W, Scheffler M, Valesky M, Haines JL, Pericak-Vance M, Siddique T, Horvitz HR, Brown RH Jr. Source: American Journal of Human Genetics. 2003 August; 73(2): 397-403. Epub 2003 July 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858291&dopt=Abstract

208 Sclerosis

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Idiopathic portal hypertension in a systemic sclerosis patient heterozygous for factor V Leiden mutation. Author(s): Ishii M, Katada Y. Source: Rheumatology International. 2003 January; 23(1): 44-6. Epub 2002 October 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12548441&dopt=Abstract

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IL-15 is elevated in sera of patients with relapsing-remitting multiple sclerosis. Author(s): Losy J, Niezgoda A, Zaremba J. Source: Folia Neuropathol. 2002; 40(3): 151-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12572921&dopt=Abstract

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Immune regulatory properties and interactions of copolymer-I and beta-interferon 1a in multiple sclerosis. Author(s): Zang Y, Hong J, Robinson R, Li S, Rivera VM, Zhang JZ. Source: Journal of Neuroimmunology. 2003 April; 137(1-2): 144-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667659&dopt=Abstract

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Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection. Author(s): Neuhaus O, Archelos JJ, Hartung HP. Source: Trends in Pharmacological Sciences. 2003 March; 24(3): 131-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628358&dopt=Abstract

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Impact of clinical nurse specialists in multiple sclerosis--synthesis of the evidence. Author(s): Forbes A, While A, Dyson L, Grocott T, Griffiths P. Source: Journal of Advanced Nursing. 2003 June; 42(5): 442-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12752865&dopt=Abstract

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Impaired coordination between grip force and load force in amyotrophic lateral sclerosis: a case-control study. Author(s): Nowak DA, Hermsdorfer J. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. 2002 December; 3(4): 199-207. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710509&dopt=Abstract

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Impaired fibrinolysis in multiple sclerosis: a role for tissue plasminogen activator inhibitors. Author(s): Gveric D, Herrera B, Petzold A, Lawrence DA, Cuzner ML. Source: Brain; a Journal of Neurology. 2003 July; 126(Pt 7): 1590-8. Epub 2003 June 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12805124&dopt=Abstract

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Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis. Author(s): Dunlop J, Beal McIlvain H, She Y, Howland DS. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2003 March 1; 23(5): 1688-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12629173&dopt=Abstract

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In vitro evidence that subcutaneous administration of glatiramer acetate induces hyporesponsive T cells in patients with multiple sclerosis. Author(s): Schmied M, Duda PW, Krieger JI, Trollmo C, Hafler DA. Source: Clinical Immunology (Orlando, Fla.). 2003 March; 106(3): 163-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12706402&dopt=Abstract

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Incidence of amyotrophic lateral sclerosis in the local health district of Ferrara, Italy, 1964-1998. Author(s): Govoni V, Granieri E, Capone J, Manconi M, Casetta I. Source: Neuroepidemiology. 2003 July-August; 22(4): 229-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12792142&dopt=Abstract

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Increased brain-derived neurotrophic factor expression in white blood cells of relapsing-remitting multiple sclerosis patients. Author(s): Gielen A, Khademi M, Muhallab S, Olsson T, Piehl F. Source: Scandinavian Journal of Immunology. 2003 May; 57(5): 493-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12753507&dopt=Abstract

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Increased circulating concentrations of the counteradhesive proteins SPARC and thrombospondin-1 in systemic sclerosis (scleroderma). Relationship to platelet and endothelial cell activation. Author(s): Macko RF, Gelber AC, Young BA, Lowitt MH, White B, Wigley FM, Goldblum SE. Source: The Journal of Rheumatology. 2002 December; 29(12): 2565-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12465153&dopt=Abstract

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Increased circulating T cell reactivity to GM3 and GQ1b gangliosides in primary progressive multiple sclerosis. Author(s): Pender MP, Csurhes PA, Wolfe NP, Hooper KD, Good MF, McCombe PA, Greer JM. Source: Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. 2003 January; 10(1): 63-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12464524&dopt=Abstract

210 Sclerosis

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Increased creatine kinase and spontaneous activity on electromyography, in amyotrophic lateral sclerosis. Author(s): Lima AF, Evangelista T, de Carvalho M. Source: Electromyogr Clin Neurophysiol. 2003 April-May; 43(3): 189-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12712806&dopt=Abstract

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Increased frequency of interleukin-1beta-511T allele in patients with temporal lobe epilepsy, hippocampal sclerosis, and prolonged febrile convulsion. Author(s): Kanemoto K, Kawasaki J, Yuasa S, Kumaki T, Tomohiro O, Kaji R, Nishimura M. Source: Epilepsia. 2003 June; 44(6): 796-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790892&dopt=Abstract

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Increased gelatinase activity in systemic sclerosis dermal fibroblast cultures with unaltered gelatinase A mRNA expression. Author(s): Fakhoury H, Hillarby MC, Weiss JB. Source: Journal of Dermatological Science. 2002 May; 29(1): 62-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12007723&dopt=Abstract

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Increased hypoxic blood pressure response in patients with amyotrophic lateral sclerosis. Author(s): Hecht MJ, Brown CM, Mittelhamm F, Werner D, Heuss D, Neundorfer B, Hilz MJ. Source: Journal of the Neurological Sciences. 2003 September 15; 213(1-2): 47-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873754&dopt=Abstract

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Increasing frequency of multiple sclerosis in Padova, Italy: a 30 year epidemiological survey. Author(s): Ranzato F, Perini P, Tzintzeva E, Tiberio M, Calabrese M, Ermani M, Davetag F, De Zanche L, Garbin E, Verdelli F, Villacara A, Volpe G, Moretto G, Gallo P. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 38792. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926844&dopt=Abstract

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Induction chemotherapy strategies for primary mediastinal large B-cell lymphoma with sclerosis: a retrospective multinational study on 426 previously untreated patients. Author(s): Zinzani PL, Martelli M, Bertini M, Gianni AM, Devizzi L, Federico M, Pangalis G, Michels J, Zucca E, Cantonetti M, Cortelazzo S, Wotherspoon A, Ferreri AJ, Zaja F, Lauria F, De Renzo A, Liberati MA, Falini B, Balzarotti M, Calderoni A, Zaccaria A, Gentilini P, Fattori PP, Pavone E, Angelopoulou MK, Alinari L, Brugiatelli M, Di Renzo N, Bonifazi F, Pileri SA, Cavalli F; International Extranodal Lymphoma Study Group (IELSG). Source: Haematologica. 2002 December; 87(12): 1258-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495899&dopt=Abstract

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Induction of astrocytic cyclooxygenase-2 in epileptic patients with hippocampal sclerosis. Author(s): Desjardins P, Sauvageau A, Bouthillier A, Navarro D, Hazell AS, Rose C, Butterworth RF. Source: Neurochemistry International. 2003 March; 42(4): 299-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12470703&dopt=Abstract

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Infection and multiple sclerosis. Author(s): O'Donovan M. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 May; 74(5): 693. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700333&dopt=Abstract

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Infection and multiple sclerosis. Author(s): Anlar B. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 May; 74(5): 692-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700331&dopt=Abstract

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Infection with Chlamydia pneumoniae and risk of multiple sclerosis. Author(s): Munger KL, Peeling RW, Hernan MA, Chasan-Taber L, Olek MJ, Hankinson SE, Hunter D, Ascherio A. Source: Epidemiology (Cambridge, Mass.). 2003 March; 14(2): 141-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12606878&dopt=Abstract

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Infectious agents and multiple sclerosis--are Chlamydia pneumoniae and human herpes virus 6 involved? Author(s): Swanborg RH, Whittum-Hudson JA, Hudson AP. Source: Journal of Neuroimmunology. 2003 March; 136(1-2): 1-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12620637&dopt=Abstract

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Infectious emphysematous gastritis in multiple sclerosis. Author(s): Buyl L, Smeets P, Verstraete K. Source: Jbr-Btr. 2003 May-June; 86(3): 148-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12880158&dopt=Abstract

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Inflammation in multiple sclerosis: the good, the bad, and the complex. Author(s): Martino G, Adorini L, Rieckmann P, Hillert J, Kallmann B, Comi G, Filippi M. Source: Lancet. Neurology. 2002 December; 1(8): 499-509. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849335&dopt=Abstract

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Influence of cerebral lesion volume and lesion distribution on event-related brain potentials in multiple sclerosis. Author(s): Sailer M, Heinze HJ, Tendolkar I, Decker U, Kreye O, v Rolbicki U, Munte TF. Source: Journal of Neurology. 2001 December; 248(12): 1049-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12013581&dopt=Abstract

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Influence of creatine monohydrate ingestion on muscle metabolites and intense exercise capacity in individuals with multiple sclerosis. Author(s): Lambert CP, Archer RL, Carrithers JA, Fink WJ, Evans WJ, Trappe TA. Source: Archives of Physical Medicine and Rehabilitation. 2003 August; 84(8): 1206-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917861&dopt=Abstract

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Instability after total knee replacement with a mobile-bearing prosthesis in a patient with multiple sclerosis. Author(s): Rao V, Targett JP. Source: The Journal of Bone and Joint Surgery. British Volume. 2003 July; 85(5): 731-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12892199&dopt=Abstract

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Intense immunosuppression and autologous hematopoietic stem cell transplantation for multiple sclerosis. Author(s): Fassas A. Source: Haematologica. 2003 March; 88(3): 244-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12651258&dopt=Abstract

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Intercaudate nucleus ratio as a linear measure of brain atrophy in multiple sclerosis. Author(s): Caon C, Zvartau-Hind M, Ching W, Lisak RP, Tselis AC, Khan OA. Source: Neurology. 2003 January 28; 60(2): 323-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12552053&dopt=Abstract

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Interferon beta in multiple sclerosis: experience in a British specialist multiple sclerosis centre. Author(s): Dubois BD, Keenan E, Porter BE, Kapoor R, Rudge P, Thompson AJ, Miller DH, Giovannoni G. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 July; 74(7): 946-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810786&dopt=Abstract

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Interferons in relapsing remitting multiple sclerosis. Author(s): Kolar OJ, Bauerle JA, Lee H. Source: Lancet. 2003 May 24; 361(9371): 1825. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781563&dopt=Abstract

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Interferons in relapsing remitting multiple sclerosis. Author(s): Rudick RA, Cookfair DL, Griffin J, Hauser S, Piantadosi S. Source: Lancet. 2003 May 24; 361(9371): 1824; Author Reply 1824-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781561&dopt=Abstract

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Interferons in relapsing remitting multiple sclerosis. Author(s): Paty D, Arnason B, Li D, Traboulsee A. Source: Lancet. 2003 May 24; 361(9371): 1822; Author Reply 1823-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781559&dopt=Abstract

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Interferons in relapsing remitting multiple sclerosis. Author(s): Freedman M, King J, Oger J, Sharief M, Hartung HP; PRISMS study investigators. Source: Lancet. 2003 May 24; 361(9371): 1822-3; Author Reply 1823-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781558&dopt=Abstract

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Interferons in relapsing remitting multiple sclerosis. Author(s): Kappos L, Kesselring J. Source: Lancet. 2003 May 24; 361(9371): 1821-2; Author Reply 1823-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781557&dopt=Abstract

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Interferons in relapsing remitting multiple sclerosis. Author(s): Goodin DS. Source: Lancet. 2003 May 24; 361(9371): 1821; Author Reply 1823-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781556&dopt=Abstract

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Interferons in relapsing remitting multiple sclerosis: a systematic review. Author(s): Filippini G, Munari L, Incorvaia B, Ebers GC, Polman C, D'Amico R, Rice GP. Source: Lancet. 2003 February 15; 361(9357): 545-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598138&dopt=Abstract

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Interictal EEG, hippocampal atrophy, and cell densities in hippocampal sclerosis and hippocampal sclerosis associated with microscopic cortical dysplasia. Author(s): Diehl B, Najm I, Mohamed A, Babb T, Ying Z, Bingaman W. Source: Journal of Clinical Neurophysiology : Official Publication of the American Electroencephalographic Society. 2002 April; 19(2): 157-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11997727&dopt=Abstract

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Interleukin-10 polymorphisms in Spanish multiple sclerosis patients. Author(s): Martinez Doncel A, Rubio A, Arroyo R, de las Heras V, Martin C, FernandezArquero M, de la Concha EG. Source: Journal of Neuroimmunology. 2002 October; 131(1-2): 168-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458048&dopt=Abstract

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Intermediate uveitis in childhood preceding the diagnosis of multiple sclerosis: a 13year follow-up. Author(s): Jordan JF, Walter P, Ayertey HD, Brunner R. Source: American Journal of Ophthalmology. 2003 June; 135(6): 885-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788130&dopt=Abstract

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Interpreting change scores on the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40). Author(s): Jenkinson C, Peto V, Jones G, Fitzpatrick R. Source: Clinical Rehabilitation. 2003 July; 17(4): 380-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12785246&dopt=Abstract

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Interstitial lung disease in systemic sclerosis. Author(s): Ooi GC, Mok MY, Tsang KW, Wong Y, Khong PL, Fung PC, Chan S, Tse HF, Wong RW, Lam WK, Lau CS. Source: Acta Radiologica (Stockholm, Sweden : 1987). 2003 May; 44(3): 258-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12751995&dopt=Abstract

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Interventions for the prevention of brain atrophy in multiple sclerosis : current status. Author(s): Rovaris M, Filippi M. Source: Cns Drugs. 2003; 17(8): 563-75. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12775193&dopt=Abstract

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Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Author(s): Bo L, Vedeler CA, Nyland H, Trapp BD, Mork SJ. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 32331. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926836&dopt=Abstract

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Intrathecal B-cell clonal expansion, an early sign of humoral immunity, in the cerebrospinal fluid of patients with clinically isolated syndrome suggestive of multiple sclerosis. Author(s): Qin Y, Duquette P, Zhang Y, Olek M, Da RR, Richardson J, Antel JP, Talbot P, Cashman NR, Tourtellotte WW, Wekerle H, Van Den Noort S. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2003 July; 83(7): 1081-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861047&dopt=Abstract

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Intrathecal IgM synthesis is a prognostic factor in multiple sclerosis. Author(s): Villar LM, Masjuan J, Gonzalez-Porque P, Plaza J, Sadaba MC, Roldan E, Bootello A, Alvarez-Cermeno JC. Source: Annals of Neurology. 2003 February; 53(2): 222-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12557289&dopt=Abstract

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Investigation of a genetic variation of a variable number tandem repeat polymorphism of interleukin-6 gene in patients with multiple sclerosis. Author(s): Schmidt S, Papassotiropoulos A, Sotgiu S, Kolsch H, Arru G, Fois ML, Haase CG, Schmitz S, Konig N, Harzheim M, Heun R, Klockgether T. Source: Journal of Neurology. 2003 May; 250(5): 607-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12736743&dopt=Abstract

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In-vivo tissue characterization of multiple sclerosis and other white matter diseases using magnetic resonance based techniques. Author(s): Filippi M. Source: Journal of Neurology. 2001 December; 248(12): 1019-29. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12013577&dopt=Abstract

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Involvement of cathepsin B in the motor neuron degeneration of amyotrophic lateral sclerosis. Author(s): Kikuchi H, Yamada T, Furuya H, Doh-ura K, Ohyagi Y, Iwaki T, Kira J. Source: Acta Neuropathologica. 2003 May; 105(5): 462-8. Epub 2003 January 29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12677446&dopt=Abstract

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Is natalizumab a breakthrough in the treatment of multiple sclerosis? Author(s): Doggrell SA. Source: Expert Opinion on Pharmacotherapy. 2003 June; 4(6): 999-1001. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783595&dopt=Abstract

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Is somatosensory function abnormal in amyotrophic lateral sclerosis/parkinsonismdementia complex in Kii Peninsula? Author(s): Shibasaki H. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2003 May; 114(5): 775-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738424&dopt=Abstract

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Is the cell death in mesial temporal sclerosis apoptotic? Author(s): Uysal H, Cevik IU, Soylemezoglu F, Elibol B, Ozdemir YG, Evrenkaya T, Saygi S, Dalkara T. Source: Epilepsia. 2003 June; 44(6): 778-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790890&dopt=Abstract

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Is there mitochondrial dysfunction in amyotrophic lateral sclerosis skeletal muscle? Author(s): Vielhaber S, Kudin A, Winkler K, Wiedemann F, Schroder R, Feistner H, Heinze HJ, Elger CE, Kunz WS. Source: Annals of Neurology. 2003 May; 53(5): 686-7; Author Reply 687-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12731009&dopt=Abstract

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Issues and practices in multiple sclerosis. Author(s): Burks JS, Arnason BG, Coyle PK, Ford CC, Noronha A, Rammohan KW. Source: Neurorehabilitation and Neural Repair. 2002 December; 16(4): 307-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12462762&dopt=Abstract

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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. 2002 September; 3(3): 163-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495579&dopt=Abstract

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Key issues in the diagnosis and treatment of multiple sclerosis. An overview. Author(s): O'Connor P; Canadian Multiple Sclerosis Working Group. Source: Neurology. 2002 September 24; 59(6 Suppl 3): S1-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12448786&dopt=Abstract

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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. 2003 March 1; 71(5): 732-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12584731&dopt=Abstract

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Lack of association between estrogen receptor 1 gene polymorphisms and multiple sclerosis in southern Italy in humans. Author(s): Savettieri G, Cittadella R, Valentino P, Manna I, Andreoli V, La Russa A, La Porta G, Ruscica F, Ragonese P, Pirritano D, Bonavita S, Tedeschi G, Quattrone A. Source: Neuroscience Letters. 2002 July 19; 327(2): 115-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12098649&dopt=Abstract

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Lack of evidence for a role of the myelin basic protein gene in multiple sclerosis susceptibility in Sardinian patients. Author(s): Cocco E, Mancosu C, Fadda E, Murru MR, Costa G, Murru R, Marrosu MG. Source: Journal of Neurology. 2002 November; 249(11): 1552-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12420096&dopt=Abstract

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Lack of evidence of foetal microchimerism in female Spanish patients with systemic sclerosis. Author(s): Selva-O'Callaghan A, Mijares-Boeckh-Behrens T, Prades EB, Solans-Laque R, Simeon-Aznar CP, Fonollosa-Pla V, Vilardell-Tarres M. Source: Lupus. 2003; 12(1): 15-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12587821&dopt=Abstract

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Large-scale gene-expression studies and the challenge of multiple sclerosis. Author(s): Baranzini SE, Hauser SL. Source: Genome Biology. 2002 September 16; 3(10): Reviews1027. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372148&dopt=Abstract

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Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Author(s): Joinson C, O'Callaghan FJ, Osborne JP, Martyn C, Harris T, Bolton PF. Source: Psychological Medicine. 2003 February; 33(2): 335-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12622312&dopt=Abstract

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Leptin as a marker of multiple sclerosis activity in patients treated with interferonbeta. Author(s): Batocchi AP, Rotondi M, Caggiula M, Frisullo G, Odoardi F, Nociti V, Carella C, Tonali PA, Mirabella M. Source: Journal of Neuroimmunology. 2003 June; 139(1-2): 150-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799033&dopt=Abstract

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Life-threatening complications of systemic sclerosis. Author(s): Cossio M, Menon Y, Wilson W, deBoisblanc BP. Source: Critical Care Clinics. 2002 October; 18(4): 819-39. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12418443&dopt=Abstract

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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. 2002 September; 3(3): 109-12. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495570&dopt=Abstract

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Linkage disequilibrium analysis of chromosome 12q14-15 in multiple sclerosis: delineation of a 118-kb interval around interferon-gamma (IFNG) that is involved in male versus female differential susceptibility. Author(s): Goris A, Heggarty S, Marrosu MG, Graham C, Billiau A, Vandenbroeck K. Source: Genes and Immunity. 2002 December; 3(8): 470-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12486605&dopt=Abstract

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Lip and tongue function differently affected in individuals with multiple sclerosis. Author(s): Hartelius L, Lillvik M. Source: Folia Phoniatrica Et Logopaedica : Official Organ of the International Association of Logopedics and Phoniatrics (Ialp). 2003 January-February; 55(1): 1-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12566761&dopt=Abstract

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Lipoid pneumonia in multiple sclerosis: an insidious complication--case report. Author(s): Terzano C, Ricci A, Petroianni A, Laurendi G, Mammarella A, Paoletti V, Marziali M, De Luca N. Source: Adv Ther. 2003 May-June; 20(3): 138-42. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12956255&dopt=Abstract

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Lipoprotein oxidation, plasma total antioxidant capacity and homocysteine level in patients with multiple sclerosis. Author(s): Besler HT, Comoglu S. Source: Nutritional Neuroscience. 2003 June; 6(3): 189-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12793524&dopt=Abstract

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Liver and thyroid function and autoimmunity during interferon-beta 1b treatment for multiple sclerosis. Author(s): Tremlett H. Source: Neurology. 2002 June 25; 58(12): 1868. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12084903&dopt=Abstract

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Living with multiple sclerosis: a Roy adaptation model-based study. Author(s): Gagliardi BA, Frederickson K, Shanley DA. Source: Nursing Science Quarterly. 2002 July; 15(3): 230-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12125534&dopt=Abstract

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Localized (1)H magnetic resonance spectroscopy in mainly cortical gray matter of patients with multiple sclerosis. Author(s): Sarchielli P, Presciutti O, Tarducci R, Gobbi G, Alberti A, Pelliccioli GP, Chiarini P, Gallai V. Source: Journal of Neurology. 2002 July; 249(7): 902-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12140676&dopt=Abstract

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Longitudinal brain volume measurement in multiple sclerosis: rate of brain atrophy is independent of the disease subtype. Author(s): Kalkers NF, Ameziane N, Bot JC, Minneboo A, Polman CH, Barkhof F. Source: Archives of Neurology. 2002 October; 59(10): 1572-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12374494&dopt=Abstract

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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. 2003 August; 82(8): 597-604. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12872016&dopt=Abstract

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Longitudinal study of antimyelin T-cell reactivity in relapsing-remitting multiple sclerosis: association with clinical and MRI activity. Author(s): Hellings N, Gelin G, Medaer R, Bruckers L, Palmers Y, Raus J, Stinissen P. Source: Journal of Neuroimmunology. 2002 May; 126(1-2): 143-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12020966&dopt=Abstract

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Longitudinal study of chemokine receptor expression on peripheral lymphocytes in multiple sclerosis: CXCR3 upregulation is associated with relapse. Author(s): Mahad DJ, Lawry J, Howell SJ, Woodroofe MN. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 189-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708814&dopt=Abstract

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Longitudinal study of cognitive dysfunction in multiple sclerosis: neuropsychological, neuroradiological, and neurophysiological findings. Author(s): Piras MR, Magnano I, Canu ED, Paulus KS, Satta WM, Soddu A, Conti M, Achene A, Solinas G, Aiello I. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 July; 74(7): 878-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810771&dopt=Abstract

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Long-term benefits of early and high doses of interferon beta-1a treatment in relapsing-remitting multiple sclerosis. Author(s): Chofflon M, Ben-Amor AF. Source: Clinical Neurology and Neurosurgery. 2002 July; 104(3): 244-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12127662&dopt=Abstract

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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. 2002 March; 3(1): 23-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12061945&dopt=Abstract

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Loss of expression of tuberin and hamartin in tuberous sclerosis complex-associated but not in sporadic angiofibromas. Author(s): Fackler I, DeClue JE, Rust H, Vu PA, Kutzner H, Rutten A, Kaddu S, Sander CA, Volkenandt M, Johnson MW, Vinters HV, Wienecke R. Source: Journal of Cutaneous Pathology. 2003 March; 30(3): 174-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12641776&dopt=Abstract

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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. 2003 January 15; 206(1): 91-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12480091&dopt=Abstract

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Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1. Author(s): Feng X, Petraglia AL, Chen M, Byskosh PV, Boos MD, Reder AT. Source: Journal of Neuroimmunology. 2002 August; 129(1-2): 205-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12161037&dopt=Abstract

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Low interferon gamma producers are better treatment responders: a two-year followup of interferon beta-treated multiple sclerosis patients. Author(s): Petereit HF, Nolden S, Schoppe S, Bamborschke S, Pukrop R, Heiss WD. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 December; 8(6): 492-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474989&dopt=Abstract

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Low interleukin-10 production is associated with higher disability and MRI lesion load in secondary progressive multiple sclerosis. Author(s): Petereit HF, Pukrop R, Fazekas F, Bamborschke SU, Ropele S, Kolmel HW, Merkelbach S, Japp G, Jongen PJ, Hartung HP, Hommes OR. Source: Journal of the Neurological Sciences. 2003 February 15; 206(2): 209-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559513&dopt=Abstract

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Low leucocyte myeloperoxidase activity in patients with multiple sclerosis. Author(s): Ramsaransing G, Teelken A, Prokopenko VM, Arutjunyan AV, De Keyser J. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 July; 74(7): 953-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810789&dopt=Abstract

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Lower abdominal pressure versus external bladder stimulation to aid bladder emptying in multiple sclerosis: a randomized controlled study. Author(s): Prasad RS, Smith SJ, Wright H. Source: Clinical Rehabilitation. 2003 February; 17(1): 42-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617378&dopt=Abstract

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Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele. Author(s): Enzinger C, Ropele S, Strasser-Fuchs S, Kapeller P, Schmidt H, Poltrum B, Schmidt R, Hartung HP, Fazekas F. Source: Archives of Neurology. 2003 January; 60(1): 65-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12533090&dopt=Abstract

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Lymphangioleiomyomatosis associated with pulmonary metastasis from an occult papillary carcinoma of the thyroid: report of a case occurring in a patient without tuberous sclerosis. Author(s): Cavazza A, Roggeri A, Zini M, Rossi G, Zucchi L. Source: Pathology, Research and Practice. 2002; 198(12): 825-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12608660&dopt=Abstract

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Lymphomononuclear cells from multiple sclerosis patients spontaneously produce high levels of oncostatin M, tumor necrosis factors alpha and beta, and interferon gamma. Author(s): Ensoli F, Fiorelli V, Lugaresi A, Farina D, De Cristofaro M, Collacchi B, Muratori DS, Scala E, Di Gioacchino M, Paganelli R, Aiuti F. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 August; 8(4): 284-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12166497&dopt=Abstract

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Magnetic resonance image registration in multiple sclerosis: comparison with repositioning error and observer-based variability. Author(s): Tan IL, van Schijndel RA, van Walderveen MA, Quist M, Bos R, Pouwels PJ, Desmedt P, Ader HJ, Barkhof F. Source: Journal of Magnetic Resonance Imaging : Jmri. 2002 May; 15(5): 505-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11997890&dopt=Abstract

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Magnetic resonance imaging evidence of hippocampal sclerosis in asymptomatic, first-degree relatives of patients with familial mesial temporal lobe epilepsy. Author(s): Kobayashi E, Li LM, Lopes-Cendes I, Cendes F. Source: Archives of Neurology. 2002 December; 59(12): 1891-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12470176&dopt=Abstract

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Magnetic resonance-based techniques for the study and management of multiple sclerosis. Author(s): Rovaris M, Rocca MA, Filippi M. Source: British Medical Bulletin. 2003; 65: 133-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12697621&dopt=Abstract

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Management of multiple sclerosis: current trials and future options. Author(s): Noseworthy JH. Source: Current Opinion in Neurology. 2003 June; 16(3): 289-97. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858064&dopt=Abstract

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Management of renal angiomyolipoma in patients with tuberous sclerosis complex. Author(s): Simmons JL, Hussain SA, Riley P, Wallace DM. Source: Oncol Rep. 2003 January-February; 10(1): 237-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12469175&dopt=Abstract

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Massive facial angiofibroma in a patient with tuberous sclerosis. Author(s): Earnest L, Byrne P, Califano J. Source: Otolaryngology and Head and Neck Surgery. 2003 January; 128(1): 151-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574776&dopt=Abstract

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Matrix metalloproteinases and neuroinflammation in multiple sclerosis. Author(s): Rosenberg GA. Source: The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry. 2002 December; 8(6): 586-95. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12467380&dopt=Abstract

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Measuring fatigue in people with multiple sclerosis. Author(s): Chipchase SY, Lincoln NB, Radford KA. Source: Disability and Rehabilitation. 2003 July 22; 25(14): 778-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959358&dopt=Abstract

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Mechanisms of disability progression in primary progressive multiple sclerosis: are they different from secondary progressive multiple sclerosis? Author(s): Rudick R. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 210-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708817&dopt=Abstract

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Mesial temporal sclerosis in acute childhood leukemias. Author(s): Goyal M, Bangert BA, Wiznitzer M. Source: Epilepsia. 2003 January; 44(1): 131-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12581241&dopt=Abstract

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Metallothionein expression in the central nervous system of multiple sclerosis patients. Author(s): Penkowa M, Espejo C, Ortega-Aznar A, Hidalgo J, Montalban X, Martinez Caceres EM. Source: Cellular and Molecular Life Sciences : Cmls. 2003 June; 60(6): 1258-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861391&dopt=Abstract

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Methylprednisolone acts on peripheral blood mononuclear cells and endothelium in inhibiting migration phenomena in patients with multiple sclerosis. Author(s): Gelati M, Corsini E, De Rossi M, Masini L, Bernardi G, Massa G, Boiardi A, Salmaggi A. Source: Archives of Neurology. 2002 May; 59(5): 774-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12020259&dopt=Abstract

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Microarray analysis identifies interferon beta-regulated genes in multiple sclerosis. Author(s): Koike F, Satoh J, Miyake S, Yamamoto T, Kawai M, Kikuchi S, Nomura K, Yokoyama K, Ota K, Kanda T, Fukazawa T, Yamamura T. Source: Journal of Neuroimmunology. 2003 June; 139(1-2): 109-18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799028&dopt=Abstract

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Microchimerism in autoimmunity and transplantation: potential relevance to multiple sclerosis. Author(s): Willer CJ, Sadovnick AD, Ebers GC. Source: Journal of Neuroimmunology. 2002 May; 126(1-2): 126-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12020964&dopt=Abstract

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Migraine, memory loss, and “multiple sclerosis “. Neurological features of the antiphospholipid (Hughes') syndrome. Author(s): Hughes GR. Source: Postgraduate Medical Journal. 2003 February; 79(928): 81-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12612321&dopt=Abstract

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Misfolded CuZnSOD and amyotrophic lateral sclerosis. Author(s): Valentine JS, Hart PJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 April 1; 100(7): 3617-22. Epub 2003 March 24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12655070&dopt=Abstract

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Misoprostol in the treatment of trigeminal neuralgia associated with multiple sclerosis. Author(s): DMKG study group. Source: Journal of Neurology. 2003 May; 250(5): 542-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12736732&dopt=Abstract

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Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine. Author(s): Beretta S, Sala G, Mattavelli L, Ceresa C, Casciati A, Ferri A, Carri MT, Ferrarese C. Source: Neurobiology of Disease. 2003 August; 13(3): 213-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901835&dopt=Abstract

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Mitochondriopathy as a differential diagnosis of amyotrophic lateral sclerosis. Author(s): Finsterer J. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. 2002 December; 3(4): 219-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710512&dopt=Abstract

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Mitochondriopathy mimicking amyotrophic lateral sclerosis. Author(s): Finsterer J. Source: The Neurologist. 2003 January; 9(1): 45-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801431&dopt=Abstract

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Mitoxantrone trial in multiple sclerosis. Author(s): Chaudhuri A, Behan PO. Source: Lancet. 2003 March 29; 361(9363): 1133-4; Author Reply 1134. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12672341&dopt=Abstract

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Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis. Commentary: evaluating disease modifying treatments in multiple sclerosis. Author(s): Chilcott J, McCabe C, Tappenden P, O'Hagan A, Cooper NJ, Abrams K, Claxton K, Miller DH; Cost Effectiveness of Multiple Sclerosis Therapies Study Group. Source: Bmj (Clinical Research Ed.). 2003 March 8; 326(7388): 522; Discussion 522. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12623909&dopt=Abstract

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Modulation of monocytes matrix metalloproteinase-2, MT1-MMP and TIMP-2 by interferon-gamma and -beta: implications to multiple sclerosis. Author(s): Galboiz Y, Shapiro S, Lahat N, Miller A. Source: Journal of Neuroimmunology. 2002 October; 131(1-2): 191-200. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458052&dopt=Abstract

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Molecular and cellular mechanism of glutamate receptors in relation to amyotrophic lateral sclerosis. Author(s): Iwasaki Y, Ikeda K, Kinoshita M. Source: Current Drug Targets. Cns and Neurological Disorders. 2002 October; 1(5): 5118. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12769603&dopt=Abstract

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Molecular mimicry in multiple sclerosis. Author(s): Wekerle H, Hohlfeld R. Source: The New England Journal of Medicine. 2003 July 10; 349(2): 185-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853593&dopt=Abstract

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Monocyte chemoattractant protein 3 as a mediator of fibrosis: Overexpression in systemic sclerosis and the type 1 tight-skin mouse. Author(s): Ong VH, Evans LA, Shiwen X, Fisher IB, Rajkumar V, Abraham DJ, Black CM, Denton CP. Source: Arthritis and Rheumatism. 2003 July; 48(7): 1979-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12847692&dopt=Abstract

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Monocyte-derived dendritic cells express and secrete matrix-degrading metalloproteinases and their inhibitors and are imbalanced in multiple sclerosis. Author(s): Kouwenhoven M, Ozenci V, Tjernlund A, Pashenkov M, Homman M, Press R, Link H. Source: Journal of Neuroimmunology. 2002 May; 126(1-2): 161-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12020967&dopt=Abstract

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Monocyte-derived IL12, CD86 (B7-2) and CD40L expression in relapsing and progressive multiple sclerosis. Author(s): Filion LG, Matusevicius D, Graziani-Bowering GM, Kumar A, Freedman MS. Source: Clinical Immunology (Orlando, Fla.). 2003 February; 106(2): 127-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12672403&dopt=Abstract

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Motor responses evoked by transcranial magnetic stimulation and peripheral nerve stimulation in the ulnar innervation in amyotrophic lateral sclerosis: the effect of upper and lower motor neuron lesion. Author(s): de Carvalho M, Turkman A, Swash M. Source: Journal of the Neurological Sciences. 2003 June 15; 210(1-2): 83-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12736094&dopt=Abstract

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Multiple paradigm shifts in multiple sclerosis. Author(s): Kieseier BC, Hartung HP. Source: Current Opinion in Neurology. 2003 June; 16(3): 247-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858058&dopt=Abstract

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Multiple sclerosis and Epstein-Barr virus. Author(s): Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A. Source: Jama : the Journal of the American Medical Association. 2003 March 26; 289(12): 1533-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12672770&dopt=Abstract

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Multiple sclerosis and glutamate. Author(s): Groom AJ, Smith T, Turski L. Source: Annals of the New York Academy of Sciences. 2003 May; 993: 229-75; Discussion 287-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853317&dopt=Abstract

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Multiple sclerosis and Type I diabetes. Author(s): Buzzetti R, Pozzilli P, Di Mario U, Ballerini C, Massacesi L. Source: Diabetologia. 2002 December; 45(12): 1735-6. Epub 2002 November 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12552365&dopt=Abstract

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Multiple sclerosis exacerbations and infection. Author(s): Gilden DH. Source: Lancet. Neurology. 2002 July; 1(3): 145. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849479&dopt=Abstract

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Multiple sclerosis in children. Author(s): Gadoth N. Source: Brain & Development. 2003 June; 25(4): 229-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767451&dopt=Abstract

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Multiple sclerosis in Stockholm County. A pilot study exploring the feasibility of assessment of impairment, disability and handicap by home visits. Author(s): Einarsson U, Gottberg K, Fredrikson S, Bergendal G, von Koch L, Holmqvist LW. Source: Clinical Rehabilitation. 2003 May; 17(3): 294-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12735537&dopt=Abstract

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Multiple sclerosis in the Japanese population. Author(s): Kira J. Source: Lancet. Neurology. 2003 February; 2(2): 117-27. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849268&dopt=Abstract

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Multiple sclerosis is more prevalent in northern New Zealand than previously reported. Author(s): Chancellor AM, Addidle M, Dawson K. Source: Internal Medicine Journal. 2003 March; 33(3): 79-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603579&dopt=Abstract

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Multiple sclerosis manifesting as a Brown-Sequard syndrome. Author(s): Ozaki I, Suzuki C, Baba M, Matsunaga M. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2003 March; 10(2): 190-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603299&dopt=Abstract

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Multiple sclerosis presenting as ataxic hemiparesis. Author(s): Gorman MJ. Source: Journal of the Neurological Sciences. 2002 May 15; 197(1-2): 85-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11997072&dopt=Abstract

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Multiple sclerosis presenting as neurological decompression sickness in a U.S. navy diver. Author(s): Jan MH, Jankosky CJ. Source: Aviation, Space, and Environmental Medicine. 2003 February; 74(2): 184-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12602452&dopt=Abstract

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Multiple sclerosis with open-ring enhancement in the cerebrum and spinal cord. Author(s): Dohi N, Ishikawa S, Kamijyo Y, Nakamura T, O-Hara S, Maruyama K. Source: Intern Med. 2003 March; 42(3): 273-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12705794&dopt=Abstract

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Multiple sclerosis, interferon beta and clinical thyroid dysfunction. Author(s): Kreisler A, de Seze J, Stojkovic T, Delisse B, Combelles M, Verier A, Hautecoeur P, Vermersch P; Groupe septentrional d'etude et de recherche sur la Sclerose en Plaques (G-SEP). Source: Acta Neurologica Scandinavica. 2003 February; 107(2): 154-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12580868&dopt=Abstract

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Multiple sclerosis. Author(s): Frohman EM. Source: The Medical Clinics of North America. 2003 July; 87(4): 867-97, Viii-Ix. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12834152&dopt=Abstract

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Multiple sclerosis. Author(s): Finesilver C. Source: Rn. 2003 April; 66(4): 36-43; Quiz 44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12715455&dopt=Abstract

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Multiple sclerosis. Interview by Harriet Gaze. Author(s): Hempling S. Source: Bmj (Clinical Research Ed.). 2003 June 14; 326(7402): 1323-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12805178&dopt=Abstract

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Multiple sclerosis: emerging opportunities for therapeutic intervention. Author(s): Evans CF, Shriver LP. Source: Current Drug Targets. Cns and Neurological Disorders. 2002 February; 1(1): 1730. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12769632&dopt=Abstract

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Multiple sclerosis: Neurofilament light chain antibodies are correlated to cerebral atrophy. Author(s): Eikelenboom MJ, Petzold A, Lazeron RH, Silber E, Sharief M, Thompson EJ, Barkhof F, Giovannoni G, Polman CH, Uitdehaag BM. Source: Neurology. 2003 January 28; 60(2): 219-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12552034&dopt=Abstract

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Multiple sclerosis: report on 200 cases from Iran. Author(s): Kalanie H, Gharagozli K, Kalanie AR. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 368. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617266&dopt=Abstract

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Multiple sclerosis: severity and progression rate in African Americans compared with whites. Author(s): Kaufman MD, Johnson SK, Moyer D, Bivens J, Norton HJ. Source: American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists. 2003 August; 82(8): 582-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12872014&dopt=Abstract

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Multiple sclerosis-associated retrovirus particles cause T lymphocyte-dependent death with brain hemorrhage in humanized SCID mice model. Author(s): Firouzi R, Rolland A, Michel M, Jouvin-Marche E, Hauw JJ, Malcus-Vocanson C, Lazarini F, Gebuhrer L, Seigneurin JM, Touraine JL, Sanhadji K, Marche PN, Perron H. Source: Journal of Neurovirology. 2003 February; 9(1): 79-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12587071&dopt=Abstract

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Multiple sclerosis-associated virus-related pol sequences found both in multiple sclerosis and healthy donors are more frequently expressed in multiple sclerosis patients. Author(s): Nowak J, Januszkiewicz D, Pernak M, Liwen I, Zawada M, Rembowska J, Nowicka K, Lewandowski K, Hertmanowska H, Wender M. Source: Journal of Neurovirology. 2003 February; 9(1): 112-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12587074&dopt=Abstract

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Multiple sclerosis-like disease secondary to alpha interferon. Author(s): Matsuo T, Takabatake R. Source: Ocular Immunology and Inflammation. 2002 December; 10(4): 299-304. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12854039&dopt=Abstract

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Mutant SOD1 linked to familial amyotrophic lateral sclerosis, but not wild-type SOD1, induces ER stress in COS7 cells and transgenic mice. Author(s): Tobisawa S, Hozumi Y, Arawaka S, Koyama S, Wada M, Nagai M, Aoki M, Itoyama Y, Goto K, Kato T. Source: Biochemical and Biophysical Research Communications. 2003 April 4; 303(2): 496-503. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12659845&dopt=Abstract

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Mutation analysis of TSC2 gene in 33 Turkish familial cases with tuberous sclerosis. Author(s): Apak A, Haliloglu G, Kose G, Yilmaz E, Anlar B, Aysun S. Source: Turk J Pediatr. 2003 January-March; 45(1): 1-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12718362&dopt=Abstract

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Mutations in the gene for toll-like receptor 4 and multiple sclerosis. Author(s): Reindl M, Lutterotti A, Ingram J, Schanda K, Gassner C, Deisenhammer F, Berger T, Lorenz E. Source: Tissue Antigens. 2003 January; 61(1): 85-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12622779&dopt=Abstract

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Myelin basic protein in multiple sclerosis and other neurological disorders. Author(s): Kalistova H, Havrdova E, Uhrova J, Zeman D, Tyblova M, Mrazova K. Source: Journal of Neurology. 2003 July; 250(7): 874-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883934&dopt=Abstract

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Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions. Author(s): O'Connor KC, Chitnis T, Griffin DE, Piyasirisilp S, Bar-Or A, Khoury S, Wucherpfennig KW, Hafler DA. Source: Journal of Neuroimmunology. 2003 March; 136(1-2): 140-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12620653&dopt=Abstract

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Myocardial function in patients with multiple sclerosis treated with low-dose mitoxantrone. Author(s): Strotmann JM, Spindler M, Weilbach FX, Gold R, Ertl G, Voelker W. Source: The American Journal of Cardiology. 2002 May 15; 89(10): 1222-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12008183&dopt=Abstract

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N19S, a new SOD1 mutation in sporadic amyotrophic lateral sclerosis: no evidence for disease causation. Author(s): Mayeux V, Corcia P, Besson G, Jafari-Schluep HF, Briolotti V, Camu W. Source: Annals of Neurology. 2003 June; 53(6): 815-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783432&dopt=Abstract

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Natalizumab for relapsing multiple sclerosis. Author(s): Chaudhuri A, Behan PO. Source: The New England Journal of Medicine. 2003 April 17; 348(16): 1598-9; Author Reply 1598-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700382&dopt=Abstract

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Native and transformed alpha2-macroglobulin in plasma from patients with multiple sclerosis. Author(s): Gunnarsson M, Sundstrom P, Stigbrand T, Jensen PE. Source: Acta Neurologica Scandinavica. 2003 July; 108(1): 16-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807388&dopt=Abstract

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Natural history of multiple sclerosis: implications for counselling and therapy. Author(s): Confavreux C, Vukusic S. Source: Current Opinion in Neurology. 2002 June; 15(3): 257-66. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12045722&dopt=Abstract

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Natural history of systemic sclerosis and the assessment of disease activity, severity, functional status, and psychologic well-being. Author(s): Medsger TA Jr. Source: Rheumatic Diseases Clinics of North America. 2003 May; 29(2): 255-73, Vi. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841294&dopt=Abstract

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Necrotizing skin lesions and NABs development in a multiple sclerosis patient treated with IFNbeta 1b. Author(s): Casoni F, Merelli E, Bedin R, Martella A, Cesinaro A, Bertolotto A. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 420-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926849&dopt=Abstract

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Needs assessment of persons with multiple sclerosis and significant others: using the literature review and focus groups for preliminary survey questionnaire development. Author(s): Koopman W. Source: Axone. 2003 June; 24(4): 10-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12852337&dopt=Abstract

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Nephron-sparing tumorectomy for a large benign renal mass: a case of massive bilateral renal angiomyolipomas associated with tuberous sclerosis. Author(s): Shiroyanagi Y, Kondo T, Tomita E, Onitsuka S, Ryoji O, Ito F, Nakazawa H, Toma H. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. 2002 February; 9(2): 117-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12028304&dopt=Abstract

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Neuro-Behcet's disease: a masquerader of multiple sclerosis. A prospective study of neurologic manifestations of Behcet's disease in 96 Iranian patients. Author(s): Ashjazadeh N, Borhani Haghighi A, Samangooie Sh, Moosavi H. Source: Experimental and Molecular Pathology. 2003 February; 74(1): 17-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12645628&dopt=Abstract

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Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals. Author(s): Carri MT, Ferri A, Cozzolino M, Calabrese L, Rotilio G. Source: Brain Research Bulletin. 2003 August 30; 61(4): 365-74. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12909279&dopt=Abstract

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Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Author(s): Bolton PF, Park RJ, Higgins JN, Griffiths PD, Pickles A. Source: Brain; a Journal of Neurology. 2002 June; 125(Pt 6): 1247-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12023313&dopt=Abstract

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Neurofibrillary tangles in the primary motor cortex in Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex. Author(s): Hof PR, Perl DP. Source: Neuroscience Letters. 2002 August 16; 328(3): 294-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12147329&dopt=Abstract

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Neuro-inflammation as a therapeutic target in amyotrophic lateral sclerosis. Author(s): Weydt P, Weiss MD, Moller T, Carter GT. Source: Curr Opin Investig Drugs. 2002 December; 3(12): 1720-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12528305&dopt=Abstract

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Neuropathology of multiple sclerosis-new concepts. Author(s): Kornek B, Lassmann H. Source: Brain Research Bulletin. 2003 August 15; 61(3): 321-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12909302&dopt=Abstract

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Neuropathology with clinical correlations of sporadic amyotrophic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000. Author(s): Piao YS, Wakabayashi K, Kakita A, Yamada M, Hayashi S, Morita T, Ikuta F, Oyanagi K, Takahashi H. Source: Brain Pathology (Zurich, Switzerland). 2003 January; 13(1): 10-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12580541&dopt=Abstract

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Neuroprotective effects of copper/zinc-dependent superoxide dismutase against a wide variety of death-inducing stimuli and proapoptotic effect of familial amyotrophic lateral sclerosis mutations. Author(s): Patel Y, Collaco Moraes Y, Latchman D, Coffin R, de Belleroche J. Source: Brain Research. Molecular Brain Research. 2002 December 30; 109(1-2): 189-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531528&dopt=Abstract

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Neuroprotective effects of glial cell line-derived neurotrophic factor mediated by an adeno-associated virus vector in a transgenic animal model of amyotrophic lateral sclerosis. Author(s): Wang LJ, Lu YY, Muramatsu S, Ikeguchi K, Fujimoto K, Okada T, Mizukami H, Matsushita T, Hanazono Y, Kume A, Nagatsu T, Ozawa K, Nakano I. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2002 August 15; 22(16): 6920-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12177190&dopt=Abstract

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Neutralising antibodies to interferon beta during the treatment of multiple sclerosis. Author(s): Polman CH, Kappos L, Petkau J, Thompson A. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 August; 74(8): 1162; Author Reply 1162-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876268&dopt=Abstract

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Neutralising antibodies to interferon beta during the treatment of multiple sclerosis. Author(s): Giovannoni G, Munschauer FE 3rd, Deisenhammer F. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 November; 73(5): 465-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12397132&dopt=Abstract

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New cannabinoid for multiple sclerosis. Author(s): Whelan J. Source: Drug Discovery Today. 2002 July 15; 7(14): 745-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547023&dopt=Abstract

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New diagnostic criteria for multiple sclerosis: application in first demyelinating episode. Author(s): Tintore M, Rovira A, Rio J, Nos C, Grive E, Sastre-Garriga J, Pericot I, Sanchez E, Comabella M, Montalban X. Source: Neurology. 2003 January 14; 60(1): 27-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525713&dopt=Abstract

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New immunopathologic insights into multiple sclerosis. Author(s): Hemmer B, Kieseier B, Cepok S, Hartung HP. Source: Curr Neurol Neurosci Rep. 2003 May; 3(3): 246-55. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12691630&dopt=Abstract

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New insights into remyelination failure in multiple sclerosis: implications for glial cell transplantation. Author(s): Chari DM, Blakemore WF. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 August; 8(4): 271-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12166495&dopt=Abstract

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New insights into the genetics of multiple sclerosis. Author(s): Baranzini SE, Oksenberg JR, Hauser SL. Source: Journal of Rehabilitation Research and Development. 2002 March-April; 39(2): 201-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12051464&dopt=Abstract

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New T2 lesions enable an earlier diagnosis of multiple sclerosis in clinically isolated syndromes. Author(s): Dalton CM, Brex PA, Miszkiel KA, Fernando K, MacManus DG, Plant GT, Thompson AJ, Miller DH. Source: Annals of Neurology. 2003 May; 53(5): 673-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12731004&dopt=Abstract

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Newer long-term treatments for multiple sclerosis. Author(s): Pryse-Phillips W. Source: Clinical Neurology and Neurosurgery. 2002 July; 104(3): 265-71. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12127666&dopt=Abstract

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NFkappaB and AP-1 DNA binding activity in patients with multiple sclerosis. Author(s): Flores N, Duran C, Blasco MR, Puerta C, Dorado B, Garcia-Merino A, Ballester S. Source: Journal of Neuroimmunology. 2003 February; 135(1-2): 141-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12576234&dopt=Abstract

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Nitric oxide as an activity marker in multiple sclerosis. Author(s): Acar G, Idiman F, Idiman E, Kirkali G, Cakmakci H, Ozakbas S. Source: Journal of Neurology. 2003 May; 250(5): 588-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12736739&dopt=Abstract

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Nitric oxide metabolite determinations reveal continuous inflammation in multiple sclerosis. Author(s): Danilov AI, Andersson M, Bavand N, Wiklund NP, Olsson T, Brundin L. Source: Journal of Neuroimmunology. 2003 March; 136(1-2): 112-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12620649&dopt=Abstract

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Nitric oxide metabolites and interleukin-6 in cerebrospinal fluid from multiple sclerosis patients. Author(s): Miljkovic Dj, Drulovic J, Trajkovic V, Mesaros S, Dujmovic I, Maksimovic D, Samardzic T, Stojsavljevic N, Levic Z, Mostarica Stojkovic M. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2002 July; 9(4): 413-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12099927&dopt=Abstract

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Nitric oxide synthase is present in the cerebrospinal fluid of patients with active multiple sclerosis and is associated with increases in cerebrospinal fluid protein nitrotyrosine and S-nitrosothiols and with changes in glutathione levels. Author(s): Calabrese V, Scapagnini G, Ravagna A, Bella R, Foresti R, Bates TE, Giuffrida Stella AM, Pennisi G. Source: Journal of Neuroscience Research. 2002 November 15; 70(4): 580-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12404512&dopt=Abstract

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No association of inducible nitric oxide synthase gene ( NOS2A) to multiple sclerosis. Author(s): Blanco Y, Yague J, Graus F, Saiz A. Source: Journal of Neurology. 2003 May; 250(5): 598-600. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12736741&dopt=Abstract

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No correlation between aggregates of Cu/Zn superoxide dismutase and cell death in familial amyotrophic lateral sclerosis. Author(s): Lee JP, Gerin C, Bindokas VP, Miller R, Ghadge G, Roos RP. Source: Journal of Neurochemistry. 2002 September; 82(5): 1229-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12358770&dopt=Abstract

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No effect of creatine on respiratory distress in amyotrophic lateral sclerosis. Author(s): Drory VE, Gross D. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. 2002 March; 3(1): 43-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12061948&dopt=Abstract

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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. 2003 April 17; 340(3): 245-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12672552&dopt=Abstract

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Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis. Author(s): Dupuis L, Gonzalez de Aguilar JL, di Scala F, Rene F, de Tapia M, Pradat PF, Lacomblez L, Seihlan D, Prinjha R, Walsh FS, Meininger V, Loeffler JP. Source: Neurobiology of Disease. 2002 August; 10(3): 358-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12270696&dopt=Abstract

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Nonspecific interstitial pneumonia and systemic sclerosis. Author(s): King TE Jr. Source: American Journal of Respiratory and Critical Care Medicine. 2002 June 15; 165(12): 1578-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12070054&dopt=Abstract

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Novel trends in orphan market drug discovery: amyotrophic lateral sclerosis as a case study. Author(s): Clark JE, Brennan A, Ramesh TM, Heywood JA. Source: Frontiers in Bioscience : a Journal and Virtual Library. 2002 August 1; 7: C83-96. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12133810&dopt=Abstract

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Novel TSC1 and TSC2 mutations in Japanese patients with tuberous sclerosis complex. Author(s): Yamamoto T, Pipo JR, Feng JH, Takeda H, Nanba E, Ninomiya H, Ohno K. Source: Brain & Development. 2002 June; 24(4): 227-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12015165&dopt=Abstract

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Nursing at a specialist diagnostic clinic for multiple sclerosis. Author(s): Porter B, Keenan E. Source: British Journal of Nursing (Mark Allen Publishing). 2003 June 12-25; 12(11): 650, 652-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829964&dopt=Abstract

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Occult tissue damage in patients with primary progressive multiple sclerosis is independent of T2-visible lesions--a diffusion tensor MR study. Author(s): Rocca MA, Iannucci G, Rovaris M, Comi G, Filippi M. Source: Journal of Neurology. 2003 April; 250(4): 456-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700912&dopt=Abstract

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Occupational therapy for multiple sclerosis. Author(s): Steultjens EM, Dekker J, Bouter LM, Cardol M, Van de Nes JC, Van den Ende CH. Source: Cochrane Database Syst Rev. 2003; (3): Cd003608. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917976&dopt=Abstract

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Ocular comorbidity in multiple sclerosis. Author(s): Polman CH, Uitdehaag BN, Klok AM. Source: Lancet. 2003 April 5; 361(9364): 1230. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12686079&dopt=Abstract

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Oestrogen receptor alpha gene polymorphism is related to aortic valve sclerosis in postmenopausal women. Author(s): Nordstrom P, Glader CA, Dahlen G, Birgander LS, Lorentzon R, Waldenstrom A, Lorentzon M. Source: Journal of Internal Medicine. 2003 August; 254(2): 140-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12859695&dopt=Abstract

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Oligodendrocyte injury in multiple sclerosis: a role for p53. Author(s): Wosik K, Antel J, Kuhlmann T, Bruck W, Massie B, Nalbantoglu J. Source: Journal of Neurochemistry. 2003 May; 85(3): 635-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694389&dopt=Abstract

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On receiving the diagnosis of multiple sclerosis: managing the transition. Author(s): Johnson J. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 828. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617273&dopt=Abstract

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Once weekly interferon beta for multiple sclerosis is superseded by higher and more frequent dosing. Author(s): Blumhardt LD. Source: Int J Clin Pract Suppl. 2002 September; (131): 9-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12564807&dopt=Abstract

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One year changes in disability in multiple sclerosis: neurological examination compared with patient self report. Author(s): Hoogervorst EL, Eikelenboom MJ, Uitdehaag BM, Polman CH. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 April; 74(4): 439-42. Erratum In: J Neurol Neurosurg Psychiatry. 2003 May; 74(5): 694. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640058&dopt=Abstract

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Optic neuritis and multiple sclerosis. Author(s): Levin LA, Lessell S. Source: Archives of Ophthalmology. 2003 July; 121(7): 1039-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860810&dopt=Abstract

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Optic neuritis in multiple sclerosis. Author(s): Chan JW. Source: Ocular Immunology and Inflammation. 2002 September; 10(3): 161-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12789593&dopt=Abstract

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Optokinetometry: a diagnostic tool in multiple sclerosis. Author(s): Lang J, Mester AF. Source: Advances in Oto-Rhino-Laryngology. 1983; 30: 128-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12325168&dopt=Abstract

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Oral calcitriol: a new therapeutic agent in cutaneous lichen sclerosis. Author(s): Ronger S, Viallard AM, Meunier-Mure F, Chouvet B, Balme B, Thomas L. Source: J Drugs Dermatol. 2003 January; 2(1): 23-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12852377&dopt=Abstract

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Oral interferon beta-1a in relapsing-remitting multiple sclerosis: a double-blind randomized study. Author(s): Polman C, Barkhof F, Kappos L, Pozzilli C, Sandbrink R, Dahlke F, Jakobs P, Lorenz A; European Oral Interferon Beta-1a in Relapsing-Remitting MS Study Group. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 342-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926838&dopt=Abstract

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Oral terbutaline differentially affects cytokine (IL-10, IL-12, TNF, IFNg) release in multiple sclerosis patients and controls. Author(s): Heesen C, Gold SM, Sondermann J, Tessmer W, Schulz KH. Source: Journal of Neuroimmunology. 2002 November; 132(1-2): 189-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12417450&dopt=Abstract

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Organic solvents and the risk of multiple sclerosis. Author(s): Riise T, Moen BE, Kyvik KR. Source: Epidemiology (Cambridge, Mass.). 2002 November; 13(6): 718-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12410015&dopt=Abstract

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Oro-mandibular dystonia in a case of multiple sclerosis with capsular plaque. Author(s): Rajabally YA, Farrell D, Messios N. Source: European Neurology. 2003; 49(3): 190-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12646772&dopt=Abstract

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Oscillopsia without nystagmus caused by head titubation in a patient with multiple sclerosis. Author(s): Proudlock FA, Gottlob I, Constantinescu CS. Source: Journal of Neuro-Ophthalmology : the Official Journal of the North American Neuro-Ophthalmology Society. 2002 June; 22(2): 88-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12131465&dopt=Abstract

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Osteolysis of the cervical spine and mandible in systemic sclerosis: a case report with computed tomography and magnetic resonance imaging findings. Author(s): Benitha R, Modi M, Tikly M. Source: Rheumatology (Oxford, England). 2002 October; 41(10): 1198-200. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12364647&dopt=Abstract

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Oxidation-induced misfolding and aggregation of superoxide dismutase and its implications for amyotrophic lateral sclerosis. Author(s): Rakhit R, Cunningham P, Furtos-Matei A, Dahan S, Qi XF, Crow JP, Cashman NR, Kondejewski LH, Chakrabartty A. Source: The Journal of Biological Chemistry. 2002 December 6; 277(49): 47551-6. Epub 2002 September 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12356748&dopt=Abstract

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Pain and biomechanical responses to distention of the duodenum in patients with systemic sclerosis. Author(s): Pedersen J, Gao C, Egekvist H, Bjerring P, Arendt-Nielsen L, Gregersen H, Drewes AM. Source: Gastroenterology. 2003 May; 124(5): 1230-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12730864&dopt=Abstract

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Pain in patients with multiple sclerosis: a population-based study. Author(s): Svendsen KB, Jensen TS, Overvad K, Hansen HJ, Koch-Henriksen N, Bach FW. Source: Archives of Neurology. 2003 August; 60(8): 1089-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925364&dopt=Abstract

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Parent's perceptions of interactions with health professionals in the pathway to gaining a diagnosis of tuberous sclerosis (TS) and beyond. Author(s): Whitehead LC, Gosling V. Source: Research in Developmental Disabilities. 2003 March-April; 24(2): 109-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12623081&dopt=Abstract

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Parkinsonism as a manifestation of multiple sclerosis. Author(s): Folgar S, Gatto EM, Raina G, Micheli F. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2003 January; 18(1): 108-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12518309&dopt=Abstract

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Paroxysmal supraventricular tachycardia in neonatal tuberous sclerosis complex and cardiac rhabdomyoma: report of one case. Author(s): Yen HR, Chu SM. Source: Acta Paediatr Taiwan. 2003 March-April; 44(2): 112-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845856&dopt=Abstract

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Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. Author(s): van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Simmons R, Taylor BV, Butzkueven H, Kilpatrick T. Source: Bmj (Clinical Research Ed.). 2003 August 9; 327(7410): 316. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12907484&dopt=Abstract

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Pathological mechanisms and disease progression of multiple sclerosis: therapeutic implications. Author(s): Bjartmar C, Fox RJ. Source: Drugs Today (Barc). 2002 January; 38(1): 17-29. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12532182&dopt=Abstract

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Patients with multiple sclerosis and risk of type 1 diabetes mellitus in Sardinia, Italy: a cohort study. Author(s): Marrosu MG, Cocco E, Lai M, Spinicci G, Pischedda MP, Contu P. Source: Lancet. 2002 April 27; 359(9316): 1461-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11988243&dopt=Abstract

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Patients with progressive multiple sclerosis have elevated antibodies to neurofilament subunit. Author(s): Silber E, Semra YK, Gregson NA, Sharief MK. Source: Neurology. 2002 May 14; 58(9): 1372-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12011283&dopt=Abstract

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Patterns of misdiagnosis of multiple sclerosis. Author(s): Levin N, Mor M, Ben-Hur T. Source: Isr Med Assoc J. 2003 July; 5(7): 489-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901244&dopt=Abstract

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Pecam-1 expression in patients with relapsing-remitting multiple sclerosis. Author(s): Niezgoda A, Losy J. Source: Folia Morphol (Warsz). 2002; 61(3): 143-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12416929&dopt=Abstract

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Periodic lateralized epileptiform discharges in multiple sclerosis: a case report. Author(s): Gandelman-Marton R, Rabey JM, Flechter S. Source: Journal of Clinical Neurophysiology : Official Publication of the American Electroencephalographic Society. 2003 April; 20(2): 117-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12766684&dopt=Abstract

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Persistent bitter taste as an initial symptom of amyotrophic lateral sclerosis. Author(s): Petzold GC, Einhaupl KM, Valdueza JM. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 May; 74(5): 687-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700324&dopt=Abstract

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Personality traits in multiple sclerosis (MS) patients with and without fatigue experience. Author(s): Merkelbach S, Konig J, Sittinger H. Source: Acta Neurologica Scandinavica. 2003 March; 107(3): 195-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614312&dopt=Abstract

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Pharmacological methods to overcome IFN-beta antibody formation in the treatment of multiple sclerosis. Author(s): Bagnato F, Pozzilli C. Source: Expert Opinion on Investigational Drugs. 2003 July; 12(7): 1153-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12831350&dopt=Abstract

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Phenotypic effects of familial amyotrophic lateral sclerosis mutant Sod alleles in transgenic Drosophila. Author(s): Mockett RJ, Radyuk SN, Benes JJ, Orr WC, Sohal RS. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 January 7; 100(1): 301-6. Epub 2002 December 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12502789&dopt=Abstract

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Pitfalls in the prenatal diagnosis and prognosis of Bourneville sclerosis. Author(s): Gorincour G, Gire C, Nassi C, D'Ercole C. Source: Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2003 April; 21(4): 409-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12704755&dopt=Abstract

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Plasma plasmin-alpha2-plasmin inhibitor complex levels are increased in systemic sclerosis patients with pulmonary hypertension. Author(s): Jinnin M, Ihn H, Yamane K, Asano Y, Yazawa N, Tamaki K. Source: Rheumatology (Oxford, England). 2003 February; 42(2): 240-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12595617&dopt=Abstract

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Polycystic kidney disease as a result of loss of the tuberous sclerosis 2 tumor suppressor gene during development. Author(s): Cai S, Everitt JI, Kugo H, Cook J, Kleymenova E, Walker CL. Source: American Journal of Pathology. 2003 February; 162(2): 457-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547704&dopt=Abstract

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Polymorphisms of apolipoprotein E and Japanese patients with multiple sclerosis. Author(s): Niino M, Kikuchi S, Fukazawa T, Yabe I, Tashiro K. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 382-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926843&dopt=Abstract

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Polymorphisms of toxifying and detoxifying hepatic enzymes in amyotrophic lateral sclerosis. Author(s): Bachus R, Neubert K, Roots I, Prudlo J, Brockmoller J, Ludolph AC. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 August; 74(8): 1161. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876266&dopt=Abstract

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Potential of statins for the treatment of multiple sclerosis. Author(s): Baker D, Adamson P, Greenwood J. Source: Lancet. Neurology. 2003 January; 2(1): 9-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849290&dopt=Abstract

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Potential roles of CCL2/monocyte chemoattractant protein-1 in the pathogenesis of cutaneous sclerosis. Author(s): Yamamoto T. Source: Clin Exp Rheumatol. 2003 May-June; 21(3): 369-75. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846061&dopt=Abstract

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Predicting multiple sclerosis at optic neuritis onset. Author(s): Jin YP, de Pedro-Cuesta J, Huang YH, Soderstrom M. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 135-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708808&dopt=Abstract

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Predicting the use of occupational therapy services among people with multiple sclerosis in Atlantic Canada. Author(s): Finlayson M, DalMonte J. Source: Can J Occup Ther. 2002 October; 69(4): 239-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12395625&dopt=Abstract

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Predictive value of MRI findings in multiple sclerosis. Author(s): Filippi M. Source: Lancet. Neurology. 2002 May; 1(1): 9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849538&dopt=Abstract

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Predictors and outcomes of scleroderma renal crisis: data from the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial. Author(s): Strand V. Source: Arthritis and Rheumatism. 2002 November; 46(11): 2836-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12428222&dopt=Abstract

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Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose Dpenicillamine in early diffuse systemic sclerosis trial. Author(s): DeMarco PJ, Weisman MH, Seibold JR, Furst DE, Wong WK, Hurwitz EL, Mayes M, White B, Wigley F, Barr W, Moreland L, Medsger TA Jr, Steen V, Martin RW, Collier D, Weinstein A, Lally E, Varga J, Weiner SR, Andrews B, Abeles M, Clements PJ. Source: Arthritis and Rheumatism. 2002 November; 46(11): 2983-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12428241&dopt=Abstract

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Predictors of adherence to glatiramer acetate therapy in individuals with self-reported progressive forms of multiple sclerosis. Author(s): Fraser C, Hadjimichael O, Vollmer T. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 2003 June; 35(3): 163-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12830664&dopt=Abstract

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Predictors of end stage lung disease in systemic sclerosis. Author(s): Steen V. Source: Annals of the Rheumatic Diseases. 2003 February; 62(2): 97-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525376&dopt=Abstract

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Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Author(s): Steen V, Medsger TA Jr. Source: Arthritis and Rheumatism. 2003 February; 48(2): 516-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571862&dopt=Abstract

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Premacular gliosis in a patient with tuberose sclerosis. Author(s): Davies B, Woon W, Geall M. Source: Eye (London, England). 2002 March; 16(2): 193-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11988823&dopt=Abstract

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Preservation of peritoneal catheter for prevention of encapsulating peritoneal sclerosis. Author(s): Moriishi M, Kawanishi H, Kawai T, Takahashi S, Hirai T, Shishida M, Watanabe H, Takahashi N. Source: Adv Perit Dial. 2002; 18: 149-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12402608&dopt=Abstract

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Prevalence of autoimmune thyroiditis and non-immune thyroid disease in multiple sclerosis. Author(s): Niederwieser G, Buchinger W, Bonelli RM, Berghold A, Reisecker F, Koltringer P, Archelos JJ. Source: Journal of Neurology. 2003 June; 250(6): 672-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796827&dopt=Abstract

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Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Author(s): Mayes MD, Lacey JV Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, Schottenfeld D. Source: Arthritis and Rheumatism. 2003 August; 48(8): 2246-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12905479&dopt=Abstract

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Prevention of autoimmune attack and disease progression in multiple sclerosis: current therapies and future prospects. Author(s): Pender MP, Wolfe NP. Source: Internal Medicine Journal. 2002 November; 32(11): 554-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12412939&dopt=Abstract

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Primary and secondary progressive multiple sclerosis. Author(s): Vukusic S, Confavreux C. Source: Journal of the Neurological Sciences. 2003 February 15; 206(2): 153-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559503&dopt=Abstract

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Primary lateral sclerosis: a rare upper-motor-predominant form of amyotrophic lateral sclerosis often accompanied by frontotemporal lobar degeneration with ubiquitinated neuronal inclusions? Report of an autopsy case and a review of the literature. Author(s): Tan CF, Kakita A, Piao YS, Kikugawa K, Endo K, Tanaka M, Okamoto K, Takahashi H. Source: Acta Neuropathologica. 2003 June; 105(6): 615-20. Epub 2003 March 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12734667&dopt=Abstract

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Problems with UK government's risk sharing scheme for assessing drugs for multiple sclerosis. Author(s): Sudlow CL, Counsell CE. Source: Bmj (Clinical Research Ed.). 2003 February 15; 326(7385): 388-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12586677&dopt=Abstract

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Production of IL-1beta and IL-1Ra as risk factors for susceptibility and progression of relapse-onset multiple sclerosis. Author(s): de Jong BA, Huizinga TW, Bollen EL, Uitdehaag BM, Bosma GP, van Buchem MA, Remarque EJ, Burgmans AC, Kalkers NF, Polman CH, Westendorp RG. Source: Journal of Neuroimmunology. 2002 May; 126(1-2): 172-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12020968&dopt=Abstract

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Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis. Author(s): Vukusic S, Confavreux C. Source: Journal of the Neurological Sciences. 2003 February 15; 206(2): 135-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559500&dopt=Abstract

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Progress in deciphering the genetics of multiple sclerosis. Author(s): Herrera BM, Ebers GC. Source: Current Opinion in Neurology. 2003 June; 16(3): 253-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858059&dopt=Abstract

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Progression of aortic valve sclerosis to aortic stenosis. Author(s): Faggiano P, Antonini-Canterin F, Erlicher A, Romeo C, Cervesato E, Pavan D, Piazza R, Huang G, Nicolosi GL. Source: The American Journal of Cardiology. 2003 January 1; 91(1): 99-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12505585&dopt=Abstract

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Progressive increase in incidence and prevalence of multiple sclerosis in Newcastle, Australia: a 35-year study. Author(s): Barnett MH, Williams DB, Day S, Macaskill P, McLeod JG. Source: Journal of the Neurological Sciences. 2003 September 15; 213(1-2): 1-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873746&dopt=Abstract

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Progressive systemic sclerosis: clinical manifestations and anesthetic considerations. Author(s): Roberts JG, Sabar R, Gianoli JA, Kaye AD. Source: Journal of Clinical Anesthesia. 2002 September; 14(6): 474-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393122&dopt=Abstract

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Progressive ventricular enlargement in patients with clinically isolated syndromes is associated with the early development of multiple sclerosis. Author(s): Dalton CM, Brex PA, Jenkins R, Fox NC, Miszkiel KA, Crum WR, O'Riordan JI, Plant GT, Thompson AJ, Miller DH. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 August; 73(2): 141-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12122170&dopt=Abstract

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Prolactin and prolactin receptor gene polymorphisms in multiple sclerosis and systemic lupus erythematosus. Author(s): Mellai M, Giordano M, D'Alfonso S, Marchini M, Scorza R, Giovanna Danieli M, Leone M, Ferro I, Liguori M, Trojano M, Ballerini C, Massacesi L, Cannoni S, Bomprezzi R, Momigliano-Richiardi P. Source: Human Immunology. 2003 February; 64(2): 274-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559630&dopt=Abstract

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Prolactin and thyroid hormones in patients with systemic sclerosis: correlations with disease manifestations and activity. Author(s): Shahin AA, Abdoh S, Abdelrazik M. Source: Zeitschrift Fur Rheumatologie. 2002 December; 61(6): 703-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12491136&dopt=Abstract

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Prospective analysis of diplopia after anterior temporal lobectomy for mesial temporal lobe sclerosis. Author(s): Cohen-Gadol AA, Leavitt JA, Lynch JJ, Marsh WR, Cascino GD. Source: Journal of Neurosurgery. 2003 September; 99(3): 496-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959436&dopt=Abstract

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Prostaglandin E2 is increased in amyotrophic lateral sclerosis patients. Author(s): Ilzecka J. Source: Acta Neurologica Scandinavica. 2003 August; 108(2): 125-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12859290&dopt=Abstract

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Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis. Author(s): Urushitani M, Kurisu J, Tsukita K, Takahashi R. Source: Journal of Neurochemistry. 2002 December; 83(5): 1030-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12437574&dopt=Abstract

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Protein kinase and protein phosphatase expression in amyotrophic lateral sclerosis spinal cord. Author(s): Hu JH, Zhang H, Wagey R, Krieger C, Pelech SL. Source: Journal of Neurochemistry. 2003 April; 85(2): 432-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12675919&dopt=Abstract

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Providing pharmaceutical care to the multiple sclerosis patient. Author(s): Ryan M, Piascik P. Source: Journal of the American Pharmaceutical Association (Washington,D.C. : 1996). 2002 September-October; 42(5): 753-66; Quiz 766-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12269710&dopt=Abstract

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Psychometric evaluation of the Chicago Multiscale Depression Inventory in multiple sclerosis patients. Author(s): Chang CH, Nyenhuis DL, Cella D, Luchetta T, Dineen K, Reder AT. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 160-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708812&dopt=Abstract

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Pulmonary hypertension in systemic sclerosis. Author(s): Denton CP, Black CM. Source: Rheumatic Diseases Clinics of North America. 2003 May; 29(2): 335-49, Vii. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841298&dopt=Abstract

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Pulmonary hypertension in systemic sclerosis: bete noire no more? Author(s): Varga J. Source: Current Opinion in Rheumatology. 2002 November; 14(6): 666-70. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12410089&dopt=Abstract

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Pupillocynetic activity of substance P in systemic sclerosis. Author(s): Del Rosso A, Bertinotti L, Pietrini U, Messori A, Fanciullacci M, Casale R, Giacomelli R, Generini S, Sicuteri R, Pignone A, Cozzi F, Matucci-Cerinic M. Source: The Journal of Rheumatology. 2003 June; 30(6): 1231-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12784395&dopt=Abstract

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Pure optic-spinal form of multiple sclerosis in Japan. Author(s): Misu T, Fujihara K, Nakashima I, Miyazawa I, Okita N, Takase S, Itoyama Y. Source: Brain; a Journal of Neurology. 2002 November; 125(Pt 11): 2460-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12390972&dopt=Abstract

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Pyramidal tract mapping by diffusion tensor magnetic resonance imaging in multiple sclerosis: improving correlations with disability. Author(s): Wilson M, Tench CR, Morgan PS, Blumhardt LD. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 February; 74(2): 2037. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531950&dopt=Abstract

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Quality of life and cost of multiple sclerosis. Author(s): Miltenburger C, Kobelt G. Source: Clinical Neurology and Neurosurgery. 2002 July; 104(3): 272-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12127667&dopt=Abstract

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Quality of life in multiple sclerosis patients in Spain. Author(s): Chang CH, Cella D, Fernandez O, Luque G, de Castro P, de Andres C, Casanova B, Hernandez MA, Prieto JM, Fernandez VE, de Ramon E; Grupo Espanol de Calidad de Vida en Esclerosis Multiple. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 December; 8(6): 527-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474996&dopt=Abstract

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Quality of life in multiple sclerosis: influence of interferon-beta1 a (Avonex) treatment. Author(s): Vermersch P, de Seze J, Delisse B, Lemaire S, Stojkovic T. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 October; 8(5): 37781. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12356203&dopt=Abstract

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Quality of life in patients with multiple sclerosis: the impact of fatigue and depression. Author(s): Janardhan V, Bakshi R. Source: Journal of the Neurological Sciences. 2002 December 15; 205(1): 51-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409184&dopt=Abstract

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Quantitative 1H MRS imaging 14 years after presenting with a clinically isolated syndrome suggestive of multiple sclerosis. Author(s): Kapeller P, Brex PA, Chard D, Dalton C, Griffin CM, McLean MA, Parker GJ, Thompson AJ, Miller DH. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 May; 8(3): 207-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12120691&dopt=Abstract

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Quantitative magnetization transfer imaging of pre-lesional white-matter changes in multiple sclerosis. Author(s): Fazekas F, Ropele S, Enzinger C, Seifert T, Strasser-Fuchs S. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 December; 8(6): 479-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474987&dopt=Abstract

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Quantitative oculographic characterisation of internuclear ophthalmoparesis in multiple sclerosis: the versional dysconjugacy index Z score. Author(s): Frohman EM, Frohman TC, O'Suilleabhain P, Zhang H, Hawker K, Racke MK, Frawley W, Phillips JT, Kramer PD. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 July; 73(1): 51-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12082045&dopt=Abstract

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Quiz page. Tuberous sclerosis. Author(s): Rosenberg M. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2002 July; 40(1): Xlix. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12088016&dopt=Abstract

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Radon: a possible risk factor in multiple sclerosis. Author(s): Bolviken B, Celius EG, Nilsen R, Strand T. Source: Neuroepidemiology. 2003 January-February; 22(1): 87-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12566959&dopt=Abstract

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Randomized controlled trials to assess therapies for multiple sclerosis. Author(s): Wingerchuk DM, Noseworthy JH. Source: Neurology. 2002 April 23; 58(8 Suppl 4): S40-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11971125&dopt=Abstract

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Rap1 activity is elevated in malignant astrocytomas independent of tuberous sclerosis complex-2 gene expression. Author(s): Lau N, Uhlmann EJ, Von Lintig FC, Nagy A, Boss GR, Gutmann DH, Guha A. Source: International Journal of Oncology. 2003 January; 22(1): 195-200. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12469204&dopt=Abstract

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Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. Author(s): Avasarala JR, Cross AH, Clifford DB, Singer BA, Siegel BA, Abbey EE. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 5962. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617270&dopt=Abstract

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Rasch measurement in the assessment of amytrophic lateral sclerosis patients. Author(s): Norquist JM, Fitzpatrick R, Jenkinson C. Source: J Appl Meas. 2003; 4(3): 249-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904675&dopt=Abstract

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Rational therapy for relapsing multiple sclerosis. Author(s): Wolinsky JS. Source: Lancet. Neurology. 2003 May; 2(5): 271-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849176&dopt=Abstract

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Re: Detourney, B. The value of economic modeling studies in the evaluation of treatment strategies for multiple sclerosis. (Editorial) Value Health 2002;5:1-2. Author(s): Hutton J. Source: Value in Health : the Journal of the International Society for Pharmacoeconomics and Outcomes Research. 2002 March-April; 5(2): 114-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11973801&dopt=Abstract

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Re: Hemorrhagic angiomyolipoma and tuberous sclerosis complex: a case report. Recognizing the needs of a growing population of adults with tuberous sclerosis complex. Author(s): Rothberg BE. Source: Conn Med. 2003 May; 67(5): 313-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12802849&dopt=Abstract

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Reactive astrocytes in chronic active lesions of multiple sclerosis express costimulatory molecules B7-1 and B7-2. Author(s): Zeinstra E, Wilczak N, De Keyser J. Source: Journal of Neuroimmunology. 2003 February; 135(1-2): 166-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12576238&dopt=Abstract

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Rebif offers another option for treating multiple sclerosis. Author(s): Ryan M. Source: Journal of the American Pharmaceutical Association (Washington,D.C. : 1996). 2002 November-December; 42(6): 889-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12482017&dopt=Abstract

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Recent advances in amyotrophic lateral sclerosis research. Author(s): Przedborski S, Mitsumoto H, Rowland LP. Source: Curr Neurol Neurosci Rep. 2003 January; 3(1): 70-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12507415&dopt=Abstract

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Recent advances in the therapy of amyotrophic lateral sclerosis: focus on excitotoxicity. Author(s): Brighina L, Sala G, Ceresa C, Tremolizzo L, Ferrarese C. Source: Funct Neurol. 2001; 16(4 Suppl): 189-202. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11996516&dopt=Abstract

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Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease. Author(s): Mitchell JD, Wokke JH, Borasio GD. Source: Cochrane Database Syst Rev. 2002; (3): Cd002064. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12137643&dopt=Abstract

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Recurrent anterior uveitis and healed retinal vasculitis associated with multiple sclerosis. Author(s): Narayana KM, Agrawal R, Biswas J, Arjundas D. Source: Indian J Ophthalmol. 2003 March; 51(1): 77-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701867&dopt=Abstract

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Recurrent bronchiolitis obliterans organizing pneumonia in a patient with limited cutaneous systemic sclerosis. Author(s): Shimizu Y, Tsukagoshi H, Nemoto T, Honma M, Nojima Y, Mori M. Source: Rheumatology International. 2002 September; 22(5): 216-8. Epub 2002 July 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12215870&dopt=Abstract

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Recurrent nephrotic syndrome in patient with multiple sclerosis treated with interferon beta-1a. Author(s): Tola MR, Caniatti LM, Gragnaniello D, Russo M, Stabellini N, Granieri E. Source: Journal of Neurology. 2003 June; 250(6): 768-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12862038&dopt=Abstract

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Reduced expression of the inhibitor of apoptosis proteins in T cells from patients with multiple sclerosis following interferon-beta therapy. Author(s): Sharief MK, Noori MA, Zoukos Y. Source: Journal of Neuroimmunology. 2002 August; 129(1-2): 224-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12161039&dopt=Abstract

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Reduction in metabolite transverse relaxation times in amyotrophic lateral sclerosis. Author(s): Hanstock CC, Cwik VA, Martin WR. Source: Journal of the Neurological Sciences. 2002 June 15; 198(1-2): 37-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12039662&dopt=Abstract

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Reduction of expression of tuberin, the tuberous-sclerosis-complex-gene-2 product in tuberous sclerosis complex associated connective tissue nevi and sporadic squamous and basal cell carcinomas. Author(s): Wienecke R, Klemm E, Karparti S, Swanson NA, Green AJ, DeClue JE. Source: Journal of Cutaneous Pathology. 2002 May; 29(5): 287-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12100629&dopt=Abstract

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Re-expression of PSA-NCAM by demyelinated axons: an inhibitor of remyelination in multiple sclerosis? Author(s): Charles P, Reynolds R, Seilhean D, Rougon G, Aigrot MS, Niezgoda A, Zalc B, Lubetzki C. Source: Brain; a Journal of Neurology. 2002 September; 125(Pt 9): 1972-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183343&dopt=Abstract

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Regulation by interferon beta-1a of reactive oxygen metabolites production by lymphocytes and monocytes and serum sulfhydryls in relapsing multiple sclerosis patients. Author(s): Lucas M, Rodriguez MC, Gata JM, Zayas MD, Solano F, Izquierdo G. Source: Neurochemistry International. 2003 January; 42(1): 67-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12441169&dopt=Abstract

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Regulation of cell morphology and adhesion by the tuberous sclerosis complex (TSC1/2) gene products in human kidney epithelial cells through increased Ecadherin/beta-catenin activity. Author(s): Li S, Braverman R, Li H, Vass WC, Lowy DR, DeClue JE. Source: Molecular Carcinogenesis. 2003 June; 37(2): 98-109. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12766909&dopt=Abstract

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Regulation of PCNA and CAF-1 expression by the two tuberous sclerosis gene products. Author(s): Hengstschlager M, Rosner M, Fountoulakis M, Lubec G. Source: Biochemical and Biophysical Research Communications. 2003 August 1; 307(3): 737-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12893285&dopt=Abstract

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Regulation of self-reactive T cells by human immunoglobulins--implications for multiple sclerosis therapy. Author(s): Aktas O, Zipp F. Source: Current Pharmaceutical Design. 2003; 9(3): 245-56. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12570829&dopt=Abstract

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Relapsing-remitting multiple sclerosis and whole-brain N-acetylaspartate measurement: evidence for different clinical cohorts initial observations. Author(s): Gonen O, Moriarty DM, Li BS, Babb JS, He J, Listerud J, Jacobs D, Markowitz CE, Grossman RI. Source: Radiology. 2002 October; 225(1): 261-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12355014&dopt=Abstract

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Relation between walking speed and muscle strength is affected by somatosensory loss in multiple sclerosis. Author(s): Thoumie P, Mevellec E. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 September; 73(3): 313-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12185167&dopt=Abstract

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Relationship between coping, cognitive dysfunction and depression in multiple sclerosis. Author(s): Arnett PA, Higginson CI, Voss WD, Randolph JJ, Grandey AA. Source: Clin Neuropsychol. 2002 August; 16(3): 341-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12607147&dopt=Abstract

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Relationship between urinary symptoms and disease-related parameters in multiple sclerosis. Author(s): Araki I, Matsui M, Ozawa K, Nishimura M, Kuno S, Saida T. Source: Journal of Neurology. 2002 August; 249(8): 1010-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12195446&dopt=Abstract

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Relationship functioning and sexuality among people with multiple sclerosis. Author(s): McCabe MP. Source: Journal of Sex Research. 2002 November; 39(4): 302-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12545413&dopt=Abstract

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Relationship of bladder dysfunction to lesion site in multiple sclerosis. Author(s): Araki I, Matsui M, Ozawa K, Takeda M, Kuno S. Source: The Journal of Urology. 2003 April; 169(4): 1384-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12629367&dopt=Abstract

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Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Author(s): Barker WW, Luis CA, Kashuba A, Luis M, Harwood DG, Loewenstein D, Waters C, Jimison P, Shepherd E, Sevush S, Graff-Radford N, Newland D, Todd M, Miller B, Gold M, Heilman K, Doty L, Goodman I, Robinson B, Pearl G, Dickson D, Duara R. Source: Alzheimer Disease and Associated Disorders. 2002 October-December; 16(4): 203-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12468894&dopt=Abstract

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Reliability of the El Escorial diagnostic criteria for amyotrophic lateral sclerosis. Author(s): Beghi E, Balzarini C, Bogliun G, Logroscino G, Manfredi L, Mazzini L, Micheli A, Millul A, Poloni M, Riva R, Salmoiraghi F, Tonini C, Vitelli E; Italian ALS Study Group. Source: Neuroepidemiology. 2002 November-December; 21(6): 265-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12411728&dopt=Abstract

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Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance. Author(s): Barkhof F, Bruck W, De Groot CJ, Bergers E, Hulshof S, Geurts J, Polman CH, van der Valk P. Source: Archives of Neurology. 2003 August; 60(8): 1073-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925362&dopt=Abstract

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Remyelinating strategies for the treatment of multiple sclerosis. Author(s): Stangel M, Hartung HP. Source: Progress in Neurobiology. 2002 December; 68(5): 361-76. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531235&dopt=Abstract

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Remyelination in multiple sclerosis. Author(s): Bruck W, Kuhlmann T, Stadelmann C. Source: Journal of the Neurological Sciences. 2003 February 15; 206(2): 181-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559508&dopt=Abstract

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Renal cell carcinoma in a 2-year-old child with tuberous sclerosis. Author(s): Lendvay TS, Broecker B, Smith EA. Source: The Journal of Urology. 2002 September; 168(3): 1131-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12187252&dopt=Abstract

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Renal functional reserve is impaired in patients with systemic sclerosis without clinical signs of kidney involvement. Author(s): Livi R, Teghini L, Pignone A, Generini S, Matucci-Cerinic M, Cagnoni M. Source: Annals of the Rheumatic Diseases. 2002 August; 61(8): 682-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12117672&dopt=Abstract

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Reproductive decision making in women with multiple sclerosis. Author(s): Smeltzer SC. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 2002 June; 34(3): 145-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12080870&dopt=Abstract

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Resection of hilar cholangiocarcinomas: pivotal prognostic factors and impact of tumor sclerosis. Author(s): Puhalla H, Gruenberger T, Pokorny H, Soliman T, Wrba F, Sponer U, Winkler T, Ploner M, Raderer M, Steininger R, Muhlbacher F, Laengle F. Source: World Journal of Surgery. 2003 June; 27(6): 680-4. Epub 2003 May 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12733000&dopt=Abstract

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Results of an international questionnaire on immunosuppressive treatment of multiple sclerosis. Author(s): Hommes OR, Weiner HL. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 April; 8(2): 139-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11990871&dopt=Abstract

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Rethinking cognitive function in multiple sclerosis: a nursing perspective. Author(s): Halper J, Kennedy P, Miller CM, Morgante L, Namey M, Ross AP. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 2003 April; 35(2): 70-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12795033&dopt=Abstract

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Retinal findings in systemic sclerosis: a comparison with nailfold capillaroscopic patterns. Author(s): Ushiyama O, Ushiyama K, Yamada T, Koarada S, Tada Y, Suzuki N, Ohta A, Nagasawa K. Source: Annals of the Rheumatic Diseases. 2003 March; 62(3): 204-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12594103&dopt=Abstract

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Retinol measurements and retinoid receptor gene expression in patients with multiple sclerosis. Author(s): Royal W 3rd, Gartner S, Gajewski CD. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 December; 8(6): 452-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474982&dopt=Abstract

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Reversible MRI changes of hypothalamus in a multiple sclerosis patient with homeostatic disturbances. Author(s): Tsui EY, Yip SF, Ng SH, Cheung YK. Source: European Radiology. 2002 December; 12 Suppl 3: S28-31. Epub 2002 May 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12522597&dopt=Abstract

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Revised medical criteria for evaluating amyotrophic lateral sclerosis. Final rules. Author(s): Social Security Administration. Source: Federal Register. 2003 August 28; 68(167): 51689-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12952014&dopt=Abstract

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Revisiting The pathogenesis of multiple sclerosis revisited. Author(s): Compston A. Source: Int Ms J. 2003 April; 10(1): 29-31. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906768&dopt=Abstract

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Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. Author(s): Castro AF, Rebhun JF, Clark GJ, Quilliam LA. Source: The Journal of Biological Chemistry. 2003 August 29; 278(35): 32493-6. Epub 2003 July 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842888&dopt=Abstract

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Right hippocampal sclerosis is more common than left after febrile seizures. Author(s): Janszky J, Woermann FG, Barsi P, Schulz R, Halasz P, Ebner A. Source: Neurology. 2003 April 8; 60(7): 1209-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682340&dopt=Abstract

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Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Author(s): Miller RG, Mitchell JD, Lyon M, Moore DH. Source: Cochrane Database Syst Rev. 2002; (2): Cd001447. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12076411&dopt=Abstract

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Risk factors and preventive measures for encapsulating peritoneal sclerosis--Jikei experience 2002. Author(s): Nakayama M, Yamamoto H, Ikeda M, Hasegawa T, Kato N, Takahashi H, Otsuka Y, Yokoyama K, Yamamoto R, Kawaguchi Y, Hosoya T. Source: Adv Perit Dial. 2002; 18: 144-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12402607&dopt=Abstract

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Risk of multiple sclerosis in nurse anaesthetists. Author(s): Stenager E, Bronnum-Hansen H, Koch-Henriksen N. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 427-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926851&dopt=Abstract

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Risk of sporadic amyotrophic lateral sclerosis associated with seropositivity for herpesviruses and echovirus-7. Author(s): Cermelli C, Vinceti M, Beretti F, Pietrini V, Nacci G, Pietrosemoli P, Bartoletti A, Guidetti D, Sola P, Bergomi M, Vivoli G, Portolani M. Source: European Journal of Epidemiology. 2003; 18(2): 123-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12733833&dopt=Abstract

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Risk to verbal memory following anterior temporal lobectomy in patients with severe left-sided hippocampal sclerosis. Author(s): Martin RC, Kretzmer T, Palmer C, Sawrie S, Knowlton R, Faught E, Morawetz R, Kuzniecky R. Source: Archives of Neurology. 2002 December; 59(12): 1895-901. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12470177&dopt=Abstract

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Risks of falls in subjects with multiple sclerosis. Author(s): Cattaneo D, De Nuzzo C, Fascia T, Macalli M, Pisoni I, Cardini R. Source: Archives of Physical Medicine and Rehabilitation. 2002 June; 83(6): 864-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12048669&dopt=Abstract

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Role of eye movement examination and subjective visual vertical in clinical evaluation of multiple sclerosis. Author(s): Serra A, Derwenskus J, Downey DL, Leigh RJ. Source: Journal of Neurology. 2003 May; 250(5): 569-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12736736&dopt=Abstract

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Role of magnetic resonance imaging in the diagnosis and monitoring of multiple sclerosis: consensus report of the White Matter Study Group. Author(s): Filippi M, Dousset V, McFarland HF, Miller DH, Grossman RI. Source: Journal of Magnetic Resonance Imaging : Jmri. 2002 May; 15(5): 499-504. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11997889&dopt=Abstract

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Screening for early cognitive impairment in multiple sclerosis patients using the clock drawing test. Author(s): Barak Y, Lavie M, Achiron A. Source: Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. 2002 November; 9(6): 629-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604271&dopt=Abstract

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Screening for multiple sclerosis cognitive impairment using a self-administered 15item questionnaire. Author(s): Benedict RH, Munschauer F, Linn R, Miller C, Murphy E, Foley F, Jacobs L. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 95101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617275&dopt=Abstract

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Searching for needles in haystacks-the genetics of multiple sclerosis and other common neurological diseases. Author(s): Hensiek AE, Sawcer SJ, Compston DA. Source: Brain Research Bulletin. 2003 August 15; 61(3): 229-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12909292&dopt=Abstract

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Segmental tuberous sclerosis presenting as unilateral facial angiofibromas. Author(s): Trauner MA, Ruben BS, Lynch PJ. Source: Journal of the American Academy of Dermatology. 2003 August; 49(2 Suppl Case Reports): S164-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894111&dopt=Abstract

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Seizure control and cognitive outcome after temporal lobectomy: a comparison of classic Ammon's horn sclerosis, atypical mesial temporal sclerosis, and tumoral pathologies. Author(s): York MK, Rettig GM, Grossman RG, Hamilton WJ, Armstrong DD, Levin HS, Mizrahi EM. Source: Epilepsia. 2003 March; 44(3): 387-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614395&dopt=Abstract

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Selective caudate atrophy in multiple sclerosis: a 3D MRI parcellation study. Author(s): Bermel RA, Innus MD, Tjoa CW, Bakshi R. Source: Neuroreport. 2003 March 3; 14(3): 335-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12634479&dopt=Abstract

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Selective loss of trans-acting instability determinants of neurofilament mRNA in amyotrophic lateral sclerosis spinal cord. Author(s): Ge WW, Leystra-Lantz C, Wen W, Strong MJ. Source: The Journal of Biological Chemistry. 2003 July 18; 278(29): 26558-63. Epub 2003 May 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12730211&dopt=Abstract

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Self reported stressful life events and exacerbations in multiple sclerosis: prospective study. Author(s): Buljevac D, Hop WC, Reedeker W, Janssens AC, van der Meche FG, van Doorn PA, Hintzen RQ. Source: Bmj (Clinical Research Ed.). 2003 September 20; 327(7416): 646. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500435&dopt=Abstract

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Sensitivity of laser-evoked potentials versus somatosensory evoked potentials in patients with multiple sclerosis. Author(s): Spiegel J, Hansen C, Baumgartner U, Hopf HC, Treede RD. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2003 June; 114(6): 992-1002. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804667&dopt=Abstract

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Serial gadolinium-enhanced MRI in acute attack of multiple sclerosis treated with plasma exchange. Author(s): Pericot I, Rio J, Rovira A, Castella MD, Tintore M, Montalban X. Source: Journal of Neurology. 2003 February; 250(2): 243-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12622095&dopt=Abstract

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Seroprevalence of Borna disease virus antibodies is not increased in patients with amyotrophic lateral sclerosis. Author(s): Prudlo J, Fischer A, Lapple M, Muller A, Neubert K, Gericke CA, Ludolph AC, Grasser F, Sauder C. Source: Journal of Neurology. 2002 October; 249(10): 1462-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12532937&dopt=Abstract

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Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes. Author(s): Avolio C, Ruggieri M, Giuliani F, Liuzzi GM, Leante R, Riccio P, Livrea P, Trojano M. Source: Journal of Neuroimmunology. 2003 March; 136(1-2): 46-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12620642&dopt=Abstract

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Serum uric acid and multiple sclerosis. Author(s): Sotgiu S, Pugliatti M, Sanna A, Sotgiu A, Fois ML, Arru G, Rosati G. Source: Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2002 October; 23(4): 183-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12536287&dopt=Abstract

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Severe heart failure in a young multiple sclerosis patient. Author(s): Gbadamosi J, Munchau A, Weiller C, Schafer H. Source: Journal of Neurology. 2003 February; 250(2): 241-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12622093&dopt=Abstract

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Sex differences in cognitive impairment in multiple sclerosis. Author(s): Beatty WW, Aupperle RL. Source: Clin Neuropsychol. 2002 December; 16(4): 472-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12822056&dopt=Abstract

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Sex differences in in vitro pro-inflammatory cytokine production from peripheral blood of multiple sclerosis patients. Author(s): Nguyen LT, Ramanathan M, Weinstock-Guttman B, Baier M, Brownscheidle C, Jacobs LD. Source: Journal of the Neurological Sciences. 2003 May 15; 209(1-2): 93-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12686409&dopt=Abstract

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Sexual dysfunction in multiple sclerosis: a MRI, neurophysiological and urodynamic study. Author(s): Zivadinov R, Zorzon M, Locatelli L, Stival B, Monti F, Nasuelli D, Tommasi MA, Bratina A, Cazzato G. Source: Journal of the Neurological Sciences. 2003 June 15; 210(1-2): 73-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12736092&dopt=Abstract

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Shared scheme for assessing drugs for multiple sclerosis: cost effective provision of effective treatments for multiple sclerosis. Author(s): Napier JC, Francis R, Wright G. Source: Bmj (Clinical Research Ed.). 2003 May 31; 326(7400): 1212. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12775633&dopt=Abstract

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Shared scheme for assessing drugs for multiple sclerosis: dealing with uncertainties about cost effectiveness of treatments is difficult problem. Author(s): Chadwick D, Gray R. Source: Bmj (Clinical Research Ed.). 2003 May 31; 326(7400): 1212-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12775632&dopt=Abstract

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Shared scheme for assessing drugs for multiple sclerosis: why are eyes tightly shut to considering causes other than autoimmunity? Author(s): Chaudhuri A, Behan PO. Source: Bmj (Clinical Research Ed.). 2003 May 31; 326(7400): 1213. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12775634&dopt=Abstract

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Short term predictors of unemployment in multiple sclerosis patients. Author(s): Busche KD, Fisk JD, Murray TJ, Metz LM. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2003 May; 30(2): 137-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12774953&dopt=Abstract

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Short-term correlations between clinical and MR imaging findings in relapsingremitting multiple sclerosis. Author(s): Rovaris M, Comi G, Ladkani D, Wolinsky JS, Filippi M; European/Canadian Glatiramer Acetate Study Group. Source: Ajnr. American Journal of Neuroradiology. 2003 January; 24(1): 75-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12533330&dopt=Abstract

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Simple phonic tic in multiple sclerosis. Author(s): Lana-Peixoto MA, Teixeira AL; Brazilian Committee for Treatment and Research in Multiple Sclerosis. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 December; 8(6): 510-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474993&dopt=Abstract

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Simultaneous presence of neutrophil alveolitis and Ki-67 positivity of alveolar macrophages in dermato-/polymyositis and systemic sclerosis. Author(s): Kumanovics G, Magyarlaki T, Komocsi A, Szekeres G, Czirjak L. Source: Rheumatology International. 2003 January; 23(1): 6-10. Epub 2002 September 11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12548435&dopt=Abstract

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Single-cell analysis of mtDNA in amyotrophic lateral sclerosis: towards the characterization of individual neurons in neurodegenerative disorders. Author(s): Mawrin C, Kirches E, Dietzmann K. Source: Pathology, Research and Practice. 2003; 199(6): 415-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12924443&dopt=Abstract

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Single-nucleotide polymorphisms in uncoding regions of ALS2 gene of Japanese patients with autosomal-recessive amyotrophic lateral sclerosis. Author(s): Nagano I, Murakami T, Shiote M, Manabe Y, Hadano S, Yanagisawa Y, Ikeda JE, Abe K. Source: Neurological Research. 2003 July; 25(5): 505-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866199&dopt=Abstract

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Skeletal muscle properties in a transgenic mouse model for amyotrophic lateral sclerosis: effects of creatine treatment. Author(s): Derave W, Van Den Bosch L, Lemmens G, Eijnde BO, Robberecht W, Hespel P. Source: Neurobiology of Disease. 2003 August; 13(3): 264-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901841&dopt=Abstract

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Skewed autoantibody reactivity to the extracellular domain of myelin oligodendrocyte glycoprotein in multiple sclerosis. Author(s): Tejada-Simon MV, Hong J, Rivera VM, Zhang JZ. Source: Immunology. 2002 December; 107(4): 403-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12460184&dopt=Abstract

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Somatosensory evoked potential recovery in kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (kii AlS/PDC). Author(s): Machii K, Ugawa Y, Kokubo Y, Sasaki R, Kuzuhara S. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2003 March; 114(3): 564-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12705437&dopt=Abstract

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Spanish centre for rehabilitation of multiple sclerosis to be built. Author(s): Bosch X. Source: Lancet. Neurology. 2003 July; 2(7): 391. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849112&dopt=Abstract

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Spasticity in multiple sclerosis. Author(s): Barnes MP, Kent RM, Semlyen JK, McMullen KM. Source: Neurorehabilitation and Neural Repair. 2003 March; 17(1): 66-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12645447&dopt=Abstract

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Spatial clustering of amyotrophic lateral sclerosis in Finland at place of birth and place of death. Author(s): Sabel CE, Boyle PJ, Loytonen M, Gatrell AC, Jokelainen M, Flowerdew R, Maasilta P. Source: American Journal of Epidemiology. 2003 May 15; 157(10): 898-905. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746242&dopt=Abstract

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Spatial vision in visually asymptomatic subjects at high risk for multiple sclerosis. Author(s): Frisen L. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 August; 74(8): 1145-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876258&dopt=Abstract

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Specificity of autoantibodies to epitopes of myelin proteins in multiple sclerosis. Author(s): Dharmasaroja P. Source: Journal of the Neurological Sciences. 2003 January 15; 206(1): 7-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12480078&dopt=Abstract

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SPECT perfusion changes during complex partial seizures in patients with hippocampal sclerosis. Author(s): Van Paesschen W, Dupont P, Van Driel G, Van Billoen H, Maes A. Source: Brain; a Journal of Neurology. 2003 May; 126(Pt 5): 1103-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12690050&dopt=Abstract

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Spectroscopic metabolic abnormalities in mTLE with and without MRI evidence for mesial temporal sclerosis using hippocampal short-TE MRSI. Author(s): Mueller SG, Laxer KD, Suhy J, Lopez RC, Flenniken DL, Weiner MW. Source: Epilepsia. 2003 July; 44(7): 977-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823584&dopt=Abstract

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Spinal cord atrophy and disability in multiple sclerosis over four years. Author(s): Horsfield MA, Filippi M. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 August; 74(8): 1014-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876224&dopt=Abstract

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Spinal cord atrophy and disability in multiple sclerosis over four years: application of a reproducible automated technique in monitoring disease progression in a cohort of the interferon beta-1a (Rebif) treatment trial. Author(s): Lin X, Tench CR, Turner B, Blumhardt LD, Constantinescu CS. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 August; 74(8): 1090-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876240&dopt=Abstract

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Spontaneous chromosome damage (micronuclei) in systemic sclerosis and Raynaud's phenomenon. Author(s): Porciello G, Scarpato R, Ferri C, Storino F, Cagetti F, Morozzi G, Bellisai F, Migliore L, Marcolongo R, Galeazzi M. Source: The Journal of Rheumatology. 2003 June; 30(6): 1244-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12784397&dopt=Abstract

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Sporadic amyotrophic lateral sclerosis with circumscribed temporal atrophy: a report of an autopsy case without dementia and with ubiquitinated intraneuronal inclusions. Author(s): Tsuchiya K, Takahashi M, Shiotsu H, Akiyama H, Haga C, Watabiki S, Taki K, Nakano I, Ikeda K. Source: Neuropathology : Official Journal of the Japanese Society of Neuropathology. 2002 December; 22(4): 308-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12564772&dopt=Abstract

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Standardized, reproducible, high resolution global measurements of T1 relaxation metrics in cases of multiple sclerosis. Author(s): Srinivasan R, Henry R, Pelletier D, Nelson S. Source: Ajnr. American Journal of Neuroradiology. 2003 January; 24(1): 58-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12533328&dopt=Abstract

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Statistical mapping analysis of lesion location and neurological disability in multiple sclerosis: application to 452 patient data sets. Author(s): Charil A, Zijdenbos AP, Taylor J, Boelman C, Worsley KJ, Evans AC, Dagher A. Source: Neuroimage. 2003 July; 19(3): 532-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12880785&dopt=Abstract

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Stressful life events precede exacerbations of multiple sclerosis. Author(s): Ackerman KD, Heyman R, Rabin BS, Anderson BP, Houck PR, Frank E, Baum A. Source: Psychosomatic Medicine. 2002 November-December; 64(6): 916-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461197&dopt=Abstract

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Stroke in the developing brain and intractable epilepsy: effect of timing on hippocampal sclerosis. Author(s): Squier W, Salisbury H, Sisodiya S. Source: Developmental Medicine and Child Neurology. 2003 September; 45(9): 580-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12948324&dopt=Abstract

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Study of Herpesvirus saimiri immortalization of gammadelta T cells derived from peripheral blood and CSF of multiple sclerosis patients. Author(s): Pon RA, Freedman MS. Source: Journal of Neuroimmunology. 2003 June; 139(1-2): 119-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799029&dopt=Abstract

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Subependymal giant cell astrocytoma in children with tuberous sclerosis. Author(s): Cuccia V, Zuccaro G, Sosa F, Monges J, Lubienieky F, Taratuto AL. Source: Child's Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery. 2003 April; 19(4): 232-43. Epub 2003 March 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12715190&dopt=Abstract

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Subpial demyelination in the cerebral cortex of multiple sclerosis patients. Author(s): Bo L, Vedeler CA, Nyland HI, Trapp BD, Mork SJ. Source: Journal of Neuropathology and Experimental Neurology. 2003 July; 62(7): 72332. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901699&dopt=Abstract

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Successful treatment of multiple bursal cysts in systemic sclerosis. Author(s): Tanemura A, Yamaguchi Y, Kubo T, Yano K, Itami S. Source: Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [et Al.]. 2002 December; 28(12): 1177-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12472502&dopt=Abstract

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Supporting individuals with disabling multiple sclerosis. Author(s): Gibson J, Frank A. Source: Journal of the Royal Society of Medicine. 2002 December; 95(12): 580-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461142&dopt=Abstract

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Supporting individuals with disabling multiple sclerosis. Author(s): Gibson JC, Frank AO. Source: Journal of the Royal Society of Medicine. 2003 May; 96(5): 256-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724448&dopt=Abstract

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Supratentorial tuber location and autism in tuberous sclerosis complex. Author(s): Walz NC, Byars AW, Egelhoff JC, Franz DN. Source: Journal of Child Neurology. 2002 November; 17(11): 830-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12585723&dopt=Abstract

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Sympathetic dysfunction is related to the clinical activity of multiple sclerosis. Author(s): Monge-Argiles JA, Palacios-Ortega F, Vila-Sobrino JA, Matias-Guiu J. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 216; Author Reply 215. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708819&dopt=Abstract

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Symptom management and adjustment of patients with multiple sclerosis: a 4-year longitudinal intervention study. Author(s): Wassem R, Dudley W. Source: Clinical Nursing Research. 2003 February; 12(1): 102-17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12583502&dopt=Abstract

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Symptoms of depression in older adults with multiple sclerosis (MS): comparison with a matched sample of younger adults. Author(s): Kneebone II, Dunmore EC, Evans E. Source: Aging & Mental Health. 2003 May; 7(3): 182-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12775398&dopt=Abstract

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Systemic sclerosis could mask the presentation of psoriasis in a patient with symptomatic and bilateral sacroiliitis. Author(s): di Girolamo C, Rengo C, Ferrucci MG, Miniero E, Cuomo G, Crisci C, Valentini G. Source: Scandinavian Journal of Rheumatology. 2003; 32(3): 186-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12892259&dopt=Abstract

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Systemic sclerosis is not associated with clinical or ambulatory blood pressure. Author(s): Zakopoulos NA, Kotsis VT, Gialafos EJ, Papamichael CM, Pitiriga VCh, Mitsibounas DN, Mavrikakis ME. Source: Clin Exp Rheumatol. 2003 March-April; 21(2): 199-204. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12747274&dopt=Abstract

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Systemic sclerosis Th2 cells inhibit collagen production by dermal fibroblasts via membrane-associated tumor necrosis factor alpha. Author(s): Chizzolini C, Parel Y, De Luca C, Tyndall A, Akesson A, Scheja A, Dayer JM. Source: Arthritis and Rheumatism. 2003 September; 48(9): 2593-604. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13130479&dopt=Abstract

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Systemic sclerosis with bilateral hilar adenopathy. Author(s): Mountantonakis SE, Sakkas LI, Papadopoulos D, Stathakis N. Source: Rheumatology (Oxford, England). 2003 August; 42(8): 1007-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869672&dopt=Abstract

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Systemic sclerosis: the susceptible host (genetics and environment). Author(s): Tan FK. Source: Rheumatic Diseases Clinics of North America. 2003 May; 29(2): 211-37. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841292&dopt=Abstract

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T2 relaxation time histograms in multiple sclerosis. Author(s): Grenier D, Pelletier D, Normandeau M, Newitt D, Nelson S, Goodkin DE, Majumdar S. Source: Magnetic Resonance Imaging. 2002 December; 20(10): 733-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591569&dopt=Abstract

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T2-based segmentation of periventricular paragraph sign volumes for quantification of proton magnetic paragraph sign resonance spectra of multiple sclerosis lesions. Author(s): Helms G. Source: Magma (New York, N.Y.). 2003 February; 16(1): 10-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12695881&dopt=Abstract

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Tau haplotype frequency in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Author(s): Hughes A, Mann D, Pickering-Brown S. Source: Experimental Neurology. 2003 May; 181(1): 12-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710929&dopt=Abstract

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Tau protein concentrations in cerebrospinal fluid of patients with multiple sclerosis. Author(s): Jimenez-Jimenez FJ, Zurdo JM, Hernanz A, Medina-Acebron S, de Bustos F, Barcenilla B, Sayed Y, Ayuso-Peralta L. Source: Acta Neurologica Scandinavica. 2002 December; 106(6): 351-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12460140&dopt=Abstract

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T-cell vaccination for autoimmune diseases: immunologic lessons and clinical experience in multiple sclerosis. Author(s): Zhang J. Source: Expert Rev Vaccines. 2002 October; 1(3): 285-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901569&dopt=Abstract

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Temporal lobe epilepsy as a unique manifestation of multiple sclerosis. Author(s): Gambardella A, Valentino P, Labate A, Sibilia G, Ruscica F, Colosimo E, Nistico R, Messina D, Zappia M, Quattrone A. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2003 August; 30(3): 228-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12945947&dopt=Abstract

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Temporal lobectomy in congenital porencephaly associated with hippocampal sclerosis. Author(s): Burneo JG, Faught E, Knowlton RC, Martin RC, Bebin M, Morawetz R, Kuzniecky R. Source: Archives of Neurology. 2003 June; 60(6): 830-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810487&dopt=Abstract

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Test-retest reliability of the Purdue Pegboard for persons with multiple sclerosis. Author(s): Gallus J, Mathiowetz V. Source: Am J Occup Ther. 2003 January-February; 57(1): 108-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12549896&dopt=Abstract

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The Adult Memory and Information Processing Battery (AMIPB) test of informationprocessing speed: a study of its reliability and feasibility in patients with multiple sclerosis. Author(s): Vlaar AM, Wade DT. Source: Clinical Rehabilitation. 2003 July; 17(4): 386-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12785247&dopt=Abstract

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The amount of sonic hedgehog in multiple sclerosis white matter is decreased and cleavage to the signaling peptide is deficient. Author(s): Mastronardi FG, daCruz LA, Wang H, Boggs J, Moscarello MA. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 36271. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926841&dopt=Abstract

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The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Author(s): Hesselstrand R, Scheja A, Shen GQ, Wiik A, Akesson A. Source: Rheumatology (Oxford, England). 2003 April; 42(4): 534-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12649400&dopt=Abstract

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The cognitive performance of patients with multiple sclerosis during periods of high and low fatigue. Author(s): Parmenter BA, Denney DR, Lynch SG. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 111-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708805&dopt=Abstract

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The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Author(s): Kalkers NF, Barkhof F, Bergers E, van Schijndel R, Polman CH. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 December; 8(6): 532-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474997&dopt=Abstract

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The efficacy of trientine or ascorbate alone compared to that of the combined treatment with these two agents in familial amyotrophic lateral sclerosis model mice. Author(s): Nagano S, Fujii Y, Yamamoto T, Taniyama M, Fukada K, Yanagihara T, Sakoda S. Source: Experimental Neurology. 2003 February; 179(2): 176-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12618124&dopt=Abstract

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The enigma of multiple sclerosis: inflammation and neurodegeneration cause heterogeneous dysfunction and damage. Author(s): Owens T. Source: Current Opinion in Neurology. 2003 June; 16(3): 259-65. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858060&dopt=Abstract

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The expression of matrix metalloproteinase-1 mRNA induced by ultraviolet A1 (340400 nm) is phototherapy relevant to the glutathione (GSH) content in skin fibroblasts of systemic sclerosis. Author(s): Yin L, Yamauchi R, Tsuji T, Krutmann J, Morita A. Source: The Journal of Dermatology. 2003 March; 30(3): 173-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12692352&dopt=Abstract

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The hypothalamo-pituitary-adrenal axis in multiple sclerosis. Author(s): Huitinga I, Erkut ZA, van Beurden D, Swaab DF. Source: Annals of the New York Academy of Sciences. 2003 May; 992: 118-28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12794052&dopt=Abstract

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The initiation of multiple sclerosis: a new infectious hypothesis. Author(s): Haegert DG. Source: Medical Hypotheses. 2003 February; 60(2): 165-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12606229&dopt=Abstract

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The needs and experiences of caregivers of individuals with multiple sclerosis: a systematic review. Author(s): McKeown LP, Porter-Armstrong AP, Baxter GD. Source: Clinical Rehabilitation. 2003 May; 17(3): 234-48. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12735530&dopt=Abstract

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The normal appearing grey matter in primary progressive multiple sclerosis: a magnetisation transfer imaging study. Author(s): Dehmeshki J, Chard DT, Leary SM, Watt HC, Silver NC, Tofts PS, Thompson AJ, Miller DH. Source: Journal of Neurology. 2003 January; 250(1): 67-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527995&dopt=Abstract

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The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 gene product, and enhances its interaction with 14-3-3. Author(s): Li Y, Inoki K, Vacratsis P, Guan KL. Source: The Journal of Biological Chemistry. 2003 April 18; 278(16): 13663-71. Epub 2003 February 11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12582162&dopt=Abstract

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The presence of glomerular sclerosis at time zero has a significant impact on function after cadaveric renal transplantation. Author(s): Escofet X, Osman H, Griffiths DF, Woydag S, Adam Jurewicz W. Source: Transplantation. 2003 February 15; 75(3): 344-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12589156&dopt=Abstract

270 Sclerosis

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The prevalence and clinical significance of anti-U1 RNA antibodies in patients with systemic sclerosis. Author(s): Asano Y, Ihn H, Yamane K, Kubo M, Tamaki K. Source: The Journal of Investigative Dermatology. 2003 February; 120(2): 204-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12542523&dopt=Abstract

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The relationship between Bunina bodies, skein-like inclusions and neuronal loss in amyotrophic lateral sclerosis. Author(s): van Welsem ME, Hogenhuis JA, Meininger V, Metsaars WP, Hauw JJ, Seilhean D. Source: Acta Neuropathologica. 2002 June; 103(6): 583-9. Epub 2002 February 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12012090&dopt=Abstract

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The relationship between risk attitude and treatment choice in patients with relapsing-remitting multiple sclerosis. Author(s): Prosser LA, Kuntz KM, Bar-Or A, Weinstein MC. Source: Medical Decision Making : an International Journal of the Society for Medical Decision Making. 2002 November-December; 22(6): 506-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458981&dopt=Abstract

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The role of helplessness as mediator between neurological disability, emotional instability, experienced fatigue and depression in patients with multiple sclerosis. Author(s): van der Werf SP, Evers A, Jongen PJ, Bleijenberg G. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 8994. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617274&dopt=Abstract

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The role of illness severity and illness representations in adjusting to multiple sclerosis. Author(s): Jopson NM, Moss-Morris R. Source: Journal of Psychosomatic Research. 2003 June; 54(6): 503-11; Discussion 513-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781303&dopt=Abstract

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The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Author(s): Mahad DJ, Ransohoff RM. Source: Seminars in Immunology. 2003 February; 15(1): 23-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495638&dopt=Abstract

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The role of nitric oxide in multiple sclerosis. Author(s): Smith KJ, Lassmann H. Source: Lancet. Neurology. 2002 August; 1(4): 232-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849456&dopt=Abstract

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The role of the PTPRC (CD45) mutation in the development of multiple sclerosis in the North West region of the United Kingdom. Author(s): Nicholas RS, Partridge J, Donn RP, Hawkins C, Boggild MD. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 July; 74(7): 944-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810785&dopt=Abstract

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The structure of holo and metal-deficient wild-type human Cu, Zn superoxide dismutase and its relevance to familial amyotrophic lateral sclerosis. Author(s): Strange RW, Antonyuk S, Hough MA, Doucette PA, Rodriguez JA, Hart PJ, Hayward LJ, Valentine JS, Hasnain SS. Source: Journal of Molecular Biology. 2003 May 9; 328(4): 877-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729761&dopt=Abstract

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The TGF beta receptor endoglin in systemic sclerosis. Author(s): Dharmapatni AA, Smith MD, Ahern MJ, Simpson A, Li C, Kumar S, RobertsThomson PJ. Source: Asian Pac J Allergy Immunol. 2001 December; 19(4): 275-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12009077&dopt=Abstract

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The treatment of trigeminal neuralgia in patients with multiple sclerosis using percutaneous radiofrequency rhizotomy. Author(s): Berk C, Constantoyannis C, Honey CR. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2003 August; 30(3): 220-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12945945&dopt=Abstract

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The tuberous sclerosis complex and its highly variable manifestations. Author(s): Lendvay TS, Marshall FF. Source: The Journal of Urology. 2003 May; 169(5): 1635-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12686801&dopt=Abstract

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The use of individualized goal setting to facilitate behavior change in women with multiple sclerosis. Author(s): Stuifbergen AK, Becker H, Timmerman GM, Kullberg V. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 2003 April; 35(2): 94-9, 106. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12795036&dopt=Abstract

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The use of quality of life measures in multiple sclerosis research. Author(s): Nortvedt MW, Riise T. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 February; 9(1): 6372. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617271&dopt=Abstract

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The utility of computerized neuropsychological assessment of cognitive dysfunction in patients with relapsing-remitting multiple sclerosis. Author(s): Wilken JA, Kane R, Sullivan CL, Wallin M, Usiskin JB, Quig ME, Simsarian J, Saunders C, Crayton H, Mandler R, Kerr D, Reeves D, Fuchs K, Manning C, Keller M. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 119-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708806&dopt=Abstract

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Therapeutic potential of lovastatin in multiple sclerosis. Author(s): Sena A, Pedrosa R, Graca Morais M. Source: Journal of Neurology. 2003 June; 250(6): 754-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12862032&dopt=Abstract

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Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis. Author(s): Angelov DN, Waibel S, Guntinas-Lichius O, Lenzen M, Neiss WF, Tomov TL, Yoles E, Kipnis J, Schori H, Reuter A, Ludolph A, Schwartz M. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 April 15; 100(8): 4790-5. Epub 2003 March 31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12668759&dopt=Abstract

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Therapies in amyotrophic lateral sclerosis-beyond riluzole. Author(s): Morrison KE. Source: Current Opinion in Pharmacology. 2002 June; 2(3): 302-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12020475&dopt=Abstract

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Therapy-related acute myelogenous leukaemia (t-AML) in a patient with multiple sclerosis treated with mitoxantrone. Author(s): Heesen C, Bruegmann M, Gbdamosi J, Koch E, Monch A, Buhmann C. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 March; 9(2): 213-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708818&dopt=Abstract

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Three subsequent single doses of gadolinium chelate for brain MR imaging in multiple sclerosis. Author(s): Sardanelli F, Iozzelli A, Losacco C, Murialdo A, Filippi M. Source: Ajnr. American Journal of Neuroradiology. 2003 April; 24(4): 658-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12695199&dopt=Abstract

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Thymic epithelial hyperplasia with nodular sclerosis Hodgkin's disease. Author(s): Ito W, Kojima K, Fujiwara K, Nanba Y, Yoshino T, Shinagawa K, Ishimaru F, Ikeda K, Niiya K, Tanimoto M. Source: Leukemia & Lymphoma. 2002 November; 43(11): 2229-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12533053&dopt=Abstract

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Thymic export function and T cell homeostasis in patients with relapsing remitting multiple sclerosis. Author(s): Hug A, Korporal M, Schroder I, Haas J, Glatz K, Storch-Hagenlocher B, Wildemann B. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 July 1; 171(1): 432-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12817027&dopt=Abstract

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TNF-alpha and psychologically stressful events in healthy subjects: potential relevance for multiple sclerosis relapse. Author(s): Lalive PH, Burkhard PR, Chofflon M. Source: Behavioral Neuroscience. 2002 December; 116(6): 1093-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12492308&dopt=Abstract

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TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis. Author(s): Wandinger KP, Lunemann JD, Wengert O, Bellmann-Strobl J, Aktas O, Weber A, Grundstrom E, Ehrlich S, Wernecke KD, Volk HD, Zipp F. Source: Lancet. 2003 June 14; 361(9374): 2036-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814715&dopt=Abstract

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Transcriptional analysis of targets in multiple sclerosis. Author(s): Steinman L, Zamvil S. Source: Nature Reviews. Immunology. 2003 June; 3(6): 483-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12776208&dopt=Abstract

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Transforming growth factor-Beta 1 (tgf-Beta 1) in patients with amyotrophic lateral sclerosis. Author(s): Ilzecka J, Stelmasiak Z, Dobosz B. Source: Cytokine. 2002 December 7; 20(5): 239-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12550109&dopt=Abstract

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Transmantle dysplasia in tuberous sclerosis: clinical features and surgical outcome in four children. Author(s): Vigliano P, Canavese C, Bobba B, Genitori L, Papalia F, Padovan S, Forni M. Source: Journal of Child Neurology. 2002 October; 17(10): 752-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546430&dopt=Abstract

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Treatment of cutaneous calcinosis in limited systemic sclerosis with minocycline. Author(s): Robertson LP, Marshall RW, Hickling P. Source: Annals of the Rheumatic Diseases. 2003 March; 62(3): 267-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12594118&dopt=Abstract

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Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration. Author(s): Astrinidis A, Cash TP, Hunter DS, Walker CL, Chernoff J, Henske EP. Source: Oncogene. 2002 December 5; 21(55): 8470-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12466966&dopt=Abstract

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Tuberous sclerosis complex and neurofibromatosis type 1: the two most common neurocutaneous diseases. Author(s): Kandt RS. Source: Neurologic Clinics. 2002 November; 20(4): 941-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12616676&dopt=Abstract

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Tuberous sclerosis complex with disseminated telencephalic distribution of atypical cells and their relation to corticogenesis. Author(s): Roske B, Stoltenburg G, Baier PM, Konig R, Schlote W. Source: Clin Neuropathol. 2003 May-June; 22(3): 119-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809354&dopt=Abstract

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Tuberous sclerosis in pregnancy: a case report and review of the literature. Author(s): Gounden YP. Source: The Australian & New Zealand Journal of Obstetrics & Gynaecology. 2002 November; 42(5): 551-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495109&dopt=Abstract

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Tuberous sclerosis with unusual giant ungual fibromas. Author(s): Aste N, Pau M, Aste N, Biggio P. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 2003 January; 17(1): 100-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12602986&dopt=Abstract

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Tuberous sclerosis: presentation of a clinical case with oral manifestations. Author(s): Lopez E, Escovich L, Vigna A. Source: Medicina Oral : Organo Oficial De La Sociedad Espanola De Medicina Oral Y De La Academia Iberoamericana De Patologia Y Medicina Bucal. 2003 March-April; 8(2): 122-8. English, Spanish. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12618672&dopt=Abstract

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Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q. Author(s): Ruddy DM, Parton MJ, Al-Chalabi A, Lewis CM, Vance C, Smith BN, Leigh PN, Powell JF, Siddique T, Meyjes EP, Baas F, de Jong V, Shaw CE. Source: American Journal of Human Genetics. 2003 August; 73(2): 390-6. Epub 2003 July 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12840784&dopt=Abstract

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Ultrasound guided sclerosis of neovessels in painful chronic Achilles tendinosis: pilot study of a new treatment. Author(s): Ohberg L, Alfredson H. Source: British Journal of Sports Medicine. 2002 June; 36(3): 173-5; Discussion 176-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12055110&dopt=Abstract

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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. 2002 January-February; 26(1): 3-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12028652&dopt=Abstract

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Ultrastructural study of the muscle coat of the gastric wall in a case of systemic sclerosis. Author(s): Ibba-Manneschi L, Del Rosso A, Pacini S, Tani A, Bechi P, Matucci Cerinic M. Source: Annals of the Rheumatic Diseases. 2002 August; 61(8): 754-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12117690&dopt=Abstract

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Unilateral angiofibromas. An oligosymptomatic and segmentary form of tuberous sclerosis. Author(s): Del Pozo J, Martinez W, Calvo R, Almagro M, Fonseca E. Source: Eur J Dermatol. 2002 May-June; 12(3): 262. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11989480&dopt=Abstract

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Update on disease-modifying antirheumatic drugs in the treatment of systemic sclerosis. Author(s): Lin AT, Clements PJ, Furst DE. Source: Rheumatic Diseases Clinics of North America. 2003 May; 29(2): 409-26. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841302&dopt=Abstract

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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. 2002 October; 26(4): 438-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12362409&dopt=Abstract

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Upregulated expression of transforming growth factor-beta receptors in dermal fibroblasts of skin sections from patients with systemic sclerosis. Author(s): Kubo M, Ihn H, Yamane K, Tamaki K. Source: The Journal of Rheumatology. 2002 December; 29(12): 2558-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12465152&dopt=Abstract

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Upregulated survivin expression in activated T lymphocytes correlates with disease activity in multiple sclerosis. Author(s): Sharief MK, Noori MA, Douglas MR, Semra YK. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2002 September; 9(5): 503-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12220382&dopt=Abstract

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Upregulation of the apoptosis regulators cFLIP, CD95 and CD95 ligand in peripheral blood mononuclear cells in relapsing-remitting multiple sclerosis. Author(s): Gomes AC, Jonsson G, Mjornheim S, Olsson T, Hillert J, Grandien A. Source: Journal of Neuroimmunology. 2003 February; 135(1-2): 126-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12576232&dopt=Abstract

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Use of CO2 laser in the treatment of periungual fibromas associated with tuberous sclerosis. Author(s): Berlin AL, Billick RC. Source: Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [et Al.]. 2002 May; 28(5): 434-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12030880&dopt=Abstract

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Use of serial proton magnetic resonance spectroscopy to differentiate low grade glioma from tumefactive plaque in a patient with multiple sclerosis. Author(s): Butteriss DJ, Ismail A, Ellison DW, Birchall D. Source: The British Journal of Radiology. 2003 September; 76(909): 662-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500284&dopt=Abstract

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Use of the FIM instrument in a trial of intramuscular interferon beta-1a for disease progression in relapsing-remitting multiple sclerosis. Author(s): Granger CV, Wende K, Brownscheidle CM. Source: American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists. 2003 June; 82(6): 427-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820784&dopt=Abstract

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Use of the short form health survey (SF-36) in patients with amyotrophic lateral sclerosis: tests of data quality, score reliability, response rate and scaling assumptions. Author(s): Jenkinson C, Hobart J, Chandola T, Fitzpatrick R, Peto V, Swash M; ALS-HPS Steering Group. Amyotrophic Lateral Sclerosis Health Profile Study. Source: Journal of Neurology. 2002 February; 249(2): 178-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11985383&dopt=Abstract

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Using the SF-36 measure to compare the health impact of multiple sclerosis and Parkinson's disease with normal population health profiles. Author(s): Riazi A, Hobart JC, Lamping DL, Fitzpatrick R, Freeman JA, Jenkinson C, Peto V, Thompson AJ. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 June; 74(6): 710-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12754336&dopt=Abstract

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Validation of bioelectrical impedance analysis in patients with amyotrophic lateral sclerosis. Author(s): Desport JC, Preux PM, Bouteloup-Demange C, Clavelou P, Beaufrere B, Bonnet C, Couratier PP. Source: The American Journal of Clinical Nutrition. 2003 May; 77(5): 1179-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12716669&dopt=Abstract

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Validation of diagnostic magnetic resonance imaging criteria for multiple sclerosis and response to interferon beta1a. Author(s): Barkhof F, Rocca M, Francis G, Van Waesberghe JH, Uitdehaag BM, Hommes OR, Hartung HP, Durelli L, Edan G, Fernandez O, Seeldrayers P, Sorensen P, Margrie S, Rovaris M, Comi G, Filippi M; Early Treatment of Multiple Sclerosis Study Group. Source: Annals of Neurology. 2003 June; 53(6): 718-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783417&dopt=Abstract

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Validity of hospital morbidity records for amyotrophic lateral sclerosis. A populationbased study. Author(s): Chio A, Ciccone G, Calvo A, Vercellino M, Di Vito N, Ghiglione P, Mutani R; Piemonte and Valle d'Aosta Register for ALS. Source: Journal of Clinical Epidemiology. 2002 July; 55(7): 723-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12160921&dopt=Abstract

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Validity of the Beck Depression Inventory-Fast Screen in multiple sclerosis. Author(s): Benedict RH, Fishman I, McClellan MM, Bakshi R, Weinstock-Guttman B. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 393-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926845&dopt=Abstract

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Variability in constraints and functional competence in adults with multiple sclerosis. Author(s): Kasser SL, McCubbin JA, Hooker K. Source: American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists. 2003 July; 82(7): 517-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12819539&dopt=Abstract

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VCAM-1-positive microglia target oligodendrocytes at the border of multiple sclerosis lesions. Author(s): Peterson JW, Bo L, Mork S, Chang A, Ransohoff RM, Trapp BD. Source: Journal of Neuropathology and Experimental Neurology. 2002 June; 61(6): 53946. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12071637&dopt=Abstract

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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. 2003 August; 34(4): 383-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12847526&dopt=Abstract

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VEGF is increased in serum but not in spinal cord from patients with amyotrophic lateral sclerosis. Author(s): Nygren I, Larsson A, Johansson A, Askmark H. Source: Neuroreport. 2002 December 3; 13(17): 2199-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12488796&dopt=Abstract

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Ventricular late potentials in systemic sclerosis: relationship with skin involvement. Author(s): Paradiso M, Di Franco M, Musca A, Basili S, Riccieri V, Paoletti V, De Matteis A, Mammarella A. Source: The Journal of Rheumatology. 2002 July; 29(7): 1388-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12136893&dopt=Abstract

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Vestibular hyperreactivity in patients with multiple sclerosis. Author(s): Huygen PL. Source: Advances in Oto-Rhino-Laryngology. 1983; 30: 141-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12325172&dopt=Abstract

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Videomanofluorometric study in amyotrophic lateral sclerosis. Author(s): Higo R, Tayama N, Watanabe T, Nitou T. Source: The Laryngoscope. 2002 May; 112(5): 911-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12150627&dopt=Abstract

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Viral cirrhosis with chronic right heart failure and cardiac liver sclerosis: a hypothesis on the differentiation between the two diseases through pulsed Doppler sonography examination. Author(s): Zardi EM, Picardi A, Zardi DM, Costantino S. Source: Medical Hypotheses. 2002 November; 59(5): 591-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12376085&dopt=Abstract

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Visual and auditory event-related potentials in sporadic amyotrophic lateral sclerosis. Author(s): Paulus KS, Magnano I, Piras MR, Solinas MA, Solinas G, Sau GF, Aiello I. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2002 June; 113(6): 853-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12048044&dopt=Abstract

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Visual evoked potentials in multiple sclerosis before and after two years of interferon therapy. Author(s): Anlar O, Kisli M, Tombul T, Ozbek H. Source: The International Journal of Neuroscience. 2003 April; 113(4): 483-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12856477&dopt=Abstract

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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. 2003 July; 7(3): 304-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12893960&dopt=Abstract

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White matter and lesion T1 relaxation times increase in parallel and correlate with disability in multiple sclerosis. Author(s): Parry A, Clare S, Jenkinson M, Smith S, Palace J, Matthews PM. Source: Journal of Neurology. 2002 September; 249(9): 1279-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12242554&dopt=Abstract

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White matter T(1) relaxation time histograms and cerebral atrophy in multiple sclerosis. Author(s): Vaithianathar L, Tench CR, Morgan PS, Lin X, Blumhardt LD. Source: Journal of the Neurological Sciences. 2002 May 15; 197(1-2): 45-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11997065&dopt=Abstract

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Whole-brain T1-relaxation time measurements in multiple sclerosis. Author(s): Barkhof F. Source: Journal of Neurology. 2002 October; 249(10): 1451-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12532927&dopt=Abstract

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Why does remyelination fail in multiple sclerosis? Author(s): Franklin RJ. Source: Nature Reviews. Neuroscience. 2002 September; 3(9): 705-14. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12209119&dopt=Abstract

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Working memory deficits in multiple sclerosis: a controlled study with auditory P600 correlates. Author(s): Sfagos C, Papageorgiou CC, Kosma KK, Kodopadelis E, Uzunoglu NK, Vassilopoulos D, Rabavilas AD. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 September; 74(9): 1231-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12933924&dopt=Abstract

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Workshop on primary progressive multiple sclerosis: meeting summary. Author(s): Montalban X, Thompson AJ. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 April; 8(2): 177-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11990876&dopt=Abstract

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CHAPTER 2. NUTRITION AND SCLEROSIS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and sclerosis.

Finding Nutrition Studies on Sclerosis The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “sclerosis” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7

Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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The following is a typical result when searching for recently indexed consumer information on sclerosis: •

New book claims diet helps multiple sclerosis sufferers. Source: Environ-Nutr. New York, N.Y. : Environmental Nutrition, Inc. January 1988. volume 11 (1) page 2. 0893-4452

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Nutrition intervention in the management of multiple sclerosis. Source: DeLuca, H.D. Nutr-today. Baltimore , Md. : Williams & Wilkins. December 1993. volume 28 (6) page 12-22. 0029-666X

The following information is typical of that found when using the “Full IBIDS Database” to search for “sclerosis” (or a synonym): •

A double-blind pilot study of the effect of Prokarin on fatigue in multiple sclerosis. Author(s): Life Diagnostics, Calgary, Alberta, Canada. Source: Gillson, G Richard, T L Smith, R B Wright, J V Mult-Scler. 2002 February; 8(1): 30-5 1352-4585

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Activity profile in multiple sclerosis: an integrative approach. A preliminary report. Author(s): Institute of Immunology, Central University, Faculty of Medicine, Caracas, Venezuela. [email protected] Source: Zabaleta, M Marino, R Borges, J Camargo, B Ordaz, P De Sanctis, J B Bianco, N E Mult-Scler. 2002 August; 8(4): 343-9 1352-4585

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Alphabet soup: a personal, evolving, mostly evidence-based and logical, sequential approach to the “ABCNR” drugs in multiple sclerosis. Author(s): Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA. Source: Mattson, D H Semin-Neurol. 2002 March; 22(1): 17-25 0271-8235

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ALS-plus: 5 cases of concomitant amyotrophic lateral sclerosis and parkinsonism. Author(s): Department of Neurological Sciences, Ospedale Consorziale Policlinico, University of Bari, Piazza Giulio Cesare 11, I-70124 Bari, Italy. Source: Zoccolella, S Palagano, G Fraddosio, A Russo, I Ferrannini, E Serlenga, L Maggio, F Lamberti, S Iliceto, G Neurol-Sci. 2002 September; 23 Suppl 2: S123-4 15901874

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Bayesian approach to searching for susceptibility genes: Gc2 and EsD1 alleles and multiple sclerosis. Author(s): Department of Statistical Sciences, University of Bologna, Italy. Source: Di Bacco, M Luiselli, D Manca, M L Siciliano, G Coll-Antropol. 2002 June; 26(1): 77-84 0350-6134

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Cannabinoids in the treatment of pain and spasticity in multiple sclerosis. Author(s): Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, Dunedin, New Zealand. [email protected] Source: Smith, P F Curr-Opin-Investig-Drugs. 2002 June; 3(6): 859-64 1472-4472

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Coagulative modifications in patients with systemic sclerosis treated with iloprost or nifedipine. Author(s): Istituto di Clinica Medica Generale, Ematologia ed Immunologia Clinica, Universita degli Studi, Azienda Ospedaliera Umberto I di Ancona. Source: Candela, M Pansoni, A Jannino, L Menditto, V G Natalini, M Ravaglia, F Da Lio, L Scorza, R Gabrielli, A Danieli, G Ann-Ital-Med-Int. 2001 Jul-September; 16(3): 170-4 0393-9340

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Combination therapies for systemic sclerosis. Author(s): Center for Rheumatology, Royal Free Campus, University College London, Rowland Hill Street, Hampstead, NW3 2PF, UK. Source: Denton, C P Black, C M Springer-Semin-Immunopathol. 2001; 23(1-2): 109-29 0172-6641

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Cu/Zn superoxide dismutase (SOD1) mutations associated with familial amyotrophic lateral sclerosis (ALS) affect cellular free radical release in the presence of oxidative stress. Author(s): Academic Neurology Unit, University of Sheffield, UK. Source: Cookson, M R Menzies, F M Manning, P Eggett, C J Figlewicz, D A McNeil, C J Shaw, P J Amyotroph-Lateral-Scler-Other-Motor-Neuron-Disord. 2002 June; 3(2): 75-85 1466-0822

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Current concepts in multiple sclerosis: Part II. Author(s): USD School of Medicine, Vermillion, SD, USA. Source: Hanson, L J Cafruny, W A S-D-J-Med. 2002 November; 55(11): 477-81 0038-3317

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Current treatment options in systemic Sclerosis (Scleroderma). Author(s): Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Wahringer Gurtel 18-20, A-1090 Vienna. [email protected] Source: Stummvoll, G H Acta-Med-Austriaca. 2002; 29(1): 14-9 0303-8173

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Cytoarchitectural abnormalities in hippocampal sclerosis. Author(s): Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College of London, United Kingdom. Source: Thom, Maria Sisodiya, Sanjay M Beckett, Andrew Martinian, Lillian Lin, Woan Ru Harkness, William Mitchell, Tejal N Craig, John Duncan, John Scaravilli, Francesco JNeuropathol-Exp-Neurol. 2002 June; 61(6): 510-9 0022-3069

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Detection of N epsilon-(carboxymethyl)lysine (CML) and non-CML advanced glycation end-products in the anterior horn of amyotrophic lateral sclerosis spinal cord. Author(s): Department of Neurology, Hokkaido University School of Medicine, Sapporo, Japan. [email protected] Source: Kikuchi, S Shinpo, K Ogata, A Tsuji, S Takeuchi, M Makita, Z Tashiro, K Amyotroph-Lateral-Scler-Other-Motor-Neuron-Disord. 2002 June; 3(2): 63-8 1466-0822

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Differentiation of multiple sclerosis subtypes: implications for treatment. Author(s): Department of Neurology, Ruppiner Kliniken GmbH, Neuruppin, Germany. [email protected] Source: Bitsch, Andreas Bruck, Wolfgang CNS-Drugs. 2002; 16(6): 405-18 1172-7047

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Effect of amyotrophic lateral sclerosis serum on calcium channels related to spontaneous acetylcholine release. Author(s): Instituto de Investigaciones Medicas Alfredo Lanari, Facultad de Medicina, Universidad de Buenos Aires, Argentina. [email protected] Source: Muchnik, Salomon Losavio, Adriana Lorenzo, Silvana De Clin-Neurophysiol. 2002 July; 113(7): 1066-71 1388-2457

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Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud's phenomenon. A randomized, controlled study. Author(s): Clinical Immunology and Allergy, University of Milan, IRCCS Ospedale Maggiore, Milan, Italy. [email protected]

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Source: Scorza, R Caronni, M Mascagni, B Berruti, V Bazzi, S Micallef, E Arpaia, G Sardina, M Origgi, L Vanoli, M Clin-Exp-Rheumatol. 2001 Sep-October; 19(5): 503-8 0392-856X •

Efficacy of an early intensification treatment integrating chemotherapy, autologous stem cell transplantation and radiotherapy for poor risk primary mediastinal large B cell lymphoma with sclerosis. Author(s): Department of Hematology, Niguarda Ca' Granda Hospital, Piazza Ospedale Maggiore, 20162 Milan, Italy. Source: Cairoli, R Grillo, G Tedeschi, A Gargantini, L Marenco, P Tresoldi, E Barbarano, L Nosari, A M Morra, E Bone-Marrow-Transplant. 2002 Mar; 29(6): 473-7 0268-3369

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Essential fatty acid and prostaglandin metabolism in Sjogren's syndrome, systemic sclerosis and rheumatoid arthritis. Source: Horrobin, D F Scand-J-Rheumatol-Suppl. 1986; 61: 242-5 0301-3847

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Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Author(s): Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Milan, Italy. [email protected] Source: Filippi, M Bozzali, M Rovaris, M Gonen, O Kesavadas, C Ghezzi, A Martinelli, V Grossman, R I Scotti, G Comi, G Falini, A Brain. 2003 February; 126(Pt 2): 433-7 00068950

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Gene therapy for amyotrophic lateral sclerosis and other motor neuron diseases. Author(s): Program in Gene Therapy, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242, USA. Source: Alisky, J M Davidson, B L Hum-Gene-Ther. 2000 November 20; 11(17): 2315-29 1043-0342

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Hyperhomocyst(e)inemia induces accelerated transplant vascular sclerosis in syngeneic and allogeneic rat cardiac transplants. Author(s): Department of Surgery, Oregon Health and Science University, Portland 97201, USA. Source: Cook, J W Yin, Q Malinow, M R Orloff, S L Am-J-Transplant. 2002 March; 2(3): 244-51 1600-6135

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Immunologic therapy for relapsing-remitting multiple sclerosis. Author(s): Multiple Sclerosis Clinic, University of Ottawa, Ottawa Hospital-General Campus, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada. Source: MacLean, H J Freedman, M S Curr-Neurol-Neurosci-Repage 2001 May; 1(3): 277-85 1528-4042

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Immunologic therapy for secondary and primary progressive multiple sclerosis. Author(s): Multiple Sclerosis Research Center, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA. [email protected] Source: Myers, L W Curr-Neurol-Neurosci-Repage 2001 May; 1(3): 286-93 1528-4042

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Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis. Author(s): Neuroscience, Wyeth Research, Princeton, New Jersey 08543-8000, USA. Source: Dunlop, J Beal McIlvain, H She, Y Howland, D S J-Neurosci. 2003 March 1; 23(5): 1688-96 1529-2401

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Lateralizing ability of single-voxel proton mr spectroscopy in hippocampal sclerosis: comparison with mr imaging and positron emission tomography. Author(s): Department of Radiology, Seoul National University College of Medicine, Korea. Source: Park, S W Chang, K H Kim, H D Song, I C Lee, D S Lee, S K Chung, C K Yu, I K Han, M H Park, Y H AJNR-Am-J-Neuroradiol. 2001 April; 22(4): 625-31 0195-6108

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Leukotrienes in patients with clinically active multiple sclerosis. Author(s): Department of Neurology, Municipal Hospital, Academic Teaching, Hospital of Tubingen University, Sindelfingen, Germany. [email protected] Source: Neu, I S Metzger, G Zschocke, J Zelezny, R Mayatepek, E Acta-Neurol-Scand. 2002 January; 105(1): 63-6 0001-6314

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Localized (1)H magnetic resonance spectroscopy in mainly cortical gray matter of patients with multiple sclerosis. Author(s): Neurologic Clinic, Neuroscience Department, Policlinico Monteluce, Via E. Dal Pozzo, 06126 Perugia, Italy. [email protected] Source: Sarchielli, P Presciutti, O Tarducci, R Gobbi, G Alberti, A Pelliccioli, G P Chiarini, P Gallai, V J-Neurol. 2002 July; 249(7): 902-10 0340-5354

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Major depressive disorder and health care costs in multiple sclerosis. Author(s): Department of Community Health Sciences, The University of Calgary, Alberta, Canada. [email protected] Source: Patten, S B Jacobs, P Petcu, R Reimer, M A Metz, L M Int-J-Psychiatry-Med. 2002; 32(2): 167-78 0091-2174

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Management of spasticity, pain, and paroxysmal phenomena in multiple sclerosis. Author(s): Department of Neurology, Fairview Multiple Sclerosis Center and University of Minnesota, 701 25th Ave. South, #200, Minneapolis, MN 55454, USA. [email protected] Source: Schapiro, R T Curr-Neurol-Neurosci-Repage 2001 May; 1(3): 299-302 1528-4042

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Marked and sustained improvement of systemic sclerosis following polychemotherapy for coexistent multiple myeloma. Author(s): Department of Internal Medicine I, University of Vienna, Austria. Source: Bachleitner Hofmann, T Machold, K Knobler, R Drach, J Grumbeck, E Gisslinger, H Clin-Exp-Rheumatol. 2002 Jan-February; 20(1): 85-8 0392-856X

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MaxEPA in multiple sclerosis. Source: French, J M Br-J-Clin-Pract-Suppl. 1984; 31: 117-21 0262-8767

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Metabolic differences between multiple sclerosis subtypes measured by quantitative MR spectroscopy. Author(s): Department of Medicine, Brookhaven National Laboratory, State University of New York, Stony Brook, USA. [email protected] Source: Pan, J W Coyle, P K Bashir, K Whitaker, J N Krupp, L B Hetherington, H P MultScler. 2002 May; 8(3): 200-6 1352-4585

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Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Author(s): Centre for Research in Neurosciences, McGill University, Research Institute of the McGill University Health Centre, Montreal, Quebec, H3G 1A4, Canada. Source: Kriz, J Nguyen, M D Julien, J P Neurobiol-Dis. 2002 August; 10(3): 268-78 09699961

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Morphine responsiveness in a group of well-defined multiple sclerosis patients: a study with i.v. morphine. Author(s): Department of Anaesthesiology, University Hospital, S-581 85 Linkoping, Sweden. Source: Kalman, Sigga Osterberg, Anders Sorensen, January Boivie, Jorgen Bertler, Ake Eur-J-Pain. 2002; 6(1): 69-80 1090-3801

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Multiple sclerosis, an autoimmune inflammatory disease: prospects for its integrative management. Source: Kidd, P M Altern-Med-Revolume 2001 December; 6(6): 540-66 1089-5159

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Neurological manifestations of gastrointestinal disorders, with particular reference to the differential diagnosis of multiple sclerosis. Author(s): Centro Studi Sclerosi Multipla, Ospedale di Gallarate, Universita di Milano, Gallarate, Varese, Italy. Source: Ghezzi, A Zaffaroni, M Neurol-Sci. 2001 November; 22 Suppl 2: S117-22 15901874

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Newer long-term treatments for multiple sclerosis. Author(s): Department of Neurology, Health Sciences Center, Memorial University of Newfoundland, 300 Prince Phillip Parkway, St. John's, Canada NF A1B 3V6. [email protected] Source: Pryse Phillips, W Clin-Neurol-Neurosurg. 2002 July; 104(3): 265-71 0303-8467

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No effect of creatine on respiratory distress in amyotrophic lateral sclerosis. Author(s): Department of Neurology and ALS Clinic, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel. [email protected] Source: Drory, V E Gross, D Amyotroph-Lateral-Scler-Other-Motor-Neuron-Disord. 2002 March; 3(1): 43-6 1466-0822

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Peripheral blood T lymphocytes from systemic sclerosis patients show both Th1 and Th2 activation. Author(s): Rheumatology Unit, Second University of Naples, Italy. [email protected] Source: Valentini, G Baroni, A Esposito, K Naclerio, C Buommino, E Farzati, A Cuomo, G Farzati, B J-Clin-Immunol. 2001 May; 21(3): 210-7 0271-9142

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Pharmacological intervention in renal fibrosis and vascular sclerosis. Author(s): Department of Nephrology, The Royal Melbourne Hospital, Vic., Australia. [email protected] Source: Becker, G J Perkovic, V Hewitson, T D J-Nephrol. 2001 Sep-October; 14(5): 332-9 1120-3625

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Pulmonary hypertension in systemic sclerosis: bete noire no more? Source: Varga, J Curr-Opin-Rheumatol. 2002 November; 14(6): 666-70 1040-8711

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Quantitative 1H MRS imaging 14 years after presenting with a clinically isolated syndrome suggestive of multiple sclerosis. Author(s): NMR Research Unit, Institute of Neurology, University College London, UK. Source: Kapeller, P Brex, P A Chard, D Dalton, C Griffin, C M McLean, M A Parker, G J Thompson, A J Miller, D H Mult-Scler. 2002 May; 8(3): 207-10 1352-4585

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Recent advances in the therapy of amyotrophic lateral sclerosis: focus on excitotoxicity. Author(s): Department of Neurology, University of Milano-Bicocca, San Gerardo Hospital, Monza (MI), Italy.

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Source: Brighina, L Sala, G Ceresa, C Tremolizzo, L Ferrarese, C Funct-Neurol. 2001; 16 Suppl 4: 189-202 0393-5264 •

Regulation by interferon beta-1a of reactive oxygen metabolites production by lymphocytes and monocytes and serum sulfhydryls in relapsing multiple sclerosis patients. Author(s): Molecular Biology Service of the Virgen Macarena University Hospital, Avda. Dr. Fedriani 3, 41071 Seville, Spain. [email protected] Source: Lucas, M Rodriguez, M C Gata, J M Zayas, M D Solano, F Izquierdo, G Neurochem-Int. 2003 January; 42(1): 67-71 0197-0186

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Relapsing-remitting multiple sclerosis and whole-brain N-acetylaspartate measurement: evidence for different clinical cohorts initial observations. Author(s): Department of Radiology, New York University School of Medicine, 560 First Ave, New York, NY 10016, USA. Source: Gonen, O Moriarty, D M Li, B S Babb, J S He, J Listerud, J Jacobs, D Markowitz, C E Grossman, R I Radiology. 2002 October; 225(1): 261-8 0033-8419

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Serial 1H-MRS in relapsing-remitting multiple sclerosis: effects of interferon-beta therapy on absolute metabolite concentrations. Author(s): Department of Medical Physics and Metrological Information Technology, Physikalisch-Technische Bundesanstalt, Abbestrasse 2-12, D-10587, Berlin, Germany. [email protected] Source: Schubert, F Seifert, F Elster, C Link, A Walzel, M Mientus, S Haas, J Rinneberg, H MAGMA. 2002 June; 14(3): 213-22 0968-5243

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Serum levels of antioxidant vitamins and lipid peroxidation in multiple sclerosis. Author(s): Department of Nutrition and Dietetics, School of Health Technology, Hacettepe University, Sihhiye, Ankara, Turkey. [email protected] Source: Besler, H T Comoglu, S Okcu, Z Nutr-Neurosci. 2002 June; 5(3): 215-20 1028415X

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Serum uric acid levels in multiple sclerosis patients correlate with activity of disease and blood-brain barrier dysfunction. Author(s): Center of Neurology, Clinical Hospital Center Kragujevac, Svetozara Markovica, Yugoslavia. [email protected] Source: Toncev, G Milicic, B Toncev, S Samardzic, G Eur-J-Neurol. 2002 May; 9(3): 221-6 1351-5101

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Systemic sclerosis therapy with iloprost: a prospective observational study of 30 patients treated for a median of 3 years. Author(s): Servizio di Reumatologia ed Immunologia Clinica, Spedali Civili and University, I-25124 Brescia, Italy. Source: Bettoni, L Geri, A Airo, P Danieli, E Cavazzana, I Antonioli, C Chiesa, L Franceschini, F Grottolo, A Zambruni, A Radaeli, E Cattaneo, R Clin-Rheumatol. 2002 June; 21(3): 244-50 0770-3198

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The cannabinoids: an overview. Therapeutic implications in vomiting and nausea after cancer chemotherapy, in appetite promotion, in multiple sclerosis and in neuroprotection. Author(s): Hebrew University, Jerusalem, Israel. [email protected] Source: Mechoulam, R Hanu, L Pain-Res-Manag. 2001 Summer; 6(2): 67-73 1203-6765

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The diagnostic pathway in amyotrophic lateral sclerosis. Author(s): The Fourth Department of Internal Medicine, Toho University Ohashi Hospital, Tokyo, Japan.

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Source: Iwasaki, Y Ikeda, K Kinoshita, M Amyotroph-Lateral-Scler-Other-MotorNeuron-Disord. 2001 September; 2(3): 123-6 1466-0822 •

The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes. Author(s): Department of Neurological and Psychiatric Sciences, University of Bari, Italy. Source: Trojano, M Paolicelli, D Neurol-Sci. 2001 November; 22 Suppl 2: S98-102 15901874

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The immunological basis of current and novel therapies of multiple sclerosis. Author(s): Rega Institute for Medical Research, Laboratory of Molecular Immunology, University of Leuven, Belgium. Source: Dubois, B Opdenakker, G Arch-Immunol-Ther-Exp-(Warsz). 1999; 47(1): 7-16 0004-069X

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The inhibitory effect of topical N-acetylcysteine application on myringosclerosis in perforated rat tympanic membrane. Author(s): Department of Otorhinolaryngology, School of Medicine, Mersin University, Mersin, Turkey. [email protected] Source: Ozcan, Cengiz Gorur, Kemal Cinel, Leyla Talas, Derya Umit Unal, Murat Cinel, Ismail Int-J-Pediatr-Otorhinolaryngol. 2002 May 15; 63(3): 179-84 0165-5876

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The symptomatic treatment of multiple sclerosis. Author(s): Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. [email protected] Source: Poser, C M Brinar, V V Clin-Neurol-Neurosurg. 2002 July; 104(3): 231-5 03038467

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The tuberous sclerosis 2 gene product can localize to nuclei in a phosphorylationdependent manner. Author(s): Department of Biochemistry, University of Kentucky, 800 Rose Street, Lexington, KY 40536, USA. Source: Lou, D Griffith, N Noonan, D J Mol-Cell-Biol-Res-Commun. 2001 November; 4(6): 374-80 1522-4724

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Therapeutic efficacy of EGb761 (Gingko biloba extract) in a transgenic mouse model of amyotrophic lateral sclerosis. Author(s): Geriatric Research Education and Clinical Center, Bedford VA Medical Center, MA 01730, USA. [email protected] Source: Ferrante, R J Klein, A M Dedeoglu, A Beal, M F J-Mol-Neurosci. 2001 August; 17(1): 89-96 0895-8696

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Tuberous sclerosis complex: a review of neurological aspects. Author(s): Department of Neurosciences-Section of Paediatric Neurology, Tor Vergata University of Rome, Italy. [email protected] Source: Curatolo, Paolo Verdecchia, Magda Bombardieri, Roberta Eur-J-PaediatrNeurol. 2002; 6(1): 15-23 1090-3798

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White matter extracellular matrix chondroitin sulfate/dermatan sulfate proteoglycans in multiple sclerosis. Author(s): Department of Pathology, Stanford University School of Medicine, California 94305, USA. Source: Sobel, R A Ahmed, A S J-Neuropathol-Exp-Neurol. 2001 December; 60(12): 1198207 0022-3069

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Will aromatherapy be a useful treatment strategy for people with multiple sclerosis who experience pain? Author(s): Pain Management Service, Chelsea and Westminster Hospital, London, UK. [email protected] Source: Howarth, A L Complement-Ther-Nurs-Midwifery. 2002 August; 8(3): 138-41 1353-6117

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

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

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Healthnotes: http://www.healthnotes.com/

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

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

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WebMDHealth: http://my.webmd.com/nutrition

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•

WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

The following is a specific Web list relating to 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: •

Vitamins Folic Acid Source: Healthnotes, Inc. www.healthnotes.com Folic Acid Source: Integrative Medicine Communications; www.drkoop.com Folic acid Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,887,00.html Folic acid/vitamin B Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,936,00.html Pantothenic Acid Source: Integrative Medicine Communications; www.drkoop.com Pantothenic Acid and Pantethine Source: Prima Communications, Inc.www.personalhealthzone.com Provitamin A Source: Integrative Medicine Communications; www.drkoop.com Pyridoxine Source: Integrative Medicine Communications; www.drkoop.com Vitamin A Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B complex Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,962,00.html Vitamin B1 Source: Healthnotes, Inc. www.healthnotes.com Vitamin B1 Source: Prima Communications, Inc.www.personalhealthzone.com

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Vitamin B12 Source: Healthnotes, Inc. www.healthnotes.com Vitamin B12 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B3 Source: Healthnotes, Inc. www.healthnotes.com Vitamin B5 (Pantothenic Acid) Source: Integrative Medicine Communications; www.drkoop.com Vitamin B6 Source: Healthnotes, Inc. www.healthnotes.com Vitamin B6 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B6 (Pyridoxine) Source: Integrative Medicine Communications; www.drkoop.com Vitamin B9 (Folic Acid) Alternative names: Folate, Folic Acid Source: Integrative Medicine Communications; www.drkoop.com Vitamin C Source: Healthnotes, Inc. www.healthnotes.com Vitamin C Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin D Source: Healthnotes, Inc. www.healthnotes.com Vitamin D Alternative names: Calciferol, Calcitrol, Cholecalciferol, Erocalciferol Source: Integrative Medicine Communications; www.drkoop.com Vitamin E Source: Healthnotes, Inc. www.healthnotes.com Vitamin E Alternative names: Alpha-Tocopherol, Beta-Tocopherol, D-Alpha-Tocopherol, Delta-Tocopherol, Gamma-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Vitamin K Alternative names: Menadione, Menaphthone, Menaquinone, Phylloquinone Source: Integrative Medicine Communications; www.drkoop.com

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•

Minerals Alpha-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Betaine Hydrochloride Source: Prima Communications, Inc.www.personalhealthzone.com Beta-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Calcium Source: Healthnotes, Inc. www.healthnotes.com Calcium: Which Form is Best? Source: Healthnotes, Inc. www.healthnotes.com Carnitine Source: Prima Communications, Inc.www.personalhealthzone.com Chondroitin Source: Prima Communications, Inc.www.personalhealthzone.com Creatine Source: Prima Communications, Inc.www.personalhealthzone.com Creatine Monohydrate Source: Healthnotes, Inc. www.healthnotes.com D-Alpha-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Delta-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Fluvastatin Source: Healthnotes, Inc. www.healthnotes.com Folate Source: Integrative Medicine Communications; www.drkoop.com Folate Source: Prima Communications, Inc.www.personalhealthzone.com Gabapentin Source: Healthnotes, Inc. www.healthnotes.com Gamma-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Iron Source: Healthnotes, Inc. www.healthnotes.com

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Lecithin and choline Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10040,00.html Magnesium Source: Healthnotes, Inc. www.healthnotes.com Magnesium Source: Integrative Medicine Communications; www.drkoop.com Magnesium Source: Prima Communications, Inc.www.personalhealthzone.com Magnesium Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,890,00.html Manganese Source: Integrative Medicine Communications; www.drkoop.com Quercetin Source: Healthnotes, Inc. www.healthnotes.com Quercetin Source: Prima Communications, Inc.www.personalhealthzone.com Selenium Source: Healthnotes, Inc. www.healthnotes.com Selenium Source: Prima Communications, Inc.www.personalhealthzone.com Spironolactone Source: Healthnotes, Inc. www.healthnotes.com •

Food and Diet Artichoke Alternative names: Cynara scolymus Source: Healthnotes, Inc. www.healthnotes.com Artichoke Source: Healthnotes, Inc. www.healthnotes.com Asparagus Source: Healthnotes, Inc. www.healthnotes.com Atkins Diet Source: Healthnotes, Inc. www.healthnotes.com

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Avocado Source: Healthnotes, Inc. www.healthnotes.com Beets Source: Healthnotes, Inc. www.healthnotes.com Betaine (Trimethylglycine) Source: Healthnotes, Inc. www.healthnotes.com Broccoflower Source: Healthnotes, Inc. www.healthnotes.com Broccoli Source: Healthnotes, Inc. www.healthnotes.com Brussels Sprouts Source: Healthnotes, Inc. www.healthnotes.com Cabbage Source: Healthnotes, Inc. www.healthnotes.com Carrots Source: Healthnotes, Inc. www.healthnotes.com Cauliflower Source: Healthnotes, Inc. www.healthnotes.com Celery Source: Healthnotes, Inc. www.healthnotes.com Chicory Source: Healthnotes, Inc. www.healthnotes.com Chondroitin Sulfate Source: Healthnotes, Inc. www.healthnotes.com Coffee Source: Healthnotes, Inc. www.healthnotes.com Collards Source: Healthnotes, Inc. www.healthnotes.com Dandelion Greens Source: Healthnotes, Inc. www.healthnotes.com Fat Alternatives and Fat Replacers Source: Healthnotes, Inc. www.healthnotes.com Flaxseeds Source: Healthnotes, Inc. www.healthnotes.com

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Garlic Alternative names: Allium sativum Source: Healthnotes, Inc. www.healthnotes.com Garlic Alternative names: Allium sativum Source: Integrative Medicine Communications; www.drkoop.com Garlic Source: Prima Communications, Inc.www.personalhealthzone.com Garlic Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,786,00.html Jerusalem Artichoke Source: Healthnotes, Inc. www.healthnotes.com Jicama Source: Healthnotes, Inc. www.healthnotes.com Juices Source: Healthnotes, Inc. www.healthnotes.com Kale Source: Healthnotes, Inc. www.healthnotes.com Kohlrabi Source: Healthnotes, Inc. www.healthnotes.com Kombu Source: Healthnotes, Inc. www.healthnotes.com Leeks Source: Healthnotes, Inc. www.healthnotes.com Low-Fat Diet Source: Healthnotes, Inc. www.healthnotes.com Monounsaturated Fats Source: Healthnotes, Inc. www.healthnotes.com Mustard Greens Source: Healthnotes, Inc. www.healthnotes.com Okra Source: Healthnotes, Inc. www.healthnotes.com Omega-3 Fatty Acids Source: Integrative Medicine Communications; www.drkoop.com

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Omega-6 Fatty Acids Source: Integrative Medicine Communications; www.drkoop.com Onions Source: Healthnotes, Inc. www.healthnotes.com Oyster Mushrooms Source: Healthnotes, Inc. www.healthnotes.com Parsnips Source: Healthnotes, Inc. www.healthnotes.com Polyunsaturated Fats Source: Healthnotes, Inc. www.healthnotes.com Porcini Mushrooms Source: Healthnotes, Inc. www.healthnotes.com Radishes Source: Healthnotes, Inc. www.healthnotes.com Romaine Lettuce Source: Healthnotes, Inc. www.healthnotes.com Rutabagas Source: Healthnotes, Inc. www.healthnotes.com Snow Peas Source: Healthnotes, Inc. www.healthnotes.com Soy products Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,135,00.html Spinach Source: Healthnotes, Inc. www.healthnotes.com Summer Squash Source: Healthnotes, Inc. www.healthnotes.com Sweet Peppers Source: Healthnotes, Inc. www.healthnotes.com Sweet Potatoes Source: Healthnotes, Inc. www.healthnotes.com Tea Source: Healthnotes, Inc. www.healthnotes.com The Dean Ornish Diet Source: Healthnotes, Inc. www.healthnotes.com

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Tomatoes Source: Healthnotes, Inc. www.healthnotes.com Trans-Fats Source: Healthnotes, Inc. www.healthnotes.com Turnips Source: Healthnotes, Inc. www.healthnotes.com Winter Squash Source: Healthnotes, Inc. www.healthnotes.com Yams Source: Healthnotes, Inc. www.healthnotes.com Zucchini Source: Healthnotes, Inc. www.healthnotes.com

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CHAPTER 3. ALTERNATIVE MEDICINE AND SCLEROSIS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to sclerosis. At the conclusion of this chapter, we will provide additional sources.

The Combined Health Information Database The Combined Health Information Database (CHID) is a bibliographic database produced by health-related agencies of the U.S. federal government (mostly from the National Institutes of Health) that can offer concise information for a targeted search. The CHID database is updated four times a year at the end of January, April, July, and October. Check the titles, summaries, and availability of CAM-related information by using the “Simple Search” option at the following Web site: http://chid.nih.gov/simple/simple.html. In the drop box at the top, select “Complementary and Alternative Medicine.” Then type “sclerosis” (or synonyms) in the second search box. We recommend that you select 100 “documents per page” and to check the “whole records” options. The following was extracted using this technique: •

NIH Funds Multi-Site, Collaborative ACM Studies in Portland, Oregon Source: Alternative and Complementary Therapies. 6(1): 32-37. February 2000. Summary: This journal article describes the collaborative alternative and complementary medicine (ACM) studies under way in Portland, Oregon. The studies were made possible by grants from the National Institutes of Health to the Oregon Health Sciences University (OHSU) and the Kaiser Permanente Center for Health Research (CHR). The money will fund collaboration among these two institutions and four of Portland's ACM colleges: the National College of Naturopathic Medicine, the Oregon College of Oriental Medicine, the Western States Chiropractic College, and the Oregon School of Massage. OHSU researchers will investigate the effects of ginkgo in neurologic disease and age-related cognitive disorders, the effects of antioxidants in multiple sclerosis (MS), and the effects of yoga in older people with MS. CHR studies will examine the effects of nutritional and herbal supplements on periodontal disease; the effects of acupuncture, chiropractic, and massage therapy on temporomandibular

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joint disorder (TMD); and the effects of traditional Chinese medicine (TCM) and naturopathic medicine in the treatment of women with TMD and multiple health problems. The article includes brief descriptions of the collaborating institutions, the TCM protocol for TMD, and 2 references.

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 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 “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 sclerosis: •

A controlled investigation of bodywork in multiple sclerosis. Author(s): Johnson SK, Frederick J, Kaufman M, Mountjoy B. Source: Journal of Alternative and Complementary Medicine (New York, N.Y.). 1999 June; 5(3): 237-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10381247&dopt=Abstract

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A review on traditional Chinese medicine in prevention and treatment of multiple sclerosis. Author(s): Sun Y, Liu X. Source: J Tradit Chin Med. 1999 March; 19(1): 65-73. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10453588&dopt=Abstract

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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. 2000 January 7; 267(1): 22-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10623568&dopt=Abstract

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Alternative therapies and multiple sclerosis: two case reports. Author(s): Fawcett J, Hanson MJ, Riley-Lawless K, Sidney JS. Source: Alternative Therapies in Health and Medicine. 1996 September; 2(5): 67-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8795939&dopt=Abstract

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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). 2002 December; 55(12): 2131-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409126&dopt=Abstract

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An exploratory study of the relationship between alternative therapies, functional status, and symptom severity among people with multiple sclerosis. Author(s): Fawcett J, Sidney JS, Riley-Lawless K, Hanson MJ. Source: Journal of Holistic Nursing : Official Journal of the American Holistic Nurses' Association. 1996 June; 14(2): 115-29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8708345&dopt=Abstract

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Antiphospholipid syndrome associated with progressive systemic sclerosis. Author(s): Chun WH, Bang D, Lee SK. Source: The Journal of Dermatology. 1996 May; 23(5): 347-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8675827&dopt=Abstract

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Anxiety in patients with multiple sclerosis. Author(s): Riether AM. Source: Semin Clin Neuropsychiatry. 1999 April; 4(2): 103-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10378954&dopt=Abstract

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Application of weak electromagnetic fields facilitates sensory-motor integration in patients with multiple sclerosis. Author(s): Sandyk R. Source: The International Journal of Neuroscience. 1996 March; 85(1-2): 101-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8727686&dopt=Abstract

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Assistance arrangements and use of services among persons with multiple sclerosis and their caregivers. Author(s): Aronson KJ, Cleghorn G, Goldenberg E. Source: Disability and Rehabilitation. 1996 July; 18(7): 354-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8799676&dopt=Abstract

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Auditory brainstem, middle-latency, and slow cortical responses in multiple sclerosis. Author(s): Japaridze G, Shakarishvili R, Kevanishvili Z. Source: Acta Neurologica Scandinavica. 2002 July; 106(1): 47-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12067329&dopt=Abstract

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Binaural interference in multiple sclerosis: case study. Author(s): Silman S. Source: Journal of the American Academy of Audiology. 1995 May; 6(3): 193-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7620194&dopt=Abstract

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Bioelectromagnetic applications for multiple sclerosis. Author(s): Richards TL, Lappin MS, Lawrie FW, Stegbauer KC.

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Source: Phys Med Rehabil Clin N Am. 1998 August; 9(3): 659-74. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9894116&dopt=Abstract •

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. 2003 June; 17(4): 327-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12822849&dopt=Abstract

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Cannabinoids and multiple sclerosis. Author(s): Pertwee RG. Source: Pharmacology & Therapeutics. 2002 August; 95(2): 165-74. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12182963&dopt=Abstract

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Cannabinoids in the treatment of pain and spasticity in multiple sclerosis. Author(s): Smith PF. Source: Curr Opin Investig Drugs. 2002 June; 3(6): 859-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12137404&dopt=Abstract

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Cannabis use as described by people with multiple sclerosis. Author(s): Page SA, Verhoef MJ, Stebbins RA, Metz LM, Levy JC. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2003 August; 30(3): 201-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12945941&dopt=Abstract

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Cannabis use in multiple sclerosis: excited interest. Author(s): Killestein J, Polman CH. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2003 August; 30(3): 181-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12945937&dopt=Abstract

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Cerebrospinal fluid protein changes in multiple sclerosis after dental amalgam removal. Author(s): Huggins HA, Levy TE. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 1998 August; 3(4): 295-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9727079&dopt=Abstract

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Circadian and hypothermia-induced effects on visual and auditory evoked potentials in multiple sclerosis. Author(s): Romani A, Bergamaschi R, Versino M, Zilioli A, Callieco R, Cosi V.

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Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2000 September; 111(9): 1602-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10964071&dopt=Abstract •

Clinical role of positron emission tomography in children with tuberous sclerosis complex. Author(s): Rintahaka PJ, Chugani HT. Source: Journal of Child Neurology. 1997 January; 12(1): 42-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9010795&dopt=Abstract

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Cognitive therapy for multiple sclerosis: a preliminary study. Author(s): Rodgers D, Khoo K, MacEachen M, Oven M, Beatty WW. Source: Alternative Therapies in Health and Medicine. 1996 September; 2(5): 70-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8795940&dopt=Abstract

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Cold effect on oxygen uptake, perceived exertion, and spasticity in patients with multiple sclerosis. Author(s): Chiara T, Carlos J Jr, Martin D, Miller R, Nadeau S. Source: Archives of Physical Medicine and Rehabilitation. 1998 May; 79(5): 523-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9596392&dopt=Abstract

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Community programs and resources for persons with multiple sclerosis. Author(s): McLaughlin CM. Source: Phys Med Rehabil Clin N Am. 1998 August; 9(3): 689-702. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9894118&dopt=Abstract

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Complementary and alternative therapies for treating multiple sclerosis symptoms: a systematic review. Author(s): Huntley A, Ernst E. Source: Complementary Therapies in Medicine. 2000 June; 8(2): 97-105. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10859602&dopt=Abstract

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Complementary and alternative therapy use in persons with multiple sclerosis. Author(s): Stuifbergen AK, Harrison TC. Source: Rehabilitation Nursing : the Official Journal of the Association of Rehabilitation Nurses. 2003 September-October; 28(5): 141-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14521002&dopt=Abstract

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Compromising and containing: self-management strategies used by men and women who live with multiple sclerosis and urinary incontinence. Author(s): Eastwood S, Kralik D, Koch T.

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Controversies about amyotrophic lateral sclerosis. Author(s): Rowland LP. Source: Neurologia (Barcelona, Spain). 1996 December; 11 Suppl 5: 72-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9011143&dopt=Abstract

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Conversion disorder presenting as multiple sclerosis. Author(s): Russo MB, Brooks FR, Fontenot J, Dopler BM, Neely ET, Halliday AW. Source: Military Medicine. 1998 October; 163(10): 709-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9795550&dopt=Abstract

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Cortical deficits in multiple sclerosis on the basis of subcortical lesions. Author(s): Jeffery DR, Absher J, Pfeiffer FE, Jackson H. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2000 February; 6(1): 505. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10694846&dopt=Abstract

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Current Complementary and Alternative Therapies for Multiple Sclerosis. Author(s): Bowling AC, Stewart TM. Source: Current Treatment Options in Neurology. 2003 January; 5(1): 55-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12521563&dopt=Abstract

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Cytokine profile in patients with multiple sclerosis following vitamin D supplementation. Author(s): Mahon BD, Gordon SA, Cruz J, Cosman F, Cantorna MT. Source: Journal of Neuroimmunology. 2003 January; 134(1-2): 128-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12507780&dopt=Abstract

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Development of tympanosclerosis: can predicting factors be identified? Author(s): Forseni M, Eriksson A, Bagger-Sjoback D, Nilsson J, Hultcrantz M. Source: The American Journal of Otology. 1997 May; 18(3): 298-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9149821&dopt=Abstract

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Dietary advice in systemic sclerosis: the dangers of a high fibre diet. Author(s): Gough A, Sheeran T, Bacon P, Emery P. Source: Annals of the Rheumatic Diseases. 1998 November; 57(11): 641-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9924203&dopt=Abstract

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Dietary fat in relation to risk of multiple sclerosis among two large cohorts of women. Author(s): Zhang SM, Willett WC, Hernan MA, Olek MJ, Ascherio A.

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Disease severity of 100 patients with systemic sclerosis over a period of 14 years: using a modified Medsger scale. Author(s): Geirsson AJ, Wollheim FA, Akesson A. Source: Annals of the Rheumatic Diseases. 2001 December; 60(12): 1117-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11709453&dopt=Abstract

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Double-blind study of pulsing magnetic field effects on multiple sclerosis. Author(s): Richards TL, Lappin MS, Acosta-Urquidi J, Kraft GH, Heide AC, Lawrie FW, Merrill TE, Melton GB, Cunningham CA. Source: Journal of Alternative and Complementary Medicine (New York, N.Y.). 1997 Spring; 3(1): 21-9. Erratum In: J Altern Complement Med 1997 Summer; 3(2): 205. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9395691&dopt=Abstract

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Effect of inspiratory muscle training in patients with multiple sclerosis. Author(s): Klefbeck B, Hamrah Nedjad J. Source: Archives of Physical Medicine and Rehabilitation. 2003 July; 84(7): 994-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881823&dopt=Abstract

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Effects of a pulsed electromagnetic therapy on multiple sclerosis fatigue and quality of life: a double-blind, placebo controlled trial. Author(s): Lappin MS, Lawrie FW, Richards TL, Kramer ED. Source: Alternative Therapies in Health and Medicine. 2003 July-August; 9(4): 38-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12868251&dopt=Abstract

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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. 2001 October 15; 191(1-2): 139-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11677005&dopt=Abstract

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Effects of osteopathic manipulative treatment and concentric and eccentric maximaleffort exercise on women with multiple sclerosis: a pilot study. Author(s): Yates HA, Vardy TC, Kuchera ML, Ripley BD, Johnson JC. Source: J Am Osteopath Assoc. 2002 May; 102(5): 267-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12033756&dopt=Abstract

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Effects of polyunsaturated fatty acids on rat glomerulosclerosis induced by hypercholesterolaemic diet. Author(s): Romero R, Higueruelo S, Vaquero M, Biosca C, Martinez-Ocana JC, Pastor C.

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Effects of psychological group therapy in patients with multiple sclerosis. Author(s): Tesar N, Baumhackl U, Kopp M, Gunther V. Source: Acta Neurologica Scandinavica. 2003 June; 107(6): 394-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757470&dopt=Abstract

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Efficacy of an early intensification treatment integrating chemotherapy, autologous stem cell transplantation and radiotherapy for poor risk primary mediastinal large B cell lymphoma with sclerosis. Author(s): Cairoli R, Grillo G, Tedeschi A, Gargantini L, Marenco P, Tresoldi E, Barbarano L, Nosari AM, Morra E. Source: Bone Marrow Transplantation. 2002 March; 29(6): 473-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11960265&dopt=Abstract

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Electrical sensation during Tai-Chi practice as the first manifestation of multiple sclerosis. Author(s): Achiron A, Barak Y, Stern Y, Noy S. Source: Clinical Neurology and Neurosurgery. 1997 December; 99(4): 280-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9491306&dopt=Abstract

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Emerging potentials for an antioxidant therapy as a new approach to the treatment of systemic sclerosis. Author(s): Simonini G, Pignone A, Generini S, Falcini F, Cerinic MM, Gabriele S, Alberto P, Sergio G, Fernanda F, Marco MC. Source: Toxicology. 2000 November 30; 155(1-3): 1-15. Review. Erratum In: Toxicology 2001 April 12; 162(1): 69. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11154792&dopt=Abstract

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Essential fatty acids and related molecular and cellular mechanisms in multiple sclerosis: new looks at old concepts. Author(s): Mayer M. Source: Folia Biol (Praha). 1999; 45(4): 133-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10732726&dopt=Abstract

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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. 1984 March; 4(1): 83-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11649670&dopt=Abstract

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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). 1999; 59(4): 329-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10645638&dopt=Abstract

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Exercise in 94 degrees F water for a patient with multiple sclerosis. Author(s): Peterson C. Source: Physical Therapy. 2001 April; 81(4): 1049-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11276186&dopt=Abstract

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Fatal hyperthermia in hot baths in individuals with multiple sclerosis. Author(s): Kohlmeier RE, DiMaio VJ, Kagan-Hallet K. Source: The American Journal of Forensic Medicine and Pathology : Official Publication of the National Association of Medical Examiners. 2000 September; 21(3): 201-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10990274&dopt=Abstract

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Fatal hyperthermia secondary to sunbathing in a patient with multiple sclerosis. Author(s): Henke AF, Cohle SD, Cottingham SL. Source: The American Journal of Forensic Medicine and Pathology : Official Publication of the National Association of Medical Examiners. 2000 September; 21(3): 204-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10990275&dopt=Abstract

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Fatigue in multiple sclerosis. Author(s): Krupp LB, Christodoulou C. Source: Curr Neurol Neurosci Rep. 2001 May; 1(3): 294-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11898532&dopt=Abstract

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FDG-PET and MRI in temporal lobe epilepsy: relationship to febrile seizures, hippocampal sclerosis and outcome. Author(s): Salanova V, Markand O, Worth R, Smith R, Wellman H, Hutchins G, Park H, Ghetti B, Azzarelli B. Source: Acta Neurologica Scandinavica. 1998 March; 97(3): 146-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9531429&dopt=Abstract

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Further evidence for corticomotor hyperexcitability in amyotrophic lateral sclerosis. Author(s): Naka D, Mills KR. Source: Muscle & Nerve. 2000 July; 23(7): 1044-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10882998&dopt=Abstract

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Genistein is neuroprotective in murine models of familial amyotrophic lateral sclerosis and stroke. Author(s): Trieu VN, Uckun FM.

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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. 1998; 17(3-4): 3259. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9726810&dopt=Abstract

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Gut focused behavioural treatment (biofeedback) for constipation and faecal incontinence in multiple sclerosis. Author(s): Wiesel PH, Norton C, Roy AJ, Storrie JB, Bowers J, Kamm MA. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2000 August; 69(2): 240-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10896701&dopt=Abstract

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High-dose immunosuppressive therapy with PBPC support in the treatment of poor risk multiple sclerosis. Author(s): Kozak T, Havrdova E, Pit'ha J, Gregora E, Pytlik R, Maaloufova J, Mareckova H, Kobylka P, Vodvarkova S. Source: Bone Marrow Transplantation. 2000 March; 25(5): 525-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10713630&dopt=Abstract

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High-dose methylprednisolone therapy in multiple sclerosis induces apoptosis in peripheral blood leukocytes. Author(s): Leussink VI, Jung S, Merschdorf U, Toyka KV, Gold R. Source: Archives of Neurology. 2001 January; 58(1): 91-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11176941&dopt=Abstract

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High-transport membrane is a risk factor for encapsulating peritoneal sclerosis developing after long-term continuous ambulatory peritoneal dialysis treatment. Author(s): Yamamoto R, Nakayama M, Hasegawa T, Miwako N, Yamamoto H, Yokoyami K, Ikeda M, Kato N, Hayakawa H, Takahashi H, Otsuka Y, Kawaguchi Y, Hosoya T. Source: Adv Perit Dial. 2002; 18: 131-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12402604&dopt=Abstract

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Homeopathy in multiple sclerosis. Author(s): Whitmarsh TE.

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Hyperbaric oxygen for multiple sclerosis. Review of controlled trials. Author(s): Kleijnen J, Knipschild P. Source: Acta Neurologica Scandinavica. 1995 May; 91(5): 330-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7639061&dopt=Abstract

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Hyperbaric oxygen therapy and multiple sclerosis. Author(s): Perrins DJ, James PB. Source: Undersea & Hyperbaric Medicine : Journal of the Undersea and Hyperbaric Medical Society, Inc. 2002 Winter; 29(4): 236-8; Discussion 238-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797664&dopt=Abstract

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Hypnosis as adjunctive therapy for multiple sclerosis: a progress report. Author(s): Sutcher H. Source: Am J Clin Hypn. 1997 April; 39(4): 283-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9141305&dopt=Abstract

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Hypnosis for pain and neuromuscular rehabilitation with multiple sclerosis: case summary, literature review, and analysis of outcomes. Author(s): Dane JR. Source: Int J Clin Exp Hypn. 1996 July; 44(3): 208-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8690534&dopt=Abstract

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I. Role of the pineal gland in multiple sclerosis: a hypothesis. Author(s): Sandyk R. Source: Journal of Alternative and Complementary Medicine (New York, N.Y.). 1997 Fall; 3(3): 267-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9430330&dopt=Abstract

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Identifying strategies for managing urinary incontinence with women who have multiple sclerosis. Author(s): Koch T, Kelly S. Source: Journal of Clinical Nursing. 1999 September; 8(5): 550-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10786527&dopt=Abstract

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Immune-mediated oligodendrocyte injury in multiple mechanisms and therapeutic interventions. Author(s): Buntinx M, Stinissen P, Steels P, Ameloot M, Raus J.

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Immunoablative therapy with autologous stem cell transplantation in the treatment of poor risk multiple sclerosis. Author(s): Kozak T, Havrdova E, Pit'ha J, Gregora E, Pytlik R, Maaloufova J, Kobylka P, Vodvarkova S. Source: Transplantation Proceedings. 2001 May; 33(3): 2179-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11377494&dopt=Abstract

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Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis. Author(s): Killestein J, Hoogervorst EL, Reif M, Blauw B, Smits M, Uitdehaag BM, Nagelkerken L, Polman CH. Source: Journal of Neuroimmunology. 2003 April; 137(1-2): 140-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667658&dopt=Abstract

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Implications for the use of topoisomerase I inhibitors in treatment of patients with systemic sclerosis. Author(s): Rudnicka L, Czuwara J, Barusinska A, Nowicka U, Makiela B, Jablonska S. Source: Annals of the New York Academy of Sciences. 1996 December 13; 803: 318-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8993528&dopt=Abstract

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Improving quality of life for people with chronic conditions: the example of t'ai chi and multiple sclerosis. Author(s): Husted C, Pham L, Hekking A, Niederman R. Source: Alternative Therapies in Health and Medicine. 1999 September; 5(5): 70-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10484833&dopt=Abstract

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Increased expression of “peripheral-type” benzodiazepine receptors in human temporal lobe epilepsy: implications for PET imaging of hippocampal sclerosis. Author(s): Sauvageau A, Desjardins P, Lozeva V, Rose C, Hazell AS, Bouthillier A, Butterwort RF. Source: Metabolic Brain Disease. 2002 March; 17(1): 3-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11893007&dopt=Abstract

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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. 2001 April; 77(2): 383-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11299300&dopt=Abstract

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Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Author(s): Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U, Amadio S, Bergami A, Furlan R, Comi G, Vescovi AL, Martino G. Source: Nature. 2003 April 17; 422(6933): 688-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700753&dopt=Abstract

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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. 2000 March; 6(2): 128, 120-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10710808&dopt=Abstract

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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. 2003 June; 12(3): 255-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857367&dopt=Abstract

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Lateralizing ability of single-voxel proton mr spectroscopy in hippocampal sclerosis: comparison with mr imaging and positron emission tomography. Author(s): Park SW, Chang KH, Kim HD, Song IC, Lee DS, Lee SK, Chung CK, Yu IK, Han MH, Park YH. Source: Ajnr. American Journal of Neuroradiology. 2001 April; 22(4): 625-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11290468&dopt=Abstract

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Lead poisoning from complementary and alternative medicine in multiple sclerosis. Author(s): Levinson A, Chinn J. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2001 August; 71(2): 281-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11488280&dopt=Abstract

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Lead poisoning from complementary and alternative medicine in multiple sclerosis. Author(s): Fisher AA, Le Couteur DG. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2000 November; 69(5): 687-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11032631&dopt=Abstract

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Long-lasting depression of soleus motoneurons excitability following repetitive magnetic stimuli of the spinal cord in multiple sclerosis patients. Author(s): Nielsen JF, Sinkjaer T.

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Long-latency cerebral event-related potentials in multiple sclerosis. Author(s): Aminoff JC, Goodin DS. Source: Journal of Clinical Neurophysiology : Official Publication of the American Electroencephalographic Society. 2001 July; 18(4): 372-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11673703&dopt=Abstract

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MACOP-B and involved field radiation therapy is an effective therapy for primary mediastinal large B-cell lymphoma with sclerosis. Author(s): Martelli MP, Martelli M, Pescarmona E, De Sanctis V, Donato V, Palombi F, Todisco E, Rendina EA, Pau FM, Mandelli F. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 1998 September; 9(9): 1027-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9818079&dopt=Abstract

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Major depressive disorder and health care costs in multiple sclerosis. Author(s): Patten SB, Jacobs P, Petcu R, Reimer MA, Metz LM. Source: International Journal of Psychiatry in Medicine. 2002; 32(2): 167-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12269597&dopt=Abstract

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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. 1998 August; 30(4): 257-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9791781&dopt=Abstract

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Management of spasticity, pain, and paroxysmal phenomena in multiple sclerosis. Author(s): Schapiro RT. Source: Curr Neurol Neurosci Rep. 2001 May; 1(3): 299-302. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11898533&dopt=Abstract

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Managing early multiple sclerosis. Author(s): Jordan N. Source: Practitioner. 1998 May; 242(1586): 400-4. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10492952&dopt=Abstract

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Marijuana in the management of amyotrophic lateral sclerosis. Author(s): Carter GT, Rosen BS.

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Marked and sustained improvement of systemic sclerosis following polychemotherapy for coexistent multiple myeloma. Author(s): Bachleitner-Hofmann T, Machold K, Knobler R, Drach J, Grumbeck E, Gisslinger H. Source: Clin Exp Rheumatol. 2002 January-February; 20(1): 85-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11892717&dopt=Abstract

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Meeting the challenge of multiple sclerosis. Part II. Author(s): Halper J, Holland N. Source: The American Journal of Nursing. 1998 November; 98(11): 39-45; Quiz 46. Review. Erratum In: Am J Nurs 1999 January; 99(1 Pt 1): 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9826934&dopt=Abstract

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Mindfulness of movement as a coping strategy in multiple sclerosis. A pilot study. Author(s): Mills N, Allen J. Source: General Hospital Psychiatry. 2000 November-December; 22(6): 425-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11072058&dopt=Abstract

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Mini-forum on multiple sclerosis (MS) and hyperbaric oxygen therapy. Author(s): Moon RE. Source: Undersea & Hyperbaric Medicine : Journal of the Undersea and Hyperbaric Medical Society, Inc. 2002 Winter; 29(4): 235-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797663&dopt=Abstract

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Motor evoked potentials from the pelvic floor in patients with multiple sclerosis. Author(s): Brostrom S, Frederiksen JL, Jennum P, Lose G. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 April; 74(4): 498-500. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640072&dopt=Abstract

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MRI, monosclerosis, and multiple sclerosis. Author(s): James PB. Source: Lancet. 2002 April 20; 359(9315): 1436. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11978368&dopt=Abstract

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Multiple sclerosis and hypnotherapy. Author(s): Sutcher H. Source: Alternative Therapies in Health and Medicine. 1997 May; 3(3): 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9141285&dopt=Abstract

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Multiple sclerosis article ignores conventional and osteopathic treatment options. Author(s): Schreier EM. Source: J Am Osteopath Assoc. 2000 March; 100(3): 140. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10763305&dopt=Abstract

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Multiple sclerosis in Mexico: hospital cases at the National Institute of Neurology and Neurosurgery, Mexico City. Author(s): Corona T, Rodrigues JL, Otero E, Stopp L. Source: Neurologia (Barcelona, Spain). 1996 May; 11(5): 170-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8754632&dopt=Abstract

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Multiple sclerosis, an autoimmune inflammatory disease: prospects for its integrative management. Author(s): Kidd PM. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2001 December; 6(6): 540-66. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11804546&dopt=Abstract

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Multiple sclerosis. The long wait for legal cannabis. Author(s): Turner T. Source: Nurs Times. 2001 May 17-23; 97(20): 14-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11962028&dopt=Abstract

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Music therapy as a treatment method for improving respiratory muscle strength in patients with advanced multiple sclerosis: a pilot study. Author(s): Wiens ME, Reimer MA, Guyn HL. Source: Rehabilitation Nursing : the Official Journal of the Association of Rehabilitation Nurses. 1999 March-April; 24(2): 74-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10410058&dopt=Abstract

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My journey with amyotrophic lateral sclerosis. Author(s): Nowotny ML. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 1998 February; 30(1): 68-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9604825&dopt=Abstract

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Neocortical temporal FDG-PET hypometabolism correlates with temporal lobe atrophy in hippocampal sclerosis associated with microscopic cortical dysplasia. Author(s): Diehl B, LaPresto E, Najm I, Raja S, Rona S, Babb T, Ying Z, Bingaman W, Luders HO, Ruggieri P. Source: Epilepsia. 2003 April; 44(4): 559-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12681005&dopt=Abstract

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Neural therapy in the treatment of multiple sclerosis. Author(s): Gibson RG, Gibson SL. Source: Journal of Alternative and Complementary Medicine (New York, N.Y.). 1999 December; 5(6): 543-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10630348&dopt=Abstract

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New animal models for encapsulating peritoneal sclerosis--role of acidic solution. Author(s): Nakamoto H, Imai H, Ishida Y, Yamanouchi Y, Inoue T, Okada H, Suzuki H. Source: Perit Dial Int. 2001; 21 Suppl 3: S349-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11887851&dopt=Abstract

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Nociceptive R3 reflex in relapsing-remitting multiple sclerosis patients. Author(s): D'Aleo G, Sessa E, D'Aleo P, Rifici C, Di Bella P, Petix M, Bramanti P. Source: Funct Neurol. 1999 January-March; 14(1): 43-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10321329&dopt=Abstract

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Nutrition, latitude, and multiple sclerosis mortality: an ecologic study. Author(s): Esparza ML, Sasaki S, Kesteloot H. Source: American Journal of Epidemiology. 1995 October 1; 142(7): 733-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7572944&dopt=Abstract

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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. 2002 November; 5(6): 631-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12394638&dopt=Abstract

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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. 1998 August; 245 Suppl 2: S13-9; Discussion S29. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9747929&dopt=Abstract

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Otoacoustic emissions in sudden unilateral hearing loss associated with multiple sclerosis. Author(s): Cevette MJ, Robinette MS, Carter J, Knops JL. Source: Journal of the American Academy of Audiology. 1995 May; 6(3): 197-202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7620195&dopt=Abstract

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Pathophysiology and management of bowel dysfunction in multiple sclerosis. Author(s): Wiesel PH, Norton C, Glickman S, Kamm MA.

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Source: European Journal of Gastroenterology & Hepatology. 2001 April; 13(4): 441-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11338078&dopt=Abstract •

Peritoneal sclerosis in peritoneal dialysis patients related to dialysis settings and peritoneal transport properties. Author(s): Plum J, Hermann S, Fussholler A, Schoenicke G, Donner A, Rohrborn A, Grabensee B. Source: Kidney International. Supplement. 2001 February; 78: S42-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11168981&dopt=Abstract

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Primary Mediastinal B-cell lymphoma with sclerosis: clinical and therapeutic evaluation of 22 patients. Author(s): Zinzani PL, Bendandi M, Frezza G, Gherlinzoni F, Merla E, Salvucci M, Magagnoli M, Babini L, Tura S. Source: Leukemia & Lymphoma. 1996 April; 21(3-4): 311-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8726412&dopt=Abstract

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Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and adolescent patients: treatment and results from three therapeutic studies of the Berlin-FrankfurtMunster Group. Author(s): Seidemann K, Tiemann M, Lauterbach I, Mann G, Simonitsch I, Stankewitz K, Schrappe M, Zimmermann M, Niemeyer C, Parwaresch R, Riehm H, Reiter A; NHL Berlin-Frankfurt-Munster Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 May 1; 21(9): 1782-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12721255&dopt=Abstract

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Primary mediastinal large B-cell lymphoma with sclerosis: a clinical study of 89 patients treated with MACOP-B chemotherapy and radiation therapy. Author(s): Zinzani PL, Martelli M, Bendandi M, De Renzo A, Zaccaria A, Pavone E, Bocchia M, Falini B, Gobbi M, Gherlinzoni F, Stefoni V, Tani M, Tura S. Source: Haematologica. 2001 February; 86(2): 187-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11224489&dopt=Abstract

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Psychotherapy with multiple-sclerosis patients. Author(s): Langenmayr A, Schottes N. Source: Psychological Reports. 2000 April; 86(2): 495-508. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10840903&dopt=Abstract

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R3 nociceptive reflex in multiple sclerosis patients with paroxysmal symptoms treated with gabapentin. Author(s): D'Aleo G, Rifici C, Sessa E, Di Bella P, Bramanti P.

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Source: Funct Neurol. 2000 October-December; 15(4): 205-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11213523&dopt=Abstract •

Radiologically confirmed de novo glioblastoma multiforme and hippocampal sclerosis associated with the first onset of nonconvulsive simple partial status epilepticus. Author(s): Chang JW, Chang JH, Park SC, Kim TS, Park YG, Chung SS. Source: Acta Neurochirurgica. 2001; 143(3): 297-300; Discussion 300-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11460918&dopt=Abstract

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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. 2002 May 1; 32(9): 920-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11978494&dopt=Abstract

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Reflexology treatment relieves symptoms of multiple sclerosis: a randomized controlled study. Author(s): Siev-Ner I, Gamus D, Lerner-Geva L, Achiron A. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 August; 9(4): 35661. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926840&dopt=Abstract

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Relationship between tumour necrosis factor-alpha (TNFalpha) production and a specific multiple sclerosis (MS) associated TNF gene haplotype. Author(s): Armstrong MA, McDonnell GV, Graham CA, Kirk CW, Droogan AG, Hawkins SA. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 1999 June; 5(3): 165-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10408716&dopt=Abstract

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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. 2000 March-April; 62(2): 271-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10772408&dopt=Abstract

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Resolution of sleep paralysis by weak electromagnetic fields in a patient with multiple sclerosis. Author(s): Sandyk R. Source: The International Journal of Neuroscience. 1997 August; 90(3-4): 145-57. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9352423&dopt=Abstract

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Respiratory muscle weakness and respiratory muscle training in severely disabled multiple sclerosis patients. Author(s): Gosselink R, Kovacs L, Ketelaer P, Carton H, Decramer M.

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Source: Archives of Physical Medicine and Rehabilitation. 2000 June; 81(6): 747-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10857518&dopt=Abstract •

Sexual and urological dysfunction in multiple sclerosis: better understanding and improved therapies. Author(s): DasGupta R, Fowler CJ. Source: Current Opinion in Neurology. 2002 June; 15(3): 271-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12045724&dopt=Abstract

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Skin blood flow in patients with systemic sclerosis and Raynaud's phenomenon: effects of oral L-arginine supplementation. Author(s): Khan F, Belch JJ. Source: The Journal of Rheumatology. 1999 November; 26(11): 2389-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10555898&dopt=Abstract

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Social support: gender differences in multiple sclerosis spousal caregivers. Author(s): Good DM, Bower DA, Einsporn RL. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 1995 October; 27(5): 305-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8568348&dopt=Abstract

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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. 2000 December; 1(5): 337-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11464852&dopt=Abstract

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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. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. 2003 September; 4(3): 158-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13129802&dopt=Abstract

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Stem cells in the treatment of amyotrophic lateral sclerosis (ALS). Author(s): Silani V, Fogh I, Ratti A, Sassone J, Ciammola A, Cova L.

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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. 2002 December; 3(4): 173-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710505&dopt=Abstract •

Supporting individuals with disabling multiple sclerosis. Author(s): Ryle A. Source: Journal of the Royal Society of Medicine. 2003 February; 96(2): 104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562990&dopt=Abstract

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Symptomatic hyperekplexia in a patient with multiple sclerosis. Author(s): Ruprecht K, Warmuth-Metz M, Waespe W, Gold R. Source: Neurology. 2002 February 12; 58(3): 503-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11839869&dopt=Abstract

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Systemic sclerosis. Author(s): Werner GT, Eder U, Lohmann J. Source: Archives of Physical Medicine and Rehabilitation. 1998 April; 79(4): 471. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9552120&dopt=Abstract

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Teaching memory strategies to persons with multiple sclerosis. Author(s): Allen DN, Goldstein G, Heyman RA, Rondinelli T. Source: Journal of Rehabilitation Research and Development. 1998 October; 35(4): 40510. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10220218&dopt=Abstract

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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. 1997 October; 152 Suppl 1: S90-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9419062&dopt=Abstract

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The clonal relationship between nodular sclerosis Hodgkin's disease with a clonal Reed-Sternberg cell population and a subsequent B-cell small noncleaved cell lymphoma. Author(s): Ohno T, Trenn G, Wu G, Abou-Elella A, Reis HE, Chan WC. Source: Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. 1998 May; 11(5): 485-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9619603&dopt=Abstract

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The early history of the Multiple Sclerosis Society of Great Britain and Northern Ireland: a socio-historical study of lay/practitioner interaction in the context of a

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medical charity. Author(s): Nicolson M, Lowis GW. Source: Medical History. 2002 April; 46(2): 141-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12024806&dopt=Abstract •

The effect of electrical acupuncture-stimulation therapy using thermography and plasma endothelin (ET-1) levels in patients with progressive systemic sclerosis (PSS). Author(s): Maeda M, Kachi H, Ichihashi N, Oyama Z, Kitajima Y. Source: Journal of Dermatological Science. 1998 June; 17(2): 151-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9673897&dopt=Abstract

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The effect of transcutaneous electrical nerve stimulation on spasticity in multiple sclerosis patients: a pilot study. Author(s): Armutlu K, Meric A, Kirdi N, Yakut E, Karabudak R. Source: Neurorehabilitation and Neural Repair. 2003 June; 17(2): 79-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814052&dopt=Abstract

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The effects of high-dose intravenous methylprednisolone on event-related potentials in patients with multiple sclerosis. Author(s): Filipovic SR, Drulovic J, Stojsavljevic N, Levic Z. Source: Journal of the Neurological Sciences. 1997 November 25; 152(2): 147-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9415535&dopt=Abstract

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The effects of imagery on attitudes and moods in multiple sclerosis patients. Author(s): Maguire BL. Source: Alternative Therapies in Health and Medicine. 1996 September; 2(5): 75-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8795941&dopt=Abstract

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The experience of sexuality for individuals living with multiple sclerosis. Author(s): Gagliardi BA. Source: Journal of Clinical Nursing. 2003 July; 12(4): 571-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790871&dopt=Abstract

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The inhibitory effects of camptothecin, a topoisomerase I inhibitor, on collagen synthesis in fibroblasts from patients with systemic sclerosis. Author(s): Czuwara-Ladykowska J, Makiela B, Smith EA, Trojanowska M, Rudnicka L. Source: Arthritis Research. 2001; 3(5): 311-8. Epub 2001 August 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11549373&dopt=Abstract

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The localizing value of ictal SPECT in children with tuberous sclerosis complex and refractory partial epilepsy. Author(s): Koh S, Jayakar P, Resnick T, Alvarez L, Liit RE, Duchowny M.

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Source: Epileptic Disord. 1999 March; 1(1): 41-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10937131&dopt=Abstract •

The neuroimmunology of multiple sclerosis. Author(s): Coyle PK. Source: Advances in Neuroimmunology. 1996; 6(2): 143-54. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8876770&dopt=Abstract

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The role of executive function in imagery mnemonics: evidence from multiple sclerosis. Author(s): Canellopoulou M, Richardson JT. Source: Neuropsychologia. 1998 November; 36(11): 1181-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9842763&dopt=Abstract

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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. 1998 April; 93: 14-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9691245&dopt=Abstract

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The therapeutic potential of cannabis in multiple sclerosis. Author(s): Baker D, Pryce G. Source: Expert Opinion on Investigational Drugs. 2003 April; 12(4): 561-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12665412&dopt=Abstract

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The use and effectiveness of alternative therapies in multiple sclerosis. Author(s): Newland P. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 1999 February; 31(1): 43-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10207832&dopt=Abstract

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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. 2001 October 15; 191(1-2): 151-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11677007&dopt=Abstract

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The use of complementary and alternative therapies by people with multiple sclerosis. Author(s): Page SA, Verhoef MJ, Stebbins RA, Metz LM, Levy JC. Source: Chronic Diseases in Canada. 2003 Spring-Summer; 24(2-3): 75-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959678&dopt=Abstract

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Therapeutic effects of alternating current pulsed electromagnetic fields in multiple sclerosis. Author(s): Sandyk R. Source: Journal of Alternative and Complementary Medicine (New York, N.Y.). 1997 Winter; 3(4): 365-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9449058&dopt=Abstract

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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. 2001 August; 17(1): 89-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11665866&dopt=Abstract

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Transcranial magnetic stimulation in amyotrophic and primary lateral sclerosis. Author(s): Cruz Martinez A, Trejo JM. Source: Electromyogr Clin Neurophysiol. 1999 July-August; 39(5): 285-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10421999&dopt=Abstract

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Transdermal histamine in multiple sclerosis, part two: a proposed theoretical basis for its use. Author(s): Gillson G, Wright JV, DeLack E, Ballasiotes G. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2000 June; 5(3): 224-48. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10869103&dopt=Abstract

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Transdermal histamine in multiple sclerosis: part one -- clinical experience. Author(s): Gillson G, Wright JV, DeLack E, Ballasiotes G. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 1999 December; 4(6): 424-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10608915&dopt=Abstract

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Treatment and clinical management of primary mediastinal large B-cell lymphoma with sclerosis: MACOP-B regimen and mediastinal radiotherapy monitored by (67)Gallium scan in 50 patients. Author(s): Zinzani PL, Martelli M, Magagnoli M, Pescarmona E, Scaramucci L, Palombi F, Bendandi M, Martelli MP, Ascani S, Orcioni GF, Pileri SA, Mandelli F, Tura S. Source: Blood. 1999 November 15; 94(10): 3289-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10552937&dopt=Abstract

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Treatment of multiple sclerosis with hyperbaric oxygen therapy. Author(s): Bennett M, Heard R.

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Source: Undersea & Hyperbaric Medicine : Journal of the Undersea and Hyperbaric Medical Society, Inc. 2001 Fall; 28(3): 117-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12067146&dopt=Abstract •

Treatments for fatigue in multiple sclerosis: a rapid and systematic review. Author(s): Branas P, Jordan R, Fry-Smith A, Burls A, Hyde C. Source: Health Technology Assessment (Winchester, England). 2000; 4(27): 1-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11074395&dopt=Abstract

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Trigeminal neuralgia triggered by auditory stimuli in multiple sclerosis. Author(s): Hartmann M, Rottach KG, Wohlgemuth WA, Pfadenhauer K. Source: Archives of Neurology. 1999 June; 56(6): 731-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10369314&dopt=Abstract

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Tuberous sclerosis: epileptogenicity and multimodal presurgical evaluations. Author(s): Ohta Y, Nariai T, Akimoto H, Shimohira M, Sugimoto J, Ohno K, Senda M, Hirakawa K. Source: Child's Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery. 2001 May; 17(6): 313-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11417410&dopt=Abstract

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Use of unconventional therapies by individuals with multiple sclerosis. Author(s): Nayak S, Matheis RJ, Schoenberger NE, Shiflett SC. Source: Clinical Rehabilitation. 2003 March; 17(2): 181-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12625659&dopt=Abstract

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Use of videotape to assess mobility in a controlled randomized crossover trial of physiotherapy in chronic multiple sclerosis. Author(s): Wiles CM, Newcombe RG, Fuller KJ, Jones A, Price M. Source: Clinical Rehabilitation. 2003 May; 17(3): 256-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12735532&dopt=Abstract

•

Vestibular evoked myogenic potentials in multiple sclerosis patients. Author(s): Versino M, Colnaghi S, Callieco R, Bergamaschi R, Romani A, Cosi V. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2002 September; 113(9): 1464-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12169329&dopt=Abstract

•

Vestibular evoked myogenic potentials in multiple sclerosis. Author(s): Shimizu K, Murofushi T, Sakurai M, Halmagyi M.

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Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2000 August; 69(2): 276-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10960289&dopt=Abstract •

Vestibular-evoked myogenic potentials: a method to assess vestibulo-spinal conduction in multiple sclerosis patients. Author(s): Sartucci F, Logi F. Source: Brain Research Bulletin. 2002 October 15; 59(1): 59-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372550&dopt=Abstract

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Vincristine and focal segmental sclerosis: do we need a multicentre trial? Author(s): Goonasekera CD, Koziell AB, Hulton SA, Dillon MJ. Source: Pediatric Nephrology (Berlin, Germany). 1998 May; 12(4): 284-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9655358&dopt=Abstract

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White-matter change in mesial temporal sclerosis: correlation of MRI with PET, pathology, and clinical features. Author(s): Choi D, Na DG, Byun HS, Suh YL, Kim SE, Ro DW, Chung IG, Hong SC, Hong SB. Source: Epilepsia. 1999 November; 40(11): 1634-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10565593&dopt=Abstract

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Will aromatherapy be a useful treatment strategy for people with multiple sclerosis who experience pain? Author(s): Howarth AL. Source: Complementary Therapies in Nursing & Midwifery. 2002 August; 8(3): 138-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12353614&dopt=Abstract

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://search.aol.com/cat.adp?id=169&layer=&from=subcats

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Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.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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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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

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HealthGate: http://www.tnp.com/

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WebMDHealth: http://my.webmd.com/drugs_and_herbs

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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

The following is a specific Web list relating to 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: •

General Overview Angina Source: Healthnotes, Inc. www.healthnotes.com Arteriosclerosis Source: Integrative Medicine Communications; www.drkoop.com Atherosclerosis Source: Healthnotes, Inc. www.healthnotes.com Atherosclerosis Source: Integrative Medicine Communications; www.drkoop.com Atherosclerosis and Heart Disease Prevention Source: Prima Communications, Inc.www.personalhealthzone.com Cancer Prevention (Reducing the Risk) Source: Prima Communications, Inc.www.personalhealthzone.com Cardiomyopathy Source: Healthnotes, Inc. www.healthnotes.com Cardiovascular Disease Overview Source: Healthnotes, Inc. www.healthnotes.com Cataracts (Prevention) Source: Prima Communications, Inc.www.personalhealthzone.com Cholesterol, High Source: Integrative Medicine Communications; www.drkoop.com Chronic Obstructive Pulmonary Disease Source: Healthnotes, Inc. www.healthnotes.com

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Colds and Flus Source: Prima Communications, Inc.www.personalhealthzone.com Congestive Heart Failure Source: Prima Communications, Inc.www.personalhealthzone.com Coronary Artery Disease Source: Integrative Medicine Communications; www.drkoop.com Diabetes Source: Healthnotes, Inc. www.healthnotes.com Diabetes Source: Prima Communications, Inc.www.personalhealthzone.com Diabetes Mellitus Source: Integrative Medicine Communications; www.drkoop.com Erectile Dysfunction Source: Healthnotes, Inc. www.healthnotes.com Gout Source: Integrative Medicine Communications; www.drkoop.com Heart Attack Source: Healthnotes, Inc. www.healthnotes.com Heart Attack Source: Integrative Medicine Communications; www.drkoop.com High Cholesterol Source: Healthnotes, Inc. www.healthnotes.com High Cholesterol Source: Integrative Medicine Communications; www.drkoop.com High Cholesterol Source: Prima Communications, Inc.www.personalhealthzone.com High Homocysteine Source: Healthnotes, Inc. www.healthnotes.com High Triglycerides Source: Healthnotes, Inc. www.healthnotes.com Hypercholesterolemia Source: Integrative Medicine Communications; www.drkoop.com Hypertension Alternative names: High Blood Pressure Source: Prima Communications, Inc.www.personalhealthzone.com

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Incontinence, Urinary Source: Integrative Medicine Communications; www.drkoop.com Insulin Resistance Syndrome Source: Healthnotes, Inc. www.healthnotes.com Intermittent Claudication Source: Healthnotes, Inc. www.healthnotes.com Intermittent Claudication Alternative names: Peripheral Vascular Disease Source: Prima Communications, Inc.www.personalhealthzone.com Ménière's Disease Source: Healthnotes, Inc. www.healthnotes.com Macular Degeneration Source: Prima Communications, Inc.www.personalhealthzone.com Menopausal Symptoms (Other Than Osteoporosis) Source: Prima Communications, Inc.www.personalhealthzone.com Menopause Source: Integrative Medicine Communications; www.drkoop.com Multiple Sclerosis Source: Healthnotes, Inc. www.healthnotes.com Multiple Sclerosis Source: Integrative Medicine Communications; www.drkoop.com Myocardial Infarction Source: Integrative Medicine Communications; www.drkoop.com Parkinson's Disease Source: Integrative Medicine Communications; www.drkoop.com Peripheral Vascular Disease Source: Healthnotes, Inc. www.healthnotes.com Scleroderma Source: Integrative Medicine Communications; www.drkoop.com Sickle Cell Anemia Source: Healthnotes, Inc. www.healthnotes.com Stroke Source: Healthnotes, Inc. www.healthnotes.com Stroke Source: Integrative Medicine Communications; www.drkoop.com

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Stroke, Transient Source: Integrative Medicine Communications; www.drkoop.com Systemic Lupus Erythematosus Source: Healthnotes, Inc. www.healthnotes.com TIAs Source: Integrative Medicine Communications; www.drkoop.com Transient Ischemic Attacks Source: Integrative Medicine Communications; www.drkoop.com Urinary Incontinence Source: Integrative Medicine Communications; www.drkoop.com Uveitis Source: Integrative Medicine Communications; www.drkoop.com •

Alternative Therapy Apitherapy Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,669,00.html Cell Therapy Source: Healthnotes, Inc. www.healthnotes.com Chelation Therapy Source: Healthnotes, Inc. www.healthnotes.com Chelation therapy Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,679,00.html Feldenkrais Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,695,00.html Homeopathy Source: Integrative Medicine Communications; www.drkoop.com Meditation Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,717,00.html Myotherapy Source: WholeHealthMD.com, LLC. www.wholehealthmd.com

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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,931,00.html Nutrition Source: Integrative Medicine Communications; www.drkoop.com Reiki Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,731,00.html Tai chi Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,737,00.html Traditional Chinese medicine Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10085,00.html •

Herbs and Supplements Aesculus Alternative names: Horse Chestnut; Aesculus hippocastanum L. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org ALA Source: Integrative Medicine Communications; www.drkoop.com Alfalfa Alternative names: Medicago sativa Source: Healthnotes, Inc. www.healthnotes.com Allium sativum Source: Integrative Medicine Communications; www.drkoop.com Alpha-Linolenic Acid (ALA) Source: Integrative Medicine Communications; www.drkoop.com Amantadine Source: Healthnotes, Inc. www.healthnotes.com Amiloride Source: Healthnotes, Inc. www.healthnotes.com Ananas comosus Source: Integrative Medicine Communications; www.drkoop.com Angelica sinensis Source: Integrative Medicine Communications; www.drkoop.com

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Anticonvulsants Source: Healthnotes, Inc. www.healthnotes.com Antioxidants and Free Radicals Source: Healthnotes, Inc. www.healthnotes.com Aortic Glycosaminoglycans Source: Prima Communications, Inc.www.personalhealthzone.com Arginine Source: Prima Communications, Inc.www.personalhealthzone.com Arginine Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10005,00.html Astragalus Source: Prima Communications, Inc.www.personalhealthzone.com Baclofen Source: Healthnotes, Inc. www.healthnotes.com BCAAs Source: Prima Communications, Inc.www.personalhealthzone.com B-carotene Source: Integrative Medicine Communications; www.drkoop.com Beta-Carotene Source: Healthnotes, Inc. www.healthnotes.com Beta-Carotene Alternative names: b-carotene, Trans-beta Carotene; Provitamin A, Betacarotenum Source: Integrative Medicine Communications; www.drkoop.com Betacarotenum Source: Integrative Medicine Communications; www.drkoop.com Beta-Sitosterol Source: Healthnotes, Inc. www.healthnotes.com Bilberry Alternative names: Vaccinium myrtillus Source: Healthnotes, Inc. www.healthnotes.com Bilberry Source: Prima Communications, Inc.www.personalhealthzone.com Branched-Chain Amino Acids Source: Healthnotes, Inc. www.healthnotes.com

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Bromelain Alternative names: Ananas comosus, Bromelainum Source: Integrative Medicine Communications; www.drkoop.com Bromelainum Source: Integrative Medicine Communications; www.drkoop.com Butcher’s Broom Alternative names: Ruscus aculeatus Source: Healthnotes, Inc. www.healthnotes.com Calciferol Source: Integrative Medicine Communications; www.drkoop.com Calcitrol Source: Integrative Medicine Communications; www.drkoop.com Cat’s Claw Alternative names: Uncaria tomentosa Source: Healthnotes, Inc. www.healthnotes.com Centella Alternative names: Gotu Kola; Centella asiatica (Linn.) Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Cephalosporins Source: Integrative Medicine Communications; www.drkoop.com Cherry fruit extract Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10015,00.html Chinese Angelica Source: Integrative Medicine Communications; www.drkoop.com Cholecalciferol Source: Integrative Medicine Communications; www.drkoop.com Cholesterol-Lowering Drugs Source: Healthnotes, Inc. www.healthnotes.com Clopidogrel Source: Healthnotes, Inc. www.healthnotes.com Coenzyme Q Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,768,00.html Colloidal Silver Source: Healthnotes, Inc. www.healthnotes.com

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Conjugated Linoleic Acid Source: Healthnotes, Inc. www.healthnotes.com Cornus Alternative names: Dogwood; Cornus florida & officinalis Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Crataegus Alternative names: Hawthorn; Crataegus oxyacantha L. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Crataegus laevigata Source: Integrative Medicine Communications; www.drkoop.com Crataegus monogyna Source: Integrative Medicine Communications; www.drkoop.com Danggui Alternative names: Angelica sinensis, Chinese Angelica, Dang Gui, Danngui, Dong Qua, Tang Kuei, Tan Kue Bai zhi(Note: Dong quai should not be confused with Angelica root or Angelica seed.) Source: Integrative Medicine Communications; www.drkoop.com Dehydroepiandrosterone (DHEA) Source: Healthnotes, Inc. www.healthnotes.com Dehydroepiandrosterone (DHEA) Source: Integrative Medicine Communications; www.drkoop.com DHEA Source: Integrative Medicine Communications; www.drkoop.com Diuretics Source: Healthnotes, Inc. www.healthnotes.com Dong Quai Alternative names: Angelica sinensis, Chinese Angelica, Dang Gui, Danngui, Dong Qua, Tang Kuei, Tan Kue Bai zhi(Note: Dong quai should not be confused with Angelica root or Angelica seed.) Source: Integrative Medicine Communications; www.drkoop.com Echinacea Alternative names: Echinacea purpurea, Echinacea angustifolia, Echinacea pallida Source: Healthnotes, Inc. www.healthnotes.com Echinacea Alternative names: Echinacea angustifolia, Echinacea pallida, Echinacea purpurea, Purple Coneflower Source: Integrative Medicine Communications; www.drkoop.com

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Echinacea Source: Prima Communications, Inc.www.personalhealthzone.com Echinacea Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,775,00.html Echinacea angustifolia Source: Integrative Medicine Communications; www.drkoop.com Echinacea pallida Source: Integrative Medicine Communications; www.drkoop.com Echinacea purpurea Source: Integrative Medicine Communications; www.drkoop.com EDTA Source: Integrative Medicine Communications; www.drkoop.com Erocalciferol Source: Integrative Medicine Communications; www.drkoop.com Ethylenediaminetetraacetic Acid (EDTA) Source: Integrative Medicine Communications; www.drkoop.com Fenofibrate Source: Healthnotes, Inc. www.healthnotes.com Fenugreek Alternative names: Trigonella foenum-graecum Source: Healthnotes, Inc. www.healthnotes.com Fiber Source: Healthnotes, Inc. www.healthnotes.com Flavonoids Source: Healthnotes, Inc. www.healthnotes.com Flaxseed Alternative names: Linum usitatissimum, Linseed Source: Integrative Medicine Communications; www.drkoop.com Fo-Ti Alternative names: Polygonum multiflorum Source: Healthnotes, Inc. www.healthnotes.com Ginger Alternative names: Zingiber officinale Source: Healthnotes, Inc. www.healthnotes.com

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Ginger Source: Prima Communications, Inc.www.personalhealthzone.com Ginkgo Alternative names: Ginkgo biloba Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Ginkgo Source: Prima Communications, Inc.www.personalhealthzone.com Ginkgo Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Ginkgo biloba Source: Healthnotes, Inc. www.healthnotes.com Ginkgo biloba Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,788,00.html Glutamic Acid Source: Healthnotes, Inc. www.healthnotes.com Grape Seed Alternative names: Vitis vinifera Source: Integrative Medicine Communications; www.drkoop.com Green Tea Alternative names: Camellia sinensis Source: Healthnotes, Inc. www.healthnotes.com Guggul Alternative names: Commiphora mukul Source: Healthnotes, Inc. www.healthnotes.com Gugulipid Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10033,00.html Hawthorn Alternative names: Crataegus monogyna, Crataegus laevigata Source: Integrative Medicine Communications; www.drkoop.com Hawthorn Source: Prima Communications, Inc.www.personalhealthzone.com Hibiscus Alternative names: Hibiscus, Roselle; Hibiscus sp. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org

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Inhalant, Systemic, and Topical Corticosteroids Source: Integrative Medicine Communications; www.drkoop.com Interferon Source: Healthnotes, Inc. www.healthnotes.com Linden Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Linseed Source: Integrative Medicine Communications; www.drkoop.com Linum usitatissimum Source: Integrative Medicine Communications; www.drkoop.com Loop Diuretics Source: Healthnotes, Inc. www.healthnotes.com Lutein Source: Prima Communications, Inc.www.personalhealthzone.com Lycopene Source: Healthnotes, Inc. www.healthnotes.com Melatonin Source: Healthnotes, Inc. www.healthnotes.com Melatonin Source: Integrative Medicine Communications; www.drkoop.com Melatonin Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,804,00.html Menadione Source: Integrative Medicine Communications; www.drkoop.com Menaphthone Source: Integrative Medicine Communications; www.drkoop.com Menaquinone Source: Integrative Medicine Communications; www.drkoop.com Methionine Source: Healthnotes, Inc. www.healthnotes.com Methionine Source: WholeHealthMD.com, LLC. www.wholehealthmd.com

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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10084,00.html NAC (N-acetylcysteine) Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,809,00.html Olive Leaf Alternative names: Olea europa Source: Healthnotes, Inc. www.healthnotes.com OPCs (Oligomeric Proanthocyanidins) Source: Prima Communications, Inc.www.personalhealthzone.com Phenylalanine Source: Integrative Medicine Communications; www.drkoop.com Phylloquinone Source: Integrative Medicine Communications; www.drkoop.com Progesterone Source: Healthnotes, Inc. www.healthnotes.com Psyllium Alternative names: Plantago ovata, Plantago ispaghula Source: Healthnotes, Inc. www.healthnotes.com Purple Coneflower Source: Integrative Medicine Communications; www.drkoop.com Red Clover Alternative names: Trifolium pratense , beebread, cow clover, cow grass, meadow clover, purple clover Source: Integrative Medicine Communications; www.drkoop.com Reishi Alternative names: Ganoderma lucidum Source: Healthnotes, Inc. www.healthnotes.com Resveratrol Source: Healthnotes, Inc. www.healthnotes.com Resveratrol Source: Prima Communications, Inc.www.personalhealthzone.com Rosemary Alternative names: Rosmarinus officinalis Source: Healthnotes, Inc. www.healthnotes.com Royal Jelly Source: Healthnotes, Inc. www.healthnotes.com

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Ruta Alternative names: Rue; Ruta graveolens L. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org SAMe Source: Healthnotes, Inc. www.healthnotes.com Siberian ginseng Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,821,00.html Tang Kuei Source: Integrative Medicine Communications; www.drkoop.com Taurine Source: Prima Communications, Inc.www.personalhealthzone.com Terminalia Alternative names: Myrobalans; Terminalia arjuna Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Thiazide Diuretics Source: Healthnotes, Inc. www.healthnotes.com Ticlopidine Source: Healthnotes, Inc. www.healthnotes.com TMG (Trimethylglycine) Source: Prima Communications, Inc.www.personalhealthzone.com Tocotrienols Source: Healthnotes, Inc. www.healthnotes.com Trans-Beta-Carotene Source: Integrative Medicine Communications; www.drkoop.com Triamterene Source: Healthnotes, Inc. www.healthnotes.com Turmeric Alternative names: Curcuma longa Source: Healthnotes, Inc. www.healthnotes.com Valproic Acid Source: Healthnotes, Inc. www.healthnotes.com Vitis vinifera Source: Integrative Medicine Communications; www.drkoop.com

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Warfarin Source: Healthnotes, Inc. www.healthnotes.com Zingiber Alternative names: Ginger; Zingiber officinale Roscoe Source: Alternative Medicine Foundation, Inc. www.amfoundation.org

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 4. DISSERTATIONS ON SCLEROSIS Overview In this chapter, we will give you a bibliography on recent dissertations relating to sclerosis. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “sclerosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on sclerosis, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Sclerosis ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to sclerosis. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

A History of Multiple Sclerosis and Medicine in the United States, 1870-1960 by Talley, Colin Lee, Phd from University of California, San Francisco, 1998, 257 pages http://wwwlib.umi.com/dissertations/fullcit/9903313

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A Meta-analysis of Multiple Sclerosis and Nonverbal Conceptual Reasoning Deficits by Bofill, Martha S. Psyd from Carlos Albizu University, 2002, 74 pages http://wwwlib.umi.com/dissertations/fullcit/3057609

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A Term by any Other Name: Bizarreness, Acceptability, Naturalness and Normalcy Judgments of Speakers with Amyotrophic Lateral Sclerosis by Southwood, Mary Helen, Phd from The University of Wisconsin - Madison, 1990, 295 pages http://wwwlib.umi.com/dissertations/fullcit/9101565

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An Investigation of Stress and Personality Factors Associated with Multiple Sclerosis by Ashlock, Larry Edward, Phd from University of Missouri - Kansas City, 1981, 103 pages http://wwwlib.umi.com/dissertations/fullcit/8207600

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Anti-dna Topoisomerase I Specific Autoimmune Response in Systemic Sclerosis Patients and Healthy Controls by Hu, Paul Qingru; Phd from University of Pittsburgh, 2002, 171 pages http://wwwlib.umi.com/dissertations/fullcit/3054291

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Biophysical Nmr Studies of Stellacyanin, the Copper Chaperone for Copper-zinc Superoxide Dismutase, and Mutant Copper-zinc Superoxide Dismutase G93a with Implication for Its Association with Amyotrophic Lateral Sclerosis by Shipp, Eric L. Phd from University of California, Los Angeles, 2002, 122 pages http://wwwlib.umi.com/dissertations/fullcit/3078114

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Biophysical Studies of Human Copper-zinc Superoxide Dismutases: an Examination of Their Role in the Neurodegenerative Disease, Familial Amyotrophic Lateral Sclerosis (fals) by Malek, Kevin N. Phd from University of California, Los Angeles, 2002, 124 pages http://wwwlib.umi.com/dissertations/fullcit/3063924

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Caregiving in Chronic Illness: the Experience of Married Persons Whose Spouses Have Ms (multiple Sclerosis) by Miller, Deborah Mary, Phd from Case Western Reserve University, 1990, 183 pages http://wwwlib.umi.com/dissertations/fullcit/9110775

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Cellular Mechanisms of Muscle Weakness and Fatigability in Individuals with Multiple Sclerosis by Garner, Dena J. P. Phd from Oregon State University, 2002, 76 pages http://wwwlib.umi.com/dissertations/fullcit/3056550

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Changing Activity Space of Persons with Multiple Sclerosis by Thapar, Neela; Phd from Kent State University, 1999, 295 pages http://wwwlib.umi.com/dissertations/fullcit/9963724

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Chlamydia Pneumoniae in Aortic Valve Sclerosis and Thoracic Aortic Disease: Aspects on Pathogenesis and Therapy by Nystrom-rosander, Christina; Phd from Uppsala Universitet (sweden), 2002, 65 pages http://wwwlib.umi.com/dissertations/fullcit/f660833

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Cognitive Flexibility and Empathy in Individuals with Multiple Sclerosis by Wickie, Susanne Kay; Phd from University of Missouri - Saint Louis, 2002, 76 pages http://wwwlib.umi.com/dissertations/fullcit/3046103

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Coping Strategies of Multiple Sclerosis Patients and Their Families by Stauber, Donna Beth, Phd from Texas Woman's University, 1993, 97 pages http://wwwlib.umi.com/dissertations/fullcit/9417364

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Coping with Multiple Sclerosis: the Role of Negative Affectivity (physical Disability) by Malone, June S., Phd from University of Illinois at Urbana-champaign, 1991, 220 pages http://wwwlib.umi.com/dissertations/fullcit/9210906

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Delineation of Elements of a Sexuality Program for Individuals with Multiple Sclerosis Through a Needs Assessment by Teske, Ann Engelhardt, Phd from The Ohio State University, 1980, 173 pages http://wwwlib.umi.com/dissertations/fullcit/8100266

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Disability Progression in Multiple Sclerosis in a Nova Scotia Cohort by Richard, Julie Carla; Msc from Dalhousie University (canada), 2002, 82 pages http://wwwlib.umi.com/dissertations/fullcit/MQ67536

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Effect of Gender, Age, and Disease Progression on Emotional Adjustment in Multiple Sclerosis Patients by Nichols, Eric Charles, Phd from Arizona State University, 1984, 129 pages http://wwwlib.umi.com/dissertations/fullcit/8504252

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Elucidating the Molecular Mechanisms of Sod1-linked Familial Amyotrophic Lateral Sclerosis by Wang, Jiou; Phd from The Johns Hopkins University, 2002, 89 pages http://wwwlib.umi.com/dissertations/fullcit/3046575

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Evaluation of a Test for Contrast Letter Acuity for Inclusion in the Multiple Sclerosis Functional Composite by Baier, Monika Luise; Phd from University of Colorado Health Sciences Center, 2002, 152 pages http://wwwlib.umi.com/dissertations/fullcit/3069578

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Exercising Control in the Face of Uncertainty: Multiple Sclerosis and Other Chronic Illnesses by Lopez, Mary Diana; Phd from Northwestern University, 2001, 242 pages http://wwwlib.umi.com/dissertations/fullcit/3012032

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Explanatory Models of Women with Multiple Sclerosis by Farra, Linda Karen, Phd from University of Pennsylvania, 1997, 182 pages http://wwwlib.umi.com/dissertations/fullcit/9800861

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Factors Affecting the Design and Evaluation of an Online Site for Care Givers of Individuals with Multiple Sclerosis by Velazquez, Lynn W., Edd from Pepperdine University, 1998, 132 pages http://wwwlib.umi.com/dissertations/fullcit/9832281

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Gene Therapy for Motor Neuron Degeneration in Murine Tissue Culture and Transgenic Mouse Models of Familial Amyotrophic Lateral Sclerosis by Roehmholdt, Brian Francis; Phd from University of Southern California, 2002, 188 pages http://wwwlib.umi.com/dissertations/fullcit/3073841

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Genetic and Epidemiologic Aspects of Multiple Sclerosis in British Columbia by Sadovnick, Adele D; Phd from The University of British Columbia (canada), 1980 http://wwwlib.umi.com/dissertations/fullcit/NK50042

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Growing Up with a Parent Who Has Multiple Sclerosis: a Micro-historical Sociological Perspective (disabilities) by Blackford, Karen A., Phd from York University (canada), 1995, 318 pages http://wwwlib.umi.com/dissertations/fullcit/NN03793

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Healing from Within: the Effect of an Educational Program on Adjustment and Knowledge in Women with Multiple Sclerosis by Doughty, Jhan Deneen; Ded from The Pennsylvania State University, 2001, 130 pages http://wwwlib.umi.com/dissertations/fullcit/3014617

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Immunopharmacological Aspects of Methylprednisolone and Interferon-beta Therapies in Multiple Sclerosis by Boylan, Michael Terence; Phd from Queen's University of Belfast (northern Ireland), 2002, 330 pages http://wwwlib.umi.com/dissertations/fullcit/f657857

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Impact of Multiple Sclerosis on Marital Life by Grant, Lynda Carol, Phd from University of Alberta (canada), 1997, 249 pages http://wwwlib.umi.com/dissertations/fullcit/NQ21573

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Individuals Living with Multiple Sclerosis: Factors Contributing to the Maintenance of Pre-existing Friendships by Pinto, Louis P. Ms from D'youville College, 2002, 132 pages http://wwwlib.umi.com/dissertations/fullcit/1410119

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Information Seeking Behaviors of Persons with Multiple Sclerosis (patient Education) by Phillips, Kathleen Marie, Phd from Northwestern University, 1986, 143 pages http://wwwlib.umi.com/dissertations/fullcit/8621849

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Literacy As an Ongoing System of Support during the Lifetime of an Individual Diagnosed with Multiple Sclerosis by Mckimmey, Martha Anne Stovall, Phd from Texas Woman's University, 1995, 236 pages http://wwwlib.umi.com/dissertations/fullcit/9601173

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Maximal Exercise Performance of Individuals with Multiple Sclerosis: Influence of Disease-related Muscular- and Temperature-induced Dysfunction (muscular-induced Dysfunction) by Ponichtera, Janet Ann, Phd from The University of Connecticut, 1989, 170 pages http://wwwlib.umi.com/dissertations/fullcit/9019366

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Mechanisms That Mediate the Secretion of Chemokines by Human Microglia: Implications for Hiv-1 Encephalitis and Multiple Sclerosis (immune Deficiency) by D'aversa, Teresa Giulia; Phd from Yeshiva University, 2002, 236 pages http://wwwlib.umi.com/dissertations/fullcit/3047283

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Memory Function in Multiple Sclerosis by Shaw, Patricia Noreen; Phd from University of Alberta (canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL42966

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Mothers with Multiple Sclerosis: Their Perceptions of the Effects of Physical Disability on Parenting by Monroe, Gail Nadine, Edd from University of San Francisco, 1988, 121 pages http://wwwlib.umi.com/dissertations/fullcit/8820729

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Multiple Sclerosis and Estrogen: the Role of Lifelong Estrogen Exposure in Disease Course and Cognition by Showalter, Shelley M. Phd from Fuller Theological Seminary, School of Psychology, 2002, 188 pages http://wwwlib.umi.com/dissertations/fullcit/3046370

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Narrative Use in Communities of Learners: Reconstructing Wellness in Persons with Multiple Sclerosis by Neufeld, Peggy Strecker; Phd from Washington University, 2002, 215 pages http://wwwlib.umi.com/dissertations/fullcit/3065077

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Probabilistic Models of the Natural History of Multiple Sclerosis by Wolfson, Christina; Phd from Mcgill University (canada), 1985 http://wwwlib.umi.com/dissertations/fullcit/NL20845

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Proton Spin Relaxation As a Means of Characterizing the Pathology of Multiple Sclerosis by Stewart, Wendy Anne; Phd from The University of British Columbia (canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL50843

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Psychological Stress, Coping, and Illness Uncertainty in Individuals with Multiple Sclerosis: Relationship with Cytokine Production by Sorenson, Matthew Robert; Phd from Loyola University of Chicago, 2002, 181 pages http://wwwlib.umi.com/dissertations/fullcit/3039306

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Psychophysiological Assessment of Raynaud's Patients with Progressive Systemic Sclerosis by Belanger Varhely, Muriel; Phd from Universite Laval (canada), 1985 http://wwwlib.umi.com/dissertations/fullcit/NL25341

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Regulation of in Vitro Immunoglobulin Secretion in Healthy Individuals and Multiple Sclerosis Patients by O'gorman, Maurice R. G; Phd from The University of British Columbia (canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL47405

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Resources for Emotional Adjustment of Mulitple Sclerosis Patients by Rodgers, Jennifer; Phd from University of Alberta (canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL42963

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Resources for Emotional Adjustment of Multiple Sclerosis Patients by Rodgers, Jennifer Kaye, Phd from University of Alberta (canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/f44629

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Self-care Behavior of Persons with Multiple Sclerosis in Denmark: Development of a Behavioral Instrument by Mclaughlin, Judith Francis, Phd from Southern Illinois University at Carbondale, 1981, 270 pages http://wwwlib.umi.com/dissertations/fullcit/8120687

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Self-directed Learning by Family Members of Individuals with Multiple Sclerosis by Francabandera, Frances Louise, Edd from Columbia University Teachers College, 1992, 283 pages http://wwwlib.umi.com/dissertations/fullcit/9228464

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Self-directed Learning by Individuals with Multiple Sclerosis (adaptive Behavior) by Holland, Nancy Joyce, Edd from Columbia University Teachers College, 1992, 279 pages http://wwwlib.umi.com/dissertations/fullcit/9228482

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The Association of Human Herpesvirus Type 6 (hhv-6) and Multiple Sclerosis (ms): Increased Hhv-6 Specific Immune Responses, Detection of Cell Free Serum Hhv-6 Dna, and Elevated Serum Soluble Hhv-6 Receptor in Ms by Soldan, Samantha Standish; Phd from The George Washington University, 2002, 212 pages http://wwwlib.umi.com/dissertations/fullcit/3032769

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The Construction of Reality Through Language: Women Living with Multiple Sclerosis by London, Deborah Kaye; Phd from Ohio University, 2001, 114 pages http://wwwlib.umi.com/dissertations/fullcit/3007463

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The Digital Manipulation of Vowel Formant Frequencies for Persons with Amyotrophic Lateral Sclerosis by Richter, Melanie May; Phd from The University of Nebraska - Lincoln, 2002, 174 pages http://wwwlib.umi.com/dissertations/fullcit/3059967

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The Effect of Mutant Superoxide Dismutase 1 (sod1) on Cognitive Behavior in the Transgenic Model of Amyotrophic Lateral Sclerosis (als) by Murphy, Peregrine L. Phd from City University of New York, 2002, 186 pages http://wwwlib.umi.com/dissertations/fullcit/3037427

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The Effects of Balance Training on Persons with Multiple Sclerosis by Jackson, Kurt Jerome; Phd from The Union Institute, 2002, 73 pages http://wwwlib.umi.com/dissertations/fullcit/3037915

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The Effects of Multiple Sclerosis on Work and Benefit Decisions by Kulas, Elizabeth Diane, Phd from Duke University, 1998, 206 pages http://wwwlib.umi.com/dissertations/fullcit/9839456

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The Evaluation of Multiple Sclerosis Through Static Chromatic Perimetry by Kozak, John Francis; Phd from The University of British Columbia (canada), 1987 http://wwwlib.umi.com/dissertations/fullcit/NL40083

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The Experience of Teaching with Multiple Sclerosis: an Emerging Blend of Theory with Practice by Flockhart, Katherine Marie (katie); Edd from University of Toronto (canada), 2001, 212 pages http://wwwlib.umi.com/dissertations/fullcit/NQ63574

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The Information Needs and Information-seeking Patterns of Women Coping with and Adjusting to Multiple Sclerosis by Baker, Lynda Mary, Phd from The University of Western Ontario (canada), 1994, 251 pages http://wwwlib.umi.com/dissertations/fullcit/NN93194

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The Lives of Adults with Multiple Sclerosis: a Comparative and Descriptive Study of Hope and Denial by Guerra, Francesco, Phd from The University of Michigan, 1986, 297 pages http://wwwlib.umi.com/dissertations/fullcit/8702741

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The Management of Chronic Illness: an Interactionist Investigation of Experiences with Multiple Sclerosis (support Groups) by Coleman, Patty Ann, Phd from Bryn Mawr College, the Grad. Sch. of Social Work and Social Research, 1989, 181 pages http://wwwlib.umi.com/dissertations/fullcit/9015033

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The Metabolism of Endogenous Compounds by Familial Amyotrophic Lateral Sclerosis Mutant Copper, Zinc-superoxide Dismutases by Johnson, Michael Alfred; Phd from University of Virginia, 2002, 135 pages http://wwwlib.umi.com/dissertations/fullcit/3057482

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The Relationship of Type a Behavior Patterns to Scores on Beck's Hopelessness Scale and to Varying Vital Statistics of a Sample Population of Multiple Sclerosis Patients by Kinney, Brenda M., Edd from The University of Memphis, 1997, 113 pages http://wwwlib.umi.com/dissertations/fullcit/9822840

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The Roles of Cognition and Mood in Psychosocial Adjustment to Multiple Sclerosis by Usiskin, Julie Bullard; Phd from The American University, 2003, 65 pages http://wwwlib.umi.com/dissertations/fullcit/3087069

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The Sociocultural Impact of Multiple Sclerosis. by Stewart, David C., Phd from University of California, Berkeley, 1979, 183 pages http://wwwlib.umi.com/dissertations/fullcit/8000590

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The Use of Biofeedback in the Treatment of Ataxic Dysarthria in Individuals with Multiple Sclerosis: a Pilot Study by Maddava, Karuna; Ms from Rush University, 2002, 161 pages http://wwwlib.umi.com/dissertations/fullcit/1407671

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The Use of Complementary and Alternative Medicine by People with Multiple Sclerosis by Page, Stacey Ann; Phd from University of Calgary (canada), 2002, 206 pages http://wwwlib.umi.com/dissertations/fullcit/NQ77033

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Theory and Application of Optimal Linear Resolution to Mri Truncation Artifacts, Multiexponential Decays and in Vivo Multiple Sclerosis Pathology by Cover, Keith S; Phd from The University of British Columbia (canada), 2002, 146 pages http://wwwlib.umi.com/dissertations/fullcit/NQ73265

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Tuberous Sclerosis: Clinical Factors in Long-term Outcome by Hancock, Eleanor Catherine; Md from University of Bath (united Kingdom), 2003, 252 pages http://wwwlib.umi.com/dissertations/fullcit/f113793

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Visual Adaptation in Multiple Sclerosis by Raymond, Jane Eula; Phd from Dalhousie University (canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK48245

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 5. CLINICAL TRIALS AND SCLEROSIS Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning sclerosis.

Recent Trials on Sclerosis The following is a list of recent trials dedicated to sclerosis.8 Further information on a trial is available at the Web site indicated. •

A Multi-Center Phase III Trial of Minocycline in Amyotrophic Lateral Sclerosis Condition(s): Amyotrophic Lateral Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: The purpose of this trial is to test the safety, tolerability, and effectiveness of minocycline compared to placebo in patients with amyotrophic lateral sclerosis (ALS). Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00047723

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A Phase II Study Comparing Low- and High-Dose CAMPATH and High-Dose Rebif in Patients With Early, Active Relapsing-Remitting Multiple Sclerosis Condition(s): Multiple Sclerosis, Relapsing-Remitting Study Status: This study is currently recruiting patients. Sponsor(s): ILEX Pharmaceuticals

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These are listed at www.ClinicalTrials.gov.

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Purpose - Excerpt: This is a Phase II, randomized, open-label, three-arm study comparing low-and high-dose CAMPATH and high-dose Rebif in patients with early, active relapsing-remitting Multiple Sclerosis (MS) who have not been previously treated with immunotherapies other than steroids. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00050778 •

Antibiotic treatment trial directed against Chlamydia pneumonia in multiple sclerosis Condition(s): Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); National Multiple Sclerosis Society Purpose - Excerpt: Multiple sclerosis (MS) is an inflammatory, demyelinating disease which affects the central nervous system (CNS). The etiology of MS is unknown, although the immune system appears to play a role. Many different infectious agents have been proposed as potential causes for MS, including Epstein-Barr virus, human herpesvirus 6, and coronaviruses. Recently Dr. Sriram at Vanderbilt University has found evidence for active Chlamydia pneumonia infection in the CNS of MS patients. These findings have been replicated in part by other laboratories. The purpose of the current study is to test whether antibiotic treatment aimed at eradicating Chlamydia infection will reduce the disease activity in MS. The primary outcome measure will be reduction in new enhancing MS lesions on brain MRI. Forty patients will be entered into the trial. To be eligible, patients must have evidence of chlamydia infection in their spinal fluid and enhancing lesions on their pre-randomization MRI scans. Patients who meet these criteria will be randomized to either placebo or antibiotic therapy, and followed for 6 months on treatment. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00043264

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Assessment of Patients with Multiple Sclerosis (MS) Condition(s): Herpesviridae Infection; HTLV-I Infection; Multiple Sclerosis; Tropical Spastic Paraparesis; Vasculitis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: Multiple sclerosis (MS) is a disease of the nervous system. The exact cause of MS is unknown, but it is believed to be an autoimmune condition. Autoimmune conditions are diseases that cause the body's immune system and natural defenses to attack healthy cells. In the case of MS, the immune system begins attacking myelin, the cells that make up the sheath covering nerves. Without myelin, nerves are unable to transmit signals effectively and symptoms occur. This study is directed

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toward a better understanding of the cause of Multiple Sclerosis (MS). Researchers will evaluate patients with a tentative diagnosis of MS or other neurological diseases possibly caused by a immunological reaction. Patients will undergo a series of three MRIs, taken once a month for three months and submit blood samples for immunological studies. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001156 •

Auditory Function in Patients With and Without Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): Department of Veterans Affairs Rehabilitation Research and Development Service Purpose - Excerpt: We propose to evaluate auditory function and neuropsychologic function in 150 Multiple Sclerosis (MS) patients and in 150 patients who do not have MS. Experimental subjects will be recruited by selecting patients with a verified diagnosis of MS from the registry of patients established by the Oregon Health Sciences University, Multiple Sclerosis Research Center. Control subjects will be matched with respect to age, to gender and to audiometric configuration. Phase(s): Phase II Study Type: Interventional Contact(s): David Lilly 503-220-8262 [email protected] Web Site: http://clinicaltrials.gov/ct/show/NCT00037947

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Autologous Stem Cell Transplant For Systemic Sclerosis Condition(s): Scleroderma, Systemic Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); University of Pittsburgh Cancer Institute; Amgen; Sangstat Medical Corporation Purpose - Excerpt: Patients with systemic sclerosis undergo tests,sign informed consent. Patients are admitted to hospital for a day of chemotherapy. Patients go home and receive a shot of G-CSF for about 10 days, then a procedure called Leukapheresis begins and is done as outpatient for up to 4 days. Chemotherapy is given for 5 days. The doses of chemotherapy will be increased after every three patients if there are no serious side effects. Thymoglobulin, an immunosuppressing drug, will be given for 3 days. On day 0 patient receive infusion of stem cells. It will take 2-4 weeks to recover from side effects of this treatment. Patient Involvement:Patients must be stay in the Pittsburgh area for their treatment, are required to use appropriate birth control to prevent pregnancy.Patients will have blood sample 16 times during first 2 years of treatment and return to Pittsburgh 12, 18, and 24 months after the transplant to be evaluated and to give blood samples. Phase(s): Phase I Study Type: Interventional

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00040651 •

Clinical Trial of Creatine in Amyotrophic Lateral Sclerosis Condition(s): Amyotrophic Lateral Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: The objective of this study is to determine whether creatine slows disease progression in subjects with amyotrophic lateral sclerosis (ALS). ALS is a progressive uniformly lethal neurodegenerative disorder for which there is no known cure. Recent genetic and biochemical studies implicate free radical toxicity, glutamate excitotoxicity and mitochondrial dysfunction as possible causes of familial ALS (FALS) and sporadic ALS (SALS). It has been hypothesized that in ALS there may be involvement of oxidative free radical damage and impaired mitochondrial energy metabolism that could in turn lead to excitotoxic cell death. Creatine, an agent that improves mitochondrial function, has been shown to be neuroprotective in animal models of ALS and Huntington's disease. This study is a double-blind, randomized, placebo-controlled trial of the safety and efficacy of creatine in patients with ALS enrolled at sites distributed throughout the United States, including Northeast ALS (NEALS) sites. The study will provide preliminary data on the safety and efficacy of creatine in ALS. If creatine slows disease progression in ALS and is well tolerated, a phase 3 study with survival as the primary outcome measure will be initiated. 114 eligible subjects will be randomized to receive treatment for 6 months of (1) active creatine or (2) placebo. After randomization, subjects will be followed prospectively for 6 months. The primary outcome measure for the study is the change in upper extremity motor function after 6 months of experimental therapy as tested with the Tufts Quantitative Neuromuscular Exam. Strength in eight arm muscles will be measured (bilateral shoulder and elbow flexion and extension). Secondary outcome measures include grip strength, motor unit number estimates (MUNE), the ALS functional rating score-revised (ALSFRS-R), and rate of change of a well established biochemical marker of oxidative damage to DNA (8OH2'dG levels in urine), and the safety and tolerability of creatine. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005766

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Clinical trial of creatine in amyotrophic lateral sclerosis [ALS] Condition(s): Amyotrophic Lateral Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Muscular Dystrophy Association Purpose - Excerpt: The purpose of this study is to evaluate the safety and effectiveness of creatine treatment in amyotrophic lateral sclerosis (ALS). There is currently no known effective treatment for ALS. It is known that nerve cells die in the brains and spinal cords of patients with ALS but the cause of the cell death is unknown. It has been shown

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that there is overactive nerve activity due to increased levels of a chemical called glutamate and that there is abnormal cellular metabolism along with increased production of substance called "free radicals." Improving cellular metabolism and readjusting the activity of glutamate in the brain may be beneficial to ALS patients. Creatine is a naturally occurring compound, which improves energy metabolism in cells. Creatine has been given to patients with energy metabolism defects in their muscles, and to athletes. Creatine improves survival in a mouse model of ALS. Three human subjects with ALS have received creatine for up to six months without any side effects. Overall, creatine has been well tolerated and safe. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005674 •

Combination Therapy with Avonex and BiMonthly High Dose Intravenous Methotrexate in Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): MidAmerica Neuroscience Institute; Consultants in Neurology; Biogen Purpose - Excerpt: The participant will receive weekly intramuscular treatment with AVONEX(r) (interferon beta 1-a) and bi-monthly high dose intravenous methotrexate with Leucovorin rescue. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00037102

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Creatine For the Treatment of Amyotrophic Lateral Sclerosis Condition(s): Amyotrophic Lateral Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM); Office of Dietary Supplements (ODS) Purpose - Excerpt: Creatine is a naturally occurring chemical involved in the production of energy in muscle. Abnormalities in creatine have been linked to the progression of degenerative neuromuscular diseases such as amyotrophic lateral sclerosis (ALS, or Lou Gehrig's Disease). This study will test whether taking creatine can improve the symptoms of ALS. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00070993

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Evaluation of Lyme Disease: Clinical, Microbiological and Immunological Characteristics Condition(s): Chronic Disease; Healthy; Lyme Arthritis; Lyme Disease; Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This study will determine whether patients who have been infected with the Lyme bacteria, Borrelia burgdorferi, and treated with antibiotics still have the bacteria alive inside them and whether it is causing their symptoms. The information from this study may serve as a basis for developing stringent diagnostic criteria for Lyme disease and the establishment of future treatment trials. Individuals in the following categories may be eligible for this study: chronic Lyme disease; chronic Lyme arthritis; seropositive control (are infected with the bacteria that causes Lyme disease but do not have disease symptoms); recovered control (have been sick with Lyme disease but were treated successfully and are currently well); control with multiple sclerosis (patients with multiple sclerosis); and healthy volunteers. Patients in the chronic Lyme disease category must be between 13 and 65 years of age; all others must be between 18 and 65 years of age. Candidates will be screened with blood and urine tests. Participants will have a physical examination and the following tests: Blood tests Includes HLA-typing, a genetic test of immune system markers; Leukapheresis Collection of large numbers of white blood cells Whole blood is collected through a needle in an arm vein. The blood circulates through a machine that separates it into its components. The white cells are removed and the rest of the blood is returned to the body, either through the same needle used to draw the blood or through another needle in the other arm. (Alternatively, patients will 100 cc (about 7 tablespoons) of blood drawn.); Lumbar puncture (spinal tap) - Collection of cerebrospinal fluid (CSF, fluid that bathes the brain and spinal cord). A local anesthetic is administered and a needle is inserted in the space between the bones in the lower back where the cerebrospinal fluid circulates below the spinal cord. A small amount of fluid is collected through the needle; Magnetic resonance imaging (MRI) of the brain - Imaging of the brain using a strong magnetic field and radio waves instead of X-rays. During the scan, the patient lies on a table in a narrow cylinder containing a magnetic field. He or she can speak with a staff member via an intercom at all times during the procedure; Neuropsychologic testing; Some participants may also have a hearing test and urine collection. Participants whose test results are positive for Borrelia burgdorferi will be followed at NIH at intervals of 3 to 6 months until it is determined whether there is infection. Those who are infected will be offered treatment with the antibiotic ceftriaxone. Following treatment, patients will return to the NIH Clinical Center for follow-up visits 1 week after treatment and again at 3, 6 and 12 months. The lumbar puncture, hearing examination, blood and urine tests will be repeated at these visits to evaluate the response to treatment, and the leukapheresis will be repeated for research purposes. Patients whose MRI was abnormal during therapy will have a repeat MRI at the 3-month, 6-month and 1-year visits. All participants with chronic Lyme disease, chronic Lyme arthritis, seropositive controls and recovered controls may be reevaluated at intervals of 6 to 12 months. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001539

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Genetic Study of the FBN1 Gene and Fibrillin-1 Abnormalities in Choctaw Native Americans and Other Patients with Systemic Sclerosis Condition(s): Systemic Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); University of Texas Purpose - Excerpt: Objectives: I. Determine whether defects in fibrillin-1 cellular processing are present in the tsk1 mouse model that carries a known FBN1 gene rearrangement and in a population of Choctaw Native American patients with systemic sclerosis who have a strong genetic predisposition to the disease. II. Determine the ultrastructural features of fibrillin-1 in these patients. III. Screen the FBN1 gene for mutations beginning at the regions homologous to the tsk1 duplication and latent transforming growth factor binding proteins in these patients and in an unaffected Choctaw control group. IV. Determine the correlation between fibrillin-1 abnormalities and clinical presentation, autoantibodies, and ethnicity. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006393

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IGF-1/ALS Trial Condition(s): Amyotrophic Lateral Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: The purpose of this multicenter study is to determine if insulin-like growth factor-1 (IGF-I) slows the progressive weakness in amyotrophic lateral sclerosis (ALS) patients. Study participants will be followed for 2 years once enrolled. They will receive either placebo or the active IGF-I. Examinations will take place at approximately 6-month intervals. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00035815

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Improving Memory in Patients with Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Child Health and Human Development (NICHD); National Institute on Disability and Rehabilitation Research (Dept of Education) Purpose - Excerpt: People with multiple sclerosis (MS) suffer from cognitive and other brain problems. This study will examine the effectiveness of the drug donepezil and of sugar water for enhancing memory in individuals with MS. Donepezil (also known as Aricept) has been FDA approved for improving memory and learning in individuals with Alzheimer's disease. Phase(s): Phase IV Study Type: Interventional

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00062972 •

Magnetic Resonance Imaging (MRI) to Evaluate Activity of Multiple Sclerosis (MS) Condition(s): Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: Magnetic Resonance Imaging (MRI) is an advanced form of X-ray that uses magnetism to create pictures with excellent anatomical resolution. MRI is especially useful when studying the brain and nervous system. One type of MRI is done after a drug called gadolinium is injected into the vein. Gadolinium does not usually crossover from the bloodstream into the brain. However, when it does cross it can be seen by MRI. Therefore, when gadolinium is detected by MRI it means there has been some disruption of the barrier that normally exists between the blood and the brain. Researchers believe that a change in the blood-brain barrier is the first step in the development of new MS lesions. The overall goals of the study are to identify immunological processes that may contribute to the development of Multiple Sclerosis and to design specific therapies for the disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001248

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MR Perfusion Imaging and Hypercapnia (Increased Carbon Dioxide) to Study New Blood Vessel Formation in Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): Warren G Magnuson Clinical Center (CC) Purpose - Excerpt: This study will use magnetic resonance imaging (MRI) to examine and compare changes in blood flow and blood volume in the brains of normal volunteers and patients with multiple sclerosis (MS). Patients with MS-an inflammatory disease that attacks the brain and spine-may have new blood vessel formation (called angiogenesis) within the brain that may or may not contribute to the disease or help in repairing the brain. It is not known if these new vessels behave in the same way as the naturally occurring vessels. MRI uses a strong magnetic field and radio waves to generate brain images that provide information on brain chemistry, function, and blood flow. The results of this study may lead to a better understanding of MS. Healthy normal volunteers and patients with multiple sclerosis 18 years of age and older may be eligible for this study. Normal volunteers must have no history of signs or symptoms of central nervous system disease. Patients with MS will be recruited from the NIH Neuroimmunology MS clinic. All participants will undergo MRI. For this procedure, the subject lies still on a table that slides into a narrow metal cylinder (the MRI scanner). Scanning varies from 20 minutes to 3 hours, with most scans lasting between 45 and 90 minutes. During the scan, the subject wears earplugs to muffle loud knocking noises caused by electrical switching of the radio frequency circuits. The subject can communicate with the MRI staff at all times during the procedure. During the scan, the subject wears a mask and breathes in room air or air containing 6% carbon dioxide (CO2). (Room air contains approximately 0.04% CO2, which is about 150 times less than

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the 6% CO2. Air that is normally breathed out contains about 5% CO2.) Breathing 6% CO2 increases the amount of blood flow in the brain that can be measured using MRI. The total duration of a single 6 percent CO2 inhalation will not exceed 10 minutes. A catheter (thin plastic tube) is placed in a vein in the subject's arm before he or she enters the scanner. At some point during the scan, a contrast agent called gadolinium DTPA is injected into the vein through the catheter. This agent enables clearer images of the brain. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00064909 •

Phase I Study of High-Dose Cyclophosphamide and Total Body Irradiation With T Lymphocyte-Depleted Autologous Peripheral Blood Stem Cell or Bone Marrow Rescue in Patients With Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): Northwestern Memorial Hospital Purpose - Excerpt: Objectives: I. Determine the efficacy, in terms of disease progression, of high-dose cyclophosphamide and total body irradiation with T lymphocyte-depleted autologous peripheral blood stem cell or bone marrow rescue in patients with multiple sclerosis. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00017628

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Rolipram to Treat Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: This study will evaluate the safety, tolerability, and effect of the drug Rolipram on multiple sclerosis (MS). It will examine whether Rolipram can dampen the part of the immune response believed to lead to MS and reduce disease activity. Patient with multiple sclerosis who are between the ages of 18 and 65 may be eligible for this study. Candidates will be screened with a complete neurological and medical evaluation. Participants will complete three study phases-baseline, treatment and follow-up, as follows: Baseline (3 months) - Approximately four magnetic resonance imaging (MRI) scans will be obtained to assess MS activity. Participants with MS activity above a certain level will continue with the treatment phase. Treatment (8 months) Patients will take Rolipram tablets in increasing doses every 2 to 3 days for the first month of this phase until their individual maximum tolerated dose is established. Dosing will continue at that level for the rest of the treatment phase. Dosing is in the morning, midday and evening. Patients will be seen monthly in the clinic for examination and MRI scans. Follow-up - Participants will have monthly exams and MRIs for 3 months following the treatment phase, after which their participation in the study ends. Patients' monthly visits during treatment and follow-up include a

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neurological examination to assess disease status; MRI to assess brain changes; and blood and urine collection to monitor liver, kidney and other functions. In addition, a lumbar puncture (spinal tap) is done during the last month of the baseline phase and one month after treatment ends to study changes in the spinal fluid surrounding the brain and spinal cord, and leukapheresis is done once during the last month of the baseline phase and once during the last month of treatment to collect white blood cells for study. These procedures involve the following: MRI uses a strong magnetic field and radio waves instead of X-rays to produce images showing structural and chemical changes in tissues. The patient lies on a table in a narrow cylinder (the scanner) containing a magnetic field and images are taken. A contrast agent called gadolinium is injected into a vein during the last set of images to help identify new lesions. Magnetic resonance spectroscopy, which is similar to MRI, is also done once during the baseline phase, at 4 months and at 8 months to measure brain chemicals. For the spinal tap, a local anesthetic is given and a needle is inserted in the space between the bones (vertebrae) in the lower back. About 2 tablespoons of fluid is collected through the needle. For leukapheresis, whole blood is collected through a needle placed in an arm vein. The blood circulates through a machine that separates it into its components. The white cells are removed and the red cells, platelets and plasma are returned to the body through a second needle placed in the other arm. Patients may also have studies to measure levels of Rolipram in the blood. These are done on study days 1 and 29 and at months 2, 4, and 6. For days 1 and 29, a catheter is placed in an arm vein and 4 ml. of blood is drawn immediately before the morning dose and at several intervals from 20 minutes to 6 hours after the dose. For the other tests, a single 4-ml sample is collected before the noon dose. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00011375 •

Safety and Efficacy of Pseudobulbar Affect in Multiple Sclerosis Patients Condition(s): Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): Avanir Pharmaceuticals Purpose - Excerpt: Pseudobulbar Affect is a condition characterized by frequent episodes of laughing and crying out of proportion. Other terms used to describe this condition include emotional lability, emotionalism, emotion incontinence, emotional discontrol, excessive emotionalism and pathological laughing and crying. AVP-923 is a new experimental drug that may assist in the reduction of uncontrolled episodes. This study will test the safety and efficacy of AVP-923 in the treatment of MS patients suffering from pseudobulbar affect. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00050232

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Stem Cell Transplant to Treat Patients with Systemic Sclerosis. Condition(s): Systemic Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): Baylor College of Medicine; The Methodist Hospital Purpose - Excerpt: Systemic Sclerosis is a disease that may be caused by the immune system reacting against skin and certain organs. It is possible, that by changing the immune system we can modify the progression of this disease. Stem cells are created in the bone marrow. They mature into different types of blood cells that are needed including red blood cells, white blood cells, and platelets. In this study, we will stimulate the bone marrow to make extra stem cells. Next we will collect the stem cells, select specific cells, and store them. We will then give high dose chemotherapy that will destroy the patients immune system. We will then give back the selected stem cells we collected. We believe that these selected stem cells may be able to "re-create" the immune system without the portion that causes Systemic Sclerosis. The purpose of this study is to try to discover if stem cell transplantation can help patients with Systemic Sclerosis. We will also try to learn what the side effects are of this treatment in patients with Systemic Sclerosis. We hope that this treatment will help to relieve the symptoms patients are experiencing, although we do not know if it will. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00058578

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Study of Creatine Monohydrate in Patients with Amyotrophic Lateral Sclerosis Condition(s): Amyotrophic Lateral Sclerosis (ALS) Study Status: This study is currently recruiting patients. Sponsor(s): The Avicena Group; National Institutes of Health (NIH) Purpose - Excerpt: The purpose of this study is to determine whether nine months of administation of creatine monohydrate results in an increase in muscle strength in patients with amyotrophic lateral sclerosis (ALS). Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069186

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Study of Skin Tumors in Tuberous Sclerosis Condition(s): Hereditary Neoplastic Syndrome; Tuberous Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Tuberous sclerosis is a rare, hereditary disease in which patients develop multiple tumors. Although not cancerous, the tumors can affect various organs, including the heart, lungs, kidneys, skin, and central nervous system, with serious medical consequences. The severity of disease varies greatly among patients, from barely detectable to fatal. This study will investigate what causes skin tumors to develop

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in patients with this disease. Patients with tuberous sclerosis 18 years and older may enroll in this study. Participants will undergo a medical history and thorough skin examination by a dermatologist. Those with skin tumors will be asked to undergo biopsy (tissue removal) of up to four lesions, under a local anesthetic, for research purposes. The biopsies will all be done the same day. The tissue samples will be used for: examination of genetic changes, measurement of certain proteins and other substances, and growing in culture to study the genetics of tuberous sclerosis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001975 •

Treatment of Multiple Sclerosis using Over the Counter Inosine Condition(s): Multiple Sclerosis, Relapsing-Remitting Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: The purpose of this study is to determine whether raising low levels of the natural antioxidant uric acid by the administration of a precursor, inosine, has any therapeutic effect on the progression of Relapsing Remitting Multiple Sclerosis (RRMS) and secondary progressive Multiple Sclerosis (MS). Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00067327

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Treatment of Multiple Sclerosis with Copaxone and Albuterol Condition(s): Autoimmune Diseases; Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The purpose of this study is to determine the effects of Copaxone alone compared to Copaxone plus albuterol in patients with Multiple Sclerosis (MS). MS is thought to be an autoimmune disease of the central nervous system. Certain white blood cells of the immune system become abnormally active and mistakenly attack the myelin of nerve fibers. Myelin is a fatty sheath that surrounds nerve fibers and insulates the nerve like insulation around an electrical wire. Without proper myelin insulation, messages sent between the brain and other parts of the body may be confused or fail completely. Damage to myelin causes the symptoms of MS. The most common form of MS is known as relapsing-remitting (RR), where partial or total recovery occurs after attacks. Four therapies are currently approved for the treatment of MS. These therapies, however, are only moderately effective and can cause undesirable side effects. For this reason, there is a need to find new therapies that have minimal side effects and may stop the disease from getting worse. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00039988

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Zenapax to Treat Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: This study will examine the safety and effectiveness of Zenapax (a laboratory-manufactured antibody) in treating multiple sclerosis. Multiple sclerosis may be caused by an abnormal immune response in which white blood cells called T lymphocytes attack the myelin sheath that covers nerves and parts of the spinal cord. Zenapax binds to protein receptors on lymphocytes, keeping them from interacting with interleukin-2, a substance necessary for their growth. Patients with multiple sclerosis who have had at least one relapse within 18 months of the start of the study and in whom interferon-beta treatment has not been successful may be considered for this study. There are two study phases: baseline and treatment. During the baseline phase, patients will have three magnetic resonance imaging (MRI) scans over 2 months to evaluate their disease activity. During treatment, patients will receive seven intravenous (I.V.) infusions of Zenapax in the clinic. The first two infusions will be given 2 weeks apart; the next five will be given once a month. Patients will have MRI scans before each infusion. The MRIs will be done using the standard procedure and again using a contrast agent, gadolinium, injected into a vein. Gadolinium helps identify new multiple sclerosis lesions in the brain. Blood and urine samples will be taken during each clinic visit. In addition, patients will have skin tests, similar to a tuberculin test, to evaluate immune status, and will be asked to undergo two lumbar punctures (spinal tap; these will be optional)-one before the treatment phase begins, and another when treatment is completed. Lymphocytes will also be collected from patients before, during and after treatment. The lymphocytes are obtained by a procedure called apheresis: about a pint of whole blood is drawn through a needle in the arm, the lymphocytes are separated out and removed by a machine, and the rest of the blood is returned through a needle in the other arm. These studies will hopefully allow conclusions about the safety of Zenapax in MS, but also address its effectiveness with respect to modifying the inflammatory activity in the brain of MS patients and inhibit autoimmune T lymphocytes that are involved in the disease process. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001934

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A 12-week, multicenter, safety and dose-ranging study of 3 oral doses of TCH346 in patients with Amyotrophic Lateral Sclerosis Condition(s): Amyotrophic Lateral Sclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): Novartis Pharmaceuticals Purpose - Excerpt: This study is the first to be performed in Amyotrophic Lateral Sclerosis (ALS) patients with the novel compound TCH346. Its purpose is to evaluate the safety and clinical effects of 3 dose levels of TCH 346 compared to placebo in patients with a clinical diagnosis of laboratory-supported probable, probable or definite ALS. The study will require patients to visit the study center a total of at least 7 times over the course of up to 14 weeks. The study consists of 2 phases: A screening phase (up

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to 2 weeks) when patients will be evaluated for eligibility to participate in the study, and a double-blind treatment phase (12 weeks) when patients will receive daily doses of either TCH346 or placebo and will be evaluated for clinical effects. In addition, patients eligible to participate in this study will be required to have 3 magnetic resonance spectroscopic (MRS) scans. The MRS is a non-invasive, painless, "brain scan". The MRS will require traveling to a designated center in Montreal, Canada, which is very experienced in performing such MRS scans in ALS patients. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00036413 •

Determinants of Disease Severity in Amyotrophic Lateral Sclerosis Condition(s): Amyotrophic Lateral Sclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS); Massachusetts General Hospital Purpose - Excerpt: Objectives: I. Determine specific clinical features, molecular abnormalities, and laboratory-based biological markers of free radical stress that are associated with amyotrophic lateral sclerosis and influence disease severity. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004457

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Phase II Pilot Study of Cyclophosphamide and Rabbit Anti-Thymocyte Globulin as Salvage Therapy in Patients With Diffuse Systemic Sclerosis Condition(s): Systemic Sclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): Fred Hutchinson Cancer Research Center Purpose - Excerpt: Objectives: I. Determine the toxicity of cyclophosphamide and rabbit anti-thymocyte globulin in patients with diffuse systemic sclerosis. II. Determine the efficacy of this regimen in terms of controlling disease in these patients. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00016458

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Phase III Randomized, Double-Blind, Placebo-Controlled Study of Intravenous Immune Globulin for Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS); Mayo Clinic

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Purpose - Excerpt: Objectives: I. Determine whether high-dose intravenous immune globulin (IVIG) is more effective than placebo in restoring neurologic function (muscle strength) in patients with multiple sclerosis. II. Determine the time to recovery following IVIG. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004744 •

Phase III Randomized, Double-Blind, Sham-Controlled Study of Plasma Exchange for Acute Severe Attacks of Inflammatory Demyelinating Disease Refractory to Intravenous Methylprednisolone Condition(s): Acute Disseminated Encephalomyelitis; Devic's Syndrome; Marburg's variant of multiple sclerosis; Balo's Concentric Sclerosis; Acute Transverse Myelitis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS); Mayo Clinic Purpose - Excerpt: Objectives: I. Evaluate the effectiveness of plasma exchange in the treatment of acute severe attacks of inflammatory demyelinating disease in patients who have failed intravenous steroid therapy. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004645

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Registry to Evaluate Novantrone (R) Effects in Worsening Multiple Sclerosis (RENEW) Condition(s): Multiple Sclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): Immunex Corporation Purpose - Excerpt: This Phase 4 multicenter, open-label study is being conducted to obtain long-term information on how Novantrone is tolerated in patients with multiple sclerosis (MS) when it is given as recommended in the package insert. Five hundred patients with MS who receive Novantrone will be enrolled at up to 50 sites in the United States. Patients must have a diagnosis of MS as shown by clinical assessment or laboratory tests. Patients are eligible to participate in the study if they have a diagnosis of either secondary (chronic) progressive, progressive relapsing, or worsening relapsingremitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). Patients with primary progressive disease cannot be included in this study. All patients will receive commercial open-label Novantrone at 12 mg/m2 administered intravenously. Doses of Novantrone will be administered approximately every 3 months until either a 140 mg/m2 cumulative dose is reached, the patient or physician chooses to discontinue or interrupt therapy, or there is an adverse event that precludes further therapy. All patients will be evaluated for left ventricular ejection fraction (LVEF) by echocardiography or MUGA at baseline and again before

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each dose when a cumulative dose of 100 mg/m2 has been reached. LVEF evaluations will also be performed annually after Novantrone has been discontinued, for up to 5 years after administration of the first dose of Novantrone. Novantrone will not be administered to patients with a LVEF less than 50%. Patients will need to pay for or arrange for payment of their Novantrone. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00016614 •

Safety and Efficacy of Natalizumab in Combination with Avonex in the Treatment of Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): Biogen; Elan Pharmaceuticals Purpose - Excerpt: The purpose of this study is to determine if natalizumab in combination with AVONEX is safe and effective in delaying progression of individuals diagnosed with relapsing remitting MS. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00030966

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Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis Condition(s): Multiple Sclerosis, Relapsing-Remitting Study Status: This study is no longer recruiting patients. Sponsor(s): Biogen; Elan Pharmaceuticals Purpose - Excerpt: The purpose of this study is to determine the safety and efficacy of natalizumab in the treatment of individuals who have been diagnosed with relapsing remitting multiple sclerosis (MS). It is hoped that natalizumab will prevent certain types of white blood cells from moving out of the bloodstream into organs, including the brain, that are being damaged by autoimmune disease (a disease in which the body's own immune system attacks certain organs). These white blood cells are thought to cause inflammation that can result in lesions (small areas of damage) in the brain. These lesions are thought to be the cause of relapses and disability in MS. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00027300

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Safety and Efficacy study of Oral Fampridine-SR on Walking Ability in Multiple Sclerosis Condition(s): Multiple Sclerosis

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Study Status: This study is no longer recruiting patients. Sponsor(s): Acorda Therapeutics Purpose - Excerpt: Multiple Sclerosis (MS) is a disorder of the body's immune system that affects the Central Nervous System (CNS). Normally, nerve fibers carry electrical impulses through the spinal cord, providing communication between the brain and the arms and legs. In people with MS, the fatty sheath that surrounds and insulates the nerve fibers (called "myelin") deteriorates, causing nerve impulses to be slowed or stopped. As a result patients with MS may experience periods of muscle weakness and other symptoms such as numbness, loss of vision, loss of coordination, paralysis, spasticity, mental and physical fatigue and a decrease in the ability to think and/or remember. These periods of illness may come (exacerbations) and go (remissions). Fampridine-SR is an experimental drug that increases the ability of the nerve to conduct electrical impulses. This study will evaluate the effects of Fampridine-SR on the walking ability of subjects with MS, as well as to examine the effects on muscle strength and spasticity. The study will also examine the possible risks of taking Fampridine-SR. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00053417 •

Safety, Tolerability, and Pharmacokinetics of CAT-192 (Human Anti-TGF-Beta1 Monoclonal Antibody) in Patients with Early Stage Diffuse Systemic Sclerosis Condition(s): Systemic Sclerosis; Scleroderma Study Status: This study is no longer recruiting patients. Sponsor(s): Genzyme; Cambridge Antibody Technology Purpose - Excerpt: Systemic Sclerosis (also known as Scleroderma) is a chronic, autoimmune disease of the connective tissue generally classified as one of the rheumatic diseases. Systemic Sclerosis causes fibrosis (scar tissue) to be formed in the skin and internal organs. The fibrosis eventually causes the involved skin to harden, limiting mobility, and can also damage other organs. Excess Transforming Growth Factor Beta-1 (TGF-beta1) activity may result in the abnormal fibrosis characteristic of Systemic Sclerosis. An antibody against TGF-beta1 may modify pathologic processes characterized by inappropriate fibrosis. Genzyme Corporation is currently investigating a human monoclonal antibody (CAT-192) that neutralizes active TGF-beta1. This study is being conducted in the U.S. and Europe to evaluate the safety, tolerability, and pharmacokinetics of repeated treatments with CAT-192 in patients with early stage diffuse Systemic Sclerosis. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00043706

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Yoga: Effect on Attention in Aging & Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is no longer recruiting patients.

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Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: Changes in visual attention are common among elders and people with multiple sclerosis. The visual attention changes contribute to difficulty with day to day functioning including falls, driving and even finding one's keys on the kitchen counter as well as contributing to deficits in other cognitive domains. Yoga emphasizes the ability to focus attention and there is some evidence that the practice of yoga may improve one's cognitive abilities. Additionally, yoga practice may improve cognitive function through other non-specific means such as improved mood, decreased stress or declines in oxidative injury. We propose a randomized, controlled 6 month phase II trial of yoga in two separate cohorts: healthy elders and subjects with mild multiple sclerosis. We will determine if yoga intervention produces improvements on a broad attentional battery that especially emphasizes attentional control. To further understand the reported beneficial effect of yoga on its practitioners, we will also determine if there is a positive impact on measures directly related to yoga practice (flexibility and balance) as well as mood, quality of life and oxidative injury markers. The yoga intervention consists of a Hatha yoga class meeting twice per week. The class is taught by experienced yoga teachers who are supervised by a nationally known yoga instructor. There are two control groups. An exercise group will have a structured walking program prescribed by a certified Health and Fitness Instructor and Personal Trainer. The program will attempt to match the Hatha yoga class for metabolic demand. The second control group will be assigned to a 6 month waiting list. The outcome measures are assessed at baseline and after the 6 month period. The primary outcome measures are alertness (quantitative EEG and self-rated scale), ability to focus attention (Stroop) and ability to shift attention (extradimensional set shifting task). Secondary attention outcome measures include the ability to sustain attention (decrement in reaction time) and ability to divide attention (Useful Field of View). Other secondary outcome measures include flexibility, balance, mood, quality of life, fatigue (in MS cohort) and decreased markers of lipid, protein, and DNA oxidative injury. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00010998 •

A 48-Week (24-Week Baseline Followed by a 24-Week Treatment) Phase II Pilot Study of the Tolerability and Effect/Efficacy of Subcutaneously Administered Insulin-Like Growth Factor-1 (rhIGF) (CEP-151) in Multiple Sclerosis (MS) Patients Condition(s): Multiple Sclerosis Study Status: This study is completed. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: The drug rhIGF-1 (CEP-151) has been shown to play a key role preclinically in oligodendrocyte differentiation and survival, as well as, myelin integrity and function. Moreover, in an animal model of MS, myelin expression, as well as that of its receptors is upregulated at the time the myelin sheaths regenerate. Finally, administration of exogenous rhIGF-1 to rats with EAE effectively, closes the disrupted BBB, reduces the number and severity of demyelinating lesions, and improves neurological function. Thus it seems reasonable to examine the efficacy and safety, tolerability, and effect of CEP-151 on brain MRI lesions in patients with MS. Phase(s): Phase II

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Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001669 •

A Maintenance Extension of Phase I Pilot Study of Chimeric Anti-CD4 Antibody MT412 in Patients With Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); Stanford University Purpose - Excerpt: Objectives: I. Evaluate the safety and immunogenicity of single and multiple doses of M-T412, a chimeric murine-human anti-CD4 monoclonal antibody, in patients with multiple sclerosis. II. Evaluate the pharmacokinetics of M-T412. III. Obtain preliminary data on the clinical response to M-T412. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004816

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A study to evaluate the preliminary efficacy pharmacokinetics and immunogenicity of BMS-188667 administered to subjects with relapsing-remitting multiple sclerosis Condition(s): Multiple Sclerosis Study Status: This study is terminated. Sponsor(s): Bristol-Myers Squibb Purpose - Excerpt: The purpose of this study is to determine whether BMS-188667 will decrease multiple sclerosis disease activity on MRI examinations, as well as decrease the rate of clinical MS exacerbations, compared to placebo Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00035529

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Diagnostic Study of Quantitative Imaging and Spectroscopy in Patients With Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is suspended. Sponsor(s): National Center for Research Resources (NCRR); University of Pennsylvania Purpose - Excerpt: Objectives: I. Determine by quantitative magnetic resonance imaging measurements the change in the total volume of brain parenchyma as well as its gray and white matter, T2 and enhanced T1 lesion volume, and the magnetization transfer ratio histogram parameters, and correlate these measurements with clinical measures of disability in patients with multiple sclerosis. II. Measure the quantity of whole brain Nacetylaspartate in patients with multiple sclerosis and compare these values to those from age matched controls. III. Determine the correlation between specific

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neuropsychological tests which assess global cognitive functioning and the quantitative measurements taken in these patients in this study. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006060 •

High dose chemo/radiotherapy and hematopoietic stem cell transplant for patients with multiple sclerosis. Condition(s): Multiple Sclerosis Study Status: This study is terminated. Sponsor(s): Baylor College of Medicine; The Methodist Hospital Purpose - Excerpt: Multiple Sclerosis is a disease that may be caused by the immune system reacting against the nervous system. It is possible, that by changing the immune system we can modify the progression of this disease. In this study, we will try to learn whether treatment with a bone marrow transplant (BMT) can help patients with multiple sclerosis. We will also try to learn what the side effects are of this treatment in patients with multiple sclerosis. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00040482

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Is there a higher than expected occurrence of ALS among deployed veterans as compared to non-deployed Gulf War veterans? Condition(s): Amyotrophic Lateral Sclerosis Study Status: This study is completed. Sponsor(s): Department of Veterans Affairs; Department of Veterans Affairs Cooperative Studies Program; Department of Defense; Centers for Disease Control and Prevention; Department of Health and Human Services; ALS Association Purpose - Excerpt: Recently, concern has arisen regarding a possible elevated occurrence of ALS among veterans who served in the Persian Gulf during Operations Desert Shield (August 2, 1990 - January 15, 1991), Desert Storm (January 16, 1991 - February 28, 1991) and Clean-up (March 1, 1991 - July 31, 1991). This study involves an epidemiologic investigation into the occurrence of ALS among veterans of the Gulf War. This study will further define the epidemiology of this neurological disease among younger individuals while determining whether there is a higher than expected occurrence. It will also ascertain the etiologic importance of deployment to the Persian Gulf and exposure to specific environmental factors in that geographic area. VA is leading this joint federal government epidemiologic study that also involves DoD, HHS, CDC, and academic centers of excellence in neurology, with advice from the ALS Association. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00007722

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Natural Anti-Oxidants in the Treatment of Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is not yet open for patient recruitment. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: Multiple sclerosis (MS) is an immune mediated disease of the central nervous system that affects over 350,000 Americans. T lymphocytes, macrophages and soluble mediators of inflammation cause demyelination and axonal injury in MS. Chronic relapsing experimental autoimmune encephalomyelitis (EAE) in SJL mice models MS clinically and pathologically and is useful for testing potential therapies for MS. Activated macrophages release nitric oxide and oxygen free radicals that cause demyelination and axonal injury in MS and EAE. Natural anti-oxidants potentially could favorably influence the course of MS by decreasing oxidative injury. This project will assess three natural anti-oxidant regimens, ginkgo biloba, alpha-lipoic acid/essential fatty acids and vitamin E/selenium, for their potential as treatments for MS. For Aim 1, we will test each of the three anti-oxidant regimens for their ability to suppress EAE. For Aim 2, we will evaluate the anti-oxidant regimens that suppress EAE for their ability to decrease markers of lipid, protein and DNA oxidative injury in blood and cerebrospinal fluid in patients with MS. Based on the results from Aims 1 and 2, we will select the anti-oxidant regimen that appears most effective at suppressing EAE and decreasing markers of oxidative injury in patients with MS. For Aim 3, we will perform a Phase I/II trial in patients with MS to determine if the selected anti-oxidant regimen can decrease disease activity as detected with gadolinium enhanced magnetic resonance imaging. The results of this study will serve as the basis for a Phase III trial to assess the long term effectiveness of natural anti-oxidant therapy in MS. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00010842

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Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis Condition(s): Primary Lateral Sclerosis; Hereditary Spastic Paraplegia; Amyotrophic Lateral Sclerosis Study Status: This study is completed. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: This study will use a magnetic resonance imaging technique called nuclear magnetic spectroscopy (H-MRS) to define the pathology and progression of primary lateral sclerosis, hereditary spastic paraplegia and amyotrophic lateral sclerosis and assess the usefulness of this technique in evaluating patients' response to therapy. H-MRS will be used to examine metabolic changes in the parts of the brain and spinal cord (motor cortex and corticospinal tract) involved in movement. Normal volunteers and patients with primary lateral sclerosis, hereditary spastic paraplegia or amyotrophic lateral sclerosis between 21 and 65 years of age may be eligible for this study. Participants will have up to five H-MRS studies, including baseline and follow-up tests. For this procedure, the subject lies on a stretcher that is moved into a strong magnetic field. Earplugs are worn to muffle the loud knocking noise that occurs during switching of radio frequencies. The subject will be asked to lie still during each scan, for 1 to 8

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minutes at a time. Total scanning time varies from 20 minutes to 2 hours, with most examinations lasting between 45 and 90 minutes. Communication with the medical staff is possible at all times during the scan. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023075 •

Phase I Pilot Study of Total-Body Irradiation, Anti-Thymocyte Globulin and Cyclophosphamide Followed By Syngeneic or Autologous Peripheral Blood Stem Cell Transplantation in Patients With Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is completed. Sponsor(s): Fred Hutchinson Cancer Research Center Purpose - Excerpt: Objectives: I. Determine the toxicity of total-body irradiation, antithymocyte globulin, and cyclophosphamide followed by syngeneic or autologous peripheral blood stem cell (PBSC) transplantation in patients with multiple sclerosis. II. Determine the disease response of patients treated with this regimen. III. Determine the safety and efficacy of filgrastim (G-CSF) for PBSC mobilization in this patient population. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00014755

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Phase II Study of Recombinant Relaxin for Progressive Systemic Sclerosis Condition(s): Systemic Sclerosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Stanford University Purpose - Excerpt: Objectives: I. Determine whether parenteral relaxin improves skin tightness, Raynaud's phenomenon, digital morbidity, and digital ulcers in a patient with progressive systemic sclerosis (scleroderma). II. Determine whether relaxin decreases collagen production by fibroblasts in vivo and cultured from skin biopsies. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004380

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Phase III Randomized, Double-Blind, Placebo-Controlled Study of Copolymer 1 for Relapsing-Remitting Multiple Sclerosis Condition(s): Multiple Sclerosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); University of Maryland

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Purpose - Excerpt: Objectives: I. Compare tolerance to and therapeutic impact of copolymer 1, a mixture of synthetic polypeptides, with placebo in patients with relapsing-remitting multiple sclerosis. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004814 •

Phase III Randomized, Double-Blind, Placebo-Controlled Study of Oral Iloprost for Raynaud's Phenomenon Secondary to Systemic Sclerosis Condition(s): Systemic Sclerosis; Raynaud Disease Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); University of Pittsburgh Purpose - Excerpt: Objectives: I. Evaluate the safety and efficacy of oral iloprost, a prostacyclin analog, in patients with Raynaud's phenomenon secondary to systemic sclerosis. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004786

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Safety, Tolerability, and Effectiveness of CGP77116 in Patients with Multiple Sclerosis (MS) Condition(s): Multiple Sclerosis Study Status: This study is completed. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: Multiple sclerosis (MS) is a disease of the nervous system. The exact cause of MS is unknown, but it is believed to be an autoimmune condition. Autoimmune conditions are diseases that cause the body's immune system and natural defenses to attack healthy cells. In the case of MS, the immune system begins attacking myelin, the cells that make up the sheath covering nerves. Without myelin nerves are unable to transmit signals effectively and symptoms occur. Researchers are interested in testing the safety, tolerability, and effectiveness of a new therapy (CGP77116) for Multiple Sclerosis (MS). CGP77116 is a small protein similar to the protein in myelin. CGP77116 is designed to modify the immune reaction that destroys normal myelin. CGP77116 is an experimental therapy meaning it has not been approved by the U.S. Food and Drug Administration. However, in preliminary studies on animal it has been shown to be effective at modifying the autoimmune reaction associated with the development of MS. The purpose of this study is to assess the safety and effect of CGP77116 on disease activity in patients with Multiple Sclerosis as measured by magnetic resonance imaging (MRI) and immunological studies. The study is broken into three parts: I) BASELINE: in the first part of the study patients will undergo 6 MRIs over a 5 month period. During this time, patients will be evaluated based on the presence of MS lesions seen on MRI. Patients whose MS lesions are highly active will be entered into the second part of the study. II) TREATMENT: in the second part of the study, patients

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with active MS lesions will begin receiving CGP77116. The drug will be given by injection once a week for one month and then once a month for 8 additional months. III) FOLLOW-UP: in the third and final part of the study, patients will undergo an MRI every 2 months for 6 months and then every 3 months for 6 additional months. The results of the MRIs will be used to measure the effectiveness of CGP77116. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001781 •

Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS Condition(s): Amyotrophic Lateral Sclerosis Study Status: This study is completed. Sponsor(s): Avanir Pharmaceuticals Purpose - Excerpt: The purpose of this study is to compare and evaluate the safety of AVP-923 (dextromethorphan/quinidine) for the treatment of emotional lability in ALS patients. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00021697

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “sclerosis” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 6. PATENTS ON 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.9 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 “sclerosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on sclerosis, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Sclerosis By performing a patent search focusing on sclerosis, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We

9Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on sclerosis: •

3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide in the treatment of multiple sclerosis Inventor(s): Sanders; Karl (Konstanz, DE), Kley; Hans-Peter (Allensbach, DE) Assignee(s): Altana Pharma AG (Konstanz, DE) Patent Number: 6,531,493 Date filed: September 5, 2001 Abstract: The invention relates to the novel use of 3-cyclopropylmethoxy-4difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide , a pharmacologically tolerable salt thereof or its N-oxide in the treatment of multiple sclerosis. Excerpt(s): The invention relates to the novel use of 3-cyclopropylmethoxy4difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide, a pharmacologically acceptable salt thereof or its N-oxide in the treatment of multiple sclerosis. In the International Patent Application WO95/28926, PDE4 inhibitors--in particular rolipram--are proposed on their own or in combination with anti-inflammatory active compounds or immunomodulators for the treatment of multiple sclerosis. In the International Patent Application WO93/18770, tumor necrosis factor inhibitors--in particular pentoxyfylline-are proposed for the treatment of disorders of the central nervous system. In the International Patent Application WO97/19686, the use of a combination of pentoxyfilline with type I interferons is described for the treatment of multiple sclerosis. Web site: http://www.delphion.com/details?pn=US06531493__

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Agents for the diagnosis of demyelinating neuropathies, in particular multiple sclerosis Inventor(s): Vincendon; Guy (Strasbourg, FR), Zanetta; Jean-Pierre (Griesheim S/Souffel, FR), Warter; Jean-Marie (Strasbourg, FR), Kuchler; Sabine (Strasbourg, FR) Assignee(s): Centre National de la Recherche Scientifique (Quai Anatole, FR) Patent Number: 5,225,352 Date filed: September 5, 1990 Abstract: The invention relates to the use for the diagnosis of demyelinating neuropathies, in particular multiple sclerosis or MS, of endogenous lectins having an affinity for glycans rich in mannose or their protein subunits, these lectins or their subunits being immunologically related to the cerebellar soluble lectins (CSL or their protein subunits, respectively). Excerpt(s): The invention relates to agents for the in vitro diagnosis of demyelinating neuropathies, in particular multiple sclerosis or MS. Statistical studies made by the World Health Organisation show that MS is a disease which is spreading throughout the world and particularly in the regions where it is favoured which are the countries with a cold and temperate climate. 50,000 cases have been identified in France, but the actual number of cases must be higher. The same proportion of patients is found in all of the countries of Europe and North America with a cold or temperate climate, as well as in the corresponding zones of the southern hemisphere. The study of MS has shown that

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various factors, genetic and/or geographic, or even infectious factors may play a role in triggering it. The nature of these agents and their mechanism of action in the triggering of MS have hitherto not been elucidated. It is accepted, however, that at a certain stage the disease develops into an autoimmune attack on the myelin in the tissues of the central nervous system with the formation of patches of degenerated myelin. Web site: http://www.delphion.com/details?pn=US05225352__ •

Anticonvulsant derivatives useful in treating amyotrophic lateral sclerosis (ALS) Inventor(s): Shank; Richard P. (Blue Bell, PA) Assignee(s): Ortho Pharmaceutical Corporation (Raritan, NJ) Patent Number: 5,753,694 Date filed: June 23, 1997 Abstract: Disclosed herein is a method of treating amyotrophic lateral sclerosis with topiramate and related compounds. Excerpt(s): This application claims priority to provisional application Ser. No. 60/022,006, filed Jun. 28, 1996. Compounds of Formula I were initially found to possess anticonvulsant activity in the traditional maximal electroshock seizure (MES) test in mice (SHANK, R. P., GARDOCKI, J. F., VAUGHT, J. L., DAVIS, C. B., SCHUPSKY, J. J., RAFFA, R. B., DODGSON, S. J., NORTEY, S. O., and MARYANOFF, B. E., Epilepsia 35 450-460, 1994). Subsequent studies revealed that Compounds of Formula I were also highly effective in the MES test in rats. More recently topiramate was found to effectively block seizures in several rodent models of epilepsy (J. NAKAMURA, S. TAMURA, T. KANDA, A. ISHII, K. ISHIHARA, T. SERIKAWA, J. YAMADA, and M. SASA, Eur. J. Pharmacol. 254 83-89,1994), and in an animal model of kindled epilepsy (A. WAUQUIER and S. ZHOU, Epilepsy Res. 24, 73-77, 1996). Recent preclinical studies on topiramate have revealed previously unrecognized pharmacological properties which suggest that topiramate should be effective in treating some other neurological disorders. One of these is amyotrophic lateral sclerosis (ALS). Web site: http://www.delphion.com/details?pn=US05753694__

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Apparatus and method for relieving symptoms of multiple sclerosis Inventor(s): Liss; Saul (Glen Rock, NJ), Liss; Bernard (Glen Rock, NJ) Assignee(s): Pain Suppression Labs, Inc. (Dlmwood Park, NJ) Patent Number: 4,574,808 Date filed: April 26, 1984 Abstract: Apparatus and methodology for treating the symptoms of multiple sclerosis employs a transcutaneous electronic wave to suppress perceived pain, increase strength, improve the perception of sensation, reduce spasticity associated with the disease, and create a general feeling of improved well being in the patient. A positive contact electrode is placed on the center of the frontalis muscle, and a negative electrode located at the occiput of the head. Additional negative contacts are placed at the base of the spine, on the medial malleolus of each affected leg and the web space of each affected hand. An electronic current wave comprising relatively high frequency pulses with a

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low frequency amplitude modulation is then applied between the first to the second electrodes. Excerpt(s): This invention relates to medical electronic apparatus and methodology and, more specifically, apparatus and methodology for relieving symptoms of multiple sclerosis. It is an object of the present invention to provide improved apparatus and methodology for treating symptoms of multiple sclerosis. More specifically, an object of the present invention is the electronic treatment of multiple sclerosis symptoms in a safe, efficient and rapid manner to reduce spasticity and alleviate pain associated with the disease, improve perception of sensation, increase strength, and create a general feeling of well being in the patient. Web site: http://www.delphion.com/details?pn=US04574808__ •

Application of 4-carbamoyl-1-.beta.-D-ribofuranosyl imidazolium-5-olate to the treatment of multiple sclerosis Inventor(s): Saida; Kyoko (Kyoto, JP), Saida; Takahiko (Kyoto, JP) Assignee(s): Asahi Kasei Kogyo Kabushiki Kaisha (Osaka, JP) Patent Number: 5,472,947 Date filed: July 28, 1994 Abstract: A composition for the treatment or prevention of multiple sclerosis is disclosed. It comprises mizoribine (4-carbamoyl-1-.beta.-D-ribofuranosyl imidazolium5-olate) as the effective component. It is a safe drug, exhibiting a minimal degree of sideeffects, and thus can be administered over a long period of time. Administration of the drug, usually 1-20 mg/kg (body weight) per day for adults, improves the functional disturbances of multiple sclerosis. Excerpt(s): The present invention relates to a composition for the treatment or prevention of multiple sclerosis comprising 4-carbamoyl-1-.beta.-D-ribofuranosyl imidazolium-5-olate. Multiple sclerosis is a disease involving temporary and multiple disorders in the central nervous system; i.e., disorders in the medullary sheath of the brain, the spinal, and the visual nerve, producing polydomous demyelinating lesions. The disease is clinically found in young adults, and disorders are found in more than one site in the central nervous system, with repeated relapsing and remission. In many cases the initial symptom is decreased visual acuity, followed by motor paralysis, paralysis, gait disturbance, hypersthesia, double vision, and speech disorder [Encyclopedia of Medical Sciences, 31, 53-54 (1982)]. The criterion defined by Multiple Sclerosis Research Team, the Ministry of Health and Welfare, Japan, in 1989 is as follows. (1) At least two lesions are found in the central nervous system, diagnosed based on the symptoms and the views obtained by physical examinations, (2) the relapsing and remission are repeated, and (3) disturbances in the nervous system due to other diseases (e.g cerebrovascular disease, hemangioma, HTLV-I-associated myelopathy, collagen disease, Behget disease, syringomyelia, spino-cerebullar degeneration, cerevical vertebral myelopathy, subacute myelo-optico-neuropathy, syphilis, etc.) are recognized. The diseases completely satisfying all of the above 3 items are deemed the multiple sclerosis confirmed by the clinically diagnosis. Optic neuromyelitis (Devic disease) is considered to be a type of multiple sclerosis. Web site: http://www.delphion.com/details?pn=US05472947__

Patents 377

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Assay and treatment for demyelinating diseases such as multiple sclerosis, related hybridomas and monoclonal antibodies Inventor(s): Kline; Ellis L. (Pendleton, SC), Zimmerman; Daniel H. (Bethesda, MD) Assignee(s): Molecular Rx, Inc. (Pendleton, SC), Cell Med, Inc. (Bethesda, MD) Patent Number: 5,645,997 Date filed: June 7, 1995 Abstract: The present invention relates to the diagnosis of multiple sclerosis. More specifically, this invention relates to an assay for detecting antigen(s) associated with multiple sclerosis. The present invention also relates to the generation of hybridomas which produce monoclonal antibodies which are specific for the multiple sclerosisassociated antigens. The present invention's use is in diagnosing multiple sclerosis and in routine follow-up monitoring of multiple sclerosis patients as to disease progression or response to therapy. Excerpt(s): The present invention relates to the detection of demyelinating diseases such as multiple sclerosis. More specifically, this invention relates to an assay for detecting antigen(s) associated with multiple sclerosis and related diseases. The present invention also relates to the generation of hybridomas which produce monoclonal antibodies which am specific for the multiple sclerosis-associated antigens. The present invention's use is in diagnosing multiple sclerosis and in routine follow-up monitoring of multiple sclerosis patients as to disease progression or response to therapy. Multiple sclerosis is a slowly progressive disease of the central nervous system ("CNS"), characterized pathologically by disseminated patches of demyelinization in the brain and spinal cord, and clinically by multiple symptoms and signs with remissions and exacerbations. Demyelinization is the removal of the myelin, a protective, lipid substance that surrounds the axon of nerve fibers. Multiple sclerosis related diseases are those conditions which exhibit demyelinization of nerves. Onset of multiple sclerosis is usually insidious. Commonly, minor visual disturbances, a fleeting ocular palsy, transient weakness, slight stiffness or unusual fatigability of a limb, minor interference with walking, difficulties with bladder control, occasional dizziness, or mild emotional disturbances--all evidence of scattered involvement of the CNS--occur months or years before the disease is recognized. Web site: http://www.delphion.com/details?pn=US05645997__

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CDW52-specific antibody for treatment of multiple sclerosis Inventor(s): Hale; Geoffrey (University of Cambridge, Department of Pathology, Immunology Div., Tennis, Cambridge, CB2 1QP, GB), Waldmann; Herman (University of Cambridge, Department of Pathology, Immunology Div., Tennis, Cambridge, CB2 1QP, GB) Assignee(s): none reported Patent Number: 6,120,766 Date filed: June 22, 1994 Abstract: The invention relates to the use of an antibody recognizing the Cdw52 antigen in the treatment of multiple sclerosis. Preferably, the antibody is the humanized antibody in the humanized antibody CAMPATH-1H.

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Excerpt(s): The present invention relates to a method of treatment of certain autoimmune conditions in a human or animal subject. The cells and molecules in an animal body do not normally stimulate an adaptive immune response in that body as a result of a number of mechanisms which ensure a state referred to as "self-tolerance". However, in certain circumstances these mechanisms may fail to prevent the stimulation of such an immune response and this condition is referred to as "auto-immunity". A number of diseases in humans and animals are now thought to result from auto-immunity. Multiple sclerosis is a demyelinating disease of the central nervous system the onset of which generally occurs within the age range from about 15 to 45. Myelin is a fatty substance which forms a sheath around certain nerve fibres and which conducts nervous impulses at a rate which enables muscles to make precise and delicate movements. The disease is characterised by induration of the sheath substance leading to the formation of plaques of varying size and location which interfere with the impulses normally conducted by the sheath. The course of the disease can be highly variable in individual patients and may be subject to periods of spontaneous remission. However, the disease generally results in progressive deterioration of the control of muscle function with ultimate paralysis in many cases. The precise cause of multiple sclerosis is unknown and it may result form a complex interaction of a number of different factors. However, it is now generally recognised that there is at least an autoimmune component in the causation of the disease. Web site: http://www.delphion.com/details?pn=US06120766__ •

Cell lines and viral isolates associated with multiple sclerosis Inventor(s): Beseme; Frederic (Villefontaine, FR), Perron; Herve (Grenoble, FR), Mallet; Francois (Villeurbanne, FR), Mandrand; Bernard (Villeurbanne, FR), Bedin; Frederic (Lyons, FR) Assignee(s): Bio Merieux (Marcy l'Etoile, FR) Patent Number: 6,342,383 Date filed: August 13, 1998 Abstract: Composition comprising two pathogenic and/or infective agents associated with multiple sclerosis, namely a first agent which consists of a human virus possessing reverse transcriptase activity and related to a family of endogenous retroviral elements, or a variant of said virus, and a second agent, or a variant of said second agent, these two pathogenic and/or infective agents originating from the same viral strain chosen from the strains designated, respectively, POL-2 deposited with the ECACC on Jul. 22 1992 under Accession Number V92072202 and MS7PG deposited with the ECACC on Jan. 8 1993 under Accession Number V93010816, and from their variant strains. Excerpt(s): Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) the cause of which remains as yet unknown. Many studies have supported the hypothesis of a viral etiology of the disease, but none of the known viruses tested has proved to be the causal agent sought: a review of the viruses sought for several years in MS has been compiled by E. Norrby (1) and R. T. Johnson (2). Concomitantly, the possibility of an exogenous and/or infectious factor is suggested by the existence of localized epidemics or "clusters" of MS, as have been observed in the Faro Islands between 1943 and 1960 (3), in Sardinia (4), in Norway (5), and also by studies on migrant populations (6). Among all the exogenous factors suggested, viruses have been most often studied, and a viral etiology is traditionally called to mind.

Patents 379

Web site: http://www.delphion.com/details?pn=US06342383__ •

Cholecystoscopic cannula and cholecystoscopic gallbladder laser-sclerosis procedure Inventor(s): Kleiman; Aldo Sergio (Blas Parera St. No. 910, City of Rosario, Province of Santa Fe, AR) Assignee(s): none reported Patent Number: 5,860,426 Date filed: November 6, 1996 Abstract: A cholecystoscopic laser-sclerosis surgical procedure for the elimination of a human gallbladder in a single session using a local anesthesia, which utilizes a speciallydesigned cholecystoscopic cannula to couple the gallbladder fundus to the cannula by forcing a ring of gallbladder tissue into a groove in the cannula, by performing an operative endoscopy inside the gallbladder, closing the cystic duct meatus using a forceps, sealing the cystic duct using electrocoagulation, removing the gallstones, ablating the mucous membrane of the gallbladder by using a CO2 laser, injecting a biological cement into the gallbladder, applying a vacuum in order to collapse the gallbladder, eliminating the gallbladder tissue within the cannula by using a CO2 laser or electrocoagulation, and finally, releasing the coupling of the cannula to the gallbladder fundus and removing the cholecystoscopic cannula. The gallbladder disappears by means of atrophy. Excerpt(s): The present invention relates to a cannula and a procedure for gallbladder elimination. 2) the percutaneous radioscopic gallbladder chemical-sclerosis (the gallbladder disappears by means of atrophy). The object of the invention is to provide a new procedure which combines the advantages of the percutaneous gallbladder chemical-sclerosis procedure, which is very mini-invasive and utilizes only a local anesthesia, with that of the cholecystectomy which is a single session procedure. Web site: http://www.delphion.com/details?pn=US05860426__

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Compositions and methods based upon the tuberous sclerosis-1 (TSC1) gene and gene product Inventor(s): Halley; Dicky J. J. (Rotterdam, NL), Kwiatkowski; David J. (Weston, MA), van Slegtenhorst; Marjon A. (Hoogland, NL), Povey; Margaret S. (Beds, GB), Sampson; Julian R. (Cardiff, GB) Assignee(s): Brigham and Women's Hospital (Boston, MA) Patent Number: 6,326,483 Date filed: December 10, 1999 Abstract: The present invention is directed to a tumor suppressor protein which has been designated hamartin and to the gene, TSC1, which encodes this protein. Mutations in the gene have been found to be associated with certain types of tuberous sclerosis and this has served as a basis for a diagnostic method designed to identify patients that have, or are likely to develop, symptoms associated with this disease. The introduction of the TSC1 gene and subsequent expression of hamartin into cells may be used as a means for treating tuberous sclerosis and other conditions characterized by abnormal cellular growth.

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Excerpt(s): The present invention is directed to the gene TSC1 and to the protein it encodes. TSC1 has the characteristics of a tumor suppressor gene and is often mutated in individuals with a familial form of tuberous sclerosis. The invention also encompasses methods that relate to the gene and gene product. Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the development of unusual tumor-like growths (hamartomas) in a variety of organ systems (Gomez, M. R., Ann. N.Y Acad. Sci. 615:1-7 (1991); Kwiatkowski, et al., Arch. Dermatol. 130:348-354 (1994)). The development of cortical tubers in the brain (regions of abnormal cortical architecture with distinctive large neuronal cells) causes some of the most problematic clinical manifestations of TSC: mental retardation, epilepsy and abnormal behavioral phenotypes including autism and attention deficit-hyperactive disorder (Hunt, et al., J. Autism. Dev. Disorder 23:323-339 (1993); Smalley, et al, J. Autism. Dev. Disorder 22:339355 (1992)). Other organ systems commonly involved in TSC include the skin, heart, and kidneys (Kwiatkowski, et al., Arch. Dermatol. 130:348-354 (1994)). The lesions seen are often pathognomonic of TSC and include facial angiofibromas, subungual fibromas, forehead plaque, Shagreen patches, cardiac rhabdomyomas and renal angiomyolipomas and cysts. Renal cell carcinoma also occurs at higher frequency and at an earlier age of onset in TSC patients than in normal individuals (Bjornsson, et al., Am. J. Path. 149:12011208 (1996); Cook, et al., J. Med. Genet. 33:480-484 (1996)). About one-third of TSC cases are familial with the remainder being sporadic, i.e., occurring in the absence of a family history of the disease. Linkage of TSC to 9q34 was first reported in 1987 and this locus was denoted TSC1 (Fryer, et al., Lancet i:659-661 (1987)). Subsequent studies provided strong evidence for locus heterogeneity and led to the identification of 16p13 (denoted the TSC2 locus) as a second genomic region showing linkage in some TSC families (Kandt, et al., Exp. Neurol, 104:223-228 (1989)). Among families large enough to permit linkage analysis, approximately half show linkage to 9q34 and half to 16p13 (Janssen, et al, Hum. Genet. 94:437-440 (1994)). Web site: http://www.delphion.com/details?pn=US06326483__ •

Compositions including modafinil for treatment of attention deficit hyperactivity disorder and multiple sclerosis fatigue Inventor(s): Scammell; Thomas E. (Wellesley, MA), Miller; Matthew S. (Newtown, PA) Assignee(s): Cephalon, Inc. (West Chester, PA) Patent Number: 6,488,164 Date filed: December 20, 2001 Abstract: Modafinil is effective in improving symptoms of attention deficit hyperactivity disorder and symptoms of multiple sclerosis fatigue. The administration of modafinil is also shown to activate the tuberomamillary neurons of the posterior hypothalamus, and thus exhibits activity in an area of the brain associated with normal wakefulness functions. Excerpt(s): The present invention is related to the fields of neuropharmacological agents, including agents that are useful in the treatment of attention deficit hyperactivity disorder and multiple sclerosis associated fatigue. Attention-deficit/hyperactivity disorder (ADHD) is a chronic neuropsychiatric disorder in children that is characterized by developmentally inappropriate hyperactivity, impulsivity, and inattention. ADHD is estimated to affect 3%-5% of school-age children. Historically ADHD was thought not to continue beyond adolescence; however, current research suggests that ADHD persists into adulthood in 10% to 60% of childhood-onset cases. ADHD persistence is associated

Patents 381

with a high incidence of academic and occupational dysfunction, as well as a high incidence of psychiatric comorbidity (e.g., conduct, major depressive, and anxiety disorders). It is estimated that approximately 1% to 3% of adults have symptoms of ADHD. Adults with ADHD have a pattern of demographic, psychosocial, psychiatric, and cognitive features that mirrors well-documented findings among children with the disorder. This further supports the validity of the diagnosis for adults. The core ADHD symptoms in adults include a frequent and persistent pattern of inattention/distractibility and/or hyperactivity-impulsivity. The most common symptoms exhibited in ADHD adults are marked inattention, poor concentration, easy distractibility, day dreaming, forgetfulness and a frequent shift in activities. ADHD adults also report marked impulsivity, intrusiveness, low frustration/stress tolerance, temper tantrums, irritability, and extreme impatience. Less commonly reported symptoms in adults include hyperactivity, which may be confined to fidgeting, or an inward feeling of jitteriness or restlessness. In addition to the core ADHD symptoms, adults with ADHD often exhibit associated clinical characteristics such as boredom, social inappropriateness, and chronic conflicts in social situations. These features may be responsible for the high incidence of: (1) separation and divorce and (2) poor academic performance and occupational achievement that exist despite adequate intellectual abilities. In addition, adults with ADHD have a high incidence of substance abuse disorders. While the pathogenesis of ADHD remains unclear, alterations in the dopaminergic and noradrenergic functions appear to be the neurochemical basis for the disorder. Brain positron emission tomography in adults with ADHD have revealed alterations in glucose metabolism in areas of the cerebral cortex that are involved with attention and motor activity, like the frontal lobe. The most common treatment for both adult and pediatric ADHD is stimulants (e.g., dextroamphetamine, methylphenidate, and pemoline). Stimulants are thought to work by increasing the amount of dopamine available in the synapses of the neuron. The stimulants appear to do this in multiple cerebral anatomical locations. Other therapies that have been used include: antidepressants (e.g., tricyclic antidepressants such as imipramine and desipramine; novel antidepressants such as buproorion and venlafaxine), antihypertensives (e.g., clonidine and guanfacine), monoamine oxidase inhibitors ([MAO's], e.g., selegiline), amino acids (e.g., levodopa, phenylalanine, and L-tyrosine), and combined pharmacotherapies (e.g., concurrent use of a serotonin-selective reuptake inhibitor and a stimulant medication; or a stimulant and catelcholaminergic antidepressant regimen) (Bhandary et al., Psychiatric Annals 27:545-555, 1997; Wilens et al., J. Clin. Psychopharmacol. 15:270-279, 1995; Finkel, The Neurologist 3:31-44, 1997; Miller and Catellanos, Pediatrics in Review 19:373-384, 1998). Web site: http://www.delphion.com/details?pn=US06488164__ •

Detection of MSRV1 virus and MSRV2 pathogen and/or infective agent associated with multiple sclerosis, by nucleic acid hybridization Inventor(s): Mallet; Francois (Villeurbanne, FR), Perron; Herve (Grenoble, FR), Bedin; Frederic (Lyons, FR), Mandrand; Bernard (Villeurbanne, FR), Beseme; Frederic (Villefontaine, FR) Assignee(s): Bio Merieux (Marcy L'Etoile, FR) Patent Number: 5,800,980 Date filed: June 6, 1995

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Abstract: Composition including two pathogenic and/or infective agents associated with multiple sclerosis, namely a first agent which consists of a human virus possessing reverse transcriptase activity and related to a family of endogenous retroviral elements, or a variant of the virus, and a second agent, or a variant of the second agent, these two pathogenic and/or infective agents originating from the same viral strain chosen from the strains designated, respectively, POL-2 deposited with the ECACC on Jul. 22, 1992 under Accession Number V92072202 and MS7PG deposited with the ECACC on Jan. 8, 1993 under Accession Number V93010816, and from their variant strains. Excerpt(s): Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) the cause of which remains as yet unknown. Many studies have supported the hypothesis of a viral etiology of the disease, but none of the known viruses tested has proved to be the causal agent sought: a review of the viruses sought for several years in MS has been compiled by E. Norrby (1) and R. T. Johnson (2). Concomitantly, the possibility of an exogenous and/or infectious factor is suggested by the existence of localized epidemics or "clusters" of MS, as have been observed in the Faro Islands between 1943 and 1960 (3), in Sardinia (4), in Norway (5), and also by studies on migrant populations (6). Among all the exogenous factors suggested, viruses have been most often studied, and a viral etiology is traditionally called to mind. Web site: http://www.delphion.com/details?pn=US05800980__ •

Diagnosis of amyotrophic lateral sclerosis by neurotrophic factors Inventor(s): Appel; Stanley H. (Houston, TX) Assignee(s): Baylor College of Medicine (Houston, TX) Patent Number: 4,699,875 Date filed: August 23, 1985 Abstract: The present invention is based on the discovery that amyotrophic lateral sclerosis (ALS), Parkinson disease and Alzheimer disease are due to lack of a disorderspecific neurotrophic hormone. Diagnosis is accomplished by assaying hormones specific for a particular neuronal network or system: the motor neurotrophic hormones from muscle in the motor neural system are used to diagnose and treat ALS, dopamine neurotrophic hormones from striatum in the migrostriatal neural system are used to diagnose and treat parkinsonism, and cholinergic neurotrophic hormones released from the cortex and hippocampus which are specific for cholinergic neorons of the nucleus basalis and septal nucleus are used to diagnose and treat Alzheimer's disease. With tissue culture, the presence or absence of specific neurotrophic hormones can be assessed in ALS, parkinsonism, and Alzheimer disease. If there is a deficiency, extracted and purified neurotrophic hormones specific to the particular neuronal network or system can be injected in ALS and Alzheimer disease and in parkinsonism. Excerpt(s): The field of the invention is the diagnosis and treatment of ALS, Parkinson disease, and Alzheimer disease by neurotrophic factors. The causes of some of the most common and most devastating diseases of the nervous system remain unknown. Prominent on this list are amyotrophic lateral sclerosis (ALS), parkinsonism, and Alzheimer disease. Each of these conditions is presently considered to be degenerative disorder of unknown origin. In each, viral or immunological causes have been suggested, but no convincing reproducible data support the presence of an infectious agent or a cell-mediated or humoral immune factor. All three diseases reflect pathological change in a relatively limited network within the peripheral or central

Patents 383

nervous system, or both. Amyotrophic lateral sclerosis is the name given to a complex of disorders that compromise upper and lower motor neurons. Patients may present with progressive spinal muscular atrophy, progressive bulbar palsy, primary lateral sclerosis, or a combination of these conditions. The majority of patients have components of all three types, but each form may represent the sole clinical manifestation of motor system involvement [1]. (Reference numbers are to references listed in the section entitled "References Cited"). At the present time in the United States, the incidence of the combined disease is approximately 1.8 per 100,000 [2] and its prevalence is between 5 and 7 per 100,000. Males are affected more commonly than females, the ratio of males to females being 1.6:1. Approximately 10% of the cases are familial [3]. Onset may occur at any age but is most common in the later decades, and the incidence appears to increase with age. The mean age of onset is 66 years [2]. Web site: http://www.delphion.com/details?pn=US04699875__ •

Dietary calcium as a supplement to vitamin D compound treatment of multiple sclerosis Inventor(s): Cantorna; Margherite T. (Middleton, WI), DeLuca; Hector F. (Deerfield, WI), Humpal-Winter; Jean (Poynett, WI) Assignee(s): Wisconsin Alumni Research Foundation (Madison, WI) Patent Number: 6,479,474 Date filed: July 8, 1999 Abstract: A method of and composition for diminishing multiple sclerosis symptoms are disclosed. In one embodiment, the method comprises the step of administrating an amount of calcium and a vitamin D compound effect to diminish multiple sclerosis symptoms. In another embodiment, the invention is a pharmaceutical composition comprising an amount of calcium and vitamin D compound effective to diminish multiple sclerosis symptoms. Excerpt(s): Vitamin D is a recent arrival in the roster of agents that are known to regulate the immune system. Vitamin D is converted in a two-step process to the hormone, 1,25-dihydroxycholecalciferol (1,25-(OH).sub.2 D.sub.3).sup.1 that is a key factor in regulating serum calcium, phosphorus and bone (DeLuca, 1997). This hormone acts in a steroid hormone-like mechanism through a nuclear receptor, the vitamin D receptor (VDR), which is a member of the steroid hormone receptor superfamily (Pike, 1991; Ross, et al., 1993). The discovery of VDR in peripheral blood lymphocytes (Bhalla, et al., 1983; Provvedini, et al., 1983) is a factor that led to the realization that 1,25(OH).sub.2 D.sub.3 is a significant regulator of the immune system. The most striking evidence of a role for 1,25-(OH).sub.2 D.sub.3 as an immune system regulator comes from in vivo experiments. 1,25-(OH).sub.2 D.sub.3 can prevent the development of EAE (Cantorna, et al., 1996 and U.S. Pat. No. 5,716,946; Lemire and Archer, 1991), experimental arthritis (Cantorna, et al., 1998a), and 1,25-(OH).sub.2 D.sub.3 can markedly inhibit transplant rejection (Bouillon, et al., 1995; Hullett, et al., 1998).sup.1 Abbreviations: central nervous system, CNS; 1,25-dihydroxycholecalciferol, 1,25(OH).sub.2 D.sub.3; experimental autoimmune encephalomyelitis, EAE; glyceraldehyde3-phosphate dehydrogenase, lymph node, LN; multiple sclerosis, MS; interferon.gamma., IFN-.gamma. interleukin-4, IL-4; transforming growth factor.beta.1, TGF-.beta.1; tumor necrosis factor-.alpha., TNF-.alpha. type-1 helper, Th1; type-2 helper, Th2; vitamin D receptor, VDR. The present invention is a method of more effectively treating multiple sclerosis patients. The method comprises the step of administration of

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an amount of calcium that renders a vitamin D compound effective in preventing or markedly reducing MS symptoms. Preferably, this amount of calcium is 0.5-2 g per patient per day. Most preferably, the amount is between 1 and 2 g of calcium as a salt with a variety of anions, e.g. CO.sub.3.sup.=, PO.sub.4.sup.=, Cl.sub.2.sup.- acetate, gluconate, citrate, etc. Web site: http://www.delphion.com/details?pn=US06479474__ •

Fatty aldehydes in the treatment of Multiple Sclerosis Inventor(s): Horrmann; Wilhelm (Obb, DE) Assignee(s): none reported Patent Number: 4,505,933 Date filed: March 1, 1983 Abstract: This application relates to the administering of fatty aldehydes (and acids) to patients suffering from Multiple Sclerosis, for therapeutic purposes. Excerpt(s): Multiple Sclerosis is a widespread and severe disease of the central nervous system. The patients are first affected mostly in their twenties or thirties. The disease is nearly always progressive, interrupted only by temporary remissions. Pathological alterations in the white substance of the nervous system is followed by impairment of eyesight, ataxia, tremor, paralysis and other neuological disorders. After years or decades of suffering the disease usually results in invalidity or death. Many efforts of the medical sciences to explore the cause of the disease have failed so far. It is the subject of this invention that Multiple Sclerosis is caused by a structural deficiency in the bodies own plasmalogen, fatty aldehyd and fatty acids system which is the basis for inflammatory processes leading to sclerotic focuses within the central nervous system, and that a substitution therapy is therefor indicated. Web site: http://www.delphion.com/details?pn=US04505933__

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Immunoassay of free kappa light chains for the detection of multiple sclerosis Inventor(s): Rudick; Richard A. (Rochester, NY), Herndon; Robert M. (Rochester, NY), Bidlack; Jean M. (Rochester, NY) Assignee(s): University of Rochester (Rochester, NY) Patent Number: 4,792,529 Date filed: October 18, 1985 Abstract: Multiple sclerosis (MS) is diagnosed by determining with a quantitative immunoassay the quantity of free kappa light chains in the cerebrospinal fluid of a patient. The immunoassay is preferably a radioimmunoassay. In carrying out the immunoassay, the free kappa light chains are combined with antiserum specific thereto. This method of diagnosing MS has high sensitivity in distinguishing between normal patients and patients affected with MS. Excerpt(s): This invention relates to the field of diagnostic radioimmunoassays. More particularly, the invention relates to the detection of multiple sclerosis (MS) by quantifying the presence of free kappa light chains in a patient's cerebral spinal fluid (CSF). Various lines of evidence have shown that IgG is increased in CSF selectively

Patents 385

relative to other proteins. This may be due to synthesis of antibodies within the nervous system. A selective increase in CSF IgG has been observed so consistently in MS that the increase in IgG has become the best known laboratory test for confirmation of the diagnosis. The finding is nonspecific, however, in that a substantial proportion of control patients with CNS infections or inflammatory diseases also have elevated CSF IgG. Similarly, free kappa and lambda light chains also have been reported in patients with MS. Light chains (either kappa or lambda, but not both) are components of all classes of immunoglobulins, wherein they combine with the heavy chains to form a specific immunoglobulin. Light chains also may exist in a free state (i.e., not bound to a heavy chain) in patients with various forms of myeloma tumors. These free light chains are commonly known as Bence-Jones proteins. The kappa and lambda light chains form individual Bence-Jones proteins which differ in their amino acid sequence. Web site: http://www.delphion.com/details?pn=US04792529__ •

Isolated nucleotide sequences associated with multiple sclerosis or rheumatoid arthritis and a process of detecting Inventor(s): Komurian-Pradel; Florence (Saint Cyr au Mont d'Or, FR), Jolivet-Reynaud; Colette (Bron, FR), Bedin; Frederic (Lyons, FR), Beseme; Frederic (Villefontaine, FR), Paranhos-Baccala; Glaucia (Lyons, FR), Perron; Herve (Lyons, FR), Mandrand; Bernard (Villeurbanne, FR) Assignee(s): Bio Merieux (Marcy l'Etoile, FR) Patent Number: 6,582,703 Date filed: November 26, 1997 Abstract: The invention provides viral material and nucleotide fragments associated with multiple sclerosis and/or rheumatoid arthritis for use in methods of diagnosis, prophylaxis, and therapy. Excerpt(s): Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), the cause of which remains as yet unknown. Many studies have supported the hypothesis of a viral aetiology of the disease, but none of the known viruses tested has proved to be the causal agent sought: a review of the viruses sought for several years in MS has been compiled by E. Norrby (1) and R. T. Johnson (2). The discovery of pathogenic retroviruses in man (HTLVs and HIVs) was followed by great interest in their ability to impair the immune system and to provoke central nervous system inflammation and/or degeneration. In the case of HTLV-1, its association with a chronic inflammatory demyelinating disease in man (48) led to extensive investigations to search for an HTLV1-like retrovirus in MS patients. However, despite initial claims, the presence of HTLV-1 or HTLV-like retroviruses was not confirmed. Web site: http://www.delphion.com/details?pn=US06582703__

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Medicaments for the treatment of restenosis and arterial sclerosis Inventor(s): Tomaru; Takanobu (Tokyo, JP) Assignee(s): Tobishi Pharmaceutical Co., Ltd. (Tokyo, JP) Patent Number: 5,595,974 Date filed: November 9, 1995

386 Sclerosis

Abstract: A medicament for the treatment and/or prophylaxis of restenosis and arterial sclerosis after percutaneous transluminal angioplasty, characterized in that the medicament contains batroxobin as an effective component. Excerpt(s): The present invention relates to a medicament for the treatment and/or prophylaxis of restenosis and arterial sclerosis after percutaneous transluminal angioplasty, which contains batroxobin as an effective component. It has been considered that intima pachymenia in the wall of blood vessel after the percutaneous transluminal angioplasty which has been extended as a method for treating of arteriosclerotic intima pachymenia, myocardial infarction and angina pectoris is caused by endotherial injury of blood vessel, and it has been reported that intima pachymenia will be formed in such a process that smooth muscle cell wanders from media of blood vessel and repeats its proliferation in the intima. However, this phenomenon has hardly been elucidated physiologically and pharmacologically. Although it has been known that platelet-derived growth factor (PDGF) has an action for accelerating wandering of smooth muscle cell and its proliferation, there are no reports confirming that only the factor is directly involved in arteriosclerotic intima pachymenia or re-pachymenia after percutaneous transluminal angioplasty. Web site: http://www.delphion.com/details?pn=US05595974__ •

Method and pharmaceutical composition for treating leukoencephalitic demyelinization clinical patterns of autoimmune origin, particularly multiple sclerosis Inventor(s): Frank; Tibor (Budapest, HU), Szporny; Laszlo (Budapest, HU), Szegvari; Zsuzsanna (Szeged, HU), Bozoky; Bela (Szeged, HU), Tigyi; Gabor (Irvine, CA), Hajos; Gyorgy (Budapest, HU), Forgacs; Lilla (Budapest, HU) Assignee(s): Richter Gedeon Vegyeszeti Gyar Rt. (Budapest, HU) Patent Number: 4,882,336 Date filed: August 17, 1988 Abstract: A method of treating demyelinization clinical patterns of autoimmune origin, particularly multiple sclerosis. The pharmaceutical composition makes use of ethyl (+)apovincaminate as the active ingredient. Excerpt(s): The invention relates to a method for treating demyelinization clinical patterns of autoimmune origin, particularly multiple sclerosis. The invention further relates to a pharmaceutical composition which is useful for treating demyelinization clinical patterns of autoimmune origin, particularly the multiple sclerosis. The invention also relates to the use of ethyl (+)-apovincaminate for the preparation of a pharmaceutical composition which is useful for treating demyelinization clinical patterns of autoimmune origin, particularly multiple sclerosis. Web site: http://www.delphion.com/details?pn=US04882336__

Patents 387

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Method for diagnosing amyotrophic lateral sclerosis Inventor(s): Appel; Stanley H. (Houston, TX), Stefani; Enrico (Houston, TX), Smith; R. Glenn (Houston, TX) Assignee(s): Baylor College of Medicine (Houston, TX) Patent Number: 5,851,783 Date filed: February 13, 1995 Abstract: A method and kit are described that are useful in the diagnosis of amyotrophic lateral sclerosis or the evaluation of its progression. According to the method, a purified voltage-sensitive calcium channel complex is contacted with a biological fluid obtained from a person suspected of having, or known to have, amyotrophic lateral sclerosis. The voltage-sensitive calcium channel is of a type that ALS sera selectively reacts with. The reaction takes place for a time and under conditions sufficient for the calcium channel complex and anti-calcium channel complex antibodies that may be present in the biological fluid to form an antigen/antibody complex. The presence or absence of the antigen/antibody complex is then determined. Excerpt(s): This invention relates to the diagnosis of amyotrophic lateral sclerosis. Additional evidence for autoimmunity in the animal models is the ability of immunoglobulins from affected guinea pigs to passively transfer physiological abnormalities of the neuromuscular junction into mice. Following the globulin injections, there is an increase in miniature end plate potential (MEPP) frequency, with normal MEPP amplitude, decay time constant, and resting membrane potential. Similar passive transfer experiments using human immunoglobulins also demonstrate an increased MEPP frequency. The present invention relates, in one aspect, to an improvement in a procedure for diagnosis of amyotrophic lateral sclerosis, or the evaluation of the progression of that disease. The improvement involves determining, in an immunoassay, the presence in a biological fluid obtained from person having ALS of antibodies that selectively react, or cross-react, with the alpha.sub.1 subunit of L-type skeletal muscle calcium channel. In another aspect of the invention, purified L-type skeletal muscle calcium channel is contacted with a biological fluid obtained from an individual having ALS. The reaction takes place for a time and under conditions sufficient for the channel and anti-channel antibodies to form an antigen/antibody complex. The presence or absence of the complex is then determined in order to aid in ALS diagnosis or prognosis. In another aspect, the invention involves a method for determining ALS specific antibodies from a biological fluid obtained from an individual having ALS. The method comprises the steps of providing the ALS specific antibodies; selectively insolubilizing said ALS specific antibodies by an antibody/antigen reaction; determining the presence or absence of insolubilized ALS specific antibodies by means of a detectable label; and correlating the presence or absence of said detectable label with the presence or absence of the ALS specific antibodies. Web site: http://www.delphion.com/details?pn=US05851783__

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Method for treating amyotrophic lateral sclerosis Inventor(s): Brooks; Benjamin Rix (4818 Fond Du Lac Trail, Madison, WI 53705) Assignee(s): none reported Patent Number: 5,780,489 Date filed: August 21, 1996

388 Sclerosis

Abstract: The invention provides a method for treating amyotrophic lateral sclerosis in a patient which comprises administering to the patient an effective amount of a noncysteine glutathione precursor or a glutathione derivative so as to increase the intracellular glutathione levels and alleviate a symptom of amyotrophic lateral sclerosis. The non-cysteine substrate may be a thiazolidine-4-carboxylate analog, a thiazolidine-4carboxylate analogs ester, or a pharmaceutically acceptable salt thereof. Excerpt(s): The present invention relates to a method for the treatment of amyotrophic lateral sclerosis (ALS). In particular, it relates to the use of either glutathione (GSH) derivatives such as glutathione alkyl monoesters or glutathione diesters or non-cysteine glutathione precursors to increase intracellular GSH levels in neurons, particularly motor neurons. GSH derivatives or non-cysteine glutathione precursors protect neurological cells from oxidative damage, thereby preventing, reducing the progression of, alleviating the symptoms of and/or treating ALS. Preferably, the non-cysteine glutathione precursor is a thiazolidine-4-carboxylate analog, such as L-2oxothiazolidine-4-carboxylate. Clinical signs of both lower and upper motor neuron involvement are required for a definitive diagnosis. Symptoms can begin either in bulbar or limb muscles (L P Rowland, 1995). The median age of onset is 55 and the median survival is less than five years. One of the characteristics is the progressive loss of muscle strength. Age and gender are the only risk factors repeatedly documented in epidemiological studies (J F Kurtzke, 1991, "Risk Factors in Amyotrophic Lateral Sclerosis," Adv Neurol 56: 245-270). There is a slight male predominance (3:2 male to female ratio) in sporadic ALS. There is no racial or geographic predisposition. The cause of sporadic ALS is unknown. Many causes of ALS have been proposed including atypical poliovirus infection, intoxication by exogenous metal-toxins, autoimmune processes targeting motor neurons, cytoskeletal abnormalities, trophic factor deprivation, mitochondrial dysfunction, and toxicity from excess excitation of the motor neuron by transmitters such as glutamate (L P Rowland, "Ten central themes in a decade of ALS research," in Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases, ed. L P Rowland, Advances in Neurology (Raven Press, 1992), 3-23). Given the clinical and epidemiological similarity between sporadic and FALS, it is a reasonable premise that an understanding of the familial disease will illuminate possible pathophysiological mechanisms in sporadic ALS. Web site: http://www.delphion.com/details?pn=US05780489__ •

Method for treating amyotrophic lateral sclerosis and a therapeutic agent therefor Inventor(s): Kaji; Ryuji (19-7, Sen-cho 2-chome, Ootsu-shi, Shiga-ken, 520-0863, JP) Assignee(s): none reported Patent Number: 5,964,224 Date filed: February 6, 1998 Abstract: A method for treating amyotrophic lateral sclerosis (ALS) and a therapeutic agent therefor are provided. The therapeutic agent comprising ultra-high doses of methylcobalamin (for example, from about 15 mg to about 500 mg per day) is administered to a patient with ALS intramuscularly, subcutaneously or intravenously for from about a week to about 2 years to ameliorate or improve both the clinical symptoms and an objective clinical measure in ALS or retard the muscle weakness caused by ALS.

Patents 389

Excerpt(s): The present invention relates to a method for treating amyotrophic lateral sclerosis (ALS) and a therapeutic agent therefor. Patients with ALS have no cure or treatment effective in improving clinical signs or parameters, although riluzole has been reported to prolong life without tracheostomy by 1-3 months in a subgroup of ALS. Other agents such as dextromethorphan, superoxide dismutase, vitamin E, ciliary neurotrophic factor have not yet convincingly shown their potency in improving the clinical symptoms or prolonging life in patients with ALS. Anecdotal or preliminary observations have also been made on the beneficial effects of cyclophosphamide and IGF-1 (insulin-like growth factor-1). It is an object of the present invention to provide a safe, simple and effective method and therapeutic agent for ameliorating or improving the clinical signs and symptoms of ALS in humans. Web site: http://www.delphion.com/details?pn=US05964224__ •

Method for treating multiple sclerosis Inventor(s): Baker; David (London, GB), Turk; John Leslie (London, GB), Feldmann; Marc (London, GB) Assignee(s): Kennedy Institute of Rheumatology (GB) Patent Number: 5,958,409 Date filed: March 13, 1996 Abstract: A method for treating multiple sclerosis, through the administration of antitumour necrosis factor antibody, of soluble tumour necrosis factor receptor or of a compound capable of blocking tumour necrosis factor production, its effects and/or tumour necrosis factor receptor signal transduction, is disclosed. The method can be used to aid in therapy for humans and other mammals. Excerpt(s): Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system which usually presents in the form of recurrent attacks of focal or multifocal neurologic dysfunction. Attacks occur, remit, and recur, seemingly randomly over many years. Remission is often incomplete and as one attack follows another, a stepwise downward progression ensues with increasing permanent deficit. Clinical disease is associated with blood-brain barrier dysfunction; infiltration of the central nervous system by mononuclear cells, mainly macrophages and T lymphocytes, and serum products; and demyelination (Harris J. O., et al., Ann. Neurol. 29:548 (1991); Kermonde A. G., et al., Brain 113:1477 (1990)). Presently the nature of autoantigens responsible for multiple sclerosis is not known, nor is the action which triggers the autoimmune response. One popular theory involves the similarity of a viral protein to a self antigen, which results in autoreactive T cells or B cells recognizing a self antigen. Whereas B-lymphocytes produce antibodies, thymus-derived or "T-cells" are associated with cell-mediated immune functions. T-cells recognize antigens presented on the surface of cells and carry out their functions in association with "antigen-presenting" cells. Web site: http://www.delphion.com/details?pn=US05958409__

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Method for treating multiple sclerosis Inventor(s): Hunter; William L. (Vancouver, CA) Assignee(s): Angiotech Pharmaceuticals, Inc. (Vancouver, CA) Patent Number: 6,495,579 Date filed: June 1, 1998 Abstract: Methods and compositions for treating or preventing inflammatory diseases such as psoriasis or multiple sclerosis are provided, comprising the step of delivering to the site of inflammation an anti-microtubule agent, or analogue or derivative thereof. Excerpt(s): The present invention relates generally to compositions and methods for treating or preventing inflammatory diseases. Inflammatory diseases, whether of a chronic or acute nature, represent a substantial problem in the healthcare industry. Briefly, chronic inflammation is considered to be inflammation of a prolonged duration (weeks or months) in which active inflammation, tissue destruction and attempts at healing are proceeding simultaneously (Robbins Pathological Basis of Disease by R. S. Cotran, V. Kumar, and S. L. Robbins, W. B. Saunders Co., p. 75, 1989). Although chronic inflammation can follow an acute inflammatory episode, it can also begin as an insidious process that progresses with time, for example, as a result of a persistent infection (e.g., tuberculosis, syphilis, fungal infection) which causes a delayed hypersensitivity reaction, prolonged exposure to endogenous (e.g., elevated plasma lipids) or exogenous (e.g., silica, asbestos, cigarette tar, surgical sutures) toxins, or, autoimmune reactions against the body's own tissues (e.g., rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis). Chronic inflammatory diseases therefore, include many common medical conditions such as rheumatoid arthritis, restenosis, psoriasis, multiple sclerosis, surgical adhesions, tuberculosis, chronic inflammatory lung diseases (e.g., asthma, pneumoconiosis, chronic obstructive pulmonary disease, nasal polyps and pulmonary fibrosis), periodontal disease (i.e., periodontitis) and polycystic kidney disease. Psoriasis is a common, chronic inflammatory skin disease characterized by raised, inflamed, thickened and scaly lesions, which itch, burn, sting and bleed easily. In approximately 10% of patients, psoriasis is accompanied by pronounced arthropathic symptoms that are similar to the changes seen in rheumatoid arthritis. Approximately 2 to 3% of the U.S. population suffers from psoriasis, with 250,000 new cases being diagnosed each year. Web site: http://www.delphion.com/details?pn=US06495579__

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Method for treating multiple sclerosis Inventor(s): Panetta; Jill A. (Zionsville, IN), Kingston; Ann E. (Camberley, GB) Assignee(s): Eli Lilly and Company (Indianapolis, IN) Patent Number: 5,633,283 Date filed: January 23, 1995 Abstract: Provided is a method of treating multiple sclerosis employing certain phenol and benzamide compounds. Excerpt(s): This invention provides a method of treating multiple sclerosis in mammals. Multiple sclerosis was first described as a clinical entity in 1868. Clinically, it is a highly variable disease, which usually begins between the second and fifth decades of life. The most common signs of multiple sclerosis are sensory and visual motor dysfunction. In

Patents 391

the chronic form the patient has periods of remission, but with each remission there is greater neurological dysfunction. Macroscopically, multiple sclerosis involves lesions of 1 to 4 cm called plaques scattered throughout the white matter of the central nervous system. Microscopically, the disease is characterized by a breakdown of the nervous system's myelin sheath. There is also a loss of myelin basic protein in the area of the lesions. Web site: http://www.delphion.com/details?pn=US05633283__ •

Method for treating multiple sclerosis Inventor(s): Harris; Richard Y. (381 Rampart Range Rd., Woodland Park, CO 80863) Assignee(s): none reported Patent Number: 5,679,715 Date filed: June 7, 1995 Abstract: The invention relates to a method of treating multiple sclerosis comprising administering an effective amount of (R)-(-)-N,2-dimethyl-N-2-propynylphenethylamine alone or in conjunction with an effective amount of interferon beta or an effective amount of amantadine. Excerpt(s): This invention relates to a method for treating multiple sclerosis and, more particularly, the use of (R)-(-)-N,2-dimethyl-N-2-propynylphenethylamine, commonly known as deprenyl, a monoamine oxidase inhibitor drug (MAO-inhibitor). Multiple sclerosis (MS) is a crippling disease that affects over 250,000 Americans. MS is characterized by neuron deterioration in the central nervous system with the associated lose of the insulating myelin sheath from around the axons of the nerve cells. This loss of myelin results in loss of electrical insulation and the "short-circuiting" of the electrical pathways mediated by the affected nerves and progressive neurological impairment. MS usually affects young adults in what should be the healthiest, most productive years of their lives and affects women more often than men. The symptoms of MS include pain and tingling in the arms and legs; localized and generalized numbness, muscle spasm and weakness; bowel and bladder dysfunction; difficulty with balance when walking or standing; and fatigue. In most cases, people afflicted with MS lose the ability to stand and/or walk entirely. Optic neuritis may occur episodically throughout the course of the disease. The symptoms are exacerbated by physical fatigue or emotional stress. Web site: http://www.delphion.com/details?pn=US05679715__

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Method for treating progressive systemic sclerosis Inventor(s): Prudden; John F. (Upper Nyack, NY) Assignee(s): Lescarden Ltd. (New York, NY) Patent Number: 4,444,752 Date filed: September 13, 1982 Abstract: Disclosed herein is a method for the treatment of progressive systemic sclerosis by the oral administration of a pharmaceutical formulation containing finely divided cartilage powder.

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Excerpt(s): This invention pertains to a method for the treatment of progressive systemic sclerosis by the oral administration of finely divided animal, fish or reptilian cartilage. Progressive systemic sclerosis (PSS) is a connective tissue disease that ultimately leads to fibrosis involving the skin (scleroderma) and widely disseminated internal organs including the gastrointestinal tract, lungs, heart, and kidney. A chronic disorder of unknown etiology, PSS is often initially identified by the appearance of tight, firm skin on the patient sometime prior to the apparent involvement of internal organs. In some patients, internal disease can occur in the absence of skin involvement. PSS is more common in women. The terms PSS, scleroderma and dermatosclerosis are used interchangeably to identify this disorder. In the advanced stages of the disease the skin becomes firm, thickened and leathery in appearance and is tightly bound to the underlying subcutaneous tissue. Taughtness of the skin over the fingers, and arms may limit full extension of these organs. Although many drugs have been used to treat PSS, there is no known cure and no single drug has produced any prolonged consistent therapeutic benefit. An article by Prudden and Balassa in "Seminars in Arthritis and Rheumatism" (Vol. III, No. 4-Summer 1974, pp. 287-321) discloses (pp. 317-319) the administration to a patient afflicted with PSS (of a five percent (5%) solution of a sterile high termperature aqueous cartilage extract) by subcutaneous injection. In this trial the patient received between about 50 and 400 cc of the 5% extract per month. The article reports that some improvement was noted in the patient's skin flexibility and thickness, but does not indicate any significant alleviation of the limited range of motion in certain body appendages that is a common feature of the disease. Also it did not comment on any improvement or effect on gastric-intestinal function or respiratory efficiency, both of which are affected by this systematic malady. The pharmaceutical formulation used by Prudden, et al. in "Seminars in Arthritis and Rheumatism" was prepared by extracting finely divided cartilage powder under high temperature and high pressure in an autoclave. All treatment was given via the parenteral route. The patient received the equivalent of between about 21/2 and 20 grams per month of finely divided cartilage powder (in divided doses administered at spaced apart intervals) through the parenteral route. In most instances it was necessary to admit the patient to the hospital to administer the large volumes of liquid medication that were required. The article by Prudden et al suggests that parenteral administration of the active agent in a liquid dosage form is required to facilitate transport of the agent throughout the body. Web site: http://www.delphion.com/details?pn=US04444752__ •

Method for treatment of amyotrophic lateral sclerosis comprising administration of DMP Inventor(s): Salazar-Grueso; Edgar F. (Chicago, IL) Assignee(s): Arch Development Corporation (Chicago, IL) Patent Number: 5,229,394 Date filed: July 30, 1990 Abstract: A method for treating ALS (Amyotrophic Lateral Sclerosis) is disclosed. The inventive method comprises the administration of controlled dosages of dextromethorphan in therapeutically effective amounts in a pharmaceutically acceptable vehicle Dextromethorphan (DMP) is a dimethylaminomethyl-substituted phenol, a sigma receptor antagonist known also as d-3-methoxy-N methylmorphinan, a d-isomer of the codeine analog, levorphanol. The inventive method has proven useful in controlling the progression of ALS in afflicted patients.

Patents 393

Excerpt(s): This invention relates to a method for treatment of Amyotrophic Lateral Sclerosis and other neurodegenerative disorders. This invention further relates to a method for treatment of Amyotrophic Lateral Sclerosis and other neurodegenerative disorders by administering a medicament in controlled doses of therapeutically effective amounts. Amyotrophic Lateral Sclerosis (ALS) is a progressive degenerative disease of the motor system which is usually relentlessly progressive, leading to death in half the cases within three years of onset. It is related to a group of diverse motor-system diseases which include Huntington's Chorea, Parkinson's disease and Alzheimer's disease. Numerous agents have been tried therapeutically in ALS, but none have been unequivocally demonstrated to benefit the disorder. This suggested to us that the LBMAA might be affecting a neuroreceptor type responsible for the ALS symptoms. It is known that other excitatory amino acids can bind in vitro to neuronal receptors. It has further been demonstrated in recent years that the dextrorotary opioid derivative dextromethorphan (DMP) binds to excitatory amino acid receptors in the brain. DMP has long been known as a highly effective cough suppressant. We, therefore, theorized that since a neuro-excitatory receptor in the brain appears to be adversely affected by LBMAA and may produce the motor degeneration characteristic of ALS, the action of LBMAA with the involved receptors might be antagonized by an agent such as DMP that suppresses central synaptic transmission. Web site: http://www.delphion.com/details?pn=US05229394__ •

Method for treatment of multiple sclerosis and related disease states Inventor(s): DeLack; Elaine Alice (17317 E. Lake Goodwin Rd., Stanwood, WA 98292) Assignee(s): none reported Patent Number: 6,277,402 Date filed: June 25, 1999 Abstract: A method for treatment of multiple sclerosis and related disease states. A histamine H2 mimicking agent is administered in an amount which is effective to stimulate production of a cyclic AMP in the body. A phosphodiesterase inhibitor is administered in conjunction with the histamine H2 mimicking agent to conserve the cyclic AMP which is thus produced. It is believed that the increased cyclic AMP levels serve to maintain the patient's myelin against self degeneration. The histamine H2 mimicking agent may be histamine phosphate and the phosphodiesterase inhibitor may be caffeine. The histamine H2 mimicking agent and the phosphodiesterase inhibitor may be mixed in a gel and administered using a transdermal patch. Excerpt(s): The present invention relates generally to methods for the treatment of multiple sclerosis and related disease states, and, more particularly, to a method for alleviating/controlling the symptoms associated with multiple sclerosis and related disease states, by administration of compositions which induce an increased presence of cyclic AMP in the body so as to reduce or reverse demyelination of the nervous system. Multiple sclerosis (referred to from time-to-time hereinafter as "MS") is a chronic degenerative disease of the central nervous system, characterized by demyelination of the nerve axons. Symptoms include varying degrees of fatigue, numbness, tremors/muscle spasms and paralysis, coupled with a heightened susceptibility to heat and other environmental stressors. Currently, approximately 2,500,000 people worldwide have been diagnosed as having multiple sclerosis. Onset of the disease usually occurs between 20 and 40 years of age. It is recognized that MS occurs in at least two general types, i.e., "remissive-relapsive", in which acute exacerbations are separated

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by periods of partial recovery, and "chronic-progressive", in which the symptoms continue generally unrelieved and there is a progressive deterioration of the patient's condition that may eventually result in total debilitation. Web site: http://www.delphion.com/details?pn=US06277402__ •

Method for treatment of systemic sclerosis and related fibrotic diseases Inventor(s): Postlethwaite; Arnold E. (Memphis, TN), Carbone; Laura (Memphis, TN), Seyer; Jerome M. (Virginia Beach, VA), McKown; Kevin (Memphis, TN), Kang; Andrew H. (Memphis, TN) Assignee(s): The University of Tennessee Research Corporation (Knoxville, TN) Patent Number: 5,962,025 Date filed: July 16, 1996 Abstract: The present invention is directed to a method and pharmaceutical formulations for the treatment of systemic sclerosis in mammals, by oral administration of collagen, including type I collagen, or biologically active peptide fragments thereof. Excerpt(s): This invention relates generally to treatments for systemic sclerosis and related fibrotic diseases. More specifically, the invention relates to the oral administration of collagen, preferably type I collagen, to treat systemic sclerosis and related fibrotic diseases. Systemic Sclerosis And Related Fibrotic Diseases. Systemic sclerosis, more commonly referred to as scleroderma, is an uncommon autoimmune disorder of unknown etiology. The disease state is characterized by widespread vascular injury, perivascular and tissue accumulation of CD4+ T cells and monocytes, and excessive extracellular matrix deposition in skin and internal organs. More particularly, manifestations of systemic sclerosis include lowered IL-10 production by peripheral blood mononuclear cells and CD4.sup.+ CD26.sup.+ levels. Improvement of systemic sclerosis has been traditionally measured by application of the Modified Rodnan Skin Score and Modified Health Assessment Questionnaire. Related disease states, including primary and secondary Raynaud's phenomena, and the severity of such states can be identified by these same characteristics and measurements. Web site: http://www.delphion.com/details?pn=US05962025__

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Method of diagnosing multiple sclerosis and other diseases by measurement of blood plasma protein streaming potential Inventor(s): Swank; Roy L. (2211 SW. 1st Ave., Portland, OR 97201), Goodwin; James W. (Chatleigh House, 6 Warminster Road, Limpley Stoke, Bath, BA36JD, GB2) Assignee(s): none reported Patent Number: 4,810,657 Date filed: October 19, 1987 Abstract: Multiple sclerosis and other diseases are diagnosed by first coating a plasm protein-adsorbing surface with a patient's blood plasm protein in an electrolyte fluid, and measuring the streaming potential of the protein-coated surface. Next, a challenge material such as a fatty acid having from 6 to 24 carbon atoms is added to the protein in electrolyte fluid mixture to alter the electro-kinetic potential of the adsorbed blood plasm protein layer. The streaming potential of the altered layer then is measured. The

Patents 395

streaming potential results thus obtained are compared with measurements of the streaming potential characteristic of a surface similarly treated, but using normal blood plasma protein. Excerpt(s): This invention relates to a method of diagnosing diseases by noting the streaming potential characteristics of a surface coated with the blood plasma protein of the patient. The phenomenon of streaming potential is observed when a charged surface is placed in contact with water or an electrolyte solution such as a salt solution. In such a situation, there is a diffuse layer of ions held close to the surface which exactly balances the charge of the charged surface. If the fluid is caused to flow parallel to the charged surface, a charge separation is produced which gives rise to an electric potential difference. This is known as streaming potential. It is to be noted, however, that there is a diffuse distribution of the attracted ions close to the charged surface, with the result that the electric potential falls off with increasing distance from the surface. When the fluid is caused to move across the surface, resulting in the creation of a streaming potential, the ions comprising the surface layer are stuck to the charged surface and don't move. The first ion movement is just outside this layer at a position known as the shear plane. Web site: http://www.delphion.com/details?pn=US04810657__ •

Method of hormone treatment for patients with symptoms consistent with multiple sclerosis Inventor(s): Chein; Edmund Y. M. (Beverly Hills, CA) Assignee(s): Everyoung Technologies, Inc. (Palm Springs, CA) Patent Number: 6,187,750 Date filed: August 25, 1999 Abstract: A method for treating patients having symptoms consistent with multiple sclerosis comprising administering a regimen of doses of human growth hormone of less than 0.5 mg/day. In one aspect, the method includes replenishing one or more of melatonin, thymus, thyroid, adrenal and sex hormones to predetermined levels in conjunction with the human growth hormone. Excerpt(s): The invention relates to hormone therapy as a treatment for patients with symptoms consistent with multiple sclerosis. It is known that the levels of a variety of hormones drop substantially with age. These include human growth hormone, sex hormones, pineal, adrenal, thyroid, and thymus hormones. Hormonal replenishment methods employed as anti-aging treatments have been developed. An example of such method is described in U.S. Pat. No. 8,855,920. The utility of this method in connection with certain degenerative diseases, often associated with hormonal deficiencies due to aging, is also known in the art. In contrast, Multiple Sclerosis (MS) is not a disease associated with degenerative conditions associated with old age. Rather, MS strikes mainly young adults and is the most common neurologic cause of disability in that age group. Overall, MS affects approximately 300,000 Americans. Web site: http://www.delphion.com/details?pn=US06187750__

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Method of treating multiple sclerosis Inventor(s): Drury; Finvola (25 Colby St., Rochester, NY 14610), Bihari; Bernard (29 W. 15th St., New York, NY 10011) Assignee(s): none reported Patent Number: 6,586,443 Date filed: September 27, 1994 Abstract: Multiple sclerosis in a human patient is treated by the administration via a pharmacologically effective route of an essentially pure opiate receptor antagonist, preferably an essentially pure opiate receptor antagonist exhibiting a substantially higher blocking effectiveness against Mu opiate receptor sites than against Delta receptor sites, exempliefied by Naltrexone and Naloxone, at a low dose concentration which produces therapeutic results corresponding to those produced by Naltrexone when administered in the range of about 1 mg to about 10 mg and at a lelel at which Delta blocking activity is small while Mu blocking activity is significant and most preferably substantially exclusive. Excerpt(s): This invention relates to the treatment of certain chronic diseases; namely, chronic infections caused by herpes virus, both herpes simplex virus and Epstein-Barr virus, chronic long-term inflammatory disease of the connective tissue, chronic fatigue syndrome and multiple sclerosis, by, the low dose administration of an essentially pure opiate receptor antagonist, such as naltrexone and naloxone. In our application Ser. No. 129,862, and now U.S. Pat. No. 4,888,346, we disclosed and claimed the treatment of humans infected with HTLV-III (AIDS) virus, including clinically diagnosed AIDS and AIDS-related complex (ARC), by the administration at low dosage levels of an essentially pure opiate receptor antagonist, preferably such antagonist having preferential blocking activity for Mu over Delta opiate receptor sites and exhibiting at the contemplated low dosage level a substantially selective blocking activity for Mu over Delta receptor sites, exemplified by naltrexone and naloxone. The patent literature relating to the medical utility proposed at the time for these and related drugs is summarized in the introductory discussion of the earlier application, the complete contents of which are hereby incorporated by reference, and include the treatment of narcotic addiction and narcotic overdose, the relief of severe itching in conjunction with Hodgkins Disease, mycosis funoides, severe jaundice, and various types of pruritis, the treatment of anorexia, the treatment of medical shock; i.e., anaphylactic, burn, cardiac, and the like shock, and the treatment of alcoholism or alcoholic intoxication. As explained in the prior applications, essentially pure opiate receptor antagonists, exemplified by naltrexone and naloxone, appear to be effective in potentiating the natural human immune system against the HTLV-III (AIDS) virus, apparently by upregulation of the endorphinergic system to thereby enhance hemostatic regulation of the natural immune function or the human body in ways by no means adequately understood. It has now been discovered that surprisingly these drugs are likewise effective for the treatment of certain chronic long-term diseases for which a specific medical treatment has been largely unavailable up to now, and even their etiology is, in a majority of instances, unknown. Web site: http://www.delphion.com/details?pn=US06586443__

Patents 397

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Method of treating multiple sclerosis with phytic acid Inventor(s): Sabin; Robert (Goosedown Estate, Box 332, Mill Neck, Long Island, NY 11765) Assignee(s): none reported Patent Number: 5,217,959 Date filed: September 6, 1990 Abstract: A method is provided for treating multiple sclerosis by administering to a subject afflicted with that disease a symptom-alleviating amount of a compound selected from the group consisting of phytic acid, mixed counterion phytate salt, an isomer or hydrolysate of phytic acid or mixed counterion phytate salt, a mixture of any combination thereof, or with one or more dephosphorylating enzymes. The preferred method of administration is by oral dosages of about 1/2 to 3 grams/kilogram bodyweight per day. Excerpt(s): The present invention relates to a novel method of treating multiple sclerosis and more precisely, to a method of treatment utilizing biologically active phytic acid and lower inositol phosphates derived from the hydrolysis of phytic acid in vivo. Phytic acid, generally accepted as having the structure myo-inositol-hexakis (dihydrogen phosphate), is a major component of plant seeds, constituting 1-3% by weight of many cereals and oil seeds. Most wheat brans contain between 4 and 5% phytic acid. Phytic acid may be prepared in pure form from various plant sources, such as wheat, corn, soybeans, sesame seeds, peanuts, lima beans, barley, oats, wild rice and sunflower seeds. It can be extracted with dilute hydrochloric acid at room temperature, precipitated with various reagents including ferric chloride, bicarbonates, potassium hydroxide, sodium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide or alcohol. It is then further purified by conventional chemical techniques. When one or more of the acidic protons of the phosphate groups in phytic acid are replaced by a counterion, the compound is usually referred to as a phytate salt. The name phytin is used for the calcium-magnesium salt of phytate derived from plant seeds (a discontinued product of Ciba-Geigy). The present invention includes the use not only of phytic acid and phytate salts, but also various isomeric forms of phytic acid and phytate salts. While the Anderson structure for myo-inositol hexakis dihydrogen phosphate is the accepted structure for phytic acid, the present invention covers other isomers which have been previously described in the literature. These isomers include the cis, epi, allo, muco, neo, D-chiro, L-chiro, and scyllo configurations. Web site: http://www.delphion.com/details?pn=US05217959__

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Method of treatment for multiple sclerosis Inventor(s): Hahn; Elliot (North Miami Beach, FL), Sherman; Fred P. (Hollywood, FL) Assignee(s): Baker Cummins Pharmaceuticals, Inc. (Miami, FL) Patent Number: 4,994,466 Date filed: June 14, 1990 Abstract: A method of treating a patient suffering from multiple sclerosis comprising daily administration to such patient of from about 1 to about 100 mg of a pure narcotic antagonist, e.g., nalmefene or naltrexone. The antagonist may be administered in

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divided doses from one to four times daily, preferably by the oral route. Parenteral, transmucosal and transdermal administration may be utilized where suitable. Excerpt(s): The invention relates to methods of treating multiple sclerosis. Multiple sclerosis is a disorder of the central nervous system white matter characterized by local areas of inflammation, demyelination and gliosis. It is characterized by episodes of disorders of the optic nerves, spinal cord and brain which remit and recur over many years. This disease has a prevalence of 80 per 100,000 in Canada, Europe and the northern United States. Most cases have their onset in which individuals between 20 and 40 years of age. Most patients are eventually disabled by progressive paraplegia and/or ataxia. Possible etiologies for multiple sclerosis include autoimmunity, viruses, free radical formation, mast cell mediation and the undecapeptide substance P which mediates augmented vascular permeability and vasodilation, possibly in a mast-cell dependent fashion. See J. E. Merrill et al., J. Clin. Immun., 9: 84-89 (1989); M. Rodriguez, Mayo Clin. Proc., 64: 570-576 (1989); E. Orr, Ann. New York Acad. Sci., 1989, 723-726; S. K. Kostyk et al., Brain Res., 504: 284-288 (1989). Web site: http://www.delphion.com/details?pn=US04994466__ •

Method to treat multiple sclerosis with GP39-specific antibodies Inventor(s): Noelle; Randolph J. (Cornish, NH), Claassen; Eric (Punacker, NL) Assignee(s): Trustees of Dartmouth College (Hanover, NH), Nederlandse Organisatie Voor Teogepastnatuurwetenschappelijk Onderzoek TNO (Rijswijk, NL) Patent Number: 6,328,964 Date filed: May 18, 1998 Abstract: Method for the treatment of multiple sclerosis and other T cell mediated autoimmune disorders is described. The method involves administering to a subject a therapeutically effective amount of an antagonist of a receptor on a surface of a T cell which mediates contact dependent helper effector functions, for example, an anti-gp39 antibody. Excerpt(s): The work leading to this invention was supported by one or more grants from the U.S. government. The government may have rights in the invention. Autoimmune diseases are characterized by attack of the immune system of an individual against its own tissues. Autoimmune diseases usually result from breakdown of tolerance of the immune system to its own antigens. The specific antigens recognized by the immune system in the various autoimmune diseases can be present systematically or they can be organ specific. For example, systemic lupus erthematosus (SLE) is characterized by the presence of autoantibodies to DNA, ribonucleoproteins, histones, and other molecules that are not organ specific. Other autoimmune diseases are characterized by the destruction of mostly one organ. Such autoimmune diseases include type I diabetes, in which the insulin producing.beta. cells of the islets of Langerhans in the pancreas are destroyed. In some autoimmune diseases, tissue destruction occurs primarily as a result of the production of high levels of autoantibodies. Such diseases include rheumatoid arthritis, characterized by destruction of the joint cartilage and inflammation of the synovium. Patients with rheumatoid arthritis have an accumulation of immune complexes in their joints which are formed by association of autoantibodies against the Fc portion of IgG and IgG molecules. These immune complexes activate the complement cascade which results in tissue damage. Myasthenia gravis, a disease of progressive muscle weakness, is caused by the

Patents 399

production of autoantibodies reactive to acetylcholine receptors in the motor end plates of neuromuscular junctions. Web site: http://www.delphion.com/details?pn=US06328964__ •

Methodology for the immunodiagnosis of multiple sclerosis and/or malignant diseases from blood sample analysis Inventor(s): Korik; Lazar (Brooklyn, NY), Angers; John W. (Red Bank, NJ) Assignee(s): The Immunology Development Corporation (Red Bank, NJ) Patent Number: 4,311,686 Date filed: April 30, 1979 Abstract: New and improved methodology for the diagnosis of a disease from blood sample analysis is disclosed and comprises: the preparation of a putative antigenic body substance extract, which is specific to disease-sensitized blood leukocytes, from the pooled, like body substances of a plurality of donors known to have the disease of interest; the mixture of said extract with the blood sample leukocytes; the promotion of the reaction therebetween to modify a characteristic of the disease-sensitized leukocytes, if any, of the blood sample; and the determination of the extent, if any, to which said characteristic has been modified. In multiple sclerosis diagnosis, said body substance may be blood or urine; while for malignant disease (for example breast cancer, or cancer of the head and neck) said body substance may be blood, urine, pleural fluid, ascites fluid, supernates of tumor cells or tumor cells grown in culture media. Excerpt(s): This invention relates to new and improved methodology for the immunodiagnosis of multiple sclerosis and/or malignant diseases from blood sample analysis. Although a variety of techniques are, of course, known for the diagnosis of multiple sclerosis, such techniques will generally be found to be costly and time consuming in requiring relatively lengthy, precise and painstaking patient examination by particularly highly trained neurological specialists in order to arrive at presumably definitive diagnostic results. Furthermore, since multiple sclerosis does not manifest itself in the form of a tumor or like diseased tissue in the body, with the possible exception of change in certain sections of the brain, it will be readily understood by those skilled in this art that traditional malignant disease diagnostic techniques in the nature, for example, of tissue and/or cell biopsy, are totally inapplicable to the diagnosis of multiple sclerosis, it having, in any event, proven impossible to date as a practical matter to identify and extract diseased tissue from a live brain for diagnostic study. In addition, and although there are, of course, a wide variety of diverse techniques available for the positive diagnosis of malignant diseases in the nature, for example, of breast cancer, and cancer of the head and neck, which are manifested in the form of diseased tissue, the diagnostic techniques will generally be found to ultimately require surgical removal and analysis of live diseased tissue and/or cell samples, with attendant patient discomfort and need for relatively lengthy, precise and painstaking administration by particularly highly trained medical specialists, to fully validate the results thereof. All of the above is to say that there is not currently known and in use any truly reliable, positive diagnostic technique which requires only blood sample analysis for the valid, specific and clinically reproducible diagnosis of multiple sclerosis and/or malignant diseases. It is, accordingly, an object of our invention to provide new and improved methodology for the immunodiagnosis of multiple sclerosis and/or malignant diseases from blood sample analysis.

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Web site: http://www.delphion.com/details?pn=US04311686__ •

Methods and compositions for use in characterizing multiple sclerosis disease activity in a subject Inventor(s): Campine; Isabelle Willie Luce (Heverlee, BE), De Meirleir; Kenny Leo (Mechelen, BE), Herst; C. V. Taylor (Oakland, CA) Assignee(s): R.E.D. Laboratories, N.V. (Zellik, BE) Patent Number: 6,080,554 Date filed: April 27, 1999 Abstract: Methods are providing for characterizing multiple sclerosis disease activity in a subject. In the subject methods, a sample is obtained from a subject suspected of having or known to have multiple sclerosis. The sample is then assayed for the presence of both high and low molecular proteins having RNAse L activity and a ratio of these two proteins is derived. The resultant ratio is then used to characterize the MS disease activity in the subject, e.g. to confirm an initial MS diagnosis, to determine the stage of the disease, to monitor disease progression, to predict disease attacks, and the like. Also provided by the subject invention are kits for practicing the methods. Excerpt(s): The field of this invention is multiple sclerosis. Multiple sclerosis (MS) is a neurological illness of unknown etiology associated with attacks of focal or multifocal neurological dysfunction arising from lesions within the central nervous system (CNS). In America and Northern Europe, MS is the most common neurological disease, with prevalence rates estimated between 50-100 per 100,000 population. The onset of disease is most common in early adulthood. Recurrent attacks can occur over many years, with approximately 30 percent of the patients progressing to a severe form of the disease which can be fatal. The most common form of the disease is episodic. Symptoms develop with subsequent recovery, then another attack occurs. In approximately 50 percent of all patients with MS, attacks become more frequent, usually with a worsening of symptomatology. In 30 percent of all patients, the disease develops into what is referred to as "progressive/relapsing," the most severe form of the disease. In this state remissions are rare and patients frequently become wheelchair bound. Web site: http://www.delphion.com/details?pn=US06080554__

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Methods and materials for detection of multiple sclerosis Inventor(s): Spaulding; James G. (Saegertown, PA), Kline; Ellis L. (Pendleton, SC), McMichael; John (Cambridge Springs, PA) Assignee(s): University Patents, Inc. (Norwalk, CT) Patent Number: 4,294,818 Date filed: July 30, 1979 Abstract: Methods and materials for diagnosis of a multiple sclerosis disease state. Antigenic blood fractions from patients clinically diagnosed for multiple sclerosis are employed to generate heterologous species antibodies. Novel antibody preparations are employed to detect the presence or absence, in a blood sample of a patient to be tested, of immunologically significant components specifically associated with a multiple sclerosis disease state.

Patents 401

Excerpt(s): The present invention relates generally to diagnosis of a multiple sclerosis disease state in humans and more specifically to novel antigen and antibody preparations and immunological reagents containing same which are useful in diagnosis of multiple sclerosis. Multiple sclerosis, sometimes referred to as disseminated sclerosis, is a slowly progressive disease of the central nervous system characterized morphologically by disseminated patches of demyelinization in the brain and spinal cord and clinically by multiple symptoms and signs with remissions and exacerbations. The etiology of multiple sclerosis is essentially unknown and the disease has been variously attributed to: autoimmune mechanisms; infection by a slow virus; toxic agents such as metallic poisons; metabolic elements such as myelin-splitting factor; and vascular lesions resulting from abnormal blood clotting mechanisms. Web site: http://www.delphion.com/details?pn=US04294818__ •

Methods for diagnosing tuberous sclerosis by detecting mutation in the TSC-1 gene Inventor(s): Halley; Dicky J. J. (Rotterdam, NL), van Slegtenhorst; Marjon A. (Hoogland, NL), Sampson; Julian R. (Llandaff, GB), Kwiatkowski; David J. (Weston, MA), Povey; Margaret S. (Leighton Buzzard, GB) Assignee(s): Brigham and Women's Hospital (Boston, MA) Patent Number: 6,548,258 Date filed: September 12, 2001 Abstract: The present invention is directed to a tumor suppressor protein which has been designated hamartin and to the gene, TSC1, which encodes this protein. Mutations in the gene have been found to be associated with certain types of tuberous sclerosis and this has served as a basis for a diagnostic method designed to identify patients that have, or are likely to develop, symptoms associated with this disease. The introduction of the TSC1 gene and subsequent expression of hamartin into cells may be used as a means for treating tuberous sclerosis and other conditions characterized by abnormal cellular growth. Excerpt(s): The present invention is directed to the gene TSC1 and to the protein it encodes. TSC1 has the characteristics of a tumor suppressor gene and is often mutated in individuals with a familial form of tuberous sclerosis. The invention also encompasses methods that relate to the gene and gene product. Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the development of unusual tumor-like growths (hamartomas) in a variety of organ systems (Gomez, M. R., Ann. N.Y. Acad. Sci. 615:1-7 (1991); Kwiatkowski, et al., Arch. Dermatol. 130:348-354 (1994)). The development of cortical tubers in the brain (regions of abnormal cortical architecture with distinctive large neuronal cells) causes some of the most problematic clinical manifestations of TSC: mental retardation, epilepsy and abnormal behavioral phenotypes including autism and attention deficit-hyperactive disorder (Hunt, et a., J. Autism. Dev. Disorder 23:323-339 (1993); Smalley, et al., J. Autism. Dev. Disorder 22:339355 (1992)). Other organ systems commonly involved in TSC include the skin, heart, and kidneys (Kwiatkowski, et al., Arch. Dermatol. 130:348-354 (1994)). The lesions seen are often pathognomonic of TSC and include facial angiofibromas, subungual fibromas, forehead plaque, Shagreen patches, cardiac rhabdomyomas and renal angiomyolipomas and cysts. Renal cell carcinoma also occurs at higher frequency and at an earlier age of onset in TSC patients than in normal individuals (Bjornsson, et al., Am. J. Path. 149:12011208 (1996); Cook, et al., J. Med. Genet. 33:480-484 (1996)). About one-third of TSC cases are familial with the remainder being sporadic, i.e., occurring in the absence of a family

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history of the disease. Linkage of TSC to 9q34 was first reported in 1987 and this locus was denoted TSC1 (Fryer, et al., Lancet i:659-661 (1987)). Subsequent studies provided strong evidence for locus heterogeneity and led to the identification of 16p13 (denoted the TSC2 locus) as a second genomic region showing linkage in some TSC families (Kandt, et al., Exp. Neurol. 104:223-228 (1989)). Among families large enough to permit linkage analysis, approximately half show linkage to 9q34 and half to 16p13 (Janssen, et al., Hum. Genet. 94:437-440 (1994)). Web site: http://www.delphion.com/details?pn=US06548258__ •

Methods for the daignosis, of familial amyotrophic lateral sclerosis Inventor(s): Rosen; Daniel R. (Dedham, MA), Brown; Robert (Needham, MA), Horvitz; H. Robert (Cambridge, MA) Assignee(s): General Hospital Corporation, The (Boston, MA), Massachusetts Institute of Technology (Cambridge, MA) Patent Number: 5,843,641 Date filed: February 26, 1993 Abstract: Disclosed is the family of genes responsible for the neurodegenerative diseases, particularly Amyotrophic Lateral Sclerosis. Methods and compounds for the diagnosis, prevention, and therapy of the disease are also disclosed. Excerpt(s): The invention relates to cell death diseases. Neurodegenerative diseases include familial and sporadic amyotrophic lateral sclerosis (FALS and ALS, respectively), familial and sporadic Parkinson's disease, Huntington's disease, familial and sporadic Alzheimer's disease, olivopontocerebellar atrophy, multiple system atrophy, progressive supranuclear palsy, diffuse lewy body disease, corticodentatonigral degeneration, progressive familial myoclonic epilepsy, strionigral degeneration, torsion dystonia, familial tremor, gilles de la tourette syndrome, and Hallervorden-Spatz disease. Most of the diseases are typified by onset during the middle adult years and lead to rapid degeneration of specific subsets of neurons within the neural system, ultimately resulting in premature death. There is no known cure nor is there an effective therapy to slow the progression for any of the stated diseases. Amyotrophic lateral sclerosis (ALS) is the most commonly diagnosed progressive motor neuron disease. The disease is characterized by degeneration of motor neurons in the cortex, brainstem and spinal cord (Principles of Internal Medicine, 1991 McGraw-Hill, Inc., New York; Tandan et al. Ann. Neurol, 18:271-280, 419-431, 1985). Generally, the onset is between the third and sixth decade, typically in the sixth decade. ALS is uniformly fatal, typically within five years (Kurland et al., Proc Staff Meet Mayo Clin, 32:449-462, 1957). The cause of the disease is unknown and ALS may only be diagnosed when the patient begins to experience asymmetric limb weakness and fatigue, localized fasciculation in the upper limbs and/or spasticity in the legs which typifies onset. Web site: http://www.delphion.com/details?pn=US05843641__

Patents 403

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Methods for the prevention and treatment of fibrosis and sclerosis Inventor(s): Neely; Constance F. (Raleigh, NC) Assignee(s): Link Technology Inc. (Research Triangle Park, NC) Patent Number: 6,117,445 Date filed: December 31, 1998 Abstract: Methods of treating or preventing fibrosis and sclerosis by the administration of compositions containing A.sub.1 adenosine receptor antagonists and/or P.sub.2X purinoceptor antagonists, or combinations thereof. Excerpt(s): The present invention relates to methods of treating fibrosis and sclerosis, using A.sub.1 adenosine receptor antagonists and P.sub.2X purinoceptor antagonists, or combinations thereof. Purinergic receptors can be classified into the P.sub.1 (adenosine) receptors and the P.sub.2 (adenosine 5' triphosphate) receptors. Adenosine receptors can further be delineated into major subclasses, the A.sub.1, A.sub.2 (A.sub.2a and A.sub.2b) and A.sub.3 adenosine receptors. These subtypes are differentiated by molecular structure, radioligand binding profiles, and by pharmacological activity and signal transduction mechanisms. Binding of adenosine, a naturally occurring nucleoside, to specific adenosine receptors leads to either stimulation (A.sub.2 -receptor activation) or inhibition (A.sub.1 -receptor activation) of adenylate cyclase activity resulting in an increase or decrease of intracellular cAMP, respectively. Most tissues and cell types possess either the A.sub.1 or A.sub.2 receptor, or both. Moreover, A.sub.1 adenosine receptors have been identified in the nuclear fraction of splenocytes (Donnabella, Life Sci. 46:1293 (1990)). Specific A.sub.1, A.sub.2, and A.sub.3 adenosine receptor antagonists and agonists are known. See, e.g., Trivedi et al., Structure-Activity Relationships of Adenosine A.sub.1 and A.sub.2 Receptors, In: Adenosine and Adenosine Receptors, M. Williams, Ed., Humana Press, Clifton, N.J., USA (1990); Jacobson et al., J. Medicinal Chem. 35:407 (1992); Fredholm et al., Pharm. Rev. 46:143 (1994); Jacobson, Abstracts from Purines '96, Drug Dev. Res., March 1996, page 112. Divalent ions (Mg.sup.2+ and Ca.sup.2 +) and allosteric enhancers enhance the binding of A.sub.1 adenosine receptor agonists to A.sub.1 adenosine receptors (Kollias-Baker, Circ. Res. 75:961 (1994)). Allosteric enhancers enhance A.sub.1 receptor mediated responses and are described in Bhattacharya, Biochim. Biophys. Acta 1265:15 (1995). Based on potency profiles of structural analogues for ATP, ATP-sensitive (P2) purinoceptors have been subclassified into P.sub.2X and P.sub.2Y purinoceptors. With few exceptions, P.sub.2X receptors are located on vascular smooth muscle cells and mediate vasoconstriction and P.sub.2Y receptors are located on endothelial cells and mediate vasodilation. Burmstock and Kennedy, Gen. Pharmacol. 16:433 (1985; Ralevic eta 1., Br. J. Phannacol. 103:1108 (1991). P.sub.2X receptors are present on arteries of a number of different species. Bo and Burnstock, J Vas Res 30:87 (1993). The presence of P.sub.2X purinoceptors on pulmonary arteries is reported in Neely, C. F., Am J Physiol 270:L889-L897, 1996. Web site: http://www.delphion.com/details?pn=US06117445__

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Methods for treating multiple sclerosis Inventor(s): Tatton; William G. (8 Halliday Ct., Purchase, NY 10577), Tatton; Nadine A. (8 Halliday Ct., Purchase, NY 10577), Shankar; L. Sai Latha (323 E. 88th St., Apt. 19, New York, NY 10128) Assignee(s): none reported Patent Number: 6,492,427 Date filed: October 8, 1999 Abstract: Methods for increasing oligodendrocyte survival are disclosed. The methods of the invention are useful for the treatment of Multiple Sclerosis. Excerpt(s): Deprenyl (also referred to herein as selegiline or R-(-)-N,.alpha.-Dimethyl-N2-propynyl phenethylamine) was first used as an adjunct to conventional drug therapy (L-dihydroxyphenylalanine (L-DOPA) plus a peripheral decarboxylase inhibitor) of Parkinson's disease (PD) in Europe over a decade ago on the basis that as a selective monoamine oxidase-B (MAO-B) inhibitor, it would elevate brain dopamine levels and potentiate the pharmacological action of dopamine formed from L-DOPA, and yet prevent the tyramine-pressor effect observed with non-selective MAO inhibitors. The combined drug therapy was reported to prolong the anti-akinetic effects of L-DOPA, resulting in the disappearance of on-off effects, reduced functional disability, and increased life-expectancy in PD patients (Bernheimer, H., et al., J. Neurolog. Sci., 1973. 20: 415-455, Birkmayer, W., et al., J. Neural Transm., 1975. 36:303-336, Birkmayer, W., et al., Mod. Prob. Pharmacopsychiatr., 1983. 19: 170-177, Birkmayer, W. and P. Riederer, Hassler, R. G. and J. F. Christ (Ed.) Advances In Neurology, 1984. 40(Y): p.0-89004, and Birkmayer, W., et al., J. Neural Transm., 1985. 64(2): p. 113-128). Studies examining deprenyl as an adjunct to conventional L-DOPA therapy have reported a short term benefit which was usually lost by 1 year or less. Some, but not all, have reported that the levodopa dose can be decreased when taken in conjunction with deprenyl (Elizan, T. S., et al., Arch Neurol, 1989. 46(12): p. 1280-1283, Fischer, P. A. and H. Baas, J. Neural Transm. (suppl.), 1987. 25: p. 137-147, Golbe, L. I., Neurology, 1989. 39: p. 1109-1111, Lieberman, A. N. et al., N.Y. State J. Med., 1987. 87: p. 646-649, Poewe, W., F. Gerstenbrand, and G. Ransomayr, J. Neural Transm. (suppl.), 1987. 25: p. 137-147, Cedarbaum, J. M., M. Hoey, and F. H. McDowell, J. Neurol. Neurosurg. Psychiatry, 1989. 52(2): p. 207-212, and Golbe, L. I., J. W. Langston, and I. Shoulson, Drugs, 1990. 39(5): p. 646-651). Increasingly, deprenyl is being administered to Parkinson's disease patients following reports (Parkinson, S. G. Arch Neurol 46, 1052-1060 (1989) and U.S.A., Parkinson, S. G. N. Engl. J. Med. 321, 1364-1371 (1989)) that it delays the disease progression; a mechanism has recently been proposed to explain its action (See, e.g., Tatton & Redman 1996). Web site: http://www.delphion.com/details?pn=US06492427__

Patents 405

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Methods for treatment of multiple sclerosis using peptide analogues at position 91 of human myelin basic protein Inventor(s): Conlon; Paul J. (Solana Beach, CA), Ling; Nicholas (San Diego, CA), Steinman; Lawrence (Palo Alto, CA), Gaur; Amitabh (San Diego, CA) Assignee(s): Neurocrine Biosciences, Inc. (San Diego, CA), Stanford University Medical Center (Palo Alto, CA) Patent Number: 6,489,299 Date filed: November 19, 2001 Abstract: Peptide analogues of human myelin basic protein containing residues 87-99 are provided. Residue 91 of the peptide analogues is altered from the L-lysine residue found in the native protein to any other amino acid. Pharmaceutical compositions of the peptide analogues are provided. In addition, the peptide analogues are administered to patients with multiple sclerosis. Excerpt(s): The present invention relates generally to methods for treating and preventing multiple sclerosis by using peptide analogues of human myelin basic protein. Multiple sclerosis (MS) is a chronic, inflammatory disease that affects approximately 250,000 individuals in the United States. Although the clinical course may be quite variable, the most common form is manifested by relapsing neurological deficits, in particular, paralysis, sensory deficits, and visual problems. The inflammatory process occurs primarily within the white matter of the central nervous system and is mediated by T lymphocytes, B lymphocytes, and macrophages. These cells are responsible for the demyelination of axons. The characteristic lesion in MS is called the plaque due to its macroscopic appearance. Web site: http://www.delphion.com/details?pn=US06489299__

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Methods for treatment of multiple sclerosis using peptide analogues of human myelin basic protein Inventor(s): Conlon; Paul J. (Solana Beach, CA), Gaur; Amitabh (San Diego, CA), Ling; Nicholas (San Diego, CA), Steinman; Lawrence (Palo Alto, CA) Assignee(s): Neurocrine Biosciences, Inc. (San Diego, CA) Patent Number: 6,329,499 Date filed: November 18, 1994 Abstract: The present invention is directed toward peptide analogues of human myelin basic protein. The peptide analogue is at least seven amino acids long and derived from residues 86 to 99 of human myelin basic protein. The analogues are altered from the native sequence at least at positions 91, 95, or 97. Additional alterations may be made at other positions. Pharmaceutical compositions containing these peptide analogues are provided. The peptide analogues are useful for treating multiple sclerosis. Excerpt(s): The present invention relates generally to methods for treating multiple sclerosis by using peptide analogues of human myelin basic protein. Multiple sclerosis (MS) is a chronic, inflammatory disease that affects approximately 250,000 individuals in the United States. Although the clinical course may be quite variable, the most common form is manifested by relapsing neurological deficits, in particular, paralysis, sensory deficits, and visual problems. The inflammatory process occurs primarily within the white matter of the central nervous system and is mediated by T lymphocytes, B

406 Sclerosis

lymphocytes, and macrophages. These cells are responsible for the demyelination of axons. The characteristic lesion in MS is called the plaque due to its macroscopic appearance. Web site: http://www.delphion.com/details?pn=US06329499__ •

Methods for treatment of multiple sclerosis utilizing peptide analogues of human myelin basic protein Inventor(s): Gaur; Amitabh (San Diego, CA), Ling; Nicholas (San Diego, CA), Conlon; Paul J. (Solana Beach, CA) Assignee(s): Neurocrine Biosciences, Inc. (San Diego, CA) Patent Number: 5,948,764 Date filed: January 9, 1997 Abstract: The present invention is directed toward peptide analogues of human myelin basic protein for use in the treatment of multiple sclerosis. Within one aspect, peptide analogues suitable for treating multiple sclerosis are provided which are at least seven amino acids long and derived from residues 86 to 99 of human myelin basic protein. In addition, such analogues may be altered from the native sequence at positions 87, 88, 97, 98 or 99 to a D-amino acid. Additional alterations may be made at other positions. Pharmaceutical compositions containing these peptide analogues are also provided, as well as methods for treating multiple sclerosis. Excerpt(s): The present invention relates generally to methods for treating multiple sclerosis utilizing peptide analogues of human proteins. Multiple sclerosis (MS) is a chronic, inflammatory disease that affects approximately 250,000 individuals in the United States. Although the clinical course may be quite variable, the most common form is manifested by relapsing neurological deficits, in particular, paralysis, sensory deficits, and visual problems. The inflammatory process occurs primarily within the white matter of the central nervous system and is mediated by T lymphocytes, B lymphocytes, and macrophages. These cells are responsible for the demyelination of axons. The characteristic lesion in MS is called the plaque due to its macroscopic appearance. Web site: http://www.delphion.com/details?pn=US05948764__

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Methods to aid in the diagnosis of multiple sclerosis Inventor(s): Scherrer; Klaus (Paris, FR) Assignee(s): Pro Soma S.A.R.L. (Paris, FR) Patent Number: 5,472,848 Date filed: May 2, 1994 Abstract: Disclosed are methods and kits useful in the differential diagnosis of multiple sclerosis. The method involves the use of an immunochemical reagent containing one or more prosomal antigens. Such a method typically involves: obtaining serum from a patient suspected of suffering from multiple sclerosis; contacting the immunochemical agent with the serum; and detecting the presence of immune complexes formed between the prosomal antigen and any antibodies reactive therewith present in the serum.

Patents 407

Excerpt(s): This invention relates to a method and apparatus useful in the differential diagnosis of multiple sclerosis. Multiple sclerosis ("MS") is a disease which usually presents itself in the form of recurrent attacks of focal or multifocal neurologic dysfunction. Its symptoms are multi-faceted and indefinite and include impaired vision, nystagmus, an inability to speak clearly, a decreased perception of vibration and position sense, intention tremor, muscular incoordination, limb weakness or paralysis, spasticity, and bladder problems. Harrison's Principles of Internal Medicine, p. 19952000 (11th ed. 1987). Unfortunately, no effective treatment of MS is known. In order to establish a definite diagnosis of MS, at least two episodes of neurological deficit must occur along with objective clinical signs of lesions at more than one site within the central nervous system. One problem with such a diagnostic method is that a period of ten to twenty years may pass between episodes of neurological deficit. Id. Web site: http://www.delphion.com/details?pn=US05472848__ •

MSRV1 virus and MSRV2 pathogen and/or infective agent associated with multiple sclerosis, and biopolymer constituents thereof Inventor(s): Mallet; Francois (Villeurbanne, FR), Beseme; Frederic (Villefontaine, FR), Mandrand; Bernard (Villeurbanne, FR), Perron; Herve (Grenoble, FR), Bedin; Frederic (Lyons, FR) Assignee(s): Bio Merieux (Marcy I'Etoile, FR) Patent Number: 5,962,217 Date filed: June 6, 1995 Abstract: Composition including two pathogenic and/or infective agents associated with multiple sclerosis, namely a first agent which consists of a human virus possessing reverse transcriptase activity and related to a family of endogenous retroviral elements, or a variant of the virus, and a second agent, or a variant of the second agent, these two pathogenic and/or infective agents originating from the same viral strain chosen from the strains designated, respectively, POL-2 deposited with the ECACC on Jul. 22, 1992 under Accession Number V92072202 and MS7PG deposited with the ECACC on Jan. 8, 1993 under Accession Number V93010816, and from their variant strains. Excerpt(s): Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) the cause of which remains as yet unknown. Many studies have supported the hypothesis of a viral etiology of the disease, but none of the known viruses tested has proved to be the causal agent sought: a review of the viruses sought for several years in MS has been compiled by E. Norrby (1) and R. T. Johnson (2). Concomitantly, the possibility of an exogenous and/or infectious factor is suggested by the existence of localized epidemics or "clusters" of MS, as have been observed in the Faro Islands between 1943 and 1960 (3), in Sardinia (4), in Norway (5), and also by studies on migrant populations (6). Among all the exogenous factors suggested, viruses have been most often studied, and a viral etiology is traditionally called to mind. Web site: http://www.delphion.com/details?pn=US05962217__

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Multiple sclerosis associated polypeptide Inventor(s): Kline; Ellis L. (Pendleton, SC), Zimmerman; Daniel H. (Bethesda, MD) Assignee(s): Molecullar Rx, Inc. (Pendleton, SC), Cell Med, Inc. (Bethesda, MD) Patent Number: 5,883,227 Date filed: October 28, 1996 Abstract: The present invention relates to the diagnosis of multiple sclerosis. More specifically, this invention relates to an assay for detecting antigen(s) associated with multiple sclerosis. The present invention also relates to the generation of hybridomas which produce monoclonal antibodies which are specific for the multiple sclerosisassociated antigens. The present invention's use is in diagnosing multiple sclerosis and in routine follow-up monitoring of multiple sclerosis patients as to disease progression or response to therapy. Excerpt(s): The present invention relates to the detection of demyelinating diseases such as multiple sclerosis. More specifically, this invention relates to an assay for detecting antigen(s) associated with multiple sclerosis and related diseases. The present invention also relates to the generation of hybridomas which produce monoclonal antibodies which are specific for the multiple sclerosis-associated antigens. The present invention's use is in diagnosing multiple sclerosis and in routine follow-up monitoring of multiple sclerosis patients as to disease progression or response to therapy. Multiple sclerosis is a slowly progressive disease of the central nervous system ("CNS"), characterized pathologically by disseminated patches of demyelinization in the brain and spinal cord, and clinically by multiple symptoms and signs with remissions and exacerbations. Demyelinization is the removal of the myelin, a protective, lipid substance that surrounds the axon of nerve fibers. Multiple sclerosis related diseases are those conditions which exhibit demyelinization of nerves. Onset of multiple sclerosis is usually insidious. Commonly, minor visual disturbances, a fleeting ocular palsy, transient weakness, slight stiffness or unusual fatigability of a limb, minor interference with walking, difficulties with bladder control, occasional dizziness, or mild emotional disturbances--all evidence of scattered involvement of the CNS--occur months or years before the disease is recognized. Web site: http://www.delphion.com/details?pn=US05883227__

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Multiple sclerosis related virus Inventor(s): Mallet; Francois (Villeurbanne, FR), Mandrand; Bernard (Villeurbanne, FR), Bedin; Frederic (Lyons, FR), Beseme; Frederic (Villefontaine, FR), Perron; Herve (Grenoble, FR) Assignee(s): Bio Merieux (Marcy l'Etoile, FR) Patent Number: 5,871,745 Date filed: June 6, 1995 Abstract: Composition including two pathogenic and/or infective agents associated with multiple sclerosis, namely a first agent which consists of a human virus possessing reverse transcriptase activity and related to a family of endogenous retroviral elements, or a variant of the virus, and a second agent, or a variant of the second agent, these two pathogenic and/or infective agents originating from the same viral strain chosen from the strains designated, respectively, POL-2 deposited with the ECACC on Jul. 22, 1992

Patents 409

under Accession Number V92072202 and MS7PG deposited with the ECACC on Jan. 8, 1993 under Accession Number V93010816, and from their variant strains. Excerpt(s): Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) the cause of which remains as yet unknown. Many studies have supported the hypothesis of a viral etiology of the disease, but none of the known viruses tested has proved to be the causal agent sought: a review of the viruses sought for several years in MS has been compiled by E. Norrby (1) and R. T. Johnson (2). Concomitantly, the possibility of an exogenous and/or infectious factor is suggested by the existence of localized epidemics or "clusters" of MS, as have been observed in the Faro Islands between 1943 and 1960 (3), in Sardinia (4), in Norway (5), and also by studies on migrant populations (6). Among all the exogenous factors suggested, viruses have been most often studied, and a viral etiology is traditionally called to mind. Web site: http://www.delphion.com/details?pn=US05871745__ •

Multiple sclerosis treatment Inventor(s): Cantorna; Margherita T. (Middleton, WI), DeLuca; Hector F. (Deerfield, WI), Hayes; Colleen E. (Madison, WI) Assignee(s): Wisconsin Alumni Research Foundation (Madison, WI) Patent Number: 5,716,946 Date filed: February 13, 1996 Abstract: A method of treating the multiple sclerosis symptoms of a multiple sclerosis patient is disclosed comprising administering to a multiple sclerosis patient an amount of a vitamin D compound effective to reduce symptoms and to enable an observation of a reduction in symptoms. Excerpt(s): The present invention relates to methods of treating multiple sclerosis. In particular, the present invention relates to the treatment of multiple sclerosis with 1,25(OH).sub.2 D.sub.3 and other vitamin D analogs. Multiple sclerosis (MS) is thought to result from central nervous system (CNS) demyelination, brought about by a chronic inflammatory autoimmune reaction (reviewed in Steinman, et al., Annu. Rev. Neurosci. 17:247, 1993; Miller, S. D. et al., Immunol. Today 15:356, 1994; Ffrench-Constant, C., Lancet 343:271-274, 1994; Brocke, S., et al., Trends in Microbiol. 2:250, 1994). In the animal model, experimental autoimmune encephalomyelitis (EAE), immunization of susceptible rodent strains with CNS proteins such as myelin basic protein (MBP) induces an MS-like paralytic disease. Inflamed MS and EAE lesions, but not normal white matter, have infiltrating CD4 T-cells that respond to self antigens presented by MHC class II molecules like human HLA-DR2 (MS) or murine I-A.sup.u (EAE). The infiltrating CD4 T-cells (Th1 cells) produce pro-inflammatory cytokines (interleukin (IL)2, interferon (IFN)-.gamma., and tumor necrosis factor (TNF)-.alpha.) that activate antigen-presenting cells like macrophage to produce inflammatory cytokines (IL-1.beta., IL-6, and IL-8) and IL-12. The IL-12 induces further IFN-.gamma. synthesis. In this cyclical manner, a chronic autoantigen-driven immune reaction is thought to produce a demyelinating attack on the CNS. At least three general therapeutic approaches have been previously tried to limit the immune-mediated CNS damage in MS by targeting the effector functions of activated Th1 cells and macrophages. Antigen-non-specific immunosuppressive drugs and treatments constitute the majority of agents currently used and under study as MS therapeutics (reviewed in Noseworthy, J. H., "Immunosuppressive therapy in multiple sclerosis: pros and cons," International MS

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Journal 1:79-89, 1994). Examples are adrenocorticotrophic hormone, corticosteroid, prednisone, methylprednisone, 2-chlorodeoxyadenosine (Cladribine), mitoxantrone, sulphasalazine, methotrexate, total lymphoid irradiation, and possibly interferon-beta, although its mechanism of action remains to be defined. Some immunosuppressants have been tried without success; examples are azathioprine, cyclophosphamide, and cyclosporin. The limitations of this approach are risk of infection during non-specific immunosuppression and the toxic side effects of some of the cytotoxic drugs. Web site: http://www.delphion.com/details?pn=US05716946__ •

Multiple sclerosis virus Inventor(s): Tuke; Philip (London, GB), Garson; Jeremy (London, GB) Assignee(s): Biomerieux S.A. (Marcy l'etoile, FR), University College London (London, GB) Patent Number: 6,136,528 Date filed: November 22, 1995 Abstract: The present invention provides a polynucleotide in substantially isolated form comprising a sequence of nucleotides which is capable of selectively hybridizing to the genome of the human multiple sclerosis virus (HMSV) or the complement thereof, wherein HMSV is characterized by:(i) a positive stranded RNA genome;(ii) said genome comprising one or more open reading frames (ORF) encoding protein(s) or polyprotein(s);(iii) said genome encoding a reverse transcriptase enzyme; and(v) said genome comprising nucleotide sequences which are homologous to or selectively hybridizable with any one of the nucleotide sequences illustrated in SEQ ID NOS:1 to 6. Excerpt(s): The present invention relates to multiple sclerosis and in particular to a virus associated with this disease. Multiple sclerosis (MS) is a debilitating wasting disease which generally strikes its victims at some time after adolescence. The disease is associated with degeneration of the myelin sheaths surrounding nerve cells which leads to a loss of motor and sensory function. There are no cures for MS and even attempts to ameliorate the symptoms and slow the progress of the disease have up to now met with only limited success. Web site: http://www.delphion.com/details?pn=US06136528__

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P-cresol sulfate, a component of urinary myelin basic protein-like material, as a correlate of multiple sclerosis status Inventor(s): Burgard; Sheila Loughran (Lake Bluff, IL), Bradley, Jr. Edwin Luther (Birmingham, AL), Kachelhofer; Robert David (Birmingham, AL), Whitaker; John Nicholas (Birmingham, AL), Layton; Beverly Ann (Birmingham, AL), Kirk; Marion (Birmingham, AL), Cao; Ligong (Birmingham, AL), Coward; Lori (Birmingham, AL), Paty; Donald Winston (Vancouver, CA), Jackson; Patricia L. (Moody, AL), Morrision; Wendy Jean (Vancouver, CA), Zhao; Guojun (Burnaby, CA), Reder; Anthony Thomas (Oak Park, IL) Assignee(s): UAB Research Foundation (Birmingham, AL) Patent Number: 6,284,473 Date filed: October 6, 1999

Patents 411

Abstract: The present invention provides a method of determining the status of a multiple sclerosis patient, i.e., predicting the transition from a status of relapsingremitting to a progressive phase of multiple sclerosis, comprising the step of measuring the amount of urinary p-cresol sulfate in the patient. The present invention also provides a method of determining the amount of lesions and total lesion area of a multiple sclerosis patient, comprising the step of measuring the amount of urinary pcresol sulfate in the patient. Further provided is a method of monitoring myelination in a developing child, comprising the step of: measuring the amount of p-cresol sulfate in the urine of said child. Excerpt(s): The present invention relates generally to the field of neurology and multiple sclerosis. More specifically, the present invention relates to an assay for measuring urinary myelin basic protein-like material, more particularly the urinary p-cresol sulfate component, and the use of this assay as a correlate of multiple sclerosis status. Multiple sclerosis (MS), an inflammatory, primary demyelinating disease of the central nervous system (CNS) affecting an estimated 350,000 persons in the United States (1), is typified by a chronic and unpredictable course. This variable course and the associated heterogeneity of the disease renders clinical trials involving large groups and clinical management of the individual patient problematic. Based on disease course, multiple sclerosis patients are usually categorized (2,3) as relapsing-remitting (RR), relapsing progressive (RP), primary progressive (PP) and secondary progressive (SP), according to the clinical appearance and persistence of neurological deficit. The development of disease progression, whether from onset, as in PP-MS, or as SP-MS subsequent to an earlier period of relapses, can be viewed as the failure of remission. The failure of remission (i.e., progression of the disease) is the principal cause of disability and decline in the quality of life. The natural history of MS has been studied extensively for clinical features or laboratory measurements which might predict, anticipate or parallel the future course of disease. Clinical characteristics which appear to predict a future progressive course include: (a) male gender; (b) later age of onset of the disease; (c) corticospinal and cerebellar involvement; (d) increased number of relapses in the first five years; and (e) shorter interval between the first and second relapse (2-4). The clinical scales for assessing progression of disability have certain limitations (5), but, in general, the functional status in a population of MS patients is better than usually envisioned (6), and patients, even with chronic progressive disease, may go through periods of spontaneous stability (7). This imprecision in clinical patterns and natural history requires clinical markers for signaling progression (8). Web site: http://www.delphion.com/details?pn=US06284473__ •

Peptide T and related peptides in the treatment of HTLV-1 myelopathy and multiple sclerosis Inventor(s): Carlen; Peter L. (Toronto, CA), MacFadden; Douglas K. (Toronto, CA), Doob; Penelope Reed (Toronto, CA) Assignee(s): Reed MacFadden, Ltd. (CA) Patent Number: 5,686,417 Date filed: November 8, 1995 Abstract: A composition useful in treating Multiple Sclerosis and HTLV-1 myelopathy in humans comprises:i) a peptide having as its active portion, an amino acid sequence of the formula:-Thr-Thr-Asn-Tyr-Thr-; andii) a pharmaceutically acceptable carrier for said peptide.

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Excerpt(s): This invention relates to compositions useful in and methods of treating HTLV-1 myelopathy and Multiple Sclerosis as well as processes for formulating such compositions. Both multiple sclerosis (MS) and HTLV-1 associated myelopathy (HAM) affect the central and peripheral nervous systems and both may be present as a myelopathy affecting both the spinal nerves and the spinal myelinated nerve fibres. Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and is the commonest chronic neurological disease of young adults. The incidence of MS and its pattern of distribution have been unchanged for decades. The disease remains essentially untreatable. Web site: http://www.delphion.com/details?pn=US05686417__ •

Peptide T and related peptides in the treatment of inflammation, including multiple sclerosis Inventor(s): Andersen; Anders Jorgen (Kokkedal, DK), Aston; Roger (Wiltshire, GB), MacFadden; Douglas Kevin (Ontario, CA), Rathjen; Deborah (New South Wales, AU), Carlen; Peter Louis (Ontario, CA), Doob; Penelope Reed (Ontario, CA), Phipps; David James (Ontario, CA), Widmer; Fred (New South Wales, AU) Assignee(s): Advanced Immunit, Inc. (Stony Brook, NY) Patent Number: 6,011,014 Date filed: May 21, 1998 Abstract: A method of treating or preventing multiple sclerosis in a patients in need of such treatment by administering an effect amount of the peptide: I-A-B-C-D-E-F-G-H-II (General Formula) wherein A is Ala, Gly, Val, Ser, Thr or absent, B is Ala, Gly, Val, Ser, Thr or absent, C is Ser, Thr or absent, D is Ser, Thr, Asn, Glu, Arg, IIe, Leu or absent, E is Ser, Thr, Asp or absent, F is Thr, Ser, Asn, Glu, Lys, Trp or absent, G is tyr or absent; H is Thr, Arg, Gly, Met, Met(O), Gys, Thr, Gly or absent, I is Cys or absent, II is Cys, an amide group, substituted amide group, an ester group or absent. Excerpt(s): The present invention relates, broadly, to the treatment or prevention of inflammation, whether caused by bacteria, viruses and/or other infective agents, opportunities infections (which may be consequent on an immunodepressed state, for example resulting from cancer or therapy, particularly cytotoxic drug therapy or radiotherapy) autoimmunity or otherwise. In particular embodiments, the invention relates to the prevention or treatment of neurodegenerative or demyelinating diseases such as HTLV-1-associated myelopathy (HAM), multiple sclerosis (MS) and symptoms or diseases in humans which are associated with chronic immune activation. The invention also relates to pharmaceutical compositions useful in such treatment and/or prevention and to certain active peptides per se. Septic shock is an illustration of a disease involving inflammation. Many of the clinical features of Gram-negative septic shock may be reproduced in animals by the administration of lipopolysaccharide (LPS). The administration of LPS to animals can prompt severe metabolic and physiological changes which can lead to death. Associated with the injection of LPS is the extensive production of tumour necrosis factor alpha (TNF-.alpha.). Mice injected with recombinant human TNF develop piloerection of the hair (ruffling), diarrhoea and a withdrawn and unkempt appearance, followed by death if sufficient amounts are given. Rats treated with TNF become hypotensive, tachypneic and die of sudden respiratory arrest (Tracey et al. 1986 Science 234, 470). Severe acidosis, marked haemoconcentration and biphasic changes in blood glucose concentration were also observed. Histopathology of such rats revealed severe leukostatsis in the lungs, haemorraphic

Patents 413

necrosis in the adrenals, pancreas and other organs and tubular necrosis of the kidneys. All of these changes were prevented if the animals were pretreated with a neutralizing monoclonal antibody against TNF. Web site: http://www.delphion.com/details?pn=US06011014__ •

Polypeptide capable of reacting with antibodies of patients suffering from multiple sclerosis and uses Inventor(s): Perron; Herve (Lyons, FR), Jolivet-Reynaud; Colette (Bron, FR), Mandrand; Bernard (Villeurbanne, FR) Assignee(s): Bio Merieux (Marcy l'Etoile, FR) Patent Number: 6,555,091 Date filed: October 18, 1999 Abstract: The invention concerns a polypeptide specifically reacting with the antibodies of patients suffering from multiple sclerosis (SEP) and whereof the peptide sequence comprises at least one sequence selected among SEQ ID No. 1 to SEQ ID NO: 19, and their equivalent sequences, and the use of this polypeptide in a reagent and a kit for detecting multiple sclerosis, an immunoreactive composition and in a method for fixing, in a biological sample, antibodies characteristic and/or specific of multiple sclerosis. Excerpt(s): The present invention relates to the determination of immunoreactive polypeptides capable of reacting specifically with the antibodies of patients suffering from multiple sclerosis (MS), and the use of these polypeptides. it comprises a sequence equivalent to SEQ ID NO: 13 exhibiting, for a succession of 12 contiguous amino acids, at least 40%, preferably 50% identity, and/or at least 55%, preferably 65% homology with a sequence p30/p10/5'v-fsm of the coding region of the feline sarcoma virus (FSV) [NCBI reference gi/554646], said polypeptide being different from the whole or part of said sequence p30/p10/5'v-fsm. Moreover, the work by the Applicant, in the search for an etiology of MS, has led to the discovery of the existence of at least one pathological and/or infective agent, the retrovirus MSRV-1, in particular associated with multiple sclerosis. Web site: http://www.delphion.com/details?pn=US06555091__

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Polypeptides useful for the purpose of treating multiple sclerosis Inventor(s): Hashim; George A. (Irvington, NY) Assignee(s): St. Luke's Hospital (New York, NY) Patent Number: 4,230,696 Date filed: September 11, 1978 Abstract: Synthetic compounds of the formula:R.sub.1 -Gln-R.sub.4 -R.sub.5and the acid addition salts thereof are disclosed wherein R.sub.1 and R.sub.5 are each independently selected from the group consisting of hydrogen, hydroxy, the residue of an amino acid and the residue of a polypeptide and R.sub.4 is selected from the group consisting of lysine and arginine residues; provided that R.sub.1 and R.sub.5 are not both hydrogen or both hydroxyl at the same time. The disclosure is also of intermediate compounds for preparing the compounds of the above formula and derivative compounds having the same biological activity.Disclosed also are pharmaceutical compositions wherein the

414 Sclerosis

essential active ingredient is a synthetic compound of the invention. The compounds and compositions of the invention are useful for the prevention, suppression, treatment and diagnosis of multiple sclerosis. Excerpt(s): The invention concerns novel synthetic polypeptides useful in the diagnosis and treatment of multiple sclerosis; intermediates and derivatives thereof. In each instance herein, it should be understood that in referring to amino acids, both the D- and L-isomeric forms are intended to be identified unless otherwise indicated. H--Thr--Thr-His--Tyr--Gly--Ser--Leu--Pro--Gln--Lys--OH. Web site: http://www.delphion.com/details?pn=US04230696__ •

Process and culture medium for the production of cells infected by a multiple sclerosis-associated virus Inventor(s): Perron; Herve (Grenoble, FR), Seigneurin; Jean-Marie (Bernin, FR) Assignee(s): Bio Merieux (Marcy l'Etoile, FR) Patent Number: 6,071,736 Date filed: November 20, 1996 Abstract: In a process for the in vitro production of a culture or cell line infected by a viral strain associated with multiple sclerosis (MS), a body sample is taken from an individual suffering from MS. The sample is cultivated in a culture medium that promotes the growth of infected cells to obtain a culture of primary infected cells. A sample of the culture of primary cells or a subculture of the latter is cultivated in series, by successive passages in the culture medium to obtain the culture or cell line infected by a virus associated with MS. The culture medium also contains a beta-interferon antibody or an antibody that is directed against an antigenically close molecule, the antibody playing an inhibiting role in viral expression and allowing long-lasting expression and propagation of the viral strain in the culture or cell line. Excerpt(s): Multiple sclerosis (MS) is a demyelinizing disease of the central nervous system (CNS) which has been suspected for several years of being associated with a virus, although the causal agent still has not been determined with certainty. Several works have supported this hypothesis of a viral etiology of the disease, but none of the known viruses tested has proved to be the causal agent sought. Consequently, the observation in patients suffering from multiple sclerosis of phenomena comparable to an autoimmunity reaction has led to an "essential" autoimmune etiological hypothesis (Lisak R. P., Zweiman B. New Engl. J. Med. 1977; 297, 850-853, and Lassmann H. and Wisniewski N. M. Arch. Neurol. 1979; 36, 490-497). However, this autoimmunity directed against certain components of the central nervous system has proven to be not very specific to MS and frequent in inflammations of the CNS, which may or may not be associated with an infection, as was demonstrated by Hirayama M. et al. (Neurology 1986; 36, 276-8) Kenneth G. Warren et al. (Annals of Neurology 1986; 20, 20-25), Suzumura A. et al. (Journal of Neuroimunology 1986; 11, 137-47) and Tourtelotte W. et al. (Journal of Neurochemistry 1986; 46, 1086-93). Furthermore, as noted by E. J. Field (The Lancet 1989; 1, 1272), none of the immunosuppressive therapeutic agents has allowed decisive results against MS to be obtained. Web site: http://www.delphion.com/details?pn=US06071736__

Patents 415

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Process and culture medium for the production of cells infected by a multiple sclerosis-associated virus Inventor(s): Seigneurin; Jean-Marie (Bernin, FR), Perron; Herve (Grenoble, FR) Assignee(s): Bio Merieux (Marcy l'Etoile, FR) Patent Number: 6,291,225 Date filed: June 7, 1995 Abstract: Process for in vitro production of a culture or cell line infected by a viral strain associated with multiple sclerosis (MS), according to which a body sample is taken from an individual suffering from MS, the sample is cultivated in a culture medium which promotes the growth of infected cells to obtain a culture of primary infected cells, and a sample of the culture of primary cells or of a subculture of the latter is cultivated in series, that is to say by successive passages, in the culture medium to obtain the culture or cell line infected by a virus associated with MS. The process includes a procedure in which the culture medium also contains a beta anti-interferon antibody or an antibody which is directed against an antigenically close molecule, the antibody playing an inhibiting role in viral expression and allowing long-lasting expression and propagation of the viral strain in the culture or cell line. Excerpt(s): The present invention relates to a medium for in vitro culture of cells infected by a virus present in individuals suffering from multiple sclerosis, a process for the production of infected cells using said medium and the infected cell lines thus obtained. Multiple sclerosis (MS) is a demyelinizing disease of the central nervous system (CNS) which has been suspected f or several years of being associated with a virus, although the causal agent still has not been determined with certainty. Several works have supported this hypothesis of a viral etiology of the disease, but none of the known viruses tested has proved to be the causal agent sought. Web site: http://www.delphion.com/details?pn=US06291225__

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Process for the production of a viable cell culture infected by a multiple sclerosisassociated virus Inventor(s): Seigneurin; Jean-Marie (Bernin, FR), Perron; Herve (Grenoble, FR) Assignee(s): Bio Merieux (L'Etoile, FR), Universite Joseph Fourier (Grenoble 1) (Grenoble Cedex, FR) Patent Number: 5,925,555 Date filed: May 22, 1996 Abstract: The present invention relates to a process for in vitro culture of cells infected by a virus associated with multiple sclerosis and to the infected cell lines thus produced. According to the invention, the process includes: a) cultivation of human cells infected by a viral strain to obtain at least one culture of primary cells infected by the viral strain, b) cultivation of non-infected human cells permissive to the viral strain to obtain at least one permissive culture, c) cocultivation of at least one sample of a culture of infected primary cells and one sample of the permissive culture to obtain a first infected derived culture, d) cultivation in series of the first infected derived culture. The invention is used in particular in the pharmaceutical diagnostics industry sector. Excerpt(s): The present invention relates to the production and maintenance of a viable cell culture or line infected by the virus associated with multiple sclerosis (MS). Such a

416 Sclerosis

culture in fact has the advantage of constituting a biological material which expresses the activity of the virus associated with MS, and as a result can be used for various experimental aims, in particular for tests for identification and characterization of the virus, but also for clinical or therapeutic aims. The present invention relates to a process for in vitro culture of cells infected by a virus present in individuals suffering from multiple sclerosis and to the infected cell lines thus obtained. Multiple sclerosis (MS) is a demyelinizing disease of the central nervous system (CNS) which has been suspected for several years of being associated with a virus, although the causal agent has still not been determined with certainty. Web site: http://www.delphion.com/details?pn=US05925555__ •

Prostacyclin and carbacyclin derivatives as agents for the treatment of multiple sclerosis Inventor(s): Blitstein-Willinger; Eveline (Berlin, DE) Assignee(s): Schering Aktiengesellschaft (Berlin, DE) Patent Number: 5,506,265 Date filed: December 6, 1994 Abstract: This invention relates to the use of prostacyclin and carbacyclin derivatives for the production of an agent for the treatment of multiple sclerosis. Excerpt(s): This application is filed under 35 USC 371 of PCT/DE93/00013 filed Jan. 9, 1995. This invention relates to agents for the treatment of multiple sclerosis, a primary inflammatory disease of the central nervous system with localized demyelination. The agents contain prostacyclin and carbacyclin derivatives and common auxiliary agents and vehicles. The invention also relates to the use of these prostacyclin and carbacyclin derivatives for the production of the above-mentioned agents. Web site: http://www.delphion.com/details?pn=US05506265__

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Reagents and method for therapeutic treatment of multiple sclerosis Inventor(s): Mercer; James B. (13109 W. 95th St., Lenexa, KS 66215) Assignee(s): none reported Patent Number: 5,102,902 Date filed: May 1, 1990 Abstract: The administration internally to humans of certain imidazol derivatives, especially N"-cyano-N-methyl-N'-[2[[(5-methyl-1H-imidazol-4-yl) methyl]thio]-ethyl]guanidine (cimetidine) or salts thereof, is an effective therapeutic treatment for multiple sclerosis, both acute and chronic. The imidazole moiety is theorized to directly inhibit spread of the virus theorized to cause multiple sclerosis. Treatment of multiple sclerosis with metronidazole with one bolus dose on a frequency of once a day or less and with cimetidine on a frequency of twice per day has been found to be highly efficatious with minimal suppression of the patient's natural immune system and minimal long term peripheral nerve damage. Excerpt(s): The invention herein described relates to an agent for, and a method of, treating progressive, nonremitting multiple sclerosis (hereinafter referred to as "multiple sclerosis"). In particular, this invention relates to the use of imidazole derivatives as general anti-viral agents. Infectious agents, possibly viral in nature, together with an

Patents 417

immune disorder, appear to cause multiple sclerosis. The following articles discuss theories relating to multiple sclerosis resulting from an infection, especially viral: Kurtzke, J. F., Hyllestad, K., Multiple Sclerosis in the Faron Islands Ann. Neurol 1979, Vol. 5, pages 6-21; Kurtzke, J. F., Gudmundson, K. R., Bergmann, S., Multiple Sclerosis in Iceland: 1. Evidence of a Postwar Epidemic Nour. 1982 Vol. 32, pages 143-50; Rosati, G., et al., Incidence of Multiple Sclerosis in Macomber, Sardinia, 1912-1981: Onset of the Disease After 1950, 14 Neurology 36, Jan. 1986. Although it is not the intent of applicant to be bound herein to any particular theory or theories it is theorized by applicant and others that measles virus is the cause of multiple sclerosis. The following articles discuss this theory: Levy, N. L., Auerbach, P. S., Hayes, E. C., A Blood Test for Multiple Sclerosis Based on the Adherence of Lymphocytes to Measles--Infected Cells, N. Engl. J. Med. 294: 1424-27, 1976; Stevenson, J. R., Ter Meulen, V., Kisseling, W., Search for CanineDistemper Virus Antibodies in Multiple Sclerosis. A Detailed Variological Evaluation, Lancet 2:772-75, 1980. Web site: http://www.delphion.com/details?pn=US05102902__ •

Retrovirus agents MSRV1 and MSRV2 associated with multiple sclerosis Inventor(s): Mandrand; Bernard (Villeurbanne, FR), Mallet; Francois (Villeurbanne, FR), Perron; Herve (Grenoble, FR), Bedin; Frederic (Lyons, FR), Beseme; Frederic (Villefontaine, FR) Assignee(s): Bio Merieux (Marcy L'Etoile, FR) Patent Number: 5,871,996 Date filed: February 6, 1995 Abstract: Composition including two pathogenic and/or infective agents associated with multiple sclerosis, namely a first agent which consists of a human virus possessing reverse transcriptase activity and related to a family of endogenous retroviral elements, or a variant of the virus, and a second agent, or a variant of the second agent, these two pathogenic and/or infective agents originating from the same viral strain chosen from the strains designated, respectively, POL-2 deposited with the ECACC on Jul. 22, 1992 under Accession Number V92072202 and MS7PG deposited with the ECACC on Jan. 8, 1993 under Accession Number V93010816, and from their variant strains. Excerpt(s): Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) the cause of which remains as yet unknown. Many studies have supported the hypothesis of a viral etiology of the disease, but none of the known viruses tested has proved to be the causal agent sought: a review of the viruses sought for several years in MS has been compiled by E. Norrby (1) and R. T. Johnson (2). Concomitantly, the possibility of an exogenous and/or infectious factor is suggested by the existence of localized epidemics or "clusters" of MS, as have been observed in the Faro Islands between 1943 and 1960 (3), in Sardinia (4), in Norway (5), and also by studies on migrant populations (6). Among all the exogenous factors suggested, viruses have been most often studied, and a viral etiology is traditionally called to mind. Web site: http://www.delphion.com/details?pn=US05871996__

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Thioether, keto-ester and alkyl phospholipids useful in treating multiple sclerosis Inventor(s): Houlihan; William J. (Mountain Lakes, NJ) Assignee(s): Sandoz Ltd. (Basel, CH) Patent Number: 5,182,271 Date filed: August 30, 1991 Abstract: The invention discloses certain thioether, keto-ester and alkyl phospholipids which are useful in treating multiple sclerosis. Excerpt(s): The present invention relates to the use of certain heterocyclic, thioether, keto-ester and alkyl phospholipids useful in treating multiple sclerosis. Multiple sclerosis, a crippling nerve disorder characterized by disseminated patches of demyelination in the brain and spinal cord, has occupied the attention of research organizations for many years without, unfortunately, any appreciable success. Although ACTH (adrenocorticotropic hormone) or prednisone appears to hasten recovery in acute attacks, especially when administered early in the episode, there is no specific therapy, even today, as spontaneous remissions make any treatment difficult to evaluate. U.S. Pat. No. 4,778,788 discloses certain lysolecithin analogs useful in treating multiple sclerosis. Web site: http://www.delphion.com/details?pn=US05182271__

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Treatment of multiple sclerosis Inventor(s): Tenoso; Harold J. (Westfield, NJ) Assignee(s): Unimed, Inc. (Somerville, NJ) Patent Number: 4,654,333 Date filed: February 18, 1986 Abstract: Multiple sclerosis is treated by the administration of azaspirane compounds, either germanium or silicon asaspirane compounds, preferably spirogermanium, most preferably dimethyl, diethyl, dipropyl or dibutyl. The diethyl or dibutyl are the most preferred. Excerpt(s): Multiple sclerosis (MS) and its variants comprise a distinct group of demyelinating diseases. A typical MS plaque or lesion is an area of grossly visible, well demarcated, demyelinated white matter. Immunocytochemical studies with monoclonal antibodies against T-cells and other inflammatory components have demonstrated that T.sub.4 + (helper, inducer) T-cells are involved in lesion extension. Generally speaking, in accordance with the present invention, it has been discovered that certain specific compounds of U.S. Pat. No. 3,825,546, namely those which contain germanium in the ring, that is the spirogermaniums, particularly the dimethyl, diethyl, dipropyl and dibutyl spirogermaniums including their acid addition salts and bis-quaternary salts, appear to be useful in reducing or preventing the development of EAE lesions in the brain, to suppress the autoimmune reaction asserted to be the ultimate cause of the EAE and MS lesions, and therefore to be useful in the treatment of multiple sclerosis. Web site: http://www.delphion.com/details?pn=US04654333__

Patents 419

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Treatment of multiple sclerosis (MS) and other demyelinating conditions using lofepramine in combination with L-phenylalanine, tyrosine or tryptophan and possibly a vitamin B12 compound Inventor(s): Loder; Cari (127 Russell Court, Woburn Place, London WC1H 0LP, GB) Assignee(s): none reported Patent Number: 6,096,737 Date filed: June 27, 1997 Abstract: The use of a combination of a tricyclic or tetracyclic antidepressant, a serotonin reuptake inhibitor, or a monoamine oxidase inhibitor with a neurotransmitter-inducing or precursor compound is proposed in the preparation of medication for the treatment or prevention of multiple sclerosis or other demyelinating conditions. For use in treatment to ameliorate the effects of a demyelinating condition, a daily regime is proposed of from 10 to 220 mg lofepramine and from 100 mg to 5 g of L-phenylalanine, optionally supplemented with injections of vitamin B.sub.12. Excerpt(s): This invention relates to the treatment of Multiple Sclerosis (MS) and other Demyelinating Conditions. Multiple sclerosis is a common and well known neurological disorder. It is characterised by episodic patches of inflammation and demyelination which can occur anywhere in the central nervous system (CNS) almost always without any involvement of the peripheral nerves. The occurrence of the patches is disseminated in time and space, hence the older alternative name of disseminated sclerosis. It is believed that the pathogenesis involves local disruption of the blood brain barrier, a local immune and inflammatory response, with consequent damage to myelin and hence to neurons. Clinically, MS can present in both sexes and at any age. However, its most common presentation is in relatively young adults, often with a single focal lesion such as damage to the optic nerve (optic neuritis), an area of anaesthesia or paraesthesia or muscular weakness. Vertigo, nystagmus double vision, pain, incontinence, cerebellar signs, L'Hermitte's sign (paraesthesia or pain in the arms and legs on flexing the neck) and a large variety of less common symptoms may occur. The initial attack is often transient and it may be weeks, months or years before a further attack occurs. Some fortunate individuals may have a stable condition, while other unfortunate ones may have an unrelenting downhill course ending in complete paralysis. More commonly there is a long series of remissions and relapses, each relapse leaving the patient somewhat worse than before. Relapses may be triggered by stressful events or viral infections. Elevated body temperature almost invariably makes the condition worse whereas a reduced temperature, for example induced by a cold bath, may make the condition better. Web site: http://www.delphion.com/details?pn=US06096737__

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Treatment of multiple sclerosis (MS) and other demyelinating conditions using lofepramine in combination with L-phenylalanine, tyrosine or tyrptophan and possibly a vitamin B12 compound Inventor(s): Loder; Cari (127 Russell Court, Woburn Place, London WC1H 0LP, GB) Assignee(s): none reported Patent Number: 6,569,850 Date filed: June 1, 2000

420 Sclerosis

Abstract: Method for treating multiple sclerosis or encephalomyelitis by administering to a patient a combination of a tricyclic antidepressant drug and tyrosine or phenylalanine or both. Excerpt(s): This invention relates to the treatment of Multiple Sclerosis (MS) and other Demyelinating Conditions. Multiple sclerosis is a common and well known neurological disorder. It is characterised by episodic patches of inflammation and demyelination which can occur anywhere in the central nervous system (CNS) almost always without any involvement of the peripheral nerves. The occurrence of the patches is disseminated in time and space, hence the older alternative name of disseminated sclerosis. It is believed that the pathogenesis involves local disruption of the blood brain barrier, a local immune and inflammatory response, with consequent damage to myelin and hence to neurons. Clinically, MS can present in both sexes and at any age. However, its most common presentation is in relatively young adults, often with a single focal lesion such as damage to the optic nerve (optic neuritis), an area of anaesthesia or paraesthesia or muscular weakness. Vertigo, nystagmus double vision, pain, incontinence, cerebellar signs, L'Hermitte's sign (paraesthesia or pain in the arms and legs on flexing the neck) and a large variety of less common symptoms may occur. The initial attack is often transient and it may be weeks, months or years before a further attack occurs. Some fortunate individuals may have a stable condition, while other unfortunate ones may have an unrelenting downhill course ending in complete paralysis. More commonly there is a long series of remissions and relapses, each relapse leaving the patient somewhat worse than before. Relapses may be triggered by stressful events or viral infections. Elevated body temperature almost invariably makes the condition worse whereas a reduced temperature, for example induced by a cold bath, may make the condition better. There are no satisfactory treatments for MS. Steroids may produce a temporary improvement but any beneficial effect invariably wears off. Recent clinical trials have shown that interferon may somewhat reduce the risk of relapse. However, the effect is modest and most patients still deteriorate. Web site: http://www.delphion.com/details?pn=US06569850__ •

Treatment of multiple sclerosis by oral administration of bovine myelin Inventor(s): Hafler; David A. (Newton, MA), Weiner; Howard L. (Brookline, MA) Assignee(s): Autoimmune Inc. (Lexington, MA) Patent Number: 5,849,298 Date filed: August 10, 1993 Abstract: The invention is directed to a method of treating multiple sclerosis in animals, including humans, by the oral administration of bovine myelin. Excerpt(s): The present invention relates to the field of treatment of autoimmune diseases and in particular T cell-mediated or T cell-dependent autoimmune diseases. Specifically, the present invention provides the administration of autoantigens, or fragments or analogs thereof, for the prophylactic and therapeutic treatment of such autoimmune diseases. Autoimmune diseases are caused by an abnormal immune response involving either cells or antibodies directed against normal tissues. A number of strategies have been developed to suppress autoimmune diseases, most notably drugs which nonspecifically suppress the immune response. A method of inducing immunologic tolerance by the oral administration of an antigen to prevent autoimmune responses was first demonstrated by Wells in 1911. Wells, H., J. Infect. Dis. 9:147 (1911).

Patents 421

The oral induction of unresponsiveness has also been demonstrated for several T-cell dependent antigens. Ngan, J. et al., J. Immunol. 120:861 (1978), Gautam, S. et al., J. Immunol. 135:2975 (1985), Titus, R. et al., Int. Arch. Allergy Appl. Immun. 65:323 (1981). Antigen-driven peripheral immune tolerance by the oral route has recently been shown to serve as an effective immunoregulatory therapeutic approach in several experimental autoimmune diseases (Higgins, P. J., et al., J. Immunol. 140:440 (1988); Lider, O., et al., J. Immunol. 142:748-752 (1989); Bitar, D. M., et al., Cell. Immunol. 112:364 (1988); Nussenblatt, R. B., et al., J. Immunol. 144:1689 (1990); Nagler-Anderson, C., et al., Proc. Natl. Acad. Sci. USA 83:7443-7446 (1986); Thompson, H.S.G., et al., Clin. Exp. Immunol. 64:581-586 (1986)). Scientists have also studied ways to suppress autoimmune diseases in various animal models. Experimental allergic encephalomyelitis (EAE) is a T cellmediated autoimmune disease directed against myelin basic protein (MBP) and has been studied as a model for multiple sclerosis in several mammalian species. See, Alvord, E. et al., Experimental Allergic Encephalomyelitis--A Useful Model For Multiple Sclerosis (Allan R. Liss, New York, 1984). Immunoregulation of EAE is known to be at least partially dependent on suppressor T cells (Ts). It has been shown that Ts are present in rats which have recovered from EAE. Swierkosz, J. et al., J. Immunol. 119:1501 (1977). Furthermore, it has been shown that suppressor T cells account for the unresponsiveness to EAE that is exhibited by some mouse strains. Lando, Z. et al., Nature 287:551 (1980). Web site: http://www.delphion.com/details?pn=US05849298__ •

Treatment of multiple sclerosis through ingestion or inhalation of copolymer-1 Inventor(s): Teitelbaum; Dvora (Rehovot, IL), Sela; Michael (Rehovot, IL), Gilbert; Adrian (Kfar-Saba, IL), Linenberg; Milka (Tel-Mond, IL), Arnon; Ruth (Rehovot, IL), Riven-Kreitmann; Rivka (Kfar-Saba, IL) Assignee(s): Yeda Research and Development Co. Ltd. (Rehovot, IL) Patent Number: 6,214,791 Date filed: January 12, 2000 Abstract: The present invention relates to the treatment of multiple sclerosis by ingestion or inhalation of copolymet-1 and pharmaceutical compositions useful for such treatment. Excerpt(s): This invention relates to the treatment of multiple sclerosis by ingestion or inhalation of copolymer-1 (as defined below). The present invention also relates to a pharmaceutical composition comprising copolymer-1 used for the treatment of multiple sclerosis, wherein the pharmaceutical composition is formulated for administration by ingestion or inhalation. Copolymer-1, also known as glatiramer acetate and marketed under the tradename Copaxone.RTM., comprises the acetate salts of polypeptides containing L-glutamic acid, L-alanine, L-tyrosine and L-lysine. The average molar fraction of the amino acids are 0.141, 0.427, 0.095 and 0.338, respectively, and the average molecular weight of copolymer-1 is between 4,700 and 11,000 daltons. It is a non-autoantigen which has been demonstrated to suppress experimental allergic encephalomyelitis (EAE) induced by various encephalitogens including mouse spinal cord homogenate (MSCH) which includes all myelin antigens, such as myelin basic protein (MBP) (Sela M et al., Bull Inst Pasteur (1990) 88 303-314), proteolipid protein (PLP) (Teitelbaum D et al., J Neuroimmunol (1996) 64 209-217) and myelin oligodendrocyte glycoprotein (MOG) (Ben-Nun A et al., J Neurol (1996) 243 (Suppl 1) S14-S22) in a variety of species. EAE is an accepted model for multiple sclerosis.

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Copolymer-1 has been demonstrated to be active when injected subcutaneously, intraperitoneally, intravenously or intramuscularly (D. Teitelbaum et al., Eur. J. Immunol. (1971) 1:242-248; D. Teitelbaum et al., Eur. J. Immunol. (1973) 3:273-279). Web site: http://www.delphion.com/details?pn=US06214791__ •

Treatment of multiple sclerosis using consensus interferon and IL-1 receptor antagonist Inventor(s): Martin; David (Camarillo, CA), Fischer; Norman L. (Lyons, CO) Assignee(s): Amgen, Inc. (Thousands Oaks, CA) Patent Number: 6,013,253 Date filed: August 15, 1997 Abstract: The present invention encompasses methods for preventing and treating multiple sclerosis by administering to patients in need thereof a therapeutically effective amount of IFN-con in combination with IL-1ra. Excerpt(s): The present invention relates to methods for preventing and treating, using consensus interferon (IFN-con), patients suffering from multiple sclerosis (MS). Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), characterized clinically by relapses and remissions, often leading to progressive physical impairment. MS is the most common disabling neurological disorder affecting young white adults. At least 350,000 Americans have MS, with women affected twice as often as men. MS usually starts by the ages of 15 and 50; the average age of onset is 30. The risk of MS varies for different geographical areas and one increases as one lives further north or south of the equator. The precise etiology and pathogenesis of the disease remain unknown; however, pathologic, genetic, and immunologic features have been identified which suggest that the disease has an autoimmune basis; see e.g., Waksman, et al., Proc. Soc. Exp. Biol. Med., 175:282-294 (1984) and Hafler et al., Immunol. Rev., 100:307-332 (1987). MS follows a varied, often unpredictable course, but is typically categorized into four widely recognized forms: relapsing-remitting (.about.25% of cases); relapsing-progressive (.about.40% of cases); chronic-progressive (.about.15% of cases); and benign (.about.20% of cases). Nearly all MS patients suffer such symptoms as fatigue, spasticity, tremor, decreased mobility, depression, pain, urologic complications, and cognitive impairment at some point during the course of their disease. Web site: http://www.delphion.com/details?pn=US06013253__

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Treatment of multiple immunosuppression

sclerosis

with

lymphocytapheresis

and

chemo-

Inventor(s): Bloom; Philip M. (12508 Briarwood Ter., Minnetonka, MN 55343) Assignee(s): none reported Patent Number: 4,964,848 Date filed: June 27, 1988 Abstract: Autoimmune diseases, such as multiple sclerosis, are treated by conducting lymphocytapheresis in a series of treatments until the peripheral blood lymphocyte count has been reduced to less than 500 cells/.mu.l and preferably to less than 300

Patents 423

cells/.mu.l and thereafter continuing such treatments while administering an immunosuppressive compounds such as azathioprine at about 2.5 mg/Kg per day and prednisone at about 15 mg per day sufficient to maintain the PBL count at less than 500 cells/.mu.l and preferably less than 300 cells/.mu.l. Excerpt(s): The invention relates to treatment of autoimmune diseases and particularly multiple sclerosis. More specifically, the invention is concerned with the combined use of lymphocytapheresis (LCP) and chemotherapy. Multiple sclerosis is a disease of the central nervous system with variable neurologic deficits due to demyelination in the brain and spinal cord. The course of the disease is variable, in some patients multiple sclerosis is chronic and progressive. Although the etiology is not precisely understood, there is convincing evidence that the disease is of an autoimmune nature. Defective and abnormal immune responses have been observed. Current evidence indicates that the defective immune response causes destruction of central nervous system myelin by the autoreactive (cytotoxic lymphocyte) cells. The damage is initiated in two stages: In the first stage, T4 (helper-inducer) cells stimulate the T8 CTL cells to proliferate; and in the second stage, the T4 and the T8 cells are believed to be a direct cause of primary lesions. During this process the T4 cells recruit macrophages which may also cause direct cell damage. It is thus believed that the T4 cells mediate this autoimmune process. Finally, there is evidence that a basic defect in the T4 cell is a failure to induce proliferation of another subset of T8 suppressor cells which would normally inhibit the above progression. The defective T4 suppressor-inducer cells thus fail to perform the normal inhibitory function. As a result of these immunological defects, attempts have been made to interrupt the course of the disease with immunosuppression. See: (1) "Intensive Immunosuppression in Progressive Multiple Sclerosis," New England Journal of Medicine, Vol. 308, No. 4, Jan. 1983, S. L. Hauser, et al; (2) "Plasma Exchange and Lymphocytapheresis in Multiple Sclerosis," Int J Artif Organs, 7:39-42, 1984, P. Hocker, et al; and (3) "Long-Term Lymphocytapheresis Therapy in Multiple Sclerosis," Eur Neurol, 25:225-236, 1986, E. Maida, et al. Web site: http://www.delphion.com/details?pn=US04964848__ •

Tuberous sclerosis 2 gene and uses thereof Inventor(s): van den Ouweland; Anna Maria Wilhelmina (Dorpsweg 5, 3212 LC, Simonshaven, NL), Sampson; Julian R. (34 Bridge Street, Cardiff, CF5 2EL, GB), Nellist; Mark David (Noordmolenstraat 57b, 3053 RG Rotterdam, NL), Brook-Carter; Phillip (2 Bent Street, Wonthaggi, VIC 3995, AU), Maheshwar; Magitha (88 Ynysddu, Pontyclun, Mid Glamorgan, CF7 9UB, GB), Halley; Dirkje Jorijntje Johanna (van Aerssenlaan 35d, 3039 KD Rotterdam, NL), Janssen; Lambertus Antonius Jacobus (Schokker 37, 2991 DJ Barendrecht, NL), Hesseling; Arjenne Lique Wilhelma (Haya van Someren Downerpad 7, 3207 Spijkenisse, NL), Ward; Christopher James (30 Benson Road, Oxford, OX3 7EH, GB), Breuning; Martin Hendrik (Brigantjijnstraat 57, 1503 BR, Zaandam, NL), Roelfsema; Jeroen Hendrik (Vjif Meilaan 2006, 2321 RR, Leiden, NL), Harris; Peter Charles (65 Freelands Road, Oxforrd OX4 4BS, GB) Assignee(s): none reported Patent Number: 6,232,452 Date filed: October 1, 1996 Abstract: Tuberous sclerosis (TSC) is an autosomal dominant disorder characterised by widespread development of growths in many tissues and organs. A gene (TSC2) is identified on chromosome 16 which is mutated in TSC and which may behave as a

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tumour suppressor. Screening of actual or suspected TSC patients for normal or mutated TSC2 can be used for diagnostic purposes. TSC2 protein (tuberin) may be used to treat or prevent unrestrained cell division and/or tumour development in patients with or without TSC. Excerpt(s): The present invention relates to the tuberous sclerosis 2 (TSC2) gene, mutations thereof in patients having TSC2-associated disorders, the protein encoded by the TSC2 gene, and their uses in diagnosis and therapy. All references mentioned hereinbelow are listed at the end of this description and are herein incorporated by reference in their entirety. Tuberous sclerosis (TSC) is an autosomal dominant disorder, classified as a phakomatosis (van der Hoeve, 1933) and characterised by the widespread development of growths, usually described as hamartomata, in many tissues and organs. The unpredictable distribution of these lesions, particularly within the brain, eyes, skin, kidneys, heart, lungs and skeleton results in a wide variety of signs, symptoms and complications (Gomez, 1988). Although most frequently diagnosed as a result of neurological or dermatological manifestations, renal disease was found to be the leading cause of mortality (11/40 deaths) in the largest series of TSC deaths reported so far. Renal complications including haemorrhage, hypertension and end stage renal disease (ESRD) are associated with the development of cysts and hamartomatous growths (angiomyolipomata) in the kidneys. Angiomyolipomata probably arise due to coexistent inactivating constitutional and somatic mutations, consistent with the TSC genes functioning as tumour or growth suppressor genes (Green et al (1994) and Green et al (in press)). Therefore the frequency of diagnosed cases is likely to under-represent true prevalence which may be as high as 1 in 5,800 (Osborne et al., 1991). The pathogenesis of TSC is poorly understood and efforts to establish the primary underlying defect have focused on positional cloning of the causative gene(s). Web site: http://www.delphion.com/details?pn=US06232452__ •

Use of 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyr idine for preparing drugs for treating amyotrophic lateral sclerosis Inventor(s): Fournier; Jacqueline (Plaisance-du-Touch, FR), Douillet; Patrice (St.-Gelydu-Fesc, FR) Assignee(s): Sanofi (FR) Patent Number: 6,043,251 Date filed: September 14, 1998 Abstract: The present invention relates to the use of 1-(2-naphth-2-ylethyl)-4-(3trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid ine or its addition salts with pharmaceutically acceptable acids for the preparation of drugs intended for the treatment of amyotrophic lateral sclerosis (ALS). Excerpt(s): The present invention relates to the use of 1-(2-naphth-2-ylethyl)4-(3trifluoromethylphenyl)-1,2,3,6-tetrahydropyridi ne or its addition salts with pharmaceutically acceptable acids for the preparation of drugs intended for the treatment of amyotrophic lateral sclerosis (ALS). Very few products are being studied for ALS, particular examples being peptide compounds such as IGF-1 (Insulin-like Growth Factor 1) and BDNF (Brain Derived Neurotrophic Factor), which are described in Annals of Neurology, 1995, 38, 971, and Nature, 1992, 360, 753-759. The only nonpeptide compound to have been tested for this disease is riluzole, whose chemical name is 2-amino-6-trifluoromethoxybenzothiazole, which is apparently capable of slowing

Patents 425

down the progression of the disease in a particular group of subjects suffering from ALS (G. Bensimon et al., N. Engl. J. Med., 1994, 330, 585-591; Scrip, 1995, No. 2035:21), but no product effective in the treatment of this disease is currently available on the pharmaceutical market. According to the article by G. Bensimon et al. cited above, riluzole prolongs the survival of patients suffering from ALS, but the side effects, such as asthenia, spasticity and an increase in the transaminase levels, impair the quality of life of said patients. Web site: http://www.delphion.com/details?pn=US06043251__ •

Use of 2-amino-6-(trifluoromethoxy)benzothiazole for obtaining a medicament for the treatment of amyotrophic lateral sclerosis Inventor(s): Louvel; Erik (Manosque, FR) Assignee(s): Rhone Poulenc Rorer S.A. (FR) Patent Number: 5,527,814 Date filed: October 21, 1994 Abstract: Use of 2-amino-6-(trifluoromethoxy)benzothiazole, or a salt of this compound with a pharmaceutically acceptable acid, for obtaining a medicament intended for the treatment of motor neuron diseases, in particular amyotrophic lateral sclerosis, and especially amyotrophic lateral sclerosis with early bulbar involvement or the bulbar form of the disease. Excerpt(s): The present invention relates to the use of 2-amino-6(trifluoromethoxy)benzothiazole, or a salt of this compound with a pharmaceutically acceptable acid, for obtaining a medicament intended for the treatment of motor neuron diseases, in particular amyotrophic lateral sclerosis commonly known as Lou Gehrig's Disease, and especially amyotrophic lateral sclerosis with early bulbar involvement or the bulbar form of the disease. 2-Amino-6-(trifluoromethoxy)benzothiazole (international non-proprietary name: riluzole) is known to be useful as an anticonvulsant, anxiolytic and hypnotic medicament (Patent EP 50,551), in the treatment of schizophrenia (EP 305,276), in the treatment of sleep disorders and depression (EP 305,277), in the treatment of cerebrovascular disorders and as an anaesthetic (EP 282,971). It has now been found that 2-amino-6-(trifluoromethoxy)benzothiazole, or a salt of this compound with a pharmaceutically acceptable acid, is useful in the treatment of motor neuron diseases, in particular amyotrophic lateral sclerosis, and especially amyotrophic lateral sclerosis with early bulbar involvement. Web site: http://www.delphion.com/details?pn=US05527814__

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Use of ginkgo biloba extracts for preparing a medicine for treating amyotrophic lateral sclerosis Inventor(s): Christen; Yves (Paris, FR) Assignee(s): Societe de Conseils de Recherches et d'Applications Scientifiques (FR) Patent Number: 6,524,629 Date filed: January 23, 2001 Abstract: The invention relates to the use of extracts of Ginkgo biloba, and in particular extracts of Ginkgo biloba comprising 20 to 30% of flavoneglycosides, 2.5 to 4.5% of

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ginkgolides A, B, C and J, 2 to 4% of bilobalide, less than 10% of proanthocyanidines and less than 10 ppm of compounds of alkylphenol type, for preparing a medicament intended to treat amyotrophic lateral sclerosis. Excerpt(s): The invention relates to the use of extracts of Ginkgo biloba for preparing a medicament intended to treat amyotrophic lateral sclerosis (ALS). It is already known that extracts of Ginkgo biloba have an activity in the cardiovascular field (in particular the reduction of platelet adhesion), in the central nervous field (in particular a neuroprotective activity) or in the neurosensory system (in particular retinal protection); cf. for example DeFeudis et al., Ginkgo Biloba Extract (EGb 761), Pharmaceutical Activities and Clinical Applications (Elsevier, Paris, 1991). Their preparation has been the subject of a certain number of patents, of which there can be mentioned the European Patents EP 431 535 and EP 431 536, and the American Patent U.S. Pat. No. 5,389,370. Certain products can be used in the treatment of ALS. In particular there can be mentioned riluzole, gabapentin, 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)1,2,3,6-tetrahydropyrid ine or vitamin E (cf. Gurney M. E. et al., Ann. Neurol., 39 (1996), 147-157; Patent Application PCT WO 97/15304). Web site: http://www.delphion.com/details?pn=US06524629__ •

Use of substituted adenine derivatives for treating multiple sclerosis Inventor(s): Beutler; Ernest (La Jolla, CA) Assignee(s): The Scripps Research Institute (La Jolla, CA) Patent Number: 5,506,214 Date filed: July 27, 1994 Abstract: Treatment of patients having multiple sclerosis with therapeutic agents containing substituted adenine derivatives such as 2-chloro-2'-deoxyadenosine is shown to markedly ameliorate the disease condition. Excerpt(s): This invention relates to therapeutic methods for treating multiple sclerosis. More particularly, this invention relates to the use of substituted adenine derivatives for treating multiple sclerosis. Multiple sclerosis (MS) is the result of demyelination in the brain and spinal cord (central nervous system). Symptoms resulting from this demyelination include weakness, visual impairment, incoordination, and paresthesia (abnormal tingling). The course of the disease is largely unpredictable, but often progresses through a cycle of exacerbation of symptoms followed by remission. The etiology of multiple sclerosis is unknown but is linked to a variety of genetic and environmental factors. Both cell-mediated and humoral immune responses, triggered by extraneous or autoantigens may contribute to the pathogenesis of multiple sclerosis. Certain immune response genes may be associated with an increased susceptibility to the disease. The disease may be mediated by T cells that recognize an as yet unidentified autoantigen. For example, experimental allergic encephalomyelitis (EAE), an animal model of demyelinating diseases such as multiple sclerosis, can be induced by immunizing mice with whole myelin or specific myelin components such as myelin basic protein. Web site: http://www.delphion.com/details?pn=US05506214__

Patents 427

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Use of tetracycline derivatives in treating multiple sclerosis Inventor(s): Zhang; Su-Chun (Madison, WI), Duncan; Ian D. (Madison, WI) Assignee(s): Wisconsin Alumni Research Foundation (Madison, WI) Patent Number: 6,613,756 Date filed: May 3, 2001 Abstract: A method of treating multiple sclerosis is disclosed. In one embodiment, the method comprises the step of treating a multiple sclerosis patient with a tetracycline derivative, wherein the multiple sclerosis symptoms of the patient are diminished. Excerpt(s): There is an urgent need for the development of new drugs or a new application of existing drugs to the treatment of multiple sclerosis and other incurable neurologic disorders. The application of tetracycline derivatives, such as minocycline or doxycycline, to the treatment of multiple sclerosis based on our data is an advance in the treatment of this disease, both as a primary therapy and in support of transplantinduced brain repair. Multiple sclerosis is an inflammatory disease of the central nervous system (CNS) in which demyelination results in a variety of neurologic deficits. In many patients the disease relapses and remits while in others there is a progressive worsening with no remissions. At present, the only drugs that have been found to be effective in slowing or lessening the disease burden are.beta.-interferon and copolymerI. However, neither cures the disease and in many patients there is little or no effect. While T-cells are the early inflammatory cells found in areas of demyelination (plaques) in multiple sclerosis patients, microglia in these areas become activated and are thought to produce a number of cytotoxic cytokines. These cytokines are then thought to play a key role in the subsequent demyelination and oligodendrocyte death. The best available model of multiple sclerosis is EAE (Experimental Allergic Encephalomyelitis). While there are differences between EAE and Multiple Sclerosis, EAE remains as the standard model in which to test therapeutic strategies. Indeed, some Phase I trials in multiple sclerosis patients have been based on experimental therapies of EAE. While EAE can be generated in both rats and mice and by using a number of protocols, we induce the disease in DA (Dark Agouti) rats by the injection of myelin-oligodendrocyte glycoprotein (MOG) in incomplete Freund's adjuvant. This creates a severe, often relapsing-remitting neurologic disease, like multiple sclerosis, with paralysis of the hind limbs 12-15 days after immunization. Histologically, there is scattered demyelination associated with inflammation and microglial activation. Web site: http://www.delphion.com/details?pn=US06613756__

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Use of the R-(+)-isomer of 2-methoxy-3-octadecyloxy-propanol-(1)-phosphoric acid, monocholine ester in treating multiple sclerosis Inventor(s): Houlihan; William J. (Mountain Lakes, NJ) Assignee(s): Sandoz Ltd. (Basel, CH) Patent Number: 5,082,846 Date filed: August 30, 1990 Abstract: The invention discloses the use of the R-(+)-isomer of 2-methoxy-3octadecyloxy-propanol-(1)-phosphoric acid, monocholine ester in treating multiple sclerosis and to pharmaceutical compositions containing said isomer.

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Excerpt(s): The present invention relates to the use of the R-(+)-isomer of 2-methoxy-3octadecyloxy-propanol-(1)-phosphoric acid, monocholine ester in treating multiple sclerosis and to pharmaceutical compositions containing said isomer. Multiple sclerosis, a crippling nerve disorder characterized by disseminated patches of demyelination in the brain and spinal cord, has occupied the attention of research organizations for many years without, unfortunately, any appreciable success. Although ACTH (adrenocorticotropic hormone) or prednisone appears to hasten recovery in acute attacks, especially when administered early in the episode, there is no specific therapy, even today. U.S. Pat No. 4,778,788 discloses the use of certain lysolecithin compounds in treating multiple sclerosis. Web site: http://www.delphion.com/details?pn=US05082846__ •

Uses of aloe products in the treatment of multiple sclerosis Inventor(s): McAnalley; Bill H. (Grand Prairie, TX), McDaniel; Harley R. (Dallas, TX), Carpenter; Robert H. (Bastrop, TX) Assignee(s): Carrington Laboratories, Inc. (Irving, TX) Patent Number: 5,780,453 Date filed: June 5, 1995 Abstract: Method for reducing symptoms associated with multiple sclerosis in an animal by administering to the animal an effective amount of an acetylated polymeric mannan derivative. Excerpt(s): 4) act as adjunctive therapy with other drugs in a wide range of conditions where the final step in resolution or cure of the condition requires an immune response. These polysaccharidic substances can be used with anti-infective, antitumor, antiinflammatory, and antidepressant drugs with no toxicity due to the polysaccharidic substance. The efficacy of the combination is superior over the single drug alone. Aloe is a member of the lily family. Harding, Aloes of the World: A Checklist. Index and Code, Excelsa 9:57-94 (1979). Aloe barbadensis Miller is generally recognized as the "true aloe" because of its wide use and, reportedly, most effective healing power, although in Japan, Aloe arborescens Miller traditionally has been used as a folk remedy for various ailments ranging from gastrointestinal disorders to athlete's foot. Aloe vera is a perennial plant with turgid green leaves joined at the stem in a rosette pattern. The leaves of a mature plant may be more than 25 inches long with sawlike spikes along their margins. Aloe vera contains two major liquid sources, a yellow latex (exudate) and the clear gel (mucilage). The dried exudate of Aloe barbadensis Miller leaves is referred to as aloe. The commercial name is Curacao aloe. It is composed mainly of aloin, aloeemodin and phenols. Bruce, South African Medical Journal, 41:984 (1967); Morrow et al., Archives of Dermatology, 116:1064-1065 (1980); Mapp et al., Planta Medica. 18:361-365 (1970); Rauwald, Archives Pharmazie, 315:477-478 (1982). A number of phenolics, including anthraquinones and their glycosides, are known to be pharmaceutically active. Bruce, Excelsa, 5:57-68 (1975); Suga et al., Cosmetics and Toiletries, 98:105-108 (1983). Web site: http://www.delphion.com/details?pn=US05780453__

Patents 429

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Vaccination and methods against multiple sclerosis resulting from pathogenic responses by specific T cell populations Inventor(s): Carlo; Dennis J. (Rancho Santa Fe, CA), Smith; Lawrence R. (Cardiff, CA), Wilson; Darcy B. (La Jolla, CA), Brostoff; Steven W. (Carlsbad, CA), Gold; Daniel P. (Del Mar, CA) Assignee(s): The Immune Response Corporation (Carlsbad, CA) Patent Number: 6,464,978 Date filed: April 29, 1993 Abstract: The present invention provides vaccines and a means of vaccinating a mammal so as to prevent or control specific T cell mediated pathologies or to treat the unregulated replication of T cells. The vaccine is composed of a T cell receptor (TCR) or a fragment thereof corresponding to a TCR present on the surface of T cells mediating the pathology. The vaccine fragment can be a peptide corresponding to sequences of TCRs characteristic of the T cells mediating said pathology. The vaccine is administered to the mammal in a manner that induces an immunologically effective response so as to affect the course of the disease. The invention additionally provides specific.beta.-chain variable regions of the T cell receptor, designated V.beta.6.2/3, V.beta.6.5, V.beta.2, V.beta.5.1, V.beta.13 and V.beta.7, which are central to the pathogenesis of multiple sclerosis (MS). Excerpt(s): This invention relates to the immune system and, more specifically, to methods of modifying pathological immune responses. Higher organisms are characterized by an immune system which protects them against invasion by potentially deleterious substances or microorganisms. When a substance, termed an antigen, enters the body, and is recognized as foreign, the immune system mounts both an antibodymediated response and a cell-mediated response. Cells of the immune system termed B lymphocytes, or B cells, produce antibodies which specifically recognize and bind to the foreign substance. Other lymphocytes termed T lymphocytes, or T cells, both effect and regulate the cell-mediated response resulting eventually in the elimination of the antigen. A variety of T cells are involved in the cell-mediated response. Some induce particular B cell clones to proliferate and produce antibodies specific for the antigen. Others recognize and destroy cells presenting foreign antigens on their surfaces. Certain T cells regulate the response by either stimulating or suppressing other cells. Web site: http://www.delphion.com/details?pn=US06464978__

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Viral isolates associated with multiple sclerosis Inventor(s): Bedin; Frederic (Lyon, FR), Perron; Herve (Grenoble, FR), Mandrand; Bernard (Villeurbanne, FR), Beseme; Frederic (Villefontaine, FR), Mallet; Francois (Villeurbanne, FR) Assignee(s): Bio Merieux (Marcy l'Etoile, FR) Patent Number: 6,184,025 Date filed: November 30, 1998 Abstract: Composition comprising two pathogenic and/or infective agents associated with multiple sclerosis, namely a first agent which consists of a human virus possessing reverse transcriptase activity and related to a family of endogenous retroviral elements, or a variant of said virus, and a second agent, or a variant of said second agent, these

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two pathogenic and/or infective agents originating from the same viral strain chosen from the strains designated, respectively, POL-2 deposited with the ECACC on Jul. 22, 1992 under Accession Number V92072202 and MS7PG deposited with the ECACC on Jan. 8, 1993 under Accession Number V93010816, and from their variant strains. Excerpt(s): Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) the cause of which remains as yet unknown. Many studies have supported the hypothesis of a viral etiology of the disease, but none of the known viruses tested has proved to be the causal agent sought: a review of the viruses sought for several years in MS has been compiled by E. Norrby (1) and R. T. Johnson (2). Concomitantly, the possibility of an exogenous and/or infectious factor is suggested by the existence of localized epidemics or "clusters" of MS, as have been observed in the Faro Islands between 1943 and 1960 (3), in Sardinia (4), in Norway (5), and also by studies on migrant populations (6). Among all the exogenous factors suggested, viruses have been most often studied, and a viral etiology is traditionally called to mind. Web site: http://www.delphion.com/details?pn=US06184025__ •

Zinc deficiency in multiple sclerosis Inventor(s): Leopold; Irving H. (Newport Beach, CA) Assignee(s): Allergan Pharmaceuticals, Inc. (Irvine, CA) Patent Number: 4,255,419 Date filed: September 27, 1979 Abstract: Low serum zinc concentrations in humans have been associated with multiple sclerosis in some patients, particularly those patients under 50 years of age. Increasing the concentration of serum zinc in such patients has been found to lower the number of, or decrease the severity of recurrent attacks and/or improve neurologic function in some patients. Excerpt(s): The invention relates to a method of treatment of a disease process in humans. More particularly, the invention relates to a method of treatment of humans having multiple sclerosis. While zinc has heretofor been referred to as a trace element in human nutrition, in reality its concentration in humans is second only to that of iron in the metals. The body of a 70 kg adult contains between 1.4 and 2.3 grams of zinc, about one-half of the amount of iron. Zinc is found in highest concentrations in the prostate, blood, skin, hair, liver and eyes of man. Seventy-five to eighty percent of the zinc in the blood is associated with the enzyme, carbonic anhydrase in the erythrocytes. Human serum normally contains 98-142 micrograms of zinc per deciliter. Significant quantities of zinc are also found in the muscles, brain, kidneys and spleen. The average adult human normally loses about 2-3 mg of zinc per day. Gastrointestinal losses account for approximately one-half of this total, with the remainder being lost in the urine and sweat. In young men, deficiency causes stunted growth, anemia (from concomitant iron deficiency), enlarged liver and spleen and underdevelopment of genitals and secondary sex characteristics. Deficiency of zinc may be caused by the nature of the diet (high in phytic acid), by the excretion of zinc in perspiration, or by blood loss if there is parasitic infection. In animals, zinc deficiency causes hyperirritability, anorexia, retardation of growth, loss of hair and changes in the skin and sometimes in the cornea. Web site: http://www.delphion.com/details?pn=US04255419__

Patents 431

Patent Applications on Sclerosis As of December 2000, U.S. patent applications are open to public viewing.10 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 sclerosis: •

Combination treatment of multiple sclerosis (MS), other demyelinating conditions and peripheral neuropathy, especially painful neuropathies and diabetic neuropathy Inventor(s): Howard, Harry R. JR. (Bristol, CT) Correspondence: PFIZER INC; 150 EAST 42ND STREET; 5TH FLOOR - STOP 49; NEW YORK; NY; 10017-5612; US Patent Application Number: 20020147206 Date filed: December 19, 2001 Abstract: The present invention relates to a method of treating Multiple Sclerosis, other demyelinating disorders and peripheral neuropathy in a mammal by administering to the mammal a neurotransmitter-inducing or precursor agent in combination with an (SRI) antidepressant or an anxiolytic agent with improvement in efficiency. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a neurotransmitter-inducing or precursor agent, and an SRI antidepressant or anxiolytic agent. Excerpt(s): This invention relates to a method of treating Multiple Sclerosis (MS) and other demyelinating conditions and peripheral neuropathy in a mammal by administering to the mammal a Serotonin Reuptake Inhibitor (SRIs) in combination with a neurotransmitter-inducing or precursor agent. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a Serotonin Reuptake Inhibitor (SRI) and a neurotransmitter-inducing or precursor agent. Multiple sclerosis is a common and well-known neurological disorder. It is characterized by episodic patches of inflammation and demyelination which can occur anywhere in the central nervous system (CNS) almost always without any involvement of the peripheral nerves. The occurrence of the patches is disseminated in time and space, hence the older alternative name of disseminated sclerosis. It is believed that the pathogenesis involves local disruption of the blood brain barrier, a local immune and inflammatory response, with consequent damage to myelin and hence to neurons. Clinically, MS can present in both sexes and at any age. However, its most common presentation is in relatively young adults often with a single focal lesion such as damage to the optic nerve (optic neuritis), an area of anesthesia or paresthesia or muscular weakness. Vertigo, nystagmus double vision, pain, incontinence, cerebellar signs, L'Hermitte's sign (paresthesia or pain in the arms and legs on flexing the neck) and a large variety of less common symptoms may occur. The initial attack is often transient and it may be weeks, months or years before a further attack occurs. Some individuals may have a stable condition, while others may have an unrelenting downhill course ending in complete paralysis. More commonly there is a long series of remissions and relapses, each relapse leaving the patient somewhat worse than before. Relapses may be triggered by stressful events or viral infections. Elevated body temperature almost invariably makes the condition worse whereas a reduced temperature, for example induced by a cold bath, may make the condition better.

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This has been a common practice outside the United States prior to December 2000.

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions and methods based upon the tuberous sclerosis-1 (TSC1) gene and gene product Inventor(s): Sampson, Julian R. (Cardiff, GB), Kwiatkowski, David J. (Weston, MA), Halley, Dicky J.J. (KD Rotterdam, NL), Povey, Margaret S. (Beds, GB), van Slegtenhorst, Marjon A. (WL Hoogland, NL) Correspondence: PILLSBURY WINTHROP, LLP; P.O. BOX 10500; MCLEAN; VA; 22102; US Patent Application Number: 20020151701 Date filed: September 12, 2001 Abstract: The present invention is directed to a tumor suppressor protein which has been designated hamartin and to the gene, TSC1, which encodes this protein. Mutations in the gene have been found to be associated with certain types of tuberous sclerosis and this has served as a basis for a diagnostic method designed to identify patients that have, or are likely to develop, symptoms associated with this disease. The introduction of the TSC1 gene and subsequent expression of hamartin into cells may be used as a means for treating tuberous sclerosis and other conditions characterized by abnormal cellular growth. Excerpt(s): The present invention is directed to the gene TSC1 and to the protein it encodes. TSC1 has the characteristics of a tumor suppressor gene and is often mutated in individuals with a familial form of tuberous sclerosis. The invention also encompasses methods that relate to the gene and gene product. Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the development of unusual tumor-like growths (hamartomas) in a variety of organ systems (Gomez, M. R., Ann. N.Y. Acad. Sci. 615:1-7 (1991); Kwiatkowski, et al., Arch. Dermatol. 130:348-354 (1994)). The development of cortical tubers in the brain (regions of abnormal cortical architecture with distinctive large neuronal cells) causes some of the most problematic clinical manifestations of TSC: mental retardation, epilepsy and abnormal behavioral phenotypes including autism and attention deficit-hyperactive disorder (Hunt, et a., J. Autism. Dev. Disorder 23:323-339 (1993); Smalley, et al., J. Autism. Dev. Disorder 22:339355 (1992)). Other organ systems commonly involved in TSC include the skin, heart, and kidneys (Kwiatkowski, et al., Arch. Dermatol. 130:348-354 (1994)). The lesions seen are often pathognomonic of TSC and include facial angiofibromas, subungual fibromas, forehead plaque, Shagreen patches, cardiac rhabdomyomas and renal angiomyolipomas and cysts. Renal cell carcinoma also occurs at higher frequency and at an earlier age of onset in TSC patients than in normal individuals (Bjornsson, et al., Am. J. Path. 149:12011208 (1996); Cook, et al., J. Med. Genet. 33:480-484 (1996)). About one-third of TSC cases are familial with the remainder being sporadic, i.e., occurring in the absence of a family history of the disease. Linkage of TSC to 9q34 was first reported in 1987 and this locus was denoted TSC1 (Fryer, et al., Lancet i:659-661 (1987)). Subsequent studies provided strong evidence for locus heterogeneity and led to the identification of 16p13 (denoted the TSC2 locus) as a second genomic region showing linkage in some TSC families (Kandt, et al., Exp. Neurol. 104:223-228 (1989)). Among families large enough to permit linkage analysis, approximately half show linkage to 9q34 and half to 16p13 (Janssen, et al., Hum. Genet. 94:437-440 (1994)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 433

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Compositions including modafinil for treatment of attention deficit hyperactivity disorder and multiple sclerosis fatigue Inventor(s): Scammell, Thomas E. (Wellesley, MA), Miller, Matthew S. (Newtown, PA) Correspondence: Cephalon, Inc. 145 Brandywine Parkway; West Chester; PA; 19380; US Patent Application Number: 20030069313 Date filed: October 30, 2002 Abstract: Modafinil is effective in improving symptoms of attention deficit hyperactivity disorder and symptoms of multiple sclerosis fatigue. The administration of modafinil is also shown to activate the tuberomamillary neurons of the posterior hypothalamus, and thus exhibits activity in an area of the brain associated with normal wakefulness functions. Excerpt(s): The present invention is related to the fields of neuropharmacological agents, including agents that are useful in the treatment of attention deficit hyperactivity disorder and multiple sclerosis associated fatigue. Attention-deficit/hyperactivity disorder (ADHD) is a chronic neuropsychiatric disorder in children that is characterized by developmentally inappropriate hyperactivity, impulsivity, and inattention. ADHD is estimated to affect 3%-5% of school-age children. Historically ADHD was thought not to continue beyond adolescence; however, current research suggests that ADHD persists into adulthood in 10% to 60% of childhood-onset cases. ADHD persistence is associated with a high incidence of academic and occupational dysfunction, as well as a high incidence of psychiatric comorbidity (e.g., conduct, major depressive, and anxiety disorders). It is estimated that approximately 1% to 3% of adults have symptoms of ADHD. Adults with ADHD have a pattern of demographic, psychosocial, psychiatric, and cognitive features that mirrors well-documented findings among children with the disorder. This further supports the validity of the diagnosis for adults. The core ADHD symptoms in adults include a frequent and persistent pattern of inattention/distractibility and/or hyperactivity-impulsivity. The most common symptoms exhibited in ADHD adults are marked inattention, poor concentration, easy distractibility, day dreaming, forgetfulness and a frequent shift in activities. ADHD adults also report marked impulsivity, intrusiveness, low frustration/stress tolerance, temper tantrums, irritability, and extreme impatience. Less commonly reported symptoms in adults include hyperactivity, which may be confined to fidgeting, or an inward feeling of jitteriness or restlessness. In addition to the core ADHD symptoms, adults with ADHD often exhibit associated clinical characteristics such as boredom, social inappropriateness, and chronic conflicts in social situations. These features may be responsible for the high incidence of: (1) separation and divorce and (2) poor academic performance and occupational achievement that exist despite adequate intellectual abilities. In addition, adults with ADHD have a high incidence of substance abuse disorders. While the pathogenesis of ADHD remains unclear, alterations in the dopaminergic and noradrenergic functions appear to be the neurochemical basis for the disorder. Brain positron emission tomography in adults with ADHD have revealed alterations in glucose metabolism in areas of the cerebral cortex that are involved with attention and motor activity, like the frontal lobe. The most common treatment for both adult and pediatric ADHD is stimulants (e.g., dextroamphetamine, methylphenidate, and pemoline). Stimulants are thought to work by increasing the amount of dopamine available in the synapses of the neuron. The stimulants appear to do this in multiple cerebral anatomical locations. Other therapies that have been used include: antidepressants (e.g., tricyclic antidepressants such as imipramine and desipramine;

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novel antidepressants such as buproorion and venlafaxine), antihypertensives (e.g., clonidine and guanfacine), monoamine oxidase inhibitors ([MAO's], e.g., selegiline), amino acids (e.g., levodopa, phenylalanine, and L-tyrosine), and combined pharmacotherapies (e.g., concurrent use of a serotonin-selective reuptake inhibitor and a stimulant medication; or a stimulant and catelcholaminergic antidepressant regimen) (Bhandary et al., Psychiatric Annals 27:545-555, 1997; Wilens et al., J. Clin. Psychopharmacol. 15:270-279, 1995; Finkel, The Neurologist 3:31-44, 1997; Miller and Catellanos, Pediatrics in Review 19:373-384, 1998). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Dietary calcium as a supplement to vitamin D compound treatment of multiple sclerosis Inventor(s): Cantorna, Margheritea T. (State College, PA), Humpal-Winter, Jean; (Poynette, WI), DeLuca, Hector F. (Deerfield, WI) Correspondence: QUARLES & BRADY LLP; 411 E. WISCONSIN AVENUE, SUITE 2040; MILWAUKEE; WI; 53202-4497; US Patent Application Number: 20030022873 Date filed: August 30, 2002 Abstract: A method of and composition for diminishing multiple sclerosis symptoms are disclosed. In one embodiment, the method comprises the step of administrating an amount of calcium and a vitamin D compound effect to diminish multiple sclerosis symptoms. In another embodiment, the invention is a pharmaceutical composition comprising an amount of calcium and vitamin D compound effective to diminish multiple sclerosis symptoms. Excerpt(s): Vitamin D is a recent arrival in the roster of agents that are known to regulate the immune system. Vitamin D is converted in a two-step process to the hormone, 1,25-dihydroxycholecalciferol (1,25-(OH).sub.2D.sub.3).sup.1 that is a key factor in regulating serum calcium, phosphorus and bone (DeLuca, 1997). This hormone acts in a steroid hormone-like mechanism through a nuclear receptor, the vitamin D receptor (VDR), which is a member of the steroid hormone receptor superfamily (Pike, 1991; Ross, et al., 1993). The discovery of VDR in peripheral blood lymphocytes (Bhalla, et al., 1983; Provvedini, et al. 1983) is a factor that led to the realization that 1,25(OH).sub.2D.sub.3 is a significant regulator of the immune system. The most striking evidence of a role for 1,25-(OH).sub.2D.sub.3 as an immune system regulator comes from in vivo experiments. 1,25-(OH).sub.2D.sub.3 can prevent the development of EAE (Cantorna, et al., 1996 and U.S. Pat. No. 5,716,946; Lemire and Archer, 1991), experimental arthritis (Cantorna, et al., 1998a), and 1,25-(OH).sub.2D.sub.3can markedly inhibit transplant rejection (Bouillon, et al., 1995; Hullett, et al., 1998).sup.1Abbreviations: central nervous system, CNS; 1,25-dihydroxycholecalc- iferol, 1,25-(OH).sub.2D.sub.3; experimental autoimmune encephalomyelitis, EAE; glyceraldehyde-3-phosphate dehydrogenase, lymph node, LN; multiple sclerosis, MS; interferon y, IFN-.gamma. interleukin-4, IL-4; transforming growth factor.beta.1, TGF.beta.1; tumor necrosis factor-.alpha., TNF-.alpha. type-1 helper, Th1; type-2 helper, Th2; vitamin D receptor, VDR. EAE is mediated by CD4+ T cells, which mount an inappropriate immune-mediated attack on the central nervous system (CNS). Type-1 helper (Th1) cells specific for CNS antigens induce the disease and the Th1 cytokines interferon (IFN)-.gamma. and tumor necrosis factor (TNF)-.alpha. are associated with EAE in mice (Holda and Swanborg, 1982; Powell, et al., 1990). Conversely, type-2 helper

Patents 435

(Th2) cells and other cell types which produce interleukin (IL)4 and transforming growth factor (TGF)-.beta.1 in response to CNS antigens are known to ameliorate EAE. In vivo 1,25-(OH).sub.2D.sub.3 treatments result in a net loss in the total number of lymphocytes and a net increase in the expression of IL-4 and TGF-.beta.1 (Cantorna, et al., 1998b). Conversely the in vivo 1,25- treatments had no effect on IFN-.gamma. or TNF-.alpha. expression (Cantorna, et al., 1998b). The role, if any, for calcium in the regulation of the immune response remains unclear. The present invention is a method of more effectively treating multiple sclerosis patients. The method comprises the step of administration of an amount of calcium that renders a vitamin D compound effective in preventing or markedly reducing MS symptoms. Preferably, this amount of calcium is 0.5-2 g per patient per day. Most preferably, the amount is between 1 and 2 g of calcium as a salt with a variety of anions, e.g. CO.sub.3.sup.=, PO.sub.4.sup.=, Cl.sub.2.sup.acetate, gluconate, citrate, etc. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Estriol therapy for multiple sclerosis and other autoimmune diseases Inventor(s): Voskuhl, Rhonda R. (West Hollywood, CA) Correspondence: OPPENHEIMER WOLFF & DONNELLY LLP; 38TH FLOOR; 2029 CENTURY PARK EAST; LOS ANGELES; CA; 90067-3024; US Patent Application Number: 20020183299 Date filed: April 24, 2002 Abstract: The present invention discloses administering steroid hormones to mammals to treat autoimmune related diseases, more particularly, Th1-mediated (cell-mediated) autoimmune diseases including: multiple sclerosis (MS), rheumatoid arthritis (RA), autoimmune thyroiditis and uveitis. Most preferably the invention is used to treat a patient with a therapeutically effective amount of estriol of 8 milligrams once daily via oral administration to treat the symptoms or prevent the onset of multiple sclerosis. Excerpt(s): This application claims priority from a U.S. provisional patent application No. 60/286,842 filed on Apr. 25, 2001. This invention relates generally to steroidal therapies for treating autoimmune diseases and, more particularly, to administering primary agents being estrogens or estrogen receptor active agents for the treatment of cell mediated diseases. Optionally, secondary agents which effect the immune system may also be co-administered. Finally, treatment kits are provided containing at least one primary agent and at least one secondary agent for treating a patient presenting with symptomology of an autoimmune disease. There is a distinct female preponderance of autoimmune diseases during the reproductive ages including multiple sclerosis (MS), rheumatoid arthritis (RA), uveitis, myesthenia gravis (MG), Sjogren's syndrome, and Hashimoto's thyroiditis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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ISOLATED NUCLEOTIDE SEQUENCES ASSOCIATED WITH MULTIPLE SCLEROSIS OR RHEUMATOID ARTHRITIS AND A PROCESS OF DETECTING Inventor(s): PARANHOS-BACCALA, GLAUCIA; (LYON, FR), BESEME, FREDERIC; (VILLEFONTAINE, FR), GARSON, JEREMY ALEXANDER; (GUILDFORD, GB), KOMURIAN-PRADEL, FLORENCE; (SAINT CYR AU MONT D'OR, FR), BEDIN, FREDERIC; (LYON, FR), MANDRAND, BERNARD; (VILLEURBANNE, FR), TUKE, PHILIP WILLIAM; (LONDON, GB), JOLIVET-REYNAUD, COLETTE; (BRON, FR), PERRON, HERVE; (LYON, FR) Correspondence: OLIFF & BERRIDGE, PLC; P.O. BOX 19928; ALEXANDRIA; VA; 22320; US Patent Application Number: 20030039664 Date filed: November 26, 1997 Abstract: The invention provides viral material and nucleotide fragments associated with multiple sclerosis and/or rheumatoid arthritis for use in methods of diagnosis, prophylaxis, and therapy. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 08/756,429, filed Nov. 26, 1996. Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), the cause of which remains as yet unknown. "Multiple sclerosis (MS) is the most common neurological disease of young adults with a prevalence in Europe and North America of between 20 and 200 per 100,000. It is characterized clinically by a relapsing/remitting or chronic progressive course, frequently leading to severe disability. Current knowledge suggests that MS is associated with autoimmunity, that genetic background has an important influence and that "infectious" agent(s) may be involved. Indeed, many viruses have been proposed as possible candidates but as yet, none of them has been shown to play an aetiological role. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method and pharmaceutical composition for the treatment of multiple sclerosis Inventor(s): Karin, Nathan; (Haifa, IL) Correspondence: G.E. EHRLICH (1995) LTD. c/o ANTHONY CASTORINA; SUITE 207; 2001 JEFFERSON DAVIS HIGHWAY; ARLINGTON; VA; 22202; US Patent Application Number: 20030166589 Date filed: June 5, 2001 Abstract: Methods and pharmaceutical compositions are disclosed, effective in breakingdown immunological tolerance the CXC chemokine interferon gamma-inducible protein 10 (IP-10), resulting in the generation of self specific immunity to IP-10, for the treatment of diseases, such as autoimmune diseases, in which IP-10 plays a pivotal role in disease onset and/or progression, e.g., in multiple sclerosis (MS). Excerpt(s): The present invention relates to methods and pharmaceutical compositions effective in breaking-down immunological tolerance the CXC chemokine interferon gamma-inducible protein 10 (IP-10), resulting in the generation of self specific immunity to IP-10, for the treatment of diseases, such as autoimmune diseases, in which IP-10 plays a pivotal role in disease onset and/or progression, e.g., multiple sclerosis (MS) and other inflammatory autoimmune diseases such as rheumatoid arthritis. Thus, in one particular, the present invention relates to the induction of protective immunity against

Patents 437

multiple sclerosis, so as to prevent or treat multiple sclerosis by DNA vaccines or by neutralizing antibodies directed to IP-10. Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS) which, for many years and for a variety of experimental protocols, serves as a model for the human disease, multiple sclerosis (MS), a chronic degenerative disease marked by patchy destruction of the myelin that surrounds and insulates nerve fibers and mild to severe neural and muscular impairments, since in both diseases circulating leukocytes penetrate the blood brain barrier and damage myelin resulting in impaired nerve conduction and paralysis (1, 2). Molecular biology techniques were previously used to follow leukocyte trafficking to the site of inflammation at the CNS of EAE rats, and a model that characterizes this process as a sequential multi-step event was suggested (3). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for diagnosing a person having multiple sclerosis Inventor(s): Lucas, Trevor; (Vienna, AT), Jansen, Burkhard; (Vienna, AT) Correspondence: HELLER EHRMAN WHITE & MCAULIFFE LLP; 1666 K STREET,NW; SUITE 300; WASHINGTON; DC; 20006; US Patent Application Number: 20030113752 Date filed: June 21, 2002 Abstract: Described is a method for diagnosing a person having multiple sclerosis (MS) or being at risk of developing MS, comprising the following steps:providing a sample of a body fluid or tissue from said person, said sample containing at least one of the wild type SCF-Apoptosis-Response Gene- (wt-SARG-1-) protein and nucleic acids encoding wt-SARG-1, if taken from a person not having MS or a risk of aquiring MS,detecting the presence of wt-SARG-1-protein or nucleic acids encoding wt-SARG-1 in said sample anddiagnosing MS or a risk of aquiring MS, if wt-SARG-1-protein or nucleic acids encoding wt-SARG-1 are not present in said sample. Excerpt(s): The invention relates to a method for diagnosing a person having multiple sclerosis (MS) or being at risk of developing MS. Further, the invention relates to a method for diagnosing a person having cancer or being at risk of acquiring cancer. Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system (CNS) affecting up to 0.1% of the north European caucasian population and is considered an auto-immune syndrome directed against unidentified central nervous tissue antigens. The determination of susceptibility to MS development is complex and governed by both environmental and genetic factors (Ebers et al, 1995; Sawcer and Goodfellow, 1998; Sadovnick et al, 2000) with approximately 20% of patients having one or more affected relatives (Chataway et al, 1998). Although thought to be a polygenetic disease, candidate gene approaches have been adopted to isolate genes linked to MS (Weinshenker and Kantarci, 2000). Association with the Caucasian haplotype DRB*1501DQA1*0102-DQB1*0602 (Haines et al, 1998) and a point mutation in the protein tyrosine phosphatase receptor-type C (Jacobsen et al, 2000) have been linked to some cases. Recently, the importance of apop-tosis in both T cell elimination and damage to neurons and oli-godendrocytes in MS have been recognised (reviewed in Zipp, 2000). However, to date no clear marker has been reported, although at least a portion of MS cases are clearly familial inherited. A mere recognition of MS or even providing a risk association would be very beneficial for early onset of therapy or preventive measures. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method for diagnosing multiple sclerosis and an assay therefore Inventor(s): Moscarello, Mario Anthony; (Toronto, CA), Chamczuk, Andrea; (Toronto, CA) Correspondence: MCHALE & SLAVIN; 4440 PGA BLVD; SUITE 402; PALM BEACH GARDENS; FL; 33410 Patent Application Number: 20030092089 Date filed: November 14, 2001 Abstract: This invention is directed toward a serum/plasma assay for the diagnosis and subsequent monitoring of patients with multiple sclerosis (MS). Assay performance characteristics indicate that the assay is accurate and repeatable. Using blood from patients with clinically definite multiple sclerosis, a clinical sensitivity of 77% and a specificity of 95% has been achieved through the measurement of circulating myelin basic protein autoantibodies. The assay provides a simple, rapid, and minimally invasive tool for the diagnosis and monitoring of progression of MS. Excerpt(s): The present invention relates to a method for the detection of biological materials relating to the prediction, diagnosis, or monitoring of progression of an autoimmune disease, utilizing an assay system developed to measure levels of biochemical markers involved in autoimmune disease. More specifically, this invention relates to an assay for detecting myelin basic protein (MBP) autoantibodies alone, and alternatively in conjunction with the measurement of other biochemical markers associated with multiple sclerosis (MS) and related diseases. Most specifically, the present invention is directed toward a process for initially diagnosing MS, and toward the para-clinical work-up and routine monitoring of MS patients as to disease progression. Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the human central nervous system (CNS). Pathologically, the disease presents focal areas of myelin destruction, known as plaques or lesions (Vollmer, 1999). Myelin is present as a multilamellar sheath formed by membranous extensions of oligodendrocytes within the CNS (Peters, 1960a; b). Its ability to insulate axons and facilitate rapid nerve conduction is attested to by its high lipid content (70% of the total weight). With the focal deterioration of the insulating myelin sheath, the lesions result in decreased conduction velocity through naked regions of the axons affected. Such primary demyelination manifests as the symptoms of MS. Such symptoms include motor weakness in one or more limbs, optic neuritis, diplopia, parasthesia, fatigue, and eventually paralysis and early morbidity (Pender, 1995). Although the aetiology is unknown, geographic, genetic, and immune factors, acting coordinately, often determine disease onset and severity. Given the early onset of the disease (with diagnosis in children increasing in frequency), usually in the third or fourth decade of life, MS is one of the leading causes of neurological impairment in young adults. The precise mechanism by which demyelinating lesions are formed in MS is not known, however the most promising theory is that demyelination occurs as a result of aberrant immunology resulting in immune attack of myelin. The association between histocompatibility phenotype and susceptibility in MS has immunological implications. Furthermore, clinical features in MS, such as the presumed long latent period, the chronic nature of the disease and the pattern of acute attacks followed by remission are suggestive of an immunologically mediated disease. Pathologically, MS lesions are marked by an infiltration of numerous immune cells, especially T-cell lymphocytes and macrophages (Pender, 1995). Histological and immunological similarities between MS

Patents 439

and the classic animal model of the disease, experimental allergic encephalomyelitis (EAE), have suggested that the disease may be T-cell mediated (Esiri, 1991). However, evidence of humoral immunity in MS is also abundant as reflected by the presence of Bcells and plasma cells within MS lesions and the elevated levels of cerebrospinal fluid (CSF) immunoglobulin G (IgG) in MS patients. Although the autoantigen responsible for MS has not been conclusively identified, myelin basic protein (MBP) has been proposed as a candidate autoantigen. 1. Proteolipid protein (PLP) is a 30 kDa hydrophobic protein which constitutes approximately 50% of the total myelin protein. PLP is expressed in CNS myelin and is found in the myelin membrane (Lees and Brostoff, 1984). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for treating multiple sclerosis Inventor(s): Tatton, Nadine A. (Purchase, NY), Shankar, L. Sai Latha; (New York, NY), Tatton, William G. (Purchase, NY) Correspondence: LAHIVE & COCKFIELD; 28 STATE STREET; BOSTON; MA; 02109; US Patent Application Number: 20030078295 Date filed: July 26, 2002 Abstract: Methods for increasing oligodendrocyte survival are disclosed. The methods of the invention are useful for the treatment of Multiple Sclerosis. Excerpt(s): This application claims the benefit of priority under 35 U.S.C. 119(e) to copending U.S. Provisional Application No(s). 60/103,742, filed on Oct. 9, 1998, the entire contents of which is hereby incorporated by reference. Deprenyl (also referred to herein as selegiline or R-(-)-N,.alpha.-Dimethyl-N-2-propynyl phenethylamine) was first used as an adjunct to conventional drug therapy (L-dihydroxyphenylalanine (L-DOPA) plus a peripheral decarboxylase inhibitor) of Parkinson's disease (PD) in Europe over a decade ago on the basis that as a selective monoamine oxidase-B (MAO-B) inhibitor, it would elevate brain dopamine levels and potentiate the pharmacological action of dopamine formed from L-DOPA, and yet prevent the tyramine-pressor effect observed with non-selective MAO inhibitors. The combined drug therapy was reported to prolong the anti-akinetic effects of L-DOPA, resulting in the disappearance of on-off effects, reduced functional disability, and increased life-expectancy in PD patients (Bernheimer, H., et al., J. Neurolog. Sci., 1973. 20: 415-455, Birkmayer, W., et al., J. Neural Transm., 1975. 36:303-336, Birkmayer, W., et al., Mod. Prob. Pharmacopsychiatr., 1983. 19: 170-177, Birkmayer, W. and P. Riederer, Hassler, R. G. and J. F. Christ (Ed.) Advances In Neurology, 1984. 40(Y): p.0-89004, and Birkmayer, W., et al., J. Neural Transm., 1985. 64(2): p. 113-128). Studies examining deprenyl as an adjunct to conventional L-DOPA therapy have reported a short term benefit which was usually lost by 1 year or less. Some, but not all, have reported that the levodopa dose can be decreased when taken in conjunction with deprenyl (Elizan, T. S., et al., Arch Neurol, 1989. 46(12): p. 1280-1283, Fischer, P. A. and H. Baas, J. Neural Transm. (suppl.), 1987. 25: p. 137-147, Golbe, L. I., Neurology, 1989. 39: p. 1109-1111, Lieberman, A. N. et al., N.Y. State J. Med., 1987. 87: p. 646-649, Poewe, W., F. Gerstenbrand, and G. Ransomayr, J. Neural Transm. (suppl.), 1987. 25: p. 137-147, Cedarbaum, J. M., M. Hoey, and F. H. McDowell, J. Neurol. Neurosurg. Psychiatry, 1989. 52(2): p. 207-212, and Golbe, L. I., J. W. Langston, and I. Shoulson, Drugs, 1990. 39(5): p. 646-651). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method of detecting and treating Tuberous Sclerosis Complex associated disorders Inventor(s): Gould-Rothberg, Bonnie; (Guilford, CT), Rastelli, Luca; (Guilford, CT), Murphey, Ryan; (West Haven, CT) Correspondence: Ivor R. Elrifi; MINTZ, LEVIN, COHN, FERRIS,; GLOVSKY AND POPEO, P.C. One Financial Center; Boston; MA; 02111; US Patent Application Number: 20030124534 Date filed: December 10, 2001 Abstract: Disclosed are methods of detecting and treating tuberous sclerosis complex associated disorders. Also disclosed are methods of identifying agents for treating tuberous sclerosis complex associated disorders. Excerpt(s): This application claims priority from U.S. S. No. 60/254,268, filed Dec. 8, 2000, which is incorporated by reference in its entirety. The invention relates to methods of detecting and treating Tuberous Sclerosis Complex (TSC) associated disorders. The phakomatoses, or `neuro-cutaneous disorders`, are a group of three Mendelian autosomal dominantly inherited diseases that present with phenotypes affecting multiple organ systems in affected individuals. Neuro-cutaneous disorders include for example, Neurofibromatosis (NF), Tuberous Sclerosis (TSC) and Von Hippel-Lindau (VHL). These diseases all produce both neurological and dermatological symptoms. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method of hormone treatment for patients with symptoms consistent with multiple sclerosis Inventor(s): Chein, Edmund Y.M. (Beverly Hills, CA) Correspondence: BLAKELY SOKOLOFF TAYLOR & ZAFMAN; 12400 WILSHIRE BOULEVARD, SEVENTH FLOOR; LOS ANGELES; CA; 90025; US Patent Application Number: 20010012832 Date filed: February 12, 2001 Abstract: A method for patients having symptoms consistent with multiple sclerosis comprising administering a regimen of doses of human growth hormone of less than 0.5 mg/day. In one aspect, the method includes replenishing one or more of melatonin, thymus, thyroid, adrenal and sex hormones to predetermined levels in conjunction with the human growth hormone. Excerpt(s): The invention relates to hormone therapy as a treatment for patients with symptoms consistent with multiple sclerosis. It is known that the levels of a variety of hormones drop substantially with age. These include human growth hormone, sex hormones, pineal, adrenal, thyroid, and thymus hormones. Hormonal replenishment methods employed as anti-aging treatments have been developed. An example of such method is described in U.S. Pat. No. 8,855,920. The utility of this method in connection with certain degenerative diseases, often associated with hormonal deficiencies due to aging, is also known in the art. In contrast, Multiple Sclerosis (MS) is not a disease associated with degenerative conditions associated with old age. Rather, MS strikes mainly young adults and is the most common neurologic cause of disability in that age group. Overall, MS affects approximately 300,000 Americans.

Patents 441

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Method of treatment of amyotrophic lateral sclerosis with a protein extractable from mammalian organs Inventor(s): Panerai, Albert; (Milano, IT) Correspondence: NIXON & VANDERHYE, PC; 1100 N GLEBE ROAD; 8TH FLOOR; ARLINGTON; VA; 22201-4714; US Patent Application Number: 20030162705 Date filed: March 21, 2003 Abstract: A method of treatment of patients affected by amyotrophic lateral sclerosis comprising the administration of an effective amount of a 14 kDa protein extractable from mammalian organs, particularly mammalian liver. Excerpt(s): The present invention concerns a method of treatment of patients affected by amyotrophic lateral sclerosis comprising the administration of an effective amount of a 14 kDa protein extractable from mammalian organs, particularly mammalian liver. Amyotrophic lateral sclerosis (incidence of 1.4 to 4.7/100.000) also named motor neuron disease, is a degenerative disease characterized by progressive paralysis which affects elderly subjects (65-70 years), developing into complete paralysis and death and in a short time. Several biochemical and genetic factors seem to be involved in the pathogenesis of ALS, which remains however to be still elucidated. An increase in some intracellular proteins (cytoskeleton) which affect cell activity and neurotransmission, seems to be the main cause of amyotrophic lateral sclerosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods and compositions for the detection and treatment of multiple sclerosis Inventor(s): Leppert, David; (Binningen, CH), Lindberg, Raija; (Zuzgen, CH) Correspondence: HOFFMANN-LA ROCHE INC. PATENT LAW DEPARTMENT; 340 KINGSLAND STREET; NUTLEY; NJ; 07110 Patent Application Number: 20030054397 Date filed: September 10, 2002 Abstract: The present invention relates to an in vitro method for the diagnosis of multiple sclerosis and/or the susceptibility to multiple sclerosis comprising the steps of a) obtaining a biological sample; and b) detecting and/or measuring the increase, decrease and/or absence of (a) specific marker gene(s) as disclosed herein. Excerpt(s): The present invention relates to an in vitro method for the diagnosis of multiple sclerosis and/or the susceptibility to multiple sclerosis comprising the steps of a) obtaining a biological sample; and b) detecting and/or measuring the increase, decrease and or absence of (a) specific marker gene(s) as disclosed herein. Furthermore, screening methods relating to inhibitors, activators, antagonists as well as agonists of the specific marker genes disclosed herein are provided. In addition pharmaceutical and diagnostic compositions are disclosed. Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS. It is characterized by focal inflammation, demyelination and a variable degree of axonal loss and neuronal damage. Genomic analysis indicates that susceptibility for MS is related to several not yet identified genes. Incomplete penetrance

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of presumed MS susceptibility genes and genetic heterogeneity have prevented to define any specific markers for the diagnosis and the course of MS. Brain tissue destruction occurs very early in the course of disease, when the damage is still clinically silent. Therefore, early diagnostic markers are needed as well as predictive markers for relapses to design the treatment according to disease activity. Because of the immunological characteristics of the disease several attempts to define immunological parameters for MS have been made. Blood brain barrier (BBB) breakdown and invasion of T cells into CNS are the early events of MS pathogenesis. There is an increasing body of evidence that interaction of various molecules are involved in the transendothelial migration of immune cells. These molecules comprise adhesion molecules, matrix metalloproteinases (MMPs), cytokines and chemokines. Magnetic resonance imaging (MRI) has provided the possibility to examine inflammatory activity and axonal alterations in CNS in vivo. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods for monitoring and treating amyotrophic lateral sclerosis Inventor(s): McGrath, Michael; (Burlingame, CA), Ramesh, Tennore M. (Westwood, MA), Marton, Laurence J. (Palo Alto, CA), Scott, Sean; (San Francisco, CA) Correspondence: Karen R. Zachow; Morrison & Foerster LLP; Suite 500; 3811 Valley Centre Drive; San Diego; CA; 92130-2332; US Patent Application Number: 20030175832 Date filed: November 18, 2002 Abstract: The invention provides methods of monitoring amyotrophic lateral sclerosis (ALS) disease development or progression and monitoring an ALS therapy by determining the level of HLA-DR expression by CD14+ monocytes and/or the percentage of CD16+ cells in the population of CD14+ cells and/or the number of CD14+/CD16+ cells in peripheral blood of an individual with ALS. The invention is also directed to methods for decreasing the number of circulating CD14+ monocytes and/or the population of CD14+/CD16+ cells and/or the number of CD14+/CD16+ cells in an individual with ALS. The invention is also directed to methods of screening for agents which decrease the population of CD14+ monocytes with elevated HLA-DR expression and/or the population of CD14+/CD16+ cells and/or the number of CD14+/CD16+ cells in an individual with ALS. Excerpt(s): This application claims the priority benefit of U.S. Provisional application 60/333,263, filed Nov. 16, 2001, which is hereby incorporated by reference in its entirety. The invention relates to the field of Amyotrophic Lateral Sclerosis (ALS) disease and immune function. More specifically, it pertains to the activated monocytes or abnormal macrophages and monitoring of ALS progression, monitoring ALS therapy and treating patients with ALS. Amyotrophic lateral sclerosis (ALS), known colloquially as Lou Gehrig's disease, is a heterogeneous group of progressive neurodegenerative disorders characterized by a selective loss of upper and/or lower motor neurons in the brain and spinal cord. Affected individuals demonstrate a variety of symptoms including twitching and cramping of muscles, loss of motor control in hands and arms, impaired use of the arms and legs, weakness and fatigue, tripping and falling, dropping things, slurred or thick speech and difficulty breathing or swallowing. ALS eventually results in death of the affected individual. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 443

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Methods for treating multiple sclerosis Inventor(s): Masuoka, Lorianne; (Oakland, CA) Correspondence: CHIRON CORPORATION; Intellectual Property - R440; P.O. Box 8097; Emeryville; CA; 94662-8097; US Patent Application Number: 20030082138 Date filed: September 18, 2002 Abstract: Methods for treating multiple sclerosis (MS) and clinically isolated syndromes suggestive of MS are provided. The methods comprise administering a therapeutically effective dose of interferon-beta (IFN-beta) to a subject in need thereof, where the dose is administered intramuscularly with a dosing frequency of two- to three-times per week. Excerpt(s): The present invention is directed to new treatment regimens for multiple sclerosis (MS) and clinically isolated syndromes suggestive of MS. Multiple sclerosis (MS) is a severe, chronic disabling disease that affects approximately 1 out of every 1,600 people. The majority of the affected individuals develop symptoms as young adults between 20 and 40 years of age, with roughly 60% of the cases occurring in women. The disease is characterized by neuron deterioration in the central nervous system (CNS) with the associated loss of the insulating myelin sheath from around the axons of the nerve cells, referred to as demyelination. The disease presents itself in the white matter of the brain and spinal cord as a number of sclerotic lesions or plaques (Prineas (1985) Demyelinating Diseases, Elsvevier: Amsterdam; Raine (1983) Multiple Sclerosis, Williams and Wilkins: Baltimore; Raine et al. (1988) J. Neuroimmunol. 20:189-201; and Martin (1997) J. Neural Transmission (Suppl) 49:53-67). The characteristic MS lesion is inflamed, exhibits axonal demyelination, axonal degeneration, and is found around small venules. These characteristics typically evolve early in plaque development and are hypothesized to occur as a result of a breakdown in the blood-brain barrier (BBB). As a consequence of BBB breakdown, infiltrates consisting of various lymphocytes and macrophages enter the brain or spinal cord. This inflammatory infiltrate ultimately leads to axonal degeneration and scar tissue formation, and in many instances, is asssociated with incomplete remyelination (Martin (1997) J. Neural Transmission (Suppl) 49:53-67). Further, it is hypothesized that this apparent immunologic attack targets not only the myelin sheath, but also the oligodendrocytes imperative to CNS myelin production. As a result, not only is the nerve-insulating myelin damaged, but the ability of oligodendroglial cells to repair damaged myelin is seriously compromised (Scientific American 269(1993):106-114). Development of multiple areas of scar tissue (sclerosis) along the covering of the nerve cells slows or blocks the transmission of nerve impulses in the affected area, resulting in the development of the symptoms characteristic of MS. These symptoms include pain and tingling in the arms and legs; localized and generalized numbness, muscle spasm and weakness; difficulty with balance when standing or walking; difficulty with speech and swallowing; cognitive deficits; fatigue; and bowel and bladder dysfunction. Approximately half of the people with this disease suffer from relapsing-remitting MS. In these cases, the afflicted individual experiences repeated unpredictable attacks, due to episodes of inflammation, axonal demyelination, axonal degeneration, and development of glial scar tissue. These attacks are separated by periods of remission, during which the symptoms stabilize or diminish. Acute neurological deficits occur with each attack, and in many cases, the accumulation of residual deficits as a result of these attacks eventually leads to worsening disability and impairment in quality of life. Approximately 30-40% of the afflicted population have

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chronic progressive MS (either primary or secondary) in which neurological deterioration occurs in the absence of clinically apparent attacks. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods for treatment of multiple sclerosis Inventor(s): Thompson, W. Joseph; (Doylestown, PA), Earle, Keith A. (North Wales, PA), Whitehead, Clark M. (Warminster, PA), Alila, Hector W. (North Wales, PA) Correspondence: Cell Pathways, Inc. 702 Electronic Drive; Horsham; PA; 19044; US Patent Application Number: 20030073741 Date filed: May 21, 2002 Abstract: Substituted condensation products of N-benzyl-3-indenylacetamides with heterocyclic aldehydes and other such inhibitors are useful for the treatment of multiple sclerosis. Excerpt(s): This invention relates to the treatment multiple sclerosis. Multiple sclerosis ("MS") affects approximately 1 out of 1,600 people. Women are affected about 60% of the time. The disorder most commonly begins between the ages of 20 to 40 years. MS is one of the major causes of disability in adults under age 65. Multiple sclerosis involves repeated episodes of inflammation of central nervous system tissue in any area of the brain and spinal cord. The location of the inflammation varies from person to person and from episode to episode. The inflammation destroys the mylein sheath covering the nerve cells in the affected area. This leaves multiple areas of scar tissue (sclerosis) along the covering of the nerve cells. Sclerosis slows or blocks the transmission of nerve impulses in that area, resulting in the development of the symptoms of MS. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods for treatment of multiple sclerosis using peptide analogues at position 91 of human myelin basic protein Inventor(s): Ling, Nicholas; (San Diego, CA), Gaur, Amitabh; (San Diego, CA), Steinman, Lawrence; (Palo Alto, CA), Conlon, Paul J. (Solana Beach, CA) Correspondence: SEED INTELLECTUAL PROPERTY LAW GROUP PLLC; 701 FIFTH AVE; SUITE 6300; SEATTLE; WA; 98104-7092; US Patent Application Number: 20030114380 Date filed: October 11, 2002 Abstract: Peptide analogues of human myelin basic protein containing residues 87-99 are provided. Residue 91 of the peptide analogues is altered from the L-lysine residue found in the native protein to any other amino acid. Pharmaceutical compositions of the peptide analogues are provided. In addition, the peptide analogues are administered to patients with multiple sclerosis. Excerpt(s): The present invention relates generally to methods for treating and preventing multiple sclerosis by using peptide analogues of human myelin basic protein. Multiple sclerosis (MS) is a chronic, inflammatory disease that affects approximately 250,000 individuals in the United States. Although the clinical course may be quite variable, the most common form is manifested by relapsing neurological

Patents 445

deficits, in particular, paralysis, sensory deficits, and visual problems. The inflammatory process occurs primarily within the white matter of the central nervous system and is mediated by T lymphocytes, B lymphocytes, and macrophages. These cells are responsible for the demyelination of axons. The characteristic lesion in MS is called the plaque due to its macroscopic appearance. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods for treatment of multiple sclerosis using peptide analogues of human myelin basic protein Inventor(s): Conlon, Paul J. (Solana Beach, CA), Steinman, Lawrence; (Palo Alto, CA), Ling, Nicholas; (San Diego, CA), Gaur, Amitabh; (San Diego, CA) Correspondence: SEED INTELLECTUAL PROPERTY LAW GROUP PLLC; 701 FIFTH AVE; SUITE 6300; SEATTLE; WA; 98104-7092; US Patent Application Number: 20020086976 Date filed: December 11, 2001 Abstract: The present invention is directed toward peptide analogues of human myelin basic protein. The peptide analogue is at least seven amino acids long and derived from residues 86 to 99 of human myelin basic protein. The analogues are altered from the native sequence at least at positions 91, 95, or 97. Additional alterations may be made at other positions. Pharmaceutical compositions containing these peptide analogues are provided. The peptide analogues are useful for treating multiple sclerosis. Excerpt(s): The present invention relates generally to methods for treating multiple sclerosis by using peptide analogues of human myelin basic protein. Multiple sclerosis (MS) is a chronic, inflammatory disease that affects approximately 250,000 individuals in the United States. Although the clinical course may be quite variable, the most common form is manifested by relapsing neurological deficits, in particular, paralysis, sensory deficits, and visual problems. The inflammatory process occurs primarily within the white matter of the central nervous system and is mediated by T lymphocytes, B lymphocytes, and macrophages. These cells are responsible for the demyelination of axons. The characteristic lesion in MS is called the plaque due to its macroscopic appearance. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Naaladase inhibitors for treating amyotrophic lateral sclerosis Inventor(s): Wozniak, Krystyna; (Bel Air, MD), Slusher, Barbara S. (Kingsville, MD) Correspondence: LYON & LYON LLP; 633 WEST FIFTH STREET; SUITE 4700; LOS ANGELES; CA; 90071; US Patent Application Number: 20020013295 Date filed: May 30, 2001 Abstract: The present invention relates to pharmaceutical compositions and methods for treating amyotrophic lateral sclerosis using NAALADase inhibitors. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/207,317 filed on May 30, 2000. The present invention relates to pharmaceutical

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compositions and methods for treating amyotrophic lateral sclerosis ("ALS" ) using NAALADase inhibitors. The NAALADase enzyme, also known as prostate specific membrane antigen ("PSM" or "PSMA" ) and human glutamate carboxypeptidase II ("GCP II" ), catalyzes the hydrolysis of the neuropeptide N-acetyl-aspartyl-glutamate ("NAAG") to N-acetyl-aspartate ("NAA") and glutamate. Based upon amino acid sequence homology, NAALADase has been assigned to the M28 family of peptidases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

NOVEL COMPOUNDS AND METHODS FOR TREATING MULTIPLE SCLEROSIS Inventor(s): PHILLIPS, MICHAEL L. (INDIANAPOLIS, IN), PANETTA, JILL; (ZIONSVILLE, IN) Correspondence: ARLEEN PALMBERG; ELILILLY AND COMPANY; LILLY CORPORATE CENTER/DC1104; INDIANAPOLIS; IN; 46285 Patent Application Number: 20010018437 Date filed: August 27, 1999 Abstract: This invention provides novel thiomorpholinone compounds useful for treating multiple sclerosis. Excerpt(s): This invention relates to novel thiomorpholinone compounds useful for treating multiple sclerosis. Multiple Sclerosis was first described as a clinical entity in 1868. Clinically, it is a highly variable disease, which usually begins between the second and fifth decades of life. The most common signs of multiple sclerosis are sensory and visual motor dysfunction. In the chronic form the patient has periods of remission, but with each remission there is greater neurological dysfunction. Macroscopically, multiple sclerosis involves lesions of 1 to 4 cm called plaques scattered throughout the white matter of the central nervous system. Microscopically, the disease is characterized by a break down of the nervous system's myelin sheath. There is also a loss of myelin basic protein in the area of the lesions. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Novel interferon for the treatment of multiple sclerosis Inventor(s): Croze, Edward M. (Lafayette, CA), Wagner, T. Charis; (Oakland, CA), Faulds, Daryl; (Mill Valley, CA) Correspondence: MILLEN, WHITE, ZELANO & BRANIGAN, P.C. 2200 CLARENDON BLVD. SUITE 1400; ARLINGTON; VA; 22201; US Patent Application Number: 20020025304 Date filed: November 13, 2001 Abstract: This invention relates to novel nucleic acids and polypeptide sequences, which code for an interferon-beta-2 ("IFN-.beta.2"). A pharmaceutical composition, which comprises a pharmaceutically acceptable excipient and a therapeutically effective amount of a human IFN-.beta.2 polypeptide, biologically-active fragment thereof, or biologically-active derivative thereof, is useful in treating multiple sclerosis in humans. Excerpt(s): This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 60/212,046, filed Jun. 16, 2000. Interferons are intercellular

Patents 447

signaling proteins that play an important role in variety of biological processes involving, e.g., cell proliferation and the immune response. (A) is fetal brain culture 1 with no stimulation and (B) is fetal brain culture 1 with EGF stimulation; (C) is fetal brain culture 2 with no stimulation and (D) is fetal brain culture 2 with EGF stimulation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Pharmaceutical compositions comprising vitamin B12 and interferon for treating multiple sclerosis Inventor(s): Pastrak, Aleksandra; (Toronto, CA), Cruz, Tony F. (Toronto, CA) Correspondence: BURNS DOANE SWECKER & MATHIS L L P; POST OFFICE BOX 1404; ALEXANDRIA; VA; 22313-1404; US Patent Application Number: 20030017135 Date filed: July 17, 2001 Abstract: Pharmaceutical compositions for treating multiple sclerosis are disclosed comprising an amount of vitamin B12, vitamin B12 analogues, vitamin B12 derivatives, vitamin B12 conjugates or mixtures thereof in combination with interferon. Vitamin B12 or its analogues, derivatives, conjugates or mixtures thereof are administered separately or in combination with interferon to have a synergistic effect resulting in an enhanced therapeutic efficacy for treating multiple sclerosis. Excerpt(s): The present invention relates to the treatment of multiple sclerosis with vitamin B12, vitamin B12 analogues, derivatives or conjugates thereof in combination with interferon. Multiple sclerosis is a multifactorial inflammatory disease of the human central nervous system resulting in the slowing of electrical conduction along the nerve. It is a progressively, debilitating disease that manifests itself in the prime of peoples' lives, usually between the ages of 20 and 40. Although not fatal, the disease is unpredictable and can lead to blurred vision, loss of balance, poor coordination, slurred speech, tremors, numbness, extreme fatigue, even paralysis and blindness. It is estimated that close to a third of a million people in the United States have multiple sclerosis. It is more prevalent in northern latitudes where it affects roughly 140 per 100,000 people (0.14%). Twice as many women as men have multiple sclerosis. The cause of multiple sclerosis is unknown, although genetic and environmental factors are associated with higher risk. Multiple sclerosis results from inflammation and breakdown in the myelin surrounding the nerve fibres of the central nervous system. Once the myelin is destroyed, it is replaced by sclerotic patches or plaques which can appear in multiple locations within the central nervous system. Hence the name "multiple sclerosis". The disease is further characterized by an increase in the infiltration of inflammatory cells, loss of oligodendrocytes, and increased gliosis (For review see Amit et al., 1999; Pouly et al., 1999; Steinman et al., 1993; Miller et al., 1994). Although the pathology is well established, the cause of the disease is not well elucidated. It is believed to be an autoimmune disorder where the immune system launches an attack against its own tissues, the main target being the myelin sheath. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Remedies for amyotrophic lateral sclerosis Inventor(s): Funakoshi, Hiroshi; (Osaka, JP), Nakamura, Toshikazu; (Osaka, JP), Sun, Woong; (Seoul, KR) Correspondence: BIRCH STEWART KOLASCH & BIRCH; PO BOX 747; FALLS CHURCH; VA; 22040-0747; US Patent Application Number: 20030176347 Date filed: May 14, 2003 Abstract: The invention presents a therapeutic agent (and progress suppressant) for amyotrophic lateral sclerosis (ALS) containing HGF and/or HGF gene as active ingredient. HGF has an effect of improving the motor function of ALS and life span through two actions, that is, direct neuronutrient factor activity on motoneurons, and indirect improving action of glutamate cytotoxicity on motoneurons by maintaining the level of glutamate transporter in astrocytes. Hence, HGF and/or HGF gene can be used as an effective therapeutic agent not known in the past. Excerpt(s): The present invention relates to a remedy for amyotrophic lateral sclerosis (ALS). More particular, the invention relates to a remedy for ALS containing HGF (hepatocyte growth factor) and/or HGF genes as active ingredients. Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive loss of motoneurons and degeneration of motor axons, which results in motor dysfunction and shortening of life span. About 15% of ALS patients are patients with familial ALS (FALS), and about 15% to 25% of FALS patients carry mutations in the gene encoding Cu.sup.2+/Zn.sup.2+ superoxide dismutase (SOD1). Transgenic mice with high levels of mutant SOD1 protein and activity develop diseases similar to both familial and sporadic ALS, and such muted SOD1 overexpressing transgenic mice are used as a model for ALS. In the invention, too, G93A mice (Science, 264, 1772-1775, 1994) were used as muted SOD1 (G93A) overexpressing transgenic mice. Since degeneration of motoneurons is thought to be a first sign of the disease, many approaches had been focused to directly support the survival of motoneurons. However, these attempts were not satisfactory. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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T-CELL VACCINATION FOR THE TREATMENT OF MULTIPLE SCLEROSIS Inventor(s): WEINER, LESLIE P. (LOS ANGELES, CA), CORREALE, JORGE D. (BUENOS AIRES, AR) Correspondence: MCCUTCHEN DOYLE BROWN & ENERSEN; THREE EMBARCADERO CENTER; SAN FRANCISCO; CA; 94111 Patent Application Number: 20020009448 Date filed: September 17, 1998 Abstract: Disclosed are methods and compositions useful for the treatment of autoimmune diseases. Methods for producing vaccines against autoreactive T-cells are disclosed. The vaccines so produced are capable of restoring a degree of immunologic self-tolerance sufficient to slow or halt the progression of autoimmune disorders. In a preferred embodiment of the invention, a vaccine is derived from attenuated autologous autoreactive T-cells that recognize a variety of myelin-derived proteins. Such vaccine

Patents 449

compositions are useful for immunologic therapy for the treatment of multiple sclerosis (MS). Excerpt(s): The present invention relates generally to the field of immunotherapy and to treatments for autoimmune diseases. In particular, the invention relates to methods of using T-cells as vaccines for treating autoimmune diseases, including multiple sclerosis. Autoimmune diseases affect 5-7% of the adult population in Europe and North America. (Sinha AA, M T Lopez, et al. (1990) Science 248:1380-1387). This group of diseases has a major socioeconomic impact, not only because they are accompanied by long life expectancies, but also because they strike individuals in their most productive years. For example, the patients who get multiple sclerosis (MS) are predominantly women between the ages of 18 and 40. Autoimmune diseases are thought to result from an uncontrolled immune response directed against self antigens. In contrast, individuals who do not mount an autoimmune response to self antigens are thought to have control over these responses and are believed to by "tolerant" of self antigens. Although the etiology of MS remains unknown, several lines of evidence support the hypothesis that autoimmunity plays a significant role in the development of the disease (Martin R, H F McFarland, et al. (1992) Annu. Rev. Immunol. 10: 153-187). In MS, there is evidence that the uncontrolled immune response is against the white matter of the central nervous system and more particularly to myelin proteins that are located in the white matter. Ultimately, the myelin sheath surrounding the axons is destroyed. This can result in paralysis, sensory deficits and visual problems. MS is characterized by a T-cell and macrophage infiltrate in the brain. Presently, the myelin proteins thought to be the target of an immune response in MS include myelin basic protein (MBP), proteolipid protein (PLP), myelin associated glycoprotein (MAG), and myelin-oligodendrocyte glycoprotein (MOG). Also there is an increasing body of evidence that the T-cell receptor has extraordinary flexibility, allowing it to react to many different proteins (Brock R, K H Wiesmuller, et al. (1996) Proc. Natl. Acad. Sci. (USA) 93:13108-13113; Loftus D J, Y Chen, et al. (1997) J Immunol. 158:3651-3658). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Treatment of multiple sclerosis Inventor(s): Colover, Jack; (London, GB) Correspondence: STEVENS, DAVIS, MILLER & MOSHER, L.L.P. Suite 850; 1615 L Street, N.W. Washington; DC; 20036; US Patent Application Number: 20020004525 Date filed: June 11, 2001 Abstract: Multiple sclerosis is treated by reducing the fluid pressure in the myelin sheath of nerves to reduce or prevent bursting of the sheath. Prostaglandins are the preferred agent for achieving a reduction in the pressure. Excerpt(s): This invention relates to the treatment of demyelinating diseases, for example multiple sclerosis, and to pharmaceutical compositions useful therefor. Multiple sclerosis is a chronic incurable disease of human beings for which presently known treatments have no effect or only marginal therapeutic responses. It is a demyelinating disease, i.e. the myelin sheaths surrounding the nerve fibres are destroyed, leading to severe disability, paralysis, mental illness and visual disturbances. It may be chronically progressive or relapsing in which case each relapse is associated with marked deterioration. Much of the myelin loss is due to auto-immune reactions, which destroy the myelin sheaths of the nerve fibres in the central nervous system. There are certain other generally similar demyelinating diseases. I have made some

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study of this matter and have found that very surprisingly, the cylindrical myelin sheath around nerve axons is maintained in its normal shape partly by fluid under pressure therein. That is to say, the sheath is "inflated" by hydrostatic or hydrodynamic pressure, and it is the maintenance of an appropriate pressure within the sheath that assists in keeping it in its normal shape. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Treatment of multiple sclerosis using COP-1 and Th2-enhancing cytokines Inventor(s): Marron, Ruth; (Brookline, MA), Slavin, Anthony; (Boston, MA), Weiner, Howard L. (Brookline, MA) Correspondence: DARBY & DARBY P.C. 805 Third Avenue; New York; NY; 10022; US Patent Application Number: 20010007758 Date filed: February 6, 2001 Abstract: The invention relates to a treatment for multiple sclerosis. COP-1 (copolymer1), a synthetic polymer consisting of a mixture of random synthetic polypeptides composed of L-alanine, L-glutamic acid, L-lysine and L-tyrosine in a molar ratio of about 6:2:5:1, is administered mucosally to patients afflicted with the disease in combination with Th2 enhancing cytokines such as IL-4 or IL-10. The combination treatment of IL-4 or IL-10 (preferably orally administered) with mucosally administered COP-1 shows a substantially greater suppressive effect than does treatment with cytokine or COP-1 alone. Excerpt(s): This application claims priority pursuant to 35 U.S.C. 119 based upon Provisional Application Ser. No. 60/074,696 filed Feb. 13, 1998, the entire disclosure of which is hereby incorporated by reference. This invention pertains to an improvement in the ability to reduce autoimmune reactions associated with Multiple Sclerosis. Autoimmune diseases are characterized by an abnormal immune response directed to self or autologous tissues. Based on the type of immune response (or immune reaction) involved, autoimmune diseases in mammals can generally be classified into one of two different types: cell-mediated (i.e., T-cell-mediated) or antibody-mediated disorders. Multiple sclerosis (MS) is a T-cell mediated autoimmune disease. (Trapp et al. New Eng. J. Med. 338(5):278 (1998)). More than 1,000,000 young adults worldwide between the ages of thirty and forty have MS. MS is the most common disease of the central nervous system and is the most common cause of neurological disability in young adults. Pathophysiologically, circulating autoreactive T cells mediate much of the central nervous system destruction seen in MS patients. (Rudick et al. New Eng. J. Med. 337:1604(1997)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 451

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Use of (Z) -2-cyano-3-hydroxy-but-2-enoic acid-(4' -trifluoromethylphenyl)- -amide for treating multiple sclerosis Inventor(s): Wettstein, Joseph; (Lebanon, NJ) Correspondence: AVENTIS PHARMACEUTICALS, INC. PATENTS DEPARTMENT; ROUTE 202-206, P.O. BOX 6800; BRIDGEWATER; NJ; 08807-0800; US Patent Application Number: 20020177623 Date filed: April 1, 2002 Abstract: The invention relates to the use of compound of Formula I in treating patients for the symptoms of multiple sclerosis. 1 Excerpt(s): This application claims the benefit of U. S. Provisional Application No. 60/281,685 filed Apr. 5, 2001 and Great Britain application No. 0123571.2, filed Oct. 2, 2001. The present invention relates to methods of treating multiple sclerosis. In particular, the present invention relates to the treatment of multiple sclerosis with (Z)-2cyano-3-hydroxy-but-2-enoic acid-(4'-trifluoromethylphenyl)-amide, commonly known as teriflunomide. (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluoromethylphenyl)-amide (teriflunomide ,Formula I) use in treating chronic graft-versus-host disease has been disclosed in U.S. Pat. No. 4,965,276 issued on Oct. 23, 1990, incorporated herein by reference. U.S. Pat. No. 5,459,163 issued on Oct. 21, 1997 and U.S. Pat. No. 5,679,709 issued on Oct. 21, 1997 disclose compositions useful for treating autoimmune diseases in particular lupus erythematosus. Both of the aforementioned patents are incorporated herein by reference. Teriflunomide has been shown to produce antiproliferative effects on a wide variety of immune cells and cell lines (Cherwinski H. M., et al., J Pharmacol. Exp. Ther. 1995;272:460-8; Prkash A., et al., Drugs 1999;58(6):1137-66; Bartlett R. R. et al., Agent Action 1991;32(1-2):10-21). Additionally, it inhibits the enzyme dihydrooate dehydrogenase, an enzyme essential for the synthesis of pyrimidines (Bruneau J-M, et al., Biochem. J. 1998; 36:299-303). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of bowman birk inhibitor for the treatment of multiple sclerosis and other autoimmune diseases Inventor(s): Rostami, Abdolmohamad; (Gladwynne, PA), Kennedy, Ann R. (Wynnewood, PA) Correspondence: DILWORTH PAXSON LLP; 3200 MELLON BANK CENTER; 1735 MARKET STREET; PHILADELPHIA; PA; 19103; US Patent Application Number: 20020127289 Date filed: August 31, 2001 Abstract: The present invention provides a non-toxic therapy and a novel use for Bowman Birk Inhibitor (BBI), as administered in Bowman Birk Inhibitor Concentrate (BBIC), for the treatment of autoimmune diseases in a patient, wherein the disease is characterized by chronic inflammation, such as rheumatoid arthritis; and more particularly for the treatment of those diseases that are characterized by chronic neuroinflammation and/or demyelination, such as Multiple Sclerosis (MS) and Guillain Barre Syndrome (GBS). In addition, the present invention provides methods for using BBI/BBIC to reduce, inhibit, suppress or prevent the chronic inflammation in such patients; and more particularly, to reduce, inhibit, suppress or prevent the chronic

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neuroinflammation and demyelination that occurs when the patient's nerve tissue is affected by the disease. Excerpt(s): This application claims priority to US Provisional Application 60/230568, filed Sep. 2, 2000. This invention relates generally to novel use of the Bowman-Birk protease inhibitor for the treatment of neuroinflammatory autoimmune diseases, such as Multiple Sclerosis and Guillain Barre Syndrome, and other inflammatory autoimmune diseases, such as rheumatoid arthritis. The Bowman-Birk protease inhibitor (BBI) was first described decades ago (Bowman et al., Arch. Biochem. Biophys. 16:109-113 (1948); Bowman et al., Proc. Soc. Exp. Biol. Med. 57:139-140 (1944)). The BBI protein consists of 71 amino acid residues and 7 disulfide bonds, and it has a molecular weight of 7975 daltons (Odani et al., J. Biochem. 74:697-715 (1973)). BBI contains two functional protease inhibitor domains of different specificities. It inhibits both trypsin and chymotrypsinlike proteases (Birk et al., J. Peptide Protein Res. 25:113-134 (1985)), wherein one domain inhibits chymotrypsin-like proteases, and the other inhibits trypsin-like proteases. Chymase and tryptase are serine proteases, which are stored in the cytosol, from which they may be released upon stimulation by potentially pro-inflammatory cells, such as mast cells or macrophages. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of difluoromethylornithine (DFMO) for the treatment of amyotrophic lateral sclerosis Inventor(s): Ramesh, Tennore; (Westwood, MA), Scott, Sean; (San Francisco, CA) Correspondence: NUTTER MCCLENNEN & FISH LLP; WORLD TRADE CENTER WEST; 155 SEAPORT BOULEVARD; BOSTON; MA; 02210-2604; US Patent Application Number: 20030130350 Date filed: November 1, 2002 Abstract: The present invention provides methods and compositions for modulating polyamine pathway activity as a means for ameliorating neurodegenarative disorders. In particular, for ameliorating the symptoms or onset of amyotrophic lateral sclerosis (ALS) by modulating the gene and protein products involved the polyamine pathway, such as by inhibiting the enzyme, ornithine decarboxylase (ODC), involved in the synthesis of the polyamine, putrescine. Compositions and methods are disclosed for inhibiting the polyamine pathway producing lower polyamine levels resulting in a beneficial effect on ALS. This can be accomplished by using modulating agents such as analogs, or polyamine analogs, and antiproliferative drugs. In particular, the ODC inhibitor difuoromethylornithine (DFMO) is disclosed as a useful pharmacological agent in the modulation and treatment of ALS. Screening assays for pharmacological agents that are capable of decreasing polyamine levels and/or reducing cell proliferation are also disclosed. Excerpt(s): This application claims priority to provisional application U.S. Ser. No. 60/333,263, filed Nov. 16, 2001 entitled "Methods for Monitoring and Treating Amyotrophic Lateral Sclerosis". The technical field of the invention concerns methods and compositions for the treatment of neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS). Neurodegencrative diseases are generally characterized by a degeneration of neurons in either the brain or the nervous system of an individual. In addition to ALS, various other diseases, such as Huntington's disease, Parkinson's disease, Alzheimer's disease and Multiple Sclerosis, fall within this category. These

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diseases are debilitating and the damage that they cause is often irreversible. Moreover, in the case of a number of these diseases, the outcome is invariably fatal. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of polyamine analogs for amyotrophic lateral sclerosis Inventor(s): Scott, Sean; (San Francisco, CA), Ramesh, Tennore; (Westwood, MA) Correspondence: NUTTER MCCLENNEN & FISH LLP; WORLD TRADE CENTER WEST; 155 SEAPORT BOULEVARD; BOSTON; MA; 02210-2604; US Patent Application Number: 20030130357 Date filed: November 1, 2002 Abstract: The present invention provides methods and compositions for modulating polyamine pathway activity as a means for ameliorating neurodegenarative disorders. In particular, for ameliorating the symptoms or onset of amyotrophic lateral sclerosis (ALS) by modulating the gene and protein products involved the polyamine pathway, such as by inhibiting the enzyme, ornithine decarboxylase (ODC), involved in the synthesis of the polyamine, putrescine. Compositions and methods are disclosed for inhibiting the polyamine pathway producing lower polyamine levels resulting in a beneficial effect on ALS. This can be accomplished by using modulating agents such as analogs, or polyamine analogs, and antiproliferative drugs. In particular, the polyamine analog N(1),N(11)-diethylnorspermine (DENSPM) is disclosed as a useful modulating agent in the treatment of ALS. Screening assays for pharmacological agents that are capable of decreasing polyamine levels and/or reducing cell proliferation are also disclosed. Excerpt(s): The technical field of the invention concerns methods and compositions for the treatment of neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS). Neurodegenerative diseases are generally characterized by a degeneration of neurons in either the brain or the nervous system of an individual. In addition to ALS, various other diseases, such as Huntington's disease, Parkinson's disease, Alzheimer's disease and Multiple Sclerosis, fall within this category. These diseases are debilitating and the damage that they cause is often irreversible. Moreover, in the case of a number of these diseases, the outcome is invariably fatal. Progress is being made on many fronts to find agents that can arrest the progress of these diseases. Nonetheless, the present therapies for most, if not all, of these diseases provide very little relief. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of regularly scheduled high dose intravenous methotrexate therapy, with interim administration of immunomodulatory agents, to treat multiple sclerosis and other diseases of the central nervous system Inventor(s): Rowe, Vernon D. (Kansas City, MO) Correspondence: STINSON MORRISON HECKER LLP; ATTN: PATENT GROUP; 1201 WALNUT STREET, SUITE 2800; KANSAS CITY; MO; 64106-2150; US Patent Application Number: 20030008875 Date filed: April 24, 2002

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Abstract: The present invention is directed to the treatment of multiple sclerosis by periodically administering a high dose of methotrexate at a level sufficiently high to cross the blood brain barrier. The methotrexate administration is accompanied by leucovorin rescue of the periphery. The high dose methotrexate is preferably administered at 1 to 4 month intervals. The periodic high dose methotrexate treatment may be used in conjunction with interim treatments using a therapeutic agent that is effective in treating MS, but does not cross the BBB in cytotoxic amounts. It is contemplated that the method of the present invention may be employed to treat other non-infectious, non-neoplastic inflammatory conditions of the CNS. Excerpt(s): This application is based on U.S. Provisional Application Ser. No. 60/288,567, filed on May 3, 2001, which is hereby incorporated herein by reference. Not Applicable. The present invention is directed to the treatment of non-infectious, nonneoplastic inflammatory conditions of the central nervous system using high dose methotrexate treatments. 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: 20010055592 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

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and for which there is no, or no significant, therapy as yet. The progressive decay of 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 •

Use of tetracycline derivatives in treating multiple sclerosis Inventor(s): Duncan, Ian D. (Madison, WI), Zhang, Su-Chun; (Madison, WI) Correspondence: QUARLES & BRADY LLP; 411 E. WISCONSIN AVENUE, SUITE 2040; MILWAUKEE; WI; 53202-4497; US Patent Application Number: 20020022608 Date filed: May 3, 2001 Abstract: A method of treating multiple sclerosis is disclosed. In one embodiment, the method comprises the step of treating a multiple sclerosis patient with a tetracycline derivative, wherein the multiple sclerosis symptoms of the patient are diminished. Excerpt(s): This application claims priority from U.S. provisional application Ser. No. 60/202,138, filed May 5, 2000. U.S. Ser. No. 60/202,138 is incorporated by reference herein. There is an urgent need for the development of new drugs or a new application of existing drugs to the treatment of multiple sclerosis and other incurable neurologic disorders. The application of tetracycline derivatives, such as minocycline or doxycycline, to the treatment of multiple sclerosis based on our data is an advance in the treatment of this disease, both as a primary therapy and in support of transplantinduced brain repair. Multiple sclerosis is an inflammatory disease of the central nervous system (CNS) in which demyelination results in a variety of neurologic deficits. In many patients the disease relapses and remits while in others there is a progressive worsening with no remissions. At present, the only drugs that have been found to be effective in slowing or lessening the disease burden are.beta.-interferon and copolymerI. However, neither cures the disease and in many patients there is little or no effect. While T-cells are the early inflammatory cells found in areas of demyelination (plaques) in multiple sclerosis patients, microglia in these areas become activated and are thought to produce a number of cytotoxic cytokines. These cytokines are then thought to play a key role in the subsequent demyelination and oligodendrocyte death. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Keeping Current In order to stay informed about patents and patent applications dealing with 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 “sclerosis” (or synonyms) 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 sclerosis. You can also use this procedure to view pending patent applications concerning 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 7. BOOKS ON SCLEROSIS Overview This chapter provides bibliographic book references relating to sclerosis. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on sclerosis include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “sclerosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on sclerosis: •

Systemic Sclerosis Source: Baltimore, MD: Williams and Wilkins. 1996. 679 p. Contact: Available from Williams and Wilkins, Special Sales Department. (800) 358-3583. Summary: This textbook for health professionals provides them with up-to-date information on systemic sclerosis (SSc). Part one presents information on the history, epidemiology, demographics, genetic aspects, classification, prognosis, and differential diagnosis of SSc. Localized scleroderma is described, and the role of environmental factors in scleroderma and pseudoscleroderma is examined. Part two explores the pathogenesis of scleroderma, focusing on cellular aspects, vascular involvement, serologic correlates, environmental aspects, immune aspects, and animal models of systemic sclerosis. Part three discusses pulmonary, cardiac, peripheral vascular, skin, musculoskeletal, renal, nervous system, and gastrointestinal involvement in SSc. In addition, the association between Sjogren's syndrome and SSc is examined, and the

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sexual and psychosocial aspects of SSc are explored. Part four addresses issues related to designing trials of therapeutic interventions in SSc and describes the use of disease modifying drugs, unproven remedies, surgery, and occupational and physical therapy in treating SSc. Part five examines ancillary and supportive care for SSc patients and lists available resources. Appendices list resources for devices and modalities, Scleroderma Foundation Offices, and products and services. Numerous references, numerous figures, numerous tables, and 15 color plates.

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 “sclerosis” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “sclerosis” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “sclerosis” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

300 Tips for Making Life with Multiple Sclerosis Easier by Shelly Schwarz, Shelley Peterman Schwarz; ISBN: 1888799234; http://www.amazon.com/exec/obidos/ASIN/1888799234/icongroupinterna

•

A Colour Atlas of Multiple Sclerosis and Other Myelin Disorders by C.W.M. Adams MA MD DSc FRCP FRCPath, Sir William Dunn; ISBN: 0723409528; http://www.amazon.com/exec/obidos/ASIN/0723409528/icongroupinterna

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A History of Multiple Sclerosis by T. Jock, MD Murray (2003); ISBN: 1888799803; http://www.amazon.com/exec/obidos/ASIN/1888799803/icongroupinterna

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A Practical Guide to Multiple Sclerosis: Diagnosis, Investigation and Treatment by Alasdair J. Coles (2001); ISBN: 0750648007; http://www.amazon.com/exec/obidos/ASIN/0750648007/icongroupinterna

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Advanced Concepts in Multiple Sclerosis Nursing Care by June Halper (Editor); ISBN: 1888799536; http://www.amazon.com/exec/obidos/ASIN/1888799536/icongroupinterna

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Advances in Multiple Sclerosis by Michel Clanet; ISBN: 1841840971; http://www.amazon.com/exec/obidos/ASIN/1841840971/icongroupinterna

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Advances in Multiple Sclerosis by Sten Fredrikson (Editor) (1999); ISBN: 1853178713; http://www.amazon.com/exec/obidos/ASIN/1853178713/icongroupinterna

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Advances in the Immunopathogenesis of Multiple Sclerosis by D. Gambi (Editor), et al (1999); ISBN: 884700067X; http://www.amazon.com/exec/obidos/ASIN/884700067X/icongroupinterna

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All of a Piece: A Life With Multiple Sclerosis by Barbara D. Webster (1989); ISBN: 0801861624; http://www.amazon.com/exec/obidos/ASIN/0801861624/icongroupinterna

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Alternative Medicine and Multiple Sclerosis by Allen C. Bowling; ISBN: 1888799528; http://www.amazon.com/exec/obidos/ASIN/1888799528/icongroupinterna

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Amyotrophic Lateral Sclerosis by I. Nakano (Editor), et al; ISBN: 0444822860; http://www.amazon.com/exec/obidos/ASIN/0444822860/icongroupinterna

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Amyotrophic Lateral Sclerosis by Hiroshi Mitsumoto, et al; ISBN: 0803602693; http://www.amazon.com/exec/obidos/ASIN/0803602693/icongroupinterna

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Amyotrophic Lateral Sclerosis by Robert H. Brown (Editor), et al (2000); ISBN: 1853174211; http://www.amazon.com/exec/obidos/ASIN/1853174211/icongroupinterna

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Amyotrophic Lateral Sclerosis (Progress in Clinical Neurologic Trials, Vol 1) by F. Clifford Rose (Editor); ISBN: 093995723X; http://www.amazon.com/exec/obidos/ASIN/093995723X/icongroupinterna

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Amyotrophic lateral sclerosis : proceedings of the International Symposium on Amyotrophic Lateral Sclerosis held February 2 and 3, 1978; ISBN: 0839114222; http://www.amazon.com/exec/obidos/ASIN/0839114222/icongroupinterna

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Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases (Advances in Neurology, Vol 56) by Lewis P. Rowland (Editor); ISBN: 0881677485; http://www.amazon.com/exec/obidos/ASIN/0881677485/icongroupinterna

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Amyotrophic Lateral Sclerosis: A Comprehensive Guide to Management by Hiroshi Mitsumoto, Forbes H. Norris (Contributor); ISBN: 0939957582; http://www.amazon.com/exec/obidos/ASIN/0939957582/icongroupinterna

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Amyotrophic Lateral Sclerosis: A Guide for Patients and Families, 2nd Edition by Hiroshi Mitsumoto (Editor), Theodore L. Munsat (Editor) (2001); ISBN: 1888799285; http://www.amazon.com/exec/obidos/ASIN/1888799285/icongroupinterna

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Amyotrophic Lateral Sclerosis: A Guide to Patient Care by James T. Caroscio (Photographer) (1986); ISBN: 0865772460; http://www.amazon.com/exec/obidos/ASIN/0865772460/icongroupinterna

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Amyotrophic Lateral Sclerosis: A Synthesis of Research and Clinical Practice by Andrew Eisen (Author), Charles Krieger (Author); ISBN: 0521581036; http://www.amazon.com/exec/obidos/ASIN/0521581036/icongroupinterna

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Amyotrophic Lateral Sclerosis: Concepts in Pathogenesis and Etiology by Arthur James Hudson (Editor) (1990); ISBN: 0802034462; http://www.amazon.com/exec/obidos/ASIN/0802034462/icongroupinterna

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Amyotrophic Lateral Sclerosis: Diagnosis and Management for the Clinician by Jerry M. Belsh (Editor), Philip L. Schiffman (Editor); ISBN: 0879936282; http://www.amazon.com/exec/obidos/ASIN/0879936282/icongroupinterna

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Amyotrophic Lateral Sclerosis: New Advances in Toxicology and Epidemiology by F. Clifford Rose (Editor), Forbes Norris H. (Editor); ISBN: 185463030X; http://www.amazon.com/exec/obidos/ASIN/185463030X/icongroupinterna

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Amyotrophic Lateral Sclerosis: Recent Advances in Research and Treatment: Proceedings of the International Conference on Amyotrophic Lateral Sclero (International Congress Series, No. 769) by International Conference on Amyotrophic Lateral Sclerosis; ISBN: 0444809791; http://www.amazon.com/exec/obidos/ASIN/0444809791/icongroupinterna

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Amyotrophic Lateral Sclerosis: Recent Research Trends: Proceedings of a Conference on Research Trends in Amyotrophic Lateral Sclerosis Held October by J. Andrews; ISBN: 0120597500; http://www.amazon.com/exec/obidos/ASIN/0120597500/icongroupinterna

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Amyotrophic Lateral Sclerosis: Therapeutic, Psychological, and Research Aspects (Advances in Experimental Medicine and Biology, 209) by V. Cosi, et al; ISBN: 0306425467; http://www.amazon.com/exec/obidos/ASIN/0306425467/icongroupinterna

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Amytrophic Lateral Sclerosis by Donald W. Scott, William L. C. Scott (2003); ISBN: 1553952146; http://www.amazon.com/exec/obidos/ASIN/1553952146/icongroupinterna

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An Atlas of Multiple Sclerosis by Charles M. Poser; ISBN: 1850709467; http://www.amazon.com/exec/obidos/ASIN/1850709467/icongroupinterna

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An Illustrated Pocketbook of Multiple Sclerosis by Charles M., Md. Poser; ISBN: 1842141414; http://www.amazon.com/exec/obidos/ASIN/1842141414/icongroupinterna

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As For Tomorrow, I Cannot Say: 33 Years with Multiple Sclerosis by Diana Neutze; ISBN: 1892138069; http://www.amazon.com/exec/obidos/ASIN/1892138069/icongroupinterna

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Association Studies Between HLA Class II, CD3 and CD4 Polymorphisms and Diabetes, Multiple Sclerosis and Schizophrenia by M. Zamani Ghabanbasani; ISBN: 9061866421; http://www.amazon.com/exec/obidos/ASIN/9061866421/icongroupinterna

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Body Hate : A Gay Man's Struggle with Multiple Sclerosis by William Cate; ISBN: 1892183366; http://www.amazon.com/exec/obidos/ASIN/1892183366/icongroupinterna

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Body Under Siege: Two Very Different, but Two Very Connected Stories Multiple Sclerosis - Life at the Edge and the Vidalia Onion - A Marketing Success Story by Danny S. New (2002); ISBN: 0759643350; http://www.amazon.com/exec/obidos/ASIN/0759643350/icongroupinterna

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Brain Disorders Sourcebook: Basic Consumer Health Information About Strokes, Epilepsy, Amyotrophic Lateral Sclerosis (Als/Lou Gehrig's Disease) Parkinson's Disease, Brain Tumors (Health Reference Series) by Karen Bellenir (Editor) (1999); ISBN: 0780802292; http://www.amazon.com/exec/obidos/ASIN/0780802292/icongroupinterna

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Brave Men Sometimes Cry: A Tribute to Marge Howlett, Multiple Sclerosis Victim by Joe Howlett, et al; ISBN: 053313241X; http://www.amazon.com/exec/obidos/ASIN/053313241X/icongroupinterna

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Cannabis: Multiple Sclerosis, This One. Der, Fool Life by Gary G. Graham (2000); ISBN: 1873189400; http://www.amazon.com/exec/obidos/ASIN/1873189400/icongroupinterna

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Cellular and Humoral Immunological Components of Cerebrospinal Fluid in Multiple Sclerosis (NATO Asiseries A, Life Sciences, Vol 129) by A. Lowenthal, J. Raus (Editor); ISBN: 0306425785; http://www.amazon.com/exec/obidos/ASIN/0306425785/icongroupinterna

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Changing Foootsteps: My Story and Poems of Living with Multiple Sclerosis by Elsa C. Welch (2000); ISBN: 1862481431; http://www.amazon.com/exec/obidos/ASIN/1862481431/icongroupinterna

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Chlamydia Pneumoniae in Aortic Valve Sclerosis & Thoracic Aortic Disease: Aspects of Pathogenesis & Therapy (Comprehensive Summaries of Uppsala Dissertations

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from the Faculty of mediciNe, 1168) by Christina Nystrom Rosander (2002); ISBN: 9155453562; http://www.amazon.com/exec/obidos/ASIN/9155453562/icongroupinterna •

Claude Msing Around: Meeting the Challenge of Multiple Sclerosis by John Mythen (1990); ISBN: 0969445709; http://www.amazon.com/exec/obidos/ASIN/0969445709/icongroupinterna

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Clinical studies of multiple sclerosis in Iceland A follow-up of previous survey and reappraisal by Kjartan R. Gudmundsson; ISBN: 8716005538; http://www.amazon.com/exec/obidos/ASIN/8716005538/icongroupinterna

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Clinical Trials in Multiple Sclerosis by F. Clifford Rose (Editor) (1987); ISBN: 3805545770; http://www.amazon.com/exec/obidos/ASIN/3805545770/icongroupinterna

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Coffee in the Cereal: The First Year with Multiple Sclerosis by Lorna J. Moorhead; ISBN: 0934793077; http://www.amazon.com/exec/obidos/ASIN/0934793077/icongroupinterna

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Collagen-vascular diseases; systemic lupus erythematosus, acute dermatomyositispolymyositis, progressive systemic sclerosis, polyarteritis nodosa by John Harold Talbott; ISBN: 0808908480; http://www.amazon.com/exec/obidos/ASIN/0808908480/icongroupinterna

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Color Atlas of Multiple Sclerosis & Other Myelin Disorders by C. W. M. Adams; ISBN: 0911378855; http://www.amazon.com/exec/obidos/ASIN/0911378855/icongroupinterna

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Comparative neuropathology of chronic experimental allergic encephalomyelitis and multiple sclerosis by Hans Lassmann; ISBN: 0387122435; http://www.amazon.com/exec/obidos/ASIN/0387122435/icongroupinterna

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Comprehensive Nursing Care in Multiple Sclerosis by June Halper (Editor), Nancy J. Holland (Editor); ISBN: 1888799056; http://www.amazon.com/exec/obidos/ASIN/1888799056/icongroupinterna

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Coping and Prevailing with Multiple Sclerosis and other Life Struggles by Thomas M. Bayuk; ISBN: 097176140X; http://www.amazon.com/exec/obidos/ASIN/097176140X/icongroupinterna

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Coping When a Parent Has Multiple Sclerosis (Coping Series) by Barbara Cristall (1992); ISBN: 0823914062; http://www.amazon.com/exec/obidos/ASIN/0823914062/icongroupinterna

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Coping with Multiple Sclerosis by Cynthia Benz (1996); ISBN: 0091813611; http://www.amazon.com/exec/obidos/ASIN/0091813611/icongroupinterna

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Coping With Multiple Sclerosis (Coping) by Betty Burnett, Rob Gevertz; ISBN: 0823932044; http://www.amazon.com/exec/obidos/ASIN/0823932044/icongroupinterna

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Courage: The Story of the Mighty Effort to End the Devastating Effects of Multiple Sclerosis by Richard Trubo, et al (2001); ISBN: 1566634148; http://www.amazon.com/exec/obidos/ASIN/1566634148/icongroupinterna

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Csf Analysis in Multiple Sclerosis by P. Livrea, et al (1997); ISBN: 3540750185; http://www.amazon.com/exec/obidos/ASIN/3540750185/icongroupinterna

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Current Concepts in Multiple Sclerosis: Proceedings of the 6th Congress of the European Committee for Treatment and Research in Multiple Sclerosis by Horst Wietholter, et al; ISBN: 0444814167; http://www.amazon.com/exec/obidos/ASIN/0444814167/icongroupinterna

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Diagnosis and Management of Multiple Sclerosis by John O. Fleming; ISBN: 1884735320; http://www.amazon.com/exec/obidos/ASIN/1884735320/icongroupinterna

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Diagnosis of Multiple Sclerosis by Charles M. Poser (Editor); ISBN: 0865771073; http://www.amazon.com/exec/obidos/ASIN/0865771073/icongroupinterna

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Diets to Help: Multiple Sclerosis: Helping to Control Symptoms Naturally by Rita Greer; ISBN: 0722532393; http://www.amazon.com/exec/obidos/ASIN/0722532393/icongroupinterna

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Diseases Explained: Multiple Sclerosis Wall Chart by Lexi-Comp; ISBN: 1930598211; http://www.amazon.com/exec/obidos/ASIN/1930598211/icongroupinterna

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Drug Treatment of Multiple Sclerosis by Antona Wagstaff; ISBN: 0864710704; http://www.amazon.com/exec/obidos/ASIN/0864710704/icongroupinterna

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Employment Issues and Multiple Sclerosis by Phillip D., Jr. Rumrill (1996); ISBN: 188879903X; http://www.amazon.com/exec/obidos/ASIN/188879903X/icongroupinterna

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En miljon utan jobb : suedo-sclerosis III by Ingemar Ståhl; ISBN: 9175663171; http://www.amazon.com/exec/obidos/ASIN/9175663171/icongroupinterna

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Enzyme and protein changes in myelin breakdown and multiple sclerosis: a review of some recent histochemical and biochemical studies by J. F. Hallpike; ISBN: 3437102737; http://www.amazon.com/exec/obidos/ASIN/3437102737/icongroupinterna

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Esclerosis Multiple: Guia Practica Para el Recien Diagnosticado by Nancy J. Holland, et al (2002); ISBN: 1888799587; http://www.amazon.com/exec/obidos/ASIN/1888799587/icongroupinterna

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Everything You Need to Know About Multiple Sclerosis (Need to Know Library) by Margaret J. Goldstein; ISBN: 0823932923; http://www.amazon.com/exec/obidos/ASIN/0823932923/icongroupinterna

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Experimental allergic encephalomyelitis : a useful model for multiple sclerosis : a satellite conference of the International Society of Neurochemists held at the University of Washington, Seattle, Washington, July 16-19 1983; ISBN: 0845101463; http://www.amazon.com/exec/obidos/ASIN/0845101463/icongroupinterna

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Experimental Allergic Encephalomyelitis: A Useful Model for Multiple Sclerosis by Ellsworth C. Alvord (Editor); ISBN: 0471833150; http://www.amazon.com/exec/obidos/ASIN/0471833150/icongroupinterna

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Facing Multiple Sclerosis: Our Longest Journey by Dorothy Shatzky, Joel Shatzky (1999); ISBN: 1883938384; http://www.amazon.com/exec/obidos/ASIN/1883938384/icongroupinterna

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Fall Down, Laughing: How Squiggy Caught Multiple Sclerosis and Didn't Tell Nobody by David L. Lander, Lee Montgomery (Contributor) (2000); ISBN: 1585420522; http://www.amazon.com/exec/obidos/ASIN/1585420522/icongroupinterna

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Frontiers in Multiple Sclerosis, II by Aksel Siva (Editor), et al (1998); ISBN: 1853175064; http://www.amazon.com/exec/obidos/ASIN/1853175064/icongroupinterna

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Frontiers in Multiple Sclerosis: Clinical Research and Therapy by Oded Abramsky (Editor), Haim, Ph.D. Ovadia (Editor) (1997); ISBN: 1853173843; http://www.amazon.com/exec/obidos/ASIN/1853173843/icongroupinterna

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Functional Electrical Stimulation (Fes) Resource Guide for Persons With Spinal Cord Injury or Multiple Sclerosis by Jeanne O Teeter, Carole Kantor (1995); ISBN: 1888470038; http://www.amazon.com/exec/obidos/ASIN/1888470038/icongroupinterna

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Genes and Viruses in Multiple Sclerosis by O. R. Hommes (Editor), et al; ISBN: 0444506942; http://www.amazon.com/exec/obidos/ASIN/0444506942/icongroupinterna

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Genetic Analysis of Autoimmune Diseases Using Animal Models: Mapping Susceptibility Genes for Multiple Sclerosis and Rheumatoid Arthritis (Comprehensive Summaries of Uppsala Dissertations, 927) by Hai-Tao Yang (2001); ISBN: 9155447171; http://www.amazon.com/exec/obidos/ASIN/9155447171/icongroupinterna

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Gentle Yoga for People with Arthritis, Stroke Damage, Multiple Sclerosis & in Wheelchairs by Lorna Bell, et al (1982); ISBN: 0911119019; http://www.amazon.com/exec/obidos/ASIN/0911119019/icongroupinterna

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

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Going the Distance: An Inspirational Account of Living a Full Life With Multiple Sclerosis by Moira Griffin; ISBN: 0451170210; http://www.amazon.com/exec/obidos/ASIN/0451170210/icongroupinterna

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Going the Distance: Living a Full Life With Multiple Sclerosis and Other Debilitating Diseases by Moira Griffin; ISBN: 0525247831; http://www.amazon.com/exec/obidos/ASIN/0525247831/icongroupinterna

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Handbook of Amyotrophic Lateral Sclerosis by Richard Alan Smith (Editor); ISBN: 0824786106; http://www.amazon.com/exec/obidos/ASIN/0824786106/icongroupinterna

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Handbook of Multiple Sclerosis by Khurram, Md Bashir, et al; ISBN: 0781727545; http://www.amazon.com/exec/obidos/ASIN/0781727545/icongroupinterna

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Handbook of Multiple Sclerosis (Neurological Disease and Therapy, Vol 53) by Stuart D. Cook (Editor) (2001); ISBN: 0824704851; http://www.amazon.com/exec/obidos/ASIN/0824704851/icongroupinterna

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Heal from the Heart: Odyssey through Nature, Soul and Recovery from Multiple Sclerosis by Norma Schell (2001); ISBN: 0971050708; http://www.amazon.com/exec/obidos/ASIN/0971050708/icongroupinterna

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Health Journeys for People With / Abridged Multiple Sclerosis by Belleruth Naparstek (Author); ISBN: 1570420165; http://www.amazon.com/exec/obidos/ASIN/1570420165/icongroupinterna

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Help Your Child Avoid Multiple Sclerosis: A Parenting Decision by Joseph V. Goldbach, et al (1999); ISBN: 0966909666; http://www.amazon.com/exec/obidos/ASIN/0966909666/icongroupinterna

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Immune System Disorders Sourcebook: Basic Information About Lupus, Multiple Sclerosis, Guillain-Barre Syndrome, Chronic Granulomatous Disease, and More,

464 Sclerosis

Along Statistical and demographic (Health Reference Series, Vol 18) by Allan R. Cook (Editor) (1997); ISBN: 0780802098; http://www.amazon.com/exec/obidos/ASIN/0780802098/icongroupinterna •

Immunological and Clinical Aspects of Multiple Sclerosis: Proceedings by R. E. Gonsette (Editor); ISBN: 0852007620; http://www.amazon.com/exec/obidos/ASIN/0852007620/icongroupinterna

•

Immunoregulatory Processes in Experimental Allergic Encephalomyelitis and Multiple Sclerosis (Research Monographs in Immunology, Vol 7) by Arthur A. Vandenbark, Jeff C.M. Raus (Editor); ISBN: 0444805702; http://www.amazon.com/exec/obidos/ASIN/0444805702/icongroupinterna

•

Injection Techniques for Spasticity : A Practical Guide to Treatment of Cerebral Palsy, Hemiplegia, Multiple Sclerosis, and Spinal Cord Injury by Essam A. Awad; ISBN: 9770048321; http://www.amazon.com/exec/obidos/ASIN/9770048321/icongroupinterna

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Inspirational Persuasion: Experiencing Multiple Sclerosis by W. Randy Taylor, Ila Yount (Editor) (1993); ISBN: 1566640342; http://www.amazon.com/exec/obidos/ASIN/1566640342/icongroupinterna

•

Interdisciplinary Rehabilitation of Multiple Sclerosis and Neuromuscular Disorders by F. Patrick Maloney (Editor), et al; ISBN: 0397506341; http://www.amazon.com/exec/obidos/ASIN/0397506341/icongroupinterna

•

Interferon Therapy of Multiple Sclerosis by Anthony T. Reder (Editor); ISBN: 0824797647; http://www.amazon.com/exec/obidos/ASIN/0824797647/icongroupinterna

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It's Never the Same: A Priest's Struggle With Multiple Sclerosis by Jimmy Doherty; ISBN: 1853900877; http://www.amazon.com/exec/obidos/ASIN/1853900877/icongroupinterna

•

Key Advances in the Effective Management of Multiple Sclerosis (Key Advances) by Alan Thompson (Editor), Ian McDonald (Editor); ISBN: 1853153893; http://www.amazon.com/exec/obidos/ASIN/1853153893/icongroupinterna

•

Learnign to Live With Multiple Sclerosis by Robert Povey, et al (1997); ISBN: 0859697606; http://www.amazon.com/exec/obidos/ASIN/0859697606/icongroupinterna

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Learning to Live with Multiple Sclerosis (Overcoming Common Problems) by Robin Dowie, et al; ISBN: 0859696545; http://www.amazon.com/exec/obidos/ASIN/0859696545/icongroupinterna

•

Let's Talk About Living With a Parent With Multiple Sclerosis (Let's Talk About) by Melanie Ann Apel; ISBN: 0823956210; http://www.amazon.com/exec/obidos/ASIN/0823956210/icongroupinterna

•

Life on Cripple Creek: Essays on Living With Multiple Sclerosis by Dean Kramer (2002); ISBN: 1888799684; http://www.amazon.com/exec/obidos/ASIN/1888799684/icongroupinterna

•

Living at Your Best With Multiple Sclerosis: A Handbook for Patients, by George Harry, Hess; ISBN: 0398025940; http://www.amazon.com/exec/obidos/ASIN/0398025940/icongroupinterna

Books 465

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Living Beyond Multiple Sclerosis: A Woman's Guide by Judith Lynn Nichols, Lily Jung (2000); ISBN: 0897932935; http://www.amazon.com/exec/obidos/ASIN/0897932935/icongroupinterna

•

Living with disability : a survey of social services support for multiple sclerosis patients in Scotland by Gillian S. Johnson; ISBN: 0443016968; http://www.amazon.com/exec/obidos/ASIN/0443016968/icongroupinterna

•

Living with Multiple Sclerosis by Elizabeth Forsythe; ISBN: 0571112943; http://www.amazon.com/exec/obidos/ASIN/0571112943/icongroupinterna

•

Living With Multiple Sclerosis: A Handbook for Families by Robert Shuman, et al; ISBN: 0020820267; http://www.amazon.com/exec/obidos/ASIN/0020820267/icongroupinterna

•

Living With Multiple Sclerosis: A Social Psychological Analysis by Marcella Zaleski Davis; ISBN: 0398028508; http://www.amazon.com/exec/obidos/ASIN/0398028508/icongroupinterna

•

Living with Multiple Sclerosis: A Wellness Approach, 2nd Edition by George H., Md. Kraft, et al; ISBN: 1888799269; http://www.amazon.com/exec/obidos/ASIN/1888799269/icongroupinterna

•

Living With Multiple Sclerosis: Personal Accounts of Coping and Adaptation (Developments in Nursing and Health Care) by Sarah Perry (1994); ISBN: 1856288935; http://www.amazon.com/exec/obidos/ASIN/1856288935/icongroupinterna

•

Magnetic Resonance Imaging in Multiple Sclerosis (1989); ISBN: 3137373018; http://www.amazon.com/exec/obidos/ASIN/3137373018/icongroupinterna

•

Magnetic Resonance Imaging in Multiple Sclerosis: An Atlas of Diagnosis and Differential Diagnosis by Jurg Kesselring, Kesselrin; ISBN: 0865773343; http://www.amazon.com/exec/obidos/ASIN/0865773343/icongroupinterna

•

Magnetic Resonance in Multiple Sclerosis by David H. Miller (Author), et al; ISBN: 052147325X; http://www.amazon.com/exec/obidos/ASIN/052147325X/icongroupinterna

•

Magnetic Resonance Spectroscopy in Multiple Sclerosis (Topics in Neuroscience) by M. Filippi (Editor), et al (2001); ISBN: 8847001234; http://www.amazon.com/exec/obidos/ASIN/8847001234/icongroupinterna

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Magnetic Resonance Techniques in Clinical Trials in Multiple Sclerosis (Topics in Neuroscience) by M. Filippi (Editor), et al (1999); ISBN: 8847000416; http://www.amazon.com/exec/obidos/ASIN/8847000416/icongroupinterna

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Management of Multiple Sclerosis: An Interdisciplinary Approach by William H. Stuart, et al; ISBN: 0834207583; http://www.amazon.com/exec/obidos/ASIN/0834207583/icongroupinterna

•

Managing the Symptoms of Multiple Sclerosis by Randall T. Shapiro, Randall T. Symptom Management in Multiple Sclerosis Schapiro (2003); ISBN: 1888799781; http://www.amazon.com/exec/obidos/ASIN/1888799781/icongroupinterna

•

Mastering Multiple Sclerosis; ISBN: 0914960431; http://www.amazon.com/exec/obidos/ASIN/0914960431/icongroupinterna

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Mastering Multiple Sclerosis by John K. Wolf; ISBN: 0914960652; http://www.amazon.com/exec/obidos/ASIN/0914960652/icongroupinterna

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Mastering Multiple Sclerosis: Handbook of Management [LARGE PRINT] by John K. Wolf (Editor), et al; ISBN: 1567150551; http://www.amazon.com/exec/obidos/ASIN/1567150551/icongroupinterna

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McAlpine's Multiple Sclerosis; ISBN: 0443022038; http://www.amazon.com/exec/obidos/ASIN/0443022038/icongroupinterna

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Mcalpine's Multiple Sclerosis by Alastair Compston, et al; ISBN: 0443050082; http://www.amazon.com/exec/obidos/ASIN/0443050082/icongroupinterna

•

Me and My Shadow: Learning to Live With Multiple Sclerosis by Carole MacKie, et al (2003); ISBN: 1854106279; http://www.amazon.com/exec/obidos/ASIN/1854106279/icongroupinterna

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Meeting the Challenge of Progressive Multiple Sclerosis by Patricia K. Coyle, June Halper (2001); ISBN: 1888799463; http://www.amazon.com/exec/obidos/ASIN/1888799463/icongroupinterna

•

Meningiomas : diagnostic and therapeutic problems; Multiple sclerosis : misdiagnosis; Forensic problems in neurosurgery; ISBN: 0387072373; http://www.amazon.com/exec/obidos/ASIN/0387072373/icongroupinterna

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MILLER MULTIPLE SCLEROSIS BIPR N6:3; ISBN: 0702023973; http://www.amazon.com/exec/obidos/ASIN/0702023973/icongroupinterna

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Molecular Biology of Multiple Sclerosis by W. C. Russell (Editor); ISBN: 0471969664; http://www.amazon.com/exec/obidos/ASIN/0471969664/icongroupinterna

•

Molecular Mechanism and Therapeutics of Amyotrophic Lateral Sclerosis by Koji Abe (Editor); ISBN: 0444506136; http://www.amazon.com/exec/obidos/ASIN/0444506136/icongroupinterna

•

Motor Neurone Disease: (Amyotrophic Lateral Sclerosis) by Sue Beresford; ISBN: 1565933184; http://www.amazon.com/exec/obidos/ASIN/1565933184/icongroupinterna

•

MOV LIFTING DISABL UMATIC VIDE MULT SCLEROSIS; ISBN: 0877710058; http://www.amazon.com/exec/obidos/ASIN/0877710058/icongroupinterna

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MOVING LIFTING DISABLD BETA VD MULT SCLEROSIS; ISBN: 0877710031; http://www.amazon.com/exec/obidos/ASIN/0877710031/icongroupinterna

•

Ms. Doesn't Stand for Multiple Sclerosis by Chamein T. Canton (2001); ISBN: 0595149057; http://www.amazon.com/exec/obidos/ASIN/0595149057/icongroupinterna

•

MS: Something Can Be Done and You Can Do It: A New Approach to Understanding and Managing Multiple Sclerosis by Robert W. Soll, Penelope B. Grenoble; ISBN: 0809254697; http://www.amazon.com/exec/obidos/ASIN/0809254697/icongroupinterna

•

Multiple Sclerosis by William Ritchie Russell (1976); ISBN: 0080210031; http://www.amazon.com/exec/obidos/ASIN/0080210031/icongroupinterna

•

Multiple Sclerosis; ISBN: 028565019X; http://www.amazon.com/exec/obidos/ASIN/028565019X/icongroupinterna

•

Multiple Sclerosis by Jurg Kesselring (Editor), Jane Smith (Translator) (1996); ISBN: 0521480183; http://www.amazon.com/exec/obidos/ASIN/0521480183/icongroupinterna

Books 467

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Multiple Sclerosis by Louis Rosner (Author) (1992); ISBN: 0671778099; http://www.amazon.com/exec/obidos/ASIN/0671778099/icongroupinterna

•

Multiple Sclerosis by Bernard Graham (1989); ISBN: 0722515243; http://www.amazon.com/exec/obidos/ASIN/0722515243/icongroupinterna

•

Multiple Sclerosis by Judy Graham; ISBN: 0722527772; http://www.amazon.com/exec/obidos/ASIN/0722527772/icongroupinterna

•

Multiple Sclerosis by Chris McLaughlin, Alexander Burnfield MD (Editor); ISBN: 0747528209; http://www.amazon.com/exec/obidos/ASIN/0747528209/icongroupinterna

•

Multiple Sclerosis (1987); ISBN: 0881672548; http://www.amazon.com/exec/obidos/ASIN/0881672548/icongroupinterna

•

Multiple sclerosis; ISBN: 090138772X; http://www.amazon.com/exec/obidos/ASIN/090138772X/icongroupinterna

•

Multiple Sclerosis by Russell L. Blaylock; ISBN: 0939838257; http://www.amazon.com/exec/obidos/ASIN/0939838257/icongroupinterna

•

Multiple Sclerosis by Lanny Perkins, Sara Perkins; ISBN: 0939957116; http://www.amazon.com/exec/obidos/ASIN/0939957116/icongroupinterna

•

Multiple Sclerosis by P. Rumrill (Editor); ISBN: 1586030906; http://www.amazon.com/exec/obidos/ASIN/1586030906/icongroupinterna

•

Multiple Sclerosis by Sharon Warren (Editor), et al; ISBN: 924156203X; http://www.amazon.com/exec/obidos/ASIN/924156203X/icongroupinterna

•

Multiple Sclerosis - 100 Maxims (Neurological Maxims) by Hendon/Bourdette; ISBN: 0340517670; http://www.amazon.com/exec/obidos/ASIN/0340517670/icongroupinterna

•

Multiple Sclerosis - Hallpike by Hallpike Jf; ISBN: 0412141906; http://www.amazon.com/exec/obidos/ASIN/0412141906/icongroupinterna

•

Multiple Sclerosis - the 'at Your Fingertips' Guide by Ian Robinson (1999); ISBN: 187236294X; http://www.amazon.com/exec/obidos/ASIN/187236294X/icongroupinterna

•

Multiple Sclerosis (By Appointment Only) by Jan De Vries (1992); ISBN: 0906391989; http://www.amazon.com/exec/obidos/ASIN/0906391989/icongroupinterna

•

Multiple Sclerosis (Contemporary Neurology, No 50) by Donald W. Paty (Editor), et al; ISBN: 0803667841; http://www.amazon.com/exec/obidos/ASIN/0803667841/icongroupinterna

•

Multiple Sclerosis (Diseases and Disorders) by Melissa Abramovitz, Lucent Books (2003); ISBN: 1590180429; http://www.amazon.com/exec/obidos/ASIN/1590180429/icongroupinterna

•

Multiple Sclerosis (Diseases and People) by Edward Susman; ISBN: 0766011852; http://www.amazon.com/exec/obidos/ASIN/0766011852/icongroupinterna

•

Multiple Sclerosis (Experience of Illness Series) by Ian Robinson; ISBN: 041500635X; http://www.amazon.com/exec/obidos/ASIN/041500635X/icongroupinterna

•

Multiple Sclerosis (Fast Facts) by George D Perkin, Jerry S Wolinsky (2000); ISBN: 1899541284; http://www.amazon.com/exec/obidos/ASIN/1899541284/icongroupinterna

468 Sclerosis

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Multiple Sclerosis (Health Watch) by Susan Dudley Gold; ISBN: 0766016587; http://www.amazon.com/exec/obidos/ASIN/0766016587/icongroupinterna

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Multiple Sclerosis (Progress in Rehabilitation) by Rudy Capildeo (Editor), Audrey Maxwell (Editor); ISBN: 0333309669; http://www.amazon.com/exec/obidos/ASIN/0333309669/icongroupinterna

•

Multiple Sclerosis (Single Titles-Science) by Nathan Aaseng (2000); ISBN: 0531115313; http://www.amazon.com/exec/obidos/ASIN/0531115313/icongroupinterna

•

Multiple Sclerosis (The Infinite Mind, Vol. 212) by Lichtenstein Creative Media Inc. ISBN: 1888064862; http://www.amazon.com/exec/obidos/ASIN/1888064862/icongroupinterna

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Multiple sclerosis : a concise summary for nurses and patients by Jean Atkinson; ISBN: 0723603731; http://www.amazon.com/exec/obidos/ASIN/0723603731/icongroupinterna

•

Multiple sclerosis : a guide for patients and their families; ISBN: 0890047766; http://www.amazon.com/exec/obidos/ASIN/0890047766/icongroupinterna

•

Multiple sclerosis : a guide for patients and their families; ISBN: 0890049602; http://www.amazon.com/exec/obidos/ASIN/0890049602/icongroupinterna

•

Multiple sclerosis : an analysis of 812 cases by means of electronic data processing by S. Poser; ISBN: 0387086447; http://www.amazon.com/exec/obidos/ASIN/0387086447/icongroupinterna

•

Multiple sclerosis : experimental and clinical aspects; ISBN: 0897662679; http://www.amazon.com/exec/obidos/ASIN/0897662679/icongroupinterna

•

Multiple Sclerosis : How I Won the Battle by Yvonne A. Fischer; ISBN: 0739201344; http://www.amazon.com/exec/obidos/ASIN/0739201344/icongroupinterna

•

Multiple Sclerosis 2 (Blue Books of Practical Neurology, 27) by W. Ian, Ph.D. McDonald (Editor), et al (2003); ISBN: 0750673486; http://www.amazon.com/exec/obidos/ASIN/0750673486/icongroupinterna

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Multiple Sclerosis and Having a Baby: Everything You Need to Know about Conception, Pregnancy, and Parenthood by Judy Graham; ISBN: 0892817887; http://www.amazon.com/exec/obidos/ASIN/0892817887/icongroupinterna

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Multiple Sclerosis and Me by M. H. Greenblatt; ISBN: 039802300X; http://www.amazon.com/exec/obidos/ASIN/039802300X/icongroupinterna

•

Multiple Sclerosis and Other Demyelinating Diseases (Handbook of Clinical Neurology) by P.J. Vinken (Editor), G.W. Bruyn (Editor); ISBN: 0720472091; http://www.amazon.com/exec/obidos/ASIN/0720472091/icongroupinterna

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Multiple Sclerosis and the Family by Rosalind C. Kalb, Labe Scheinberg (Editor); ISBN: 0939957388; http://www.amazon.com/exec/obidos/ASIN/0939957388/icongroupinterna

•

Multiple Sclerosis Annual by Donald W. Paty (Editor), Martin Dunitz Publishers; ISBN: 1853179124; http://www.amazon.com/exec/obidos/ASIN/1853179124/icongroupinterna

•

Multiple sclerosis Clues to its cause by Uri Leibowitz; ISBN: 0444104704; http://www.amazon.com/exec/obidos/ASIN/0444104704/icongroupinterna

Books 469

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Multiple Sclerosis East and West by Y. Kuroiwa (Editor), L. T. Kurland (Editor) (1983); ISBN: 3805536747; http://www.amazon.com/exec/obidos/ASIN/3805536747/icongroupinterna

•

Multiple Sclerosis Fact Book by Richard, Md. Lechtenberg (1995); ISBN: 0803600747; http://www.amazon.com/exec/obidos/ASIN/0803600747/icongroupinterna

•

Multiple Sclerosis Guide for Patients & Their Families by Labe C. Scheinberg (1984); ISBN: 0890049939; http://www.amazon.com/exec/obidos/ASIN/0890049939/icongroupinterna

•

Multiple sclerosis in Asia : [proceedings] of the Asian Multiple Sclerosis Workshop held March 13-14, 1975, Tokyo; ISBN: 0839109482; http://www.amazon.com/exec/obidos/ASIN/0839109482/icongroupinterna

•

Multiple Sclerosis in Childhood by Ephraim Joshua. Field; ISBN: 0398039194; http://www.amazon.com/exec/obidos/ASIN/0398039194/icongroupinterna

•

Multiple Sclerosis in Clinical Practice by Nancy J. Holland (Editor), Stanley Van Den Noort (Editor); ISBN: 1888799250; http://www.amazon.com/exec/obidos/ASIN/1888799250/icongroupinterna

•

Multiple Sclerosis in Clinical Practice by Aaron Miller, et al; ISBN: 1901865231; http://www.amazon.com/exec/obidos/ASIN/1901865231/icongroupinterna

•

Multiple Sclerosis Patient Education Manual by William H. Stuart, et al (1997); ISBN: 0834207575; http://www.amazon.com/exec/obidos/ASIN/0834207575/icongroupinterna

•

Multiple Sclerosis Q&A: Reassuring Answers to Frequently Asked Questions by Beth Ann Hill, Joanne Wojcieszek (2003); ISBN: 1583331743; http://www.amazon.com/exec/obidos/ASIN/1583331743/icongroupinterna

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Multiple sclerosis research : proceedings of a joint conference held by the Medical Research Council and the Multiple Sclerosis Society of Great Britain and Northern Ireland; ISBN: 0114500320; http://www.amazon.com/exec/obidos/ASIN/0114500320/icongroupinterna

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Multiple Sclerosis Research in Europe: Report of a Cec Conference, Nijmegen, 29, 30, 31 January 1985 by Otto R. Hommes (1986); ISBN: 0852009178; http://www.amazon.com/exec/obidos/ASIN/0852009178/icongroupinterna

•

Multiple Sclerosis Research: Proceedings of the International Multiple Sclerosis Conference: An Update on Multiple Sclerosis, Rome, 15-17 September (International Congress Series, No. 843) by International Multiple Sclerosis Conference: An Update on Multiple Scl, et al; ISBN: 0444811001; http://www.amazon.com/exec/obidos/ASIN/0444811001/icongroupinterna

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Multiple Sclerosis Therapeutics by Richard A., Md. Rudick, et al (2003); ISBN: 1841842265; http://www.amazon.com/exec/obidos/ASIN/1841842265/icongroupinterna

•

Multiple Sclerosis Through History and Human Life by Richard M. Swiderski (1998); ISBN: 0786405627; http://www.amazon.com/exec/obidos/ASIN/0786405627/icongroupinterna

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Multiple sclerosis, a reappraisal by Douglas McAlpine; ISBN: 0443008256; http://www.amazon.com/exec/obidos/ASIN/0443008256/icongroupinterna

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Multiple Sclerosis, Muscular Dystrophy & Als (Dr. Donsbach Tells You What You Need to Know About) by Kurt W. Donsbach, H. Rudolph Alseleben (1993); ISBN: 1569595666; http://www.amazon.com/exec/obidos/ASIN/1569595666/icongroupinterna

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Multiple Sclerosis, Scars of Childhood: New Horizons and Hope by John Milton Adams; ISBN: 0398035954; http://www.amazon.com/exec/obidos/ASIN/0398035954/icongroupinterna

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MULTIPLE SCLEROSIS, Self-Help.A Patients View by Ed Lash; ISBN: 0533136377; http://www.amazon.com/exec/obidos/ASIN/0533136377/icongroupinterna

•

Multiple Sclerosis: A Comprehensive Guide to Effective Treatment (The Natural Way Series) by Richard Thomas; ISBN: 1852307153; http://www.amazon.com/exec/obidos/ASIN/1852307153/icongroupinterna

•

Multiple Sclerosis: A Conceptual Reappraisal With Heuristic Implications by E.J. Field; ISBN: 0398055262; http://www.amazon.com/exec/obidos/ASIN/0398055262/icongroupinterna

•

Multiple Sclerosis: A Critical Conspectus by E. J. Field; ISBN: 0839111320; http://www.amazon.com/exec/obidos/ASIN/0839111320/icongroupinterna

•

Multiple Sclerosis: A Disease Acquired in Childhood by John Harold Dundee. Millar; ISBN: 0398013071; http://www.amazon.com/exec/obidos/ASIN/0398013071/icongroupinterna

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Multiple Sclerosis: A Guide for Families by Rosalind C., Ph.D. Kalb (Editor); ISBN: 1888799145; http://www.amazon.com/exec/obidos/ASIN/1888799145/icongroupinterna

•

Multiple Sclerosis: A Guide for Patients and Their Families by Nancy J Holland (Editor), Labe C. Scheinberg (Photographer); ISBN: 0881672556; http://www.amazon.com/exec/obidos/ASIN/0881672556/icongroupinterna

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Multiple Sclerosis: A Guide for Rehabilitation and Health Care Professionals by Phillip D. Rumrill (Editor), Mary L. Hennessey (Editor) (2001); ISBN: 0398072280; http://www.amazon.com/exec/obidos/ASIN/0398072280/icongroupinterna

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Multiple Sclerosis: A Guide for the Newly Diagnosed (2nd Edition) by Nancy J. Holland, et al; ISBN: 1888799609; http://www.amazon.com/exec/obidos/ASIN/1888799609/icongroupinterna

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Multiple Sclerosis: A Neuropsychiatric Disorder (Progress in Psychiatry Series, No. 37) by Uriel Halbreich (Editor) (1993); ISBN: 0880484632; http://www.amazon.com/exec/obidos/ASIN/0880484632/icongroupinterna

•

Multiple Sclerosis: A New Journey by Richard C., MD Senelick, Delmar (2003); ISBN: 1891525123; http://www.amazon.com/exec/obidos/ASIN/1891525123/icongroupinterna

•

Multiple Sclerosis: A Personal Exploration by Alexander Burnfield (1997); ISBN: 0285650181; http://www.amazon.com/exec/obidos/ASIN/0285650181/icongroupinterna

•

Multiple Sclerosis: a Personal View by Cynthia Birrer; ISBN: 0398038864; http://www.amazon.com/exec/obidos/ASIN/0398038864/icongroupinterna

Books 471

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Multiple Sclerosis: A Rehabilitation Approach to Management (Comprehensive Neurologic Rehabilitation, Vol. 4) by Randall T. Schapiro; ISBN: 093995737X; http://www.amazon.com/exec/obidos/ASIN/093995737X/icongroupinterna

•

Multiple Sclerosis: A Self-Care Guide to Wellness by Nancy J. Holland (Editor), et al (1998); ISBN: 0929819098; http://www.amazon.com/exec/obidos/ASIN/0929819098/icongroupinterna

•

Multiple Sclerosis: A Self-Help Guide to Its Management by Judy Graham (1990); ISBN: 0892812427; http://www.amazon.com/exec/obidos/ASIN/0892812427/icongroupinterna

•

Multiple Sclerosis: Advances in Clinical Trial Design, Treatment and Future Perspectives by D.E. Goodkin (Editor), R.A. Rudick (Editor) (1996); ISBN: 1852330333; http://www.amazon.com/exec/obidos/ASIN/1852330333/icongroupinterna

•

Multiple Sclerosis: Approaches to Management (Therapy in Practice, Vol 18) by Lorraine De Souza (Editor), et al; ISBN: 0412322307; http://www.amazon.com/exec/obidos/ASIN/0412322307/icongroupinterna

•

Multiple Sclerosis: Clinical and Pathogenetic Basis by Cedric S. Raine (Editor), et al; ISBN: 0412308908; http://www.amazon.com/exec/obidos/ASIN/0412308908/icongroupinterna

•

Multiple Sclerosis: Clinical Challenges and Controversies by Alan J. Thompson (Editor), et al (1998); ISBN: 1853174289; http://www.amazon.com/exec/obidos/ASIN/1853174289/icongroupinterna

•

Multiple Sclerosis: Continued efforts to extend product lifecycles [DOWNLOAD: PDF] by Datamonitor (Author); ISBN: B00008R3N1; http://www.amazon.com/exec/obidos/ASIN/B00008R3N1/icongroupinterna

•

Multiple Sclerosis: Control of the Disease by William Ritchie Russell; ISBN: 0080210023; http://www.amazon.com/exec/obidos/ASIN/0080210023/icongroupinterna

•

Multiple Sclerosis: Current Status and Strategies for the Future by Janet E. Joy (Editor), et al (2001); ISBN: 0309072859; http://www.amazon.com/exec/obidos/ASIN/0309072859/icongroupinterna

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Multiple Sclerosis: Current Status of Research and Treatment by Robert M. Herndon, Frederick J. Seil (Editor) (1994); ISBN: 0939957280; http://www.amazon.com/exec/obidos/ASIN/0939957280/icongroupinterna

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Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation by Jack S. Burks (Editor), Kenneth P. Johnson (Editor); ISBN: 1888799358; http://www.amazon.com/exec/obidos/ASIN/1888799358/icongroupinterna

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Multiple Sclerosis: Etiology, Diagnosis, and New Treatment Strategies by Michael Olek, Howard L. Weiner; ISBN: 1588290336; http://www.amazon.com/exec/obidos/ASIN/1588290336/icongroupinterna

•

Multiple Sclerosis: Experimental and Clinical Aspects (Annals of the New York Academy of Sciences, Vol 436) by Cedric S. Raine (Editor), Labe C. Scheinberg (1985); ISBN: 0897662660; http://www.amazon.com/exec/obidos/ASIN/0897662660/icongroupinterna

•

Multiple Sclerosis: Exploring Sickness and Health by Elizabeth Forsythe; ISBN: 0571139795; http://www.amazon.com/exec/obidos/ASIN/0571139795/icongroupinterna

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Multiple Sclerosis: Four Case Studies by Patricia Wellingham-Jones (1987); ISBN: 0939221047; http://www.amazon.com/exec/obidos/ASIN/0939221047/icongroupinterna

•

Multiple Sclerosis: Immunology, Pathology and Pathophysiology by Robert M. Herndon (Editor), Lillian S. Hawthorne (2003); ISBN: 1888799625; http://www.amazon.com/exec/obidos/ASIN/1888799625/icongroupinterna

•

Multiple Sclerosis: Its Impact from Childhood to Old Age (Mpn 26) by Helmut J. Bauer, Folker A. Hanefeld; ISBN: 0702016063; http://www.amazon.com/exec/obidos/ASIN/0702016063/icongroupinterna

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Multiple Sclerosis: Over 100 Receipes to Help Control Symptoms (Recipes for Health) by Geraldine Fitzgerald, et al; ISBN: 0722531427; http://www.amazon.com/exec/obidos/ASIN/0722531427/icongroupinterna

•

Multiple Sclerosis: Pathology, Diagnosis, and Management by J.F. and Adams, C.W.M. and Tourtellotte, W.W. Hallpike; ISBN: 0683038524; http://www.amazon.com/exec/obidos/ASIN/0683038524/icongroupinterna

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Multiple Sclerosis: Present and Future (Ettore Majorana International Sciences Series; Life Sciences, Vol 16) by G. Scarlato, W.B. Matthews (Editor) (1984); ISBN: 0306418231; http://www.amazon.com/exec/obidos/ASIN/0306418231/icongroupinterna

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Multiple Sclerosis: Psychological and Social Aspects by Aart F. Simons (Editor); ISBN: 043330295X; http://www.amazon.com/exec/obidos/ASIN/043330295X/icongroupinterna

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Multiple Sclerosis: Psychosocial and Vocational Interventions by Robert T. Fraser, et al; ISBN: 1888799595; http://www.amazon.com/exec/obidos/ASIN/1888799595/icongroupinterna

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Multiple Sclerosis: Questions and Answers by David Barnes, et al; ISBN: 1873413866; http://www.amazon.com/exec/obidos/ASIN/1873413866/icongroupinterna

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Multiple Sclerosis: Selections from "The World Market for Neurotherapeutic Drugs" [DOWNLOAD: PDF] by Kalorama Information (Author); ISBN: B00006LJ2Q; http://www.amazon.com/exec/obidos/ASIN/B00006LJ2Q/icongroupinterna

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Multiple Sclerosis: Subject Reference and Research Guide by Oliver A. Fraser (1987); ISBN: 0881645591; http://www.amazon.com/exec/obidos/ASIN/0881645591/icongroupinterna

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Multiple Sclerosis: The Facts by Bryan Matthews, W. B. Matthews; ISBN: 0192615238; http://www.amazon.com/exec/obidos/ASIN/0192615238/icongroupinterna

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Multiple Sclerosis: The Facts (Oxford Medical Publications) by Bryan Matthews, W. B. Matthews; ISBN: 0192624032; http://www.amazon.com/exec/obidos/ASIN/0192624032/icongroupinterna

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Multiple Sclerosis: The Facts You Need (Your Personal Health Series) by Paul O'Connor (1999); ISBN: 1552093670; http://www.amazon.com/exec/obidos/ASIN/1552093670/icongroupinterna

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Multiple Sclerosis: The Facts You Need (Your Personal Health) by Paul O'Connor (2004); ISBN: 1552978893; http://www.amazon.com/exec/obidos/ASIN/1552978893/icongroupinterna

Books 473

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Multiple Sclerosis: The Guide to Treatment and Management by Chris H. Polman M.D. (Editor), et al (2001); ISBN: 1888799544; http://www.amazon.com/exec/obidos/ASIN/1888799544/icongroupinterna

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Multiple Sclerosis: The Kinder Side by Lyn Risidore; ISBN: 0969298501; http://www.amazon.com/exec/obidos/ASIN/0969298501/icongroupinterna

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Multiple Sclerosis: The Questions You Have - The Answers You Need by Rosalind Kalb (Editor), Rosalind C., Phd Kallb; ISBN: 1888799439; http://www.amazon.com/exec/obidos/ASIN/1888799439/icongroupinterna

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Multiple Sclerosis: The Unseen Enemy by Arline Dean; ISBN: 0806246529; http://www.amazon.com/exec/obidos/ASIN/0806246529/icongroupinterna

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Multiple Sclerosis: Theory and Practice for Nurses by Megan Burgess; ISBN: 1861562977; http://www.amazon.com/exec/obidos/ASIN/1861562977/icongroupinterna

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Multiple Sclerosis: tissue destruction and repair by Ludwig Kappos, et al (2000); ISBN: 1853178721; http://www.amazon.com/exec/obidos/ASIN/1853178721/icongroupinterna

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Multiple Sclerosis: Your Legal Rights by Sara Perkins, Lanny E. Perkins; ISBN: 1888799315; http://www.amazon.com/exec/obidos/ASIN/1888799315/icongroupinterna

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Multiple sclerosis; immunology, virology, and ultrastructure; ISBN: 012761950X; http://www.amazon.com/exec/obidos/ASIN/012761950X/icongroupinterna

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Multiple sclerosis; progress in research Report of a symposium held under the auspices of the Multiple Sclerosis Research Committee, World Federation of Neurology, and Medical Research Council Demyelinating Diseases Unit, Newcastle upon Tyne, June 28th and 29th 1971; ISBN: 0444103449; http://www.amazon.com/exec/obidos/ASIN/0444103449/icongroupinterna

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Multiple Sclerosis--A Dragon With a Hundred Heads by Michael; ISBN: 0879491701; http://www.amazon.com/exec/obidos/ASIN/0879491701/icongroupinterna

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My Story: A Photographic History of Life With Multiple Sclerosis by Amelia Davis (2004); ISBN: 1932603018; http://www.amazon.com/exec/obidos/ASIN/1932603018/icongroupinterna

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Myelination and Demyelination: Implications for Multiple Sclerosis by Seung U. Kim (Editor) (1989); ISBN: 0306431181; http://www.amazon.com/exec/obidos/ASIN/0306431181/icongroupinterna

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Nature of Multiple Sclerosis by Paavo Riekkinen (1973); ISBN: 9998017866; http://www.amazon.com/exec/obidos/ASIN/9998017866/icongroupinterna

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Neurobehavioral Aspects of Multiple Sclerosis by Stephen M. Rao (Editor) (1990); ISBN: 0195054008; http://www.amazon.com/exec/obidos/ASIN/0195054008/icongroupinterna

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New Frontiers of Mr-Based Techniques in Multiple Sclerosis (Topics in Neuroscience) by M. Filippi (Editor), et al (2003); ISBN: 8847001986; http://www.amazon.com/exec/obidos/ASIN/8847001986/icongroupinterna

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Nursing Practice in Multiple Sclerosis: A Core Curriculum by Kathleen Costello, et al (2003); ISBN: 1888799765; http://www.amazon.com/exec/obidos/ASIN/1888799765/icongroupinterna

474 Sclerosis

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Occupational Therapy and Multiple Sclerosis by Lesley Silcox, Colin Smith (Illustrator) (2003); ISBN: 1861563485; http://www.amazon.com/exec/obidos/ASIN/1861563485/icongroupinterna

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Occupational Therapy Practice and Research With Persons With Multiple Sclerosis by Anne Elizabeth Dickerson (Editor), Marcia Finlayson (Editor) (2004); ISBN: 0789023814; http://www.amazon.com/exec/obidos/ASIN/0789023814/icongroupinterna

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One Particular Harbor: The Outrageous True Adventures of One Women With Multiple Sclerosis Living in the Alaskan Wilderness by Janet Lee James (2000); ISBN: 0595001157; http://www.amazon.com/exec/obidos/ASIN/0595001157/icongroupinterna

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Oslo international think-tank on multiple sclerosis epidemiology : proceedings of the opening seminar, Centre for Advanced Studies, Oslo, Norway, September 17-18, 1994; ISBN: 8716151585; http://www.amazon.com/exec/obidos/ASIN/8716151585/icongroupinterna

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Overcoming Multiple Sclerosis by J.C. Ogilvie; ISBN: 0686298411; http://www.amazon.com/exec/obidos/ASIN/0686298411/icongroupinterna

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Palliative Care in Amyotrophic Lateral Sclerosis (Motor Neuron Disease) by David Oliver (Editor), et al; ISBN: 0192631667; http://www.amazon.com/exec/obidos/ASIN/0192631667/icongroupinterna

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Primary Progressive Multiple Sclerosis (Topics in Neuroscience) by M. Filippi (Editor), G. Combi (2004); ISBN: 8847001676; http://www.amazon.com/exec/obidos/ASIN/8847001676/icongroupinterna

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Principles of Treatments in Multiple Sclerosis by Clive Hawkins (Editor), Jerry S. Wolinsky (Editor); ISBN: 075064270X; http://www.amazon.com/exec/obidos/ASIN/075064270X/icongroupinterna

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Progress in Multiple Sclerosis Research by H.J. Bauer (Editor); ISBN: 0387098674; http://www.amazon.com/exec/obidos/ASIN/0387098674/icongroupinterna

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Progress in multiple sclerosis: research and treatment; proceedings; ISBN: 0124413501; http://www.amazon.com/exec/obidos/ASIN/0124413501/icongroupinterna

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Progressive Systemic Sclerosis (Current Topics in Rheumatology) by Carol M. Black, Allen R. Myers (Editor); ISBN: 0912143088; http://www.amazon.com/exec/obidos/ASIN/0912143088/icongroupinterna

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Recent Advances in Multiple Sclerosis Therapy: Proceedings (International Congress Series, No 863) by R.E. Gonsette, P. Delmotte (Editor); ISBN: 0444811117; http://www.amazon.com/exec/obidos/ASIN/0444811117/icongroupinterna

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Research on multiple sclerosis by C. W. M. Adams; ISBN: 0398022143; http://www.amazon.com/exec/obidos/ASIN/0398022143/icongroupinterna

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Research on Multiple Sclerosis by Byron H. Waksman, et al; ISBN: 0939957078; http://www.amazon.com/exec/obidos/ASIN/0939957078/icongroupinterna

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Reversing Multiple Sclerosis: 9 Effective Steps to Recover Your Health by Celeste Pepe, Lisa Hammond (2001); ISBN: 1571742263; http://www.amazon.com/exec/obidos/ASIN/1571742263/icongroupinterna

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Road to the Cure for MS: How Science Is Solving the Mysteries of Mulitple Sclerosis by Howard, Dr. Weiner (2004); ISBN: 0609609009; http://www.amazon.com/exec/obidos/ASIN/0609609009/icongroupinterna

Books 475

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Scleroderma (Progressive Systemic Sclerosis) by Alfred John Barnett; ISBN: 0398029555; http://www.amazon.com/exec/obidos/ASIN/0398029555/icongroupinterna

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Sclerosis: Index of New Information and Research Bible of Current Reviews by Selinsky (1994); ISBN: 0788300385; http://www.amazon.com/exec/obidos/ASIN/0788300385/icongroupinterna

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Sharing MS: Multiple Sclerosis by Linda Ironside, et al (2003); ISBN: 0973094974; http://www.amazon.com/exec/obidos/ASIN/0973094974/icongroupinterna

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Sociodemographic Factors in the Epidemiology of Multiple Sclerosis : An Annotated Bibliography by George W. Lowis (Author) (1991); ISBN: 031326838X; http://www.amazon.com/exec/obidos/ASIN/031326838X/icongroupinterna

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Special Diet Cookbooks: Multiple Sclerosis: Healthy Menus to Help in the Management of Multiple Sclerosis by Geraldine Fitzgerald, Fenella Briscoe (Contributor); ISBN: 0722518102; http://www.amazon.com/exec/obidos/ASIN/0722518102/icongroupinterna

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Speech and Language Disorders in Multiple Sclerosis by Bruce Murdoch (Editor), Deborah Theodoros (Editor) (2000); ISBN: 1861561008; http://www.amazon.com/exec/obidos/ASIN/1861561008/icongroupinterna

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Starting over: The Autobiographical Account of a Psychologist's Experience With Multiple Sclerosis by Ernest A., Hirsch; ISBN: 0815803486; http://www.amazon.com/exec/obidos/ASIN/0815803486/icongroupinterna

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Successful Living with Multiple Sclerosis by Robert H. Phillips; ISBN: 1888614099; http://www.amazon.com/exec/obidos/ASIN/1888614099/icongroupinterna

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Sukey's Songbook of Multiple Sclerosis by Shelia Siegelman; ISBN: 0944066003; http://www.amazon.com/exec/obidos/ASIN/0944066003/icongroupinterna

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Symposium on Multiple Sclerosis (1989); ISBN: 9991703969; http://www.amazon.com/exec/obidos/ASIN/9991703969/icongroupinterna

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Symptom Management in Multiple Sclerosis by Randall T. Schapiro (1994); ISBN: 0939957027; http://www.amazon.com/exec/obidos/ASIN/0939957027/icongroupinterna

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Systemic Sclerosis by Philip J. Clements (Editor), Daniel E. Furst (Editor); ISBN: 0683017403; http://www.amazon.com/exec/obidos/ASIN/0683017403/icongroupinterna

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Systemic sclerosis: current research; ISBN: 084227202X; http://www.amazon.com/exec/obidos/ASIN/084227202X/icongroupinterna

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Systemic Sclerosis: Scleroderma by Malcolm I. Jayson (Editor), et al; ISBN: 0471908460; http://www.amazon.com/exec/obidos/ASIN/0471908460/icongroupinterna

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Taking Control of Multiple Sclerosis: Natural and Medical Therapies to Prevent the Progression of MS: Natural and Medical Therapies to Prevent Its Progression by George Jelinek; ISBN: 1864470860; http://www.amazon.com/exec/obidos/ASIN/1864470860/icongroupinterna

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T-Cell Autoimmunity and Multiple Sclerosis (Neuroscience Intelligence Unit 5) by Marco Londei (Editor); ISBN: 1570595674; http://www.amazon.com/exec/obidos/ASIN/1570595674/icongroupinterna

476 Sclerosis

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The Causation of Rheumatoid Disease & Many Human Cancers: A Precis & Addenda Including the Nature of Multiple Sclerosis by Roger Wyburn-Mason (1983); ISBN: 0931150132; http://www.amazon.com/exec/obidos/ASIN/0931150132/icongroupinterna

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The Clinical Neuropsychiatry of Multiple Sclerosis by Anthony Feinstein (Author); ISBN: 0521572746; http://www.amazon.com/exec/obidos/ASIN/0521572746/icongroupinterna

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The Creative Will: An Exhibition of Works by Thirty-One Artists With Multiple Sclerosis (Project Rembrandt X) by National Multiple Sclerosis Society, National Ms Society; ISBN: 1566405971; http://www.amazon.com/exec/obidos/ASIN/1566405971/icongroupinterna

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The Diagnosis and Symptomatic Therapy of Amyotrophic Lateral Sclerosis by Donald W. Mulder; ISBN: 0892894032; http://www.amazon.com/exec/obidos/ASIN/0892894032/icongroupinterna

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The Edgar Cayce Way of Overcoming Multiple Sclerosis: Vibratory Medicine; ISBN: 0965790339; http://www.amazon.com/exec/obidos/ASIN/0965790339/icongroupinterna

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The First Year-Multiple Sclerosis: An Essential Guide for the Newly Diagnosed (The First Year Series) by Margaret Blackstone, Saud A. Sadiq (2003); ISBN: 1569245223; http://www.amazon.com/exec/obidos/ASIN/1569245223/icongroupinterna

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The International Symposium on Multiple Sclerosis, Göteborg, Sept. 1972; ISBN: 8716017684; http://www.amazon.com/exec/obidos/ASIN/8716017684/icongroupinterna

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The King's Kid: Overcoming with Multiple Sclerosis by Ruth Duke; ISBN: 1879854104; http://www.amazon.com/exec/obidos/ASIN/1879854104/icongroupinterna

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The MS Autobiography Book: An Anthology of Autobiographical Prose & Verse Written by Persons Who Have Multiple Sclerosis by Eric Smirnow (1993); ISBN: 0963833405; http://www.amazon.com/exec/obidos/ASIN/0963833405/icongroupinterna

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The Multiple Sclerosis Diet Book: A Low-Fat Diet for the Treatment of M.S. by Roy L. Swank, Barbara Brewer Dugan; ISBN: 0385232799; http://www.amazon.com/exec/obidos/ASIN/0385232799/icongroupinterna

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The Multiple Sclerosis Diet Book: A Low-Fat Diet for the Treatment of M.S., Heart Disease, and Stroke by Roy Laver, Swank, Mary-Helen Pullen; ISBN: 0385120923; http://www.amazon.com/exec/obidos/ASIN/0385120923/icongroupinterna

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The Nature of multiple sclerosis; ISBN: 0842270701; http://www.amazon.com/exec/obidos/ASIN/0842270701/icongroupinterna

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The Official Patient's Sourcebook on Amyotrophic Lateral Sclerosis: A Revised and Updated Directory for the Internet Age by Icon Health Publications (2003); ISBN: 0597835195; http://www.amazon.com/exec/obidos/ASIN/0597835195/icongroupinterna

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The Official Patient's Sourcebook on Multiple Sclerosis: A Revised and Updated Directory for the Internet Age by Icon Health Publications (2002); ISBN: 0597830495; http://www.amazon.com/exec/obidos/ASIN/0597830495/icongroupinterna

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The Official Patient's Sourcebook on Primary Lateral Sclerosis: A Revised and Updated Directory for the Internet Age by Icon Health Publications (2002); ISBN:

Books 477

0597830983; http://www.amazon.com/exec/obidos/ASIN/0597830983/icongroupinterna •

The Official Patient's Sourcebook on Tuberous Sclerosis: A Revised and Updated Directory for the Internet Age by Icon Health Publications (2002); ISBN: 0597830142; http://www.amazon.com/exec/obidos/ASIN/0597830142/icongroupinterna

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The Suppression of Experimental Allergic Encephalomyelitis and Multiple Sclerosis by Davison; ISBN: 012206660X; http://www.amazon.com/exec/obidos/ASIN/012206660X/icongroupinterna

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Therapeutic Claims in Multiple Sclerosis by William A. Sibley; ISBN: 0939957132; http://www.amazon.com/exec/obidos/ASIN/0939957132/icongroupinterna

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Therapeutic Claims in Multiple Sclerosis: A Guide to Treatments by William A. Sibley; ISBN: 1888799080; http://www.amazon.com/exec/obidos/ASIN/1888799080/icongroupinterna

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Transpetalation: Beyond Quantitative and Qualitative Research, Applied to Multiple Sclerosis by Elanor Treece, et al; ISBN: 0805945997; http://www.amazon.com/exec/obidos/ASIN/0805945997/icongroupinterna

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Transplant Vascular Sclerosis (Medical Intelligence Unit) by Charles Orosz (Editor), International Symposium on the Etiology and Pathobiology of Transplant (1995); ISBN: 0412101211; http://www.amazon.com/exec/obidos/ASIN/0412101211/icongroupinterna

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Treatment of multiple sclerosis : trial design, results, and future perspectives; ISBN: 3540196838; http://www.amazon.com/exec/obidos/ASIN/3540196838/icongroupinterna

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Treatment of Multiple Sclerosis: Trial Design, Results, and Future Perspectives (Clinical Medicine and the Nervous System) by Richard A. Rudick, Donald E. Goodkin (Editor); ISBN: 0387196838; http://www.amazon.com/exec/obidos/ASIN/0387196838/icongroupinterna

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Trends in European Multiple Sclerosis Research: Proceedings of the European Committee for Treatment and Research in Multiple Sclerosis (Ectrims Con) by Christian Confavreux, et al; ISBN: 0444809783; http://www.amazon.com/exec/obidos/ASIN/0444809783/icongroupinterna

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Tuberous Sclerosis by Manuel R. Gomez (Editor); ISBN: 0881673978; http://www.amazon.com/exec/obidos/ASIN/0881673978/icongroupinterna

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Tuberous sclerosis; ISBN: 0890043132; http://www.amazon.com/exec/obidos/ASIN/0890043132/icongroupinterna

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Tuberous Sclerosis and Allied Disorders: Clinical, Cellular, and Molecular Studies by William G. Johnson, Maneul R. Gomez; ISBN: 0897666569; http://www.amazon.com/exec/obidos/ASIN/0897666569/icongroupinterna

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Tuberous Sclerosis and Neurofibromatosis: Epidemiology, Pathophysiology, Biology, and Management: Proceedings of the International Symposium on Neu (Japan Intractable Diseases Research Foundation Publishing Series, No. 28) by Yasumasa/ Hori, Yoshiaki/ Japan Intractable Diseases Research Foundation International Symposium on Neurocutaneous Syndrome / Ishibashi; ISBN: 0444813241; http://www.amazon.com/exec/obidos/ASIN/0444813241/icongroupinterna

478 Sclerosis

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Tuberous Sclerosis Complex (Developmental Perspectives in Psychiatry) by Manuel Rodriguez Gomez (Editor), et al; ISBN: 0195122100; http://www.amazon.com/exec/obidos/ASIN/0195122100/icongroupinterna

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Tuberous Sclerosis Complex : From Basic Science to Clinical Phenotypes by Paolo Curatolo (Editor) (2003); ISBN: 1898683395; http://www.amazon.com/exec/obidos/ASIN/1898683395/icongroupinterna

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Understanding Multiple Sclerosis (1988); ISBN: 0684189985; http://www.amazon.com/exec/obidos/ASIN/0684189985/icongroupinterna

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Understanding Multiple Sclerosis: A Guidebook for Families by Robert Shuman, Janice Schwartz (1988); ISBN: 0684189895; http://www.amazon.com/exec/obidos/ASIN/0684189895/icongroupinterna

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Virology and Immunology in Multiple Sclerosis Rationale by Cazzullo; ISBN: 0387184163; http://www.amazon.com/exec/obidos/ASIN/0387184163/icongroupinterna

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Who Said So?: A Woman's Fascinating Journey of Self Discovery and Triumph over Multiple Sclerosis by Rachelle Breslow; ISBN: 0890876304; http://www.amazon.com/exec/obidos/ASIN/0890876304/icongroupinterna

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Women Living With Multiple Sclerosis by Judith Lynn Nichols (1999); ISBN: 0897932188; http://www.amazon.com/exec/obidos/ASIN/0897932188/icongroupinterna

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Workshop on T-cell Auto-immunity in Multiple Sclerosis: Munich, 5 to 7 December 1990 (Workshop on T-cell Auto-immunity in Multiple Sclerosis) by R. Hohlfeld, et al; ISBN: 9282633594; http://www.amazon.com/exec/obidos/ASIN/9282633594/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 “Search LOCATORplus.” Once you are in the search area, simply type “sclerosis” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:11 •

Auditory and vestibular aberrations in multiple sclerosis, by Douglas Noffsinger [et al.]. Author: Noffsinger, Douglas.; Year: 1966; Uppsala, 1972

•

Commission on Multiple Sclerosis; conference report to accompany H. R. 15475. Author: United States. Congress. Conference Committees, 1972.; Year: 1972; [Washington] 1972

11

In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

Books 479

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Degenerative and regenerative axonal changes in the ventral horns, brain stem and cerebral cortex in amyotrophic lateral sclerosis. Author: Wohlfart, Gunnar.; Year: 1963; Lund, Gleerup [1959]

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Diffuse progressive leucoencephalopathy (diffuse cerebral sclerosis) and its relationship to amaurotic idiocy; histological and clinical aspects, by Lárus Einarson in collaboration with Erik Strömgren. Author: Einarson, Lárus,; Year: 1960; København, Munksgaard, 1961

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Disturbances of arterial blood supply to the spinal cord and brain stem caused by spondylosis, disc protrusions and root-sleeve fibrosis; a concept concerning factors eliciting amyotrophic lateral sclerosis. Author: Störtebecker, Tore Patrick.; Year: 1965; København, Munksgaard, 1960

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Living at your best with multiple sclerosis; a handbook for patients. Author: Hess, George Harry,; Year: 1971; Springfield, Ill., Thomas [1972]; ISBN: 0398026211 http://www.amazon.com/exec/obidos/ASIN/0398026211/icongroupinterna

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Motor neuron diseases; research on amyotrophic lateral sclerosis and related disorders. Dedicated to the memory of Lord Brain; edited by Forbes H. Norris, Jr., and Leonard T. Kurland. Author: Brain, W. Russell Brain (Walter Russell Brain),; Year: 1961; New York, Grune; Stratton [1968]

•

Multiple sclerosis and the demyelinating diseases; proceedings of the association, December 10 and 11, 1948, New York. Author: Association for Research in Nervous and Mental Disease.; Year: 1950; Baltimore, Williams; Wilkins, 1950

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Multiple sclerosis and the demyelinating diseases; proceedings of the association, December 10 and 11, 1948, New York. Author: Association for Research in Nervous and Mental Disease.; Year: 1961; Baltimore, Williams; Wilkins, 1950

•

Multiple sclerosis. Author: National Institute of Neurological Diseases and Blindness (U.S.); Year: 1972; Bethesda, Md., For sale by the Supt. of Docs., U. S. Govt. Print. Off., Washington, 1968]

•

Multiple sclerosis: grounds for hope. Author: Bardossi, Fulvio.; Year: 1968; New York, Public Affairs Committee, c1971]

•

Multiple sclerosis: progress in research, edited by E. J. Field, T. M. Bell, and P. R. Carnegie. Report of a symposium held under the auspices of the Multiple Sclerosis Research Committee, World Federation of Neurology and Medical Research Council Demyelinating Diseases Unit, Newcastle upon Tyne, June 28th and 29th 1971. Author: Bell, Thomas M. (Thomas Matthew); Year: 1991; Amsterdam, North-Holland Pub. Co., 1972; ISBN: 0720473039

•

Multiple sclerosis; a reappraisal by Douglas McAlpine [et al.]. Author: McAlpine, Douglas.; Year: 1964; Edinburgh, Livingstone, 1965

•

Multiple sclerosis; clues to its cause [by] Uri Leibowitz [and] Milton Alter. Author: Leibowitz, Uri.; Year: 1964; Amsterdam, North Holland Pub. Co. New York, American Elsevier, 1973; ISBN: 072044117X

•

National Commission on Multiple Sclerosis act. Hearing. Ninety-second Congress, second session, on H. R. 13978 (and all identical bills), bills establishing a commission to develop a realistic plan leading to the conquest of multiple sclerosis at the earliest possible date, May 23, 1972. Author: United States. Congress. House. Committee on Interstate and Foreign Commerce. Subcommittee on Public Health and Environment.; Year: 2001; Washington, U. S. Govt. Print. Off., 1972

•

The epidemiology of multiple sclerosis, compiled and edited by Milton Alter and John F. Kurtzke. Author: Alter, Milton,; Year: 2002; Springfield, Ill., Thomas [c1968]

480 Sclerosis

Chapters on Sclerosis In order to find chapters that specifically relate to sclerosis, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and sclerosis using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “sclerosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on sclerosis: •

Focal Segmental Glomerulosclerosis Source: in Schena, F.P., ed. Nephrology. New York, NY: McGraw-Hill, Inc. 2001. p. 141148. Contact: Available from McGraw-Hill, Inc. Shoppenhangers Road, Maidenhead, Berkshire SL6 2QL. 44 (0)1628 502700. Fax: +44 (0)1628 635895 E-mail: [email protected]. Website: www.mcgraw-hill.co.uk. PRICE: $79.95; plus shipping and handling. ISBN: 0077095251. Summary: Focal segmental glomerulosclerosis (FSGS) is not a disease but a pathologic lesion, a scarring of a portion of the glomerulus (a group of capillaries that are part of the filtering units of the kidney). This chapter on focal segmental glomerulosclerosis(FSGS) is from a book on nephrology (the study of the kidney and kidney diseases) designed for general practitioners and family care providers that offers strategies for the management of patients with renal (kidney) damage. Among glomerular disorders that affect children and young adults, FSGS is the most common disorder leading to end stage renal disease (ESRD). The lesion is more frequent and the severity of the disease is greater in patients of African-American origin. Clinically, the lesions of FSGS can be observed in a wide variety of disorders. In the idiopathic (of unknown cause) variety, there is proteinuria (protein in the urine), hypoalbuminemia (low levels of protein in the blood), and generalized edema (fluid accumulation), together with varying degrees of hypertriglyceridemia and hypercholesterolemia (high levels of fats in the blood). Since FSGS is a histologic diagnosis, a renal biopsy is necessary. The pathogenesis of this disease continues to be elusive; however, in recent years studies point to the role of transforming growth factor beta (TGF-b) in inducing the sclerosis. Most cases of FSGS tend to be resistant to steroid therapy as well as to therapy with alkylating agents such as cyclophosphamide. Controlled trials have documented the efficacy of cyclosporine in inducing a remission of the proteinuria, particularly in children; however, relapses tend to occur upon withdrawal of cyclosporine. In severe edema, intravenous furosemide often is necessary. Antihypertensive (high blood pressure medications) therapy should consist of ACE inhibitors and calcium channel blockers. 2 tables. 15 references.

•

AAC for Individuals with Amyotrophic Lateral Sclerosis Source: in Beukelman, D.R. Yorkston, K.M. Reichle, J., eds. Augmentative and Alternative Communication for Adults with Acquired Neurologic Disorders. Baltimore, MD: Paul H. Brookes Publishing Co. 2000. p. 183-231. Contact: Available from Paul H. Brookes Publishing Co. P.O. Box 10624, Baltimore, MD 21285. (800) 638-3775. Fax (410) 337-8539. Website: www.brookespublishing.com. PRICE: $42.00 plus shipping and handling. ISBN: 1557664730.

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Summary: The loss of speech in adulthood due to acquired neurologic disorders causes a person to confront enormous life changes. This chapter on the use of augmentative and alternative communication (AAC) strategies for individuals with amyotrophic lateral sclerosis (ALS) is from a textbook that explores the challenges these adults face during their transition, whether gradual or immediate, from speaking to using AAC. People with ALS experience a series of losses. However, speech language pathologists who work with people with ALS share a strong conviction that the loss of communication in ALS is not inevitable and that AAC strategies can preserve this critical function even in the face of profound motor deterioration. The chapter reviews the state of practice related to AAC intervention for people with ALS. Because service delivery in this population is provided within the framework of medical management, a variety of issues with implications for communication are also addressed, including the nature of the disease, respiratory issues, and communication and cognition. The authors present a system of staging of dysarthria and a classification of augmentative techniques according to communication needs, as well as data related to patterns of use of technology. Finally, intervention is described from the broad perspective of how people with ALS and their families cope with the disease, including the role of hope in the intervention process. The chapter concludes with a list of resources, including voluntary and support organizations and patient education materials. 3 figures. 5 tables. 143 references. •

Vascular Involvement in Systemic Sclerosis Source: in Clements, P.J. Furst, D.E., Eds. Systemic Sclerosis. Baltimore, MD: Williams and Wilkins. 1996. p. 153-174. Contact: Available from Williams and Wilkins, Special Sales Department. (800) 358-3583. Summary: This chapter for health professionals examines vascular involvement in systemic sclerosis (SSc). The occurrence of Raynaud's phenomenon, an early sign of SSc, is discussed. Nailfold and skin capillary abnormalities that occur in SSc are identified. The pathological features of small arteries and capillaries in SSc patients are described. The pathogenesis of vascular involvement in SSc is discussed in terms of the injury of the endothelium, the modification of endothelium functions, angiogenesis, platelet activation, the modification of vascular tone control, coagulation and fibrinolysis, and inflammation and immune response. Vascular therapeutic approaches to modifying SSc are also considered. 207 references, 2 figures, and 3 tables.

•

Amyotrophic Lateral Sclerosis Source: in Yorkston, K.M. Miller, R.M. Strand, E.A. Management of Speech and Swallowing in Degenerative Diseases. San Antonio, TX: Communication Skill Builders. 1995. p. 1-93. Contact: Available from Communication Skill Builders. Psychological Corporation, Order Service Center, 555 Academic Court, San Antonio, TX 78204-2498. Voice (800) 2118378; TTY (800) 723-1318; Fax (800) 232-1223. PRICE: $45.00 plus shipping and handling. Order Number 076-1677-364-MS799. Summary: This chapter is from a textbook that outlines the management of speech and swallowing in degenerative diseases. The chapter discusses the role of the speech language pathologist in speech and swallowing intervention for amyotrophic lateral sclerosis (ALS). The authors describe the nature of ALS, including changes in neural systems, symptoms, etiology, typical course, diagnostic considerations, rehabilitation medicine in the management of the disease, cognitive changes in ALS, and respiratory

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problems associated with the disease. The authors then outline speech disorders, including speech characteristics, the rapidity of speech changes in ALS, the information that can be obtained in a clinical examination, and speech treatment; and swallowing disorders, including the rate of progression of swallowing problems in ALS, how swallowing function is assessed, management approaches, problems with saliva management, and aspiration. The chapter concludes with three reproducible forms: a clinical examination for ALS form, an ALS severity scale, and a swallowing disorders interview worksheet. 10 figures. 13 tables. 102 references. (AA-M).

Directories In addition to the references and resources discussed earlier in this chapter, a number of directories relating to sclerosis have been published that consolidate information across various sources. The Combined Health Information Database lists the following, which you may wish to consult in your local medical library:12 •

Resources for People with Disabilities and Chronic Conditions Source: Lexington, MA: Resources for Rehabilitation. 1996. 288 p. Contact: Available from Resources for Rehabilitation. 33 Bedford Street, Suite 19A, Lexington, MA 02173. (617) 862-6455; Fax (617) 861-7517. PRICE: $49.95 plus shipping and handling. ISBN: 0929718178. Summary: This book is a resource guide covering many common conditions, including spinal cord injury, low back pain, diabetes, multiple sclerosis, hearing and speech impairments, visual impairment and blindness, and epilepsy. Each chapter includes information about the disease or condition, psychological aspects of the condition, professional service providers, environmental adaptations, assistive devices, and descriptions of related organizations and publications. Also included is information on rehabilitation services, independent living, self-help, laws that affect people with disabilities, making everyday life easier, children with disabilities, computer bulletin boards, and resources on the Internet. The book concludes with an organization name index. (AA-M).

•

Complete Directory for People with Chronic Illness. 4th ed Source: Lakeville, CT: Grey House Publishing, Inc. 2000. 1009 p. Contact: Available from Grey House Publishing, Inc. Pocket Knife Square, Lakeville, CT 06039. (860) 435-0868. Fax (860) 435-0867. PRICE: $165.00. ISBN: 0939300931. Summary: This directory provides a comprehensive overview of the support services and information resources available for people with any of 80 specific chronic illnesses. It presents information on various organizations, educational materials, publications, and databases. A chapter is devoted to each chronic illness and includes a brief description of it. The sections related to kidney and urologic diseases include: AIDS, Alzheimer's disease, cancer, cerebral palsy, diabetes, hypertension, impotence,

12

You will need to limit your search to “Directory” and “sclerosis” using the "Detailed Search" option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find directories, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Select your preferred language and the format option “Directory.” Type “sclerosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months.

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incontinence, infertility, kidney disease, multiple sclerosis, sexually transmitted diseases, spina bifida, stroke, and substance abuse. The description of each disease is followed by subchapters that identify national and State associations and agencies, libraries, research centers, reference books, children's books, magazines, newsletters, pamphlets, videotapes and films, support groups and hotlines, and websites. In addition, the directory includes a chapter on death and bereavement, as well as a chapter on Wish Foundations for terminally and chronically ill children.

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CHAPTER 8. MULTIMEDIA ON SCLEROSIS Overview In this chapter, we show you how to keep current on multimedia sources of information on sclerosis. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Video Recordings An excellent source of multimedia information on sclerosis is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “sclerosis” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” Type “sclerosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on sclerosis: •

Augmentative and Alternative Communication Intervention in Individuals with Amyotrophic Lateral Sclerosis Source: Tucson, AZ: National Center for Neurogenic Communication Disorders, University of Arizona. 2000. (videocassette). Contact: Available from National Center for Neurogenic Communication Disorders, University of Arizona. P.O. Box 210071, Tucson, AZ 85721-0071. (520) 621-1472. Fax (520) 621-2226. PRICE: $25.00 plus shipping and handling. Order Number TR-53. Summary: This videotape program, which is part of the Telerounds videoconference series from the National Center for Neurogenic Communication Disorders at the University of Arizona (funded partly by NIDCD), is the second teleconference in a three part series on augmentative and alternative communication (AAC). The speaker provides the viewer with a brief overview of speech impairments among people who have amyotrophic lateral sclerosis (ALS), focusing on the clinical features and epidemiology of ALS, the stages of speech decline, and the communication intervention

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needs of people who have ALS. The speaker reviews a staging model of communication intervention for progressive motor speech disorders. In addition, the viewer learns how to stage AAC interventions in response to changes in speech and upper and lower extremity function. Examples of interventions are provided for people who have adequate speech and hand function; people who have adequate speech but poor hand function; people who have poor speech, adequate hand function, and adequate mobility; people who have poor speech, adequate hand function, and poor mobility; people who have poor speech, poor hand function, and good mobility; and people who have poor speech, poor hand function, and poor mobility. Video segments are used to illustrate various AAC interventions. The program concludes by answering questions asked by the host and phoned in by the teleconference audience and by providing information about joining Centernet, the online forum operated by the Center.

Bibliography: Multimedia on 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 “Search LOCATORplus.” Once in the search area, simply type in sclerosis (or synonyms). Then, in the option box provided below the search box, select “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 sclerosis: •

Bee venom therapy for multiple sclerosis [videorecording]: a discussion video Source: Traditional Healing Productions; Year: 1994; Format: Videorecording; Southfield, MI: P. Singer, c1994

•

Care of the patient with multiple sclerosis [electronic resource]. Year: 1996; Format: Electronic resource; Chapel Hill, NC: Health Sciences Consortium, [1996?]

•

Chronic otitis media [videorecording]: cholesterol granuloma and tympanosclerosis Source: Ear Research Institute; Year: 1978; Format: Videorecording; [Los Angeles]: The Institute, c1978

•

Clinical syndrome of ALS (amyotrophic lateral sclerosis) [videorecording] Source: National Institute of Neurological and Communicative Disorders and Stroke; Year: 1976; Format: Videorecording; [Bethesda, Md.]: The Institute; [Atlanta: for loan by National Medical Audiovisual Center, 1976?]

•

Multiple sclerosis [motion picture] Source: National Multiple Sclerosis Society; produced by Rex Fleming Production; Year: 1967; Format: Motion picture; New York: The Society; [Atlanta: for loan by National Medical Audiovisual Center, 1967]

•

Multiple sclerosis [videorecording] Source: Marshfield Medical Foundation, in cooperation with Marshfield Clinic & St. Joseph's Hospital; Year: 1982; Format: Videorecording; Marshfield, WI: Marshfield Regional Video Network, 1982

•

Multiple sclerosis [videorecording]: update & management Source: HSN, Hospital Satellite Network program of continuing education; Year: 1986; Format: Videorecording; [Los Angeles, Calif.]: The Network, c1986

•

Multiple sclerosis update [videorecording] Source: Stuart D. Cook; Year: 1990; Format: Videorecording; Secaucus, N.J.: Network for Continuing Medical Education, c1990

•

Mystery diseases [videorecording]: multiple sclerosis and chronic fatigue Source: [presented by] the Medical University of South Carolina, College of Pharmacy and

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Health Communications Network; Year: 1995; Format: Videorecording; Charleston, S.C.: The University, c1995 •

Neuroimaging of demyelinating disease [videorecording]: a focus on multiple sclerosis Source: [presented by] American Society of Neuroimaging; produced & distributed by Health Video Dynamics, Inc; Year: 1992; Format: Videorecording; [United States]: The Society, c1992

•

The Immunology of multiple sclerosis [videorecording] Source: presented by Department of Medicine, Emory University, School of Medicine; Year: 1981; Format: Videorecording; Atlanta, Ga.: Emory Medical Television Network, 1981

•

The Management of the multiple sclerosis patient [videorecording] Source: with Labe Scheinberg and Nancy Holland; Year: 1986; Format: Videorecording; Secaucus, N.J.: Network for Continuing Medical Education, 1986

•

Tuberous sclerosis complex [videorecording]: clinical and genetic aspects Source: the University of Texas Medical School at Houston; produced by UT-TV, Houston; Year: 1992; Format: Videorecording; [Houston, Tex.: UT/TV], c1992

•

Use of cyclosporin in multiple sclerosis [videorecording] Source: [presented by] Marshfield Clinic, Saint Joseph's Hospital [and] Marshfield Medical Research Foundation; Year: 1989; Format: Videorecording; Marshfield, WI: Marshfield Video Network, [1989]

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CHAPTER 9. PERIODICALS AND NEWS ON SCLEROSIS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover sclerosis.

News Services and Press Releases One of the simplest ways of tracking press releases on sclerosis is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “sclerosis” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to sclerosis. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “sclerosis” (or synonyms). The following was recently listed in this archive for sclerosis: •

Antibodies could signal need for change in multiple sclerosis therapy Source: Reuters Industry Breifing Date: October 09, 2003

•

Rehab useful when multiple sclerosis returns Source: Reuters Health eLine Date: October 07, 2003

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•

MRI may speed diagnosis of multiple sclerosis Source: Reuters Health eLine Date: September 11, 2003

•

Sunny childhood may thwart multiple sclerosis Source: Reuters Health eLine Date: August 08, 2003

•

Increased sun exposure in childhood may reduce risk of multiple sclerosis Source: Reuters Medical News Date: August 08, 2003

•

BioMS multiple sclerosis drug performs well in phase II trial Source: Reuters Industry Breifing Date: May 23, 2003

•

Stem cells may offer hope for multiple sclerosis Source: Reuters Health eLine Date: April 16, 2003

•

Yoga, exercise beats fatigue in multiple sclerosis Source: Reuters Health eLine Date: April 10, 2003

•

Cholesterol drug promising for multiple sclerosis Source: Reuters Health eLine Date: April 03, 2003

•

Simvastatin may slow multiple sclerosis progression Source: Reuters Industry Breifing Date: April 02, 2003

•

Past viral infection linked to multiple sclerosis Source: Reuters Health eLine Date: March 25, 2003

•

Epstein-Barr virus an etiologic player in multiple sclerosis Source: Reuters Medical News Date: March 25, 2003

•

Experimental amyotrophic lateral sclerosis responds to treatment with Copaxone Source: Reuters Industry Breifing Date: March 17, 2003

•

Berlex, Chiron get Betaseron approval for rarer form of multiple sclerosis Source: Reuters Industry Breifing Date: March 17, 2003

•

FDA highlights depression risk with Avonex therapy for multiple sclerosis Source: Reuters Medical News Date: March 14, 2003

•

HHV-6 reactivation plays a role in multiple sclerosis disease activity Source: Reuters Medical News Date: January 03, 2003

•

Drug may treat multiple sclerosis, Crohn's disease Source: Reuters Health eLine Date: January 01, 2003

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The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “sclerosis” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “sclerosis” (or synonyms). If you know the name of a company that is relevant to sclerosis, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “sclerosis” (or synonyms).

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Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “sclerosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on sclerosis: •

Autoantibodies in Systemic Sclerosis Source: Bulletin on the Rheumatic Diseases. 45(6):6-7; 1996. Contact: Arthritis Foundation, 1314 Spring Street, NW, Atlanta, GA 30309. (404) 8727100. (404) 872- 9559 (fax). Summary: This newsletter article for health professionals describes autoantibodies associated with systemic sclerosis (SSc), including anticentromere, antitopoisomerase I, anti- RNA polymerase III, anti-U1RNP, anti-PM-Scl, anti-Th/To RNP, and anti-U3RNP. The clinical features of patients with these antibodies are highlighted, and the immunofluorescence staining patterns of the antibodies are presented. 1 table.

•

Therapy-Treatment of Systemic Sclerosis Source: Scleroderma Voice. p. 12-14. Winter 2000-2001. Contact: Available from Scleroderma Foundation. 12 Kent Way, Suite 101, Byfield, MA 01922. (800) 722-HOPE or (978) 463-5843. Fax (978) 463-5809. E-mail: [email protected]. Website: www.scleroderma.org. Summary: This newsletter article provides health professionals and people who have scleroderma with information on approaches to treating systemic sclerosis (SSc). Interrupting the pathogenetic cycle is a reasonable approach to the treatment of SSc. Treatment might be aimed at addressing the vascular damage, preventing fibrosis, or suppressing the immune response. The article highlights the results of recent clinical trials of a prostacyclin derivative, iloprost, interferon gamma, D-penicillamine, chlorambucil, cyclosporine A, methotrexate, and cyclophosphamide. In general, these trials support the use of prostacyclin derivatives, antifibrotic regimens, and immunosuppressive agents to treat SSc. A more definitive test of the usefulness of immunosuppression for SSc is a trial of stem cell transplantation (SCT). Although SCT results have been encouraging, there has been almost a 25 percent mortality rate among SCT treated patients.

•

Treatment of Skin Disorders Associated With Tuberous Sclerosis, The Source: NTSA Perspective. Volume 88: 6-7. Winter 2000. Contact: Available from Tuberous Sclerosis Alliance. 801 Roeder Road, Suite 750, Silver Spring, MD 20910. (800) 225-6872 or (301) 562-9890. Fax (301) 562-9870. E-mail: [email protected]. Website: www.tsalliance.org. Summary: This newsletter article provides people who have tuberous sclerosis (TS) with information on the treatment of skin disorders associated with this disease. One associated disorder is ash leaf spots. Although there is no treatment for these lightly

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colored skin patches, new treatments are being investigated for stimulating pigment production in the skin. Two other skin disorders, forehead fibrous plaque and the shagreen patch, can be surgically excised or treated with laser therapy. Another skin disorder, angiofibromas of the face, can be treated in the early, flat, red spot stage with tunable dye laser therapy. For patients who have well developed fibrous angiofibromas, treatments include surgical removal, laser resurfacing, and dermabrasion. Periungual fibromas and gingival fibromas, which are two other skin disorders associated with TS, can be treated with surgical excision or laser therapy. New, more effective treatments for skin disorders associated with TS may become available in the future.

Academic Periodicals covering Sclerosis Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to sclerosis. In addition to these sources, you can search for articles covering sclerosis that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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CHAPTER 10. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for sclerosis. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with sclerosis. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The

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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to sclerosis: Amantadine •

Systemic - U.S. Brands: Symmetrel http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202024.html

Baclofen •

Systemic - U.S. Brands: Lioresal http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202080.html

Botulinum Toxin Type A •

Parenteral-Local - U.S. Brands: Botox http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202608.html

Cyclophosphamide •

Systemic - U.S. Brands: Cytoxan; Neosar http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202174.html

Dantrolene •

Systemic - U.S. Brands: Dantrium http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202181.html

Glatiramer Acetate •

Systemic - U.S. Brands: Copaxone http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203473.html

Immune Globulin Intravenous (Human) •

Systemic - U.S. Brands: Iveegam; Sandoglobulin; Venoglobulin-I; VenoglobulinS http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202641.html

Interferon, Beta-1A •

Systemic - U.S. Brands: Avonex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203537.html

Interferon, Beta-1B •

Systemic - U.S. Brands: Betaseron http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203538.html

Mitoxantrone •

Systemic - U.S. Brands: Novantrone http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202378.html

Riluzole •

Systemic - U.S. Brands: Rilutek http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202792.html

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Thiamine (Vitamin B 1 ) •

Systemic - U.S. Brands: Biamine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202560.html

Tizanidine •

Systemic - U.S. Brands: Zanaflex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/207060.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.

Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to sclerosis by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “sclerosis” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact

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information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for sclerosis: •

Halofuginone (trade name: Stenorol) http://www.rarediseases.org/nord/search/nodd_full?code=1021

•

Interferon beta-1a (trade name: Avonex) http://www.rarediseases.org/nord/search/nodd_full?code=111

•

Interferon beta-1a (trade name: Rebif) http://www.rarediseases.org/nord/search/nodd_full?code=113

•

creatine (trade name: Creapure) http://www.rarediseases.org/nord/search/nodd_full?code=1241

•

human anti-transforming growth factor beta 1 monoc (trade name: NONE Assigned) http://www.rarediseases.org/nord/search/nodd_full?code=1243

•

Interferon beta-1b (trade name: Bataseron) http://www.rarediseases.org/nord/search/nodd_full?code=116

•

Glatiramer acetate for injection (trade name: Copaxone) http://www.rarediseases.org/nord/search/nodd_full?code=1162

•

Recombinant methionyl brain-derived neurotrophic f http://www.rarediseases.org/nord/search/nodd_full?code=367

•

creatine (trade name: Creapure) http://www.rarediseases.org/nord/search/nodd_full?code=1266

•

human anti-transforming growth factor beta 1 monoc http://www.rarediseases.org/nord/search/nodd_full?code=1271

•

L-baclofen (trade name: Neuralgon) http://www.rarediseases.org/nord/search/nodd_full?code=179

•

Myelin http://www.rarediseases.org/nord/search/nodd_full?code=190

•

L-threonine (trade name: Threostat) http://www.rarediseases.org/nord/search/nodd_full?code=200

Researching Medications 499

•

Neurotrophin-1 http://www.rarediseases.org/nord/search/nodd_full?code=219

•

8-methoxsalen (trade name: Uvadex) http://www.rarediseases.org/nord/search/nodd_full?code=505

•

Riluzole (trade name: Rilutek) http://www.rarediseases.org/nord/search/nodd_full?code=24

•

Orgotein for injection http://www.rarediseases.org/nord/search/nodd_full?code=318

•

Copolymer-1 (trade name: Copaxone) http://www.rarediseases.org/nord/search/nodd_full?code=326

•

Recombinant human relaxin http://www.rarediseases.org/nord/search/nodd_full?code=362

•

Baclofen (trade name: Lioresal Itrathecal) http://www.rarediseases.org/nord/search/nodd_full?code=571

•

Baclofen http://www.rarediseases.org/nord/search/nodd_full?code=574

•

Tizanidine HCI (trade name: Zanaflex) http://www.rarediseases.org/nord/search/nodd_full?code=58

•

Gabapentin (trade name: Neurontin) http://www.rarediseases.org/nord/search/nodd_full?code=713

•

Insulin-like growth factor-1 (trade name: Myotrophin) http://www.rarediseases.org/nord/search/nodd_full?code=72

•

Ciliary neurotrophic factor http://www.rarediseases.org/nord/search/nodd_full?code=641

•

Ciliary neurotrophic factor, recombinant human http://www.rarediseases.org/nord/search/nodd_full?code=643

•

Cladribine (trade name: Leustatin) http://www.rarediseases.org/nord/search/nodd_full?code=648

•

US http://www.rarediseases.org/nord/search/nodd_full?code=660

•

Branched chain amino acids http://www.rarediseases.org/nord/search/nodd_full?code=678

•

Glatiramer acetate (trade name: Copaxone) http://www.rarediseases.org/nord/search/nodd_full?code=808

•

Fampridine (trade name: Neurelan) http://www.rarediseases.org/nord/search/nodd_full?code=696

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•

L-2-oxothiazolidine-4-carboxylic acid (trade name: Procysteine) http://www.rarediseases.org/nord/search/nodd_full?code=784

•

Glatiramer acetate (trade name: Copaxone) http://www.rarediseases.org/nord/search/nodd_full?code=809

•

Mitoxantrone (trade name: Novantrone) http://www.rarediseases.org/nord/search/nodd_full?code=988

If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

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APPENDICES

503

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

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute13: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

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

•

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

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

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

•

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

•

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

•

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

13

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

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•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

•

Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

•

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

•

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

•

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

•

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

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.14 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:15 •

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

14

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). 15 See http://www.nlm.nih.gov/databases/databases.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

•

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 The Combined Health Information Database

A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “sclerosis” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “sclerosis” (or synonyms) into the “For these words:” box. The following is a sample result: •

Guide to Support Groups in Washington State, 1990-1991 Source: Olympia, WA: Washington Department of Social and Health Services. 1990. 78 p. Contact: Available from Aging and Adult Services Administration, Washington State Department of Social and Health Services. P.O. Box 45600, Olympia, WA 98504-0095. (800) 422-3263 or (206) 493-2500. PRICE: Free. Summary: This booklet, revised annually, provides a listing of major statewide and local support groups in Washington State designed to assist caregivers and families of patients with various diseases, including Alzheimer's disease. It provides information for caseworkers, physicians, nurses, case managers and other providers so that they can refer caregivers or family and elders to groups for support and assistance. The first section of the guide describes national or state organizations, their goals, and headquarters location. Support groups are then listed alphabetically within each county. Information about the location and the facilitator's name and telephone number is provided. Organizations listed include the Amyotrophic Lateral Sclerosis (or Lou Gehrig's Disease) Health Support Services, Alzheimer's Association, American Cancer Society, American Lung Association of Washington, National Multiple Sclerosis Society, Washington Advocates for the Mentally Ill, Washington Neurological Alliance, Washington State Head Injury Foundation, and Washington State Resources for Parkinson Disease.

•

Prevention and Management of Urinary Tract Infections in Paralyzed Persons: Summary, Evidence Report/Technology Assessment No. 6 Source: Silver Spring, MD: Agency for Health Care Policy and Research, U.S. Department of Health and Human Services. 1999. 3 p. Contact: Available from AHCPR Publications Clearinghouse. P.O. Box 8547, Silver Spring, MD 20907-8547. (800) 358-9295. TDD (888) 586-6340. Website: www.ahcpr.gov. AHCPR Publication Number 99-E007. PRICE: Single copy free; also available at website. Summary: This document summarizes the results found by a 13 member panel of experts, consumers, and a managed care organization representative, convened to

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analyze the evidence on selected aspects of the prevention and management of urinary tract infections (UTIs) in paralyzed persons. The two populations most commonly affected are persons having spinal cord injury (SCI) and people with multiple sclerosis (MS). Eighty percent of persons with SCI experience a UTI by their 16th year post injury, and diseases of the urinary system are overall the fifth most common primary or secondary cause of death in this population. Between 70 to 90 percent of persons with MS develop bladder dysfunction over the course of their disease, placing them at increased risk for UTIs. The panel utilized a literature review to address three areas: the signs, symptoms, and laboratory findings that are associated with risks to persons with paralysis due to neurogenic bladder; the risk factors for recurrent UTIs; and the risks and benefits of long term use of antibiotic prophylaxis. Risk factors can include febrile (fever) episodes in earlier years (before the UTIs), the presence of certain bacteria or of multiple organisms early after SCI, and indwelling catheterization (which is associated with more frequent infections than intermittent catheterization). Antibiotic prophylaxis significantly reduces bacteriuria among acute spinal cord injury patients; however, antibiotic prophylaxis results in a twofold increase in the occurrence of antibiotic resistant bacteria. The report concludes by calling for additional research and by providing the availability information for the full evidence report from which this summary was taken. •

Progress and Promise, 1992: A Status Report on the NINDS Implementation Plan for the Decade of the Brain Source: Bethesda, MD: National Institute of Neurological Disorders and Stroke. 1992. 50 p. Contact: National Institute of Neurological Disorders and Stroke. Information Office Building 31, 9000 Rockville Pike, Bethesda, MD 20892. (800) 352-9424. Summary: This status report reviews the National Advisory Neurological Disorders and Stroke Council's implementation plan and summarizes progress made in basic and clinical research on neurological disorders. It discusses the major areas of research opportunity, recommendations to the National Institute of Neurological Disorders and Stroke for research objectives in the Decade of the Brain, and resources needed to initiate and fully implement these efforts over the next several years. Future plans and budgets are presented for study in inherited disorders; cerebral palsy and other developmental disorders; epilepsy; traumatic brain and spinal cord injury; stroke and cerebrovascular disease; brain tumors; and various diseases that cause the brain to fail such as Alzheimer's disease, multiple sclerosis, and Parkinson's disease. Other topics include the effects of alcohol and drugs on the brain, pain control, and restoring and repairing brain function. Recommendations for research are presented for each of the areas discussed, including increases in funding and total operating budgets required.

The NLM Gateway16 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface,

16

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

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providing one-stop searching for many of NLM’s information resources or databases.17 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “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 56665 798 202 90 21 57776

HSTAT18 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.19 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.20 Simply search by “sclerosis” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists21 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.22 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.23 This site has new articles 17 The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 18 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 19

The HSTAT URL is http://hstat.nlm.nih.gov/.

20

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 21 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 22

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 23 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each

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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: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

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

The Genome Project and Sclerosis In the following section, we will discuss databases and references which relate to the Genome Project and 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).24 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “sclerosis” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for sclerosis: •

Amyotrophic Lateral Sclerosis 1 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?105400

•

Amyotrophic Lateral Sclerosis 2 Chromosome Region, Candidate 8 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?607586

•

Amyotrophic Lateral Sclerosis 2, Juvenile Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?205100

vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 24 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

510 Sclerosis

•

Amyotrophic Lateral Sclerosis 2, Juvenile, Chromosome Region Gene 2 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?607333

•

Amyotrophic Lateral Sclerosis 2, Juvenile, Chromosome Region Gene 3 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?607334

•

Amyotrophic Lateral Sclerosis 3 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?606640

•

Amyotrophic Lateral Sclerosis 4, Juvenile Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602433

•

Amyotrophic Lateral Sclerosis 5 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602099

•

Amyotrophic Lateral Sclerosis 6 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?608030

•

Amyotrophic Lateral Sclerosis 7 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?608031

•

Amyotrophic Lateral Sclerosis with Frontotemporal Dementia Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?105550

•

Amyotrophic Lateral Sclerosis with Polyglucosan Bodies Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?205250

•

Amyotrophic Lateral Sclerosis, Juvenile, with Dementia Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?205200

•

Amyotrophic Lateral Sclerosis-parkinsonism/dementia Complex of Guam Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?105500

•

Atherosclerosis, Premature, with Deafness, Nephropathy, Diabetes Mellitus, Photomyoclonus, and Degenerative Neurologic Disease Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?209010

•

Cerebellar Hypoplasia with Endosteal Sclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?213002

•

Cerebral Sclerosis Similar to Pelizaeus-merzbacher Disease Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?213900

•

Cerebral Sclerosis, Diffuse, Scholz Type Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?302700

•

Disseminated Sclerosis with Narcolepsy Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?223300

•

Distal Osteosclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?126250

•

Dysosteosclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?224300

•

Mesangial Sclerosis, Diffuse Renal, with Ocular Abnormalities Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?249660

•

Multiple Sclerosis, Susceptibility to Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?126200

•

Muscular Atrophy, Progressive, with Amyotrophic Lateral Sclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?158700

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•

Myosclerosis, Congenital, of Lowenthal Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?255600

•

Nephrotic Syndrome with Focal Glomerular Sclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?256350

•

Nephrotic Syndrome, Early-onset, with Diffuse Mesangial Sclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?256370

•

Nuclear Sclerosis of the Lens Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601371

•

Osteopathia Striata with Cranial Sclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?166500

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Osteopathia Striata with Cranial Sclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300373

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Otosclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?166800

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Pagetoid Amyotrophic Lateral Sclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?167320

•

Polycystic Kidney Disease, Infantile Severe, with Tuberous Sclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600273

•

Primary Lateral Sclerosis, Juvenile Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?606353

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Sudanophilic Cerebral Sclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?272100

•

Tuberous Sclerosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?191100

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Tuberous Sclerosis 1 Gene Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?605284

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Tuberous Sclerosis 2 Gene Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?191092

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Tuberous Sclerosis 3 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?191091

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Tuberous Sclerosis 4 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?191090 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,

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colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html •

Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

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Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

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Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html

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Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html

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Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

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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: •

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

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Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

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Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

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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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ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

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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/entrez/query.fcgi?CMD=search&DB=genome, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “sclerosis” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database25 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html.

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Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html.

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The Genome Database26 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the 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 “Keyword.” Type “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).

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Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

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APPENDIX B. 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 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 The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to 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 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 “sclerosis”:

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Other guides Amyotrophic Lateral Sclerosis http://www.nlm.nih.gov/medlineplus/amyotrophiclateralsclerosis.html Autoimmune Diseases http://www.nlm.nih.gov/medlineplus/autoimmunediseases.html Multiple Sclerosis http://www.nlm.nih.gov/medlineplus/multiplesclerosis.html Multiple Sclerosis http://www.nlm.nih.gov/medlineplus/tutorials/multiplesclerosisloader.html Scleroderma http://www.nlm.nih.gov/medlineplus/scleroderma.html Tuberous Sclerosis http://www.nlm.nih.gov/medlineplus/tuberoussclerosis.html

Within the health topic page dedicated to sclerosis, the following was listed: •

General/Overviews FAQ's about Tuberous Sclerosis Complex http://www.tsalliance.org/faq.asp

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Diagnosis/Symptoms Diagnostic and Surveillance Screening in TSC Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/WhatIsTSC/diagntesting.asp Neuroimaging in Tuberous Sclerosis Complex http://www.tsalliance.org//Fact%2520Sheets/Neuroimaging.PDF

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Treatment Psychopharmacology and the Child with TS http://www.tsalliance.org//Fact%2520Sheets/Psychopharmacology.PDF Treatment Options for Skin Involvement Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/WhatIsTSC/skintreatment.asp

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Coping Living With Tuberous Sclerosis Complex Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/LivingwithTSC/

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Specific Conditions/Aspects Brain Involvement Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/whatistsc/brain.asp

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Epilepsy/Seizure Disorders Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/whatistsc/epilepsy.asp Eye Involvement Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/whatistsc/eye.asp Facts for Teachers Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/whatistsc/Facts4teachers.asp Heart Involvement Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/WhatIsTSC/heart.asp Independent Living Options Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/livingwithtsc/independent.asp Kidney Involvement Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/WhatIsTSC/kidney.asp Lung Involvement Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/WhatIsTSC/lung.asp Psychiatric and Behavioral Involvement Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/WhatIsTSC/psychiatric.asp Seizure First-Aid Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/whatistsc/Firstaid.asp Skin Involvement Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/WhatIsTSC/skin.asp •

Children My Child has Tuberous Sclerosis: A Brochure for Parents http://www.tsalliance.org/publications/52810_NTSA.pdf Tuberous Sclerosis and Autism Spectrum Disorders Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/Fact%2520Sheets/TS%2520and%2520autism%2520spect rum%2520disorders.pdf Tuberous Sclerosis and Your Baby Source: American Academy of Family Physicians http://familydoctor.org/handouts/496.html

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From the National Institutes of Health Tuberous Sclerosis Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/health_and_medical/pubs/tuberous_sclerosis.htm Tuberous Sclerosis Information Page http://www.ninds.nih.gov/health_and_medical/disorders/tuberous_sclerosis.htm

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Organizations National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/ Tuberous Sclerosis Alliance http://www.tsalliance.org/

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Research Updates in Tuberous Sclerosis Research Source: Tuberous Sclerosis Alliance http://www.tsalliance.org/Research/researchupdate.asp

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Teenagers Adolescents with Tuberous Sclerosis Complex http://www.tsalliance.org//Fact%2520Sheets/Adolescents.PDF

You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on sclerosis. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

Clinical Manifestations of Tuberous Sclerosis: A Publication for Professionals Source: Silver Spring, MD: Tuberous Sclerosis Alliance (TSA). 2000. 24 p. Contact: Available from Tuberous Sclerosis Alliance. 801 Roeder Road, Suite 750, Silver Spring, MD 20910. (800) 225-6872 or (301) 562-9890. Fax (301) 562-9870. E-mail: [email protected]. Website: www.tsalliance.org. PRICE: Contact for pricing.

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Summary: This brochure provides community service professionals, the general public, and people who have tuberous sclerosis (TS) with information on this genetic disease that affects multiple organs and causes tumors in various organ systems. The severity of TS can range from mild to severe. Skin manifestations include hypomelanotic macules, the shagreen patch, periungual or subungual fibromas, and facial angiofibromas. TS can present as benign angiomyolipomas, cysts, malignant angiomyolipomas, oncocytomas, and renal cell carcinoma in the kidneys. Several types of brain lesions are seen in people who have TS, including cortical tubers, cortical hypoplasia, subependymal nodules, and subependymal giant cell astrocytomas. The most frequently observed neurologic problems in TS are epilepsy, mental disabilities, and psychiatric and behavioral problems. Tumors may also appear in the heart, the eyes, the lungs, and gums. The brochure describes all of these clinical manifestations; presents the diagnostic criteria for TS; and discusses diagnostic screening, treatment, and follow up treatment for each clinical manifestation. In addition, the brochure explains the genetics of TS and identifies sources of additional information about TS. 15 figures and 2 tables. •

Multiple sclerosis Source: Bethesda, MD: Warren Grant Magnuson Clinical Center, U.S. Department of Health and Human Services. 1990. 19 pp. Contact: Available from National Institutes of Health, Clinical Center Communications, Building 10, Room 1C255, 9000 Rockville Pike, Bethesda, MD 20892. Telephone: (301) 496-2563. Available at no charge. Summary: This brochure provides information about multiple sclerosis. The symptoms, causes, treatments, and the course of the disease in pregnancy are covered. This brochure is a part of the 'Medicine for the Public' patient education series produced by the National Institutes of Health.

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My Child Has Tuberous Sclerosis: A Brochure for Parents [Mi nino tien Esclerosis Tuberosa: Un folleto para padres] Source: Silver Spring, MD: Tuberous Sclerosis Alliance (TSA). 200x. 28 p. Contact: Available from Tuberous Sclerosis Alliance. 801 Roeder Road, Suite 750, Silver Spring, MD 20910. (800) 225-6872 or (301) 562-9890. Fax (301) 562-9870. E-mail: [email protected]. Website: www.tsalliance.org. PRICE: Contact for pricing. Summary: This brochure, which is available in both English and Spanish, provides parents of a child with tuberous sclerosis (TS) with information on this genetic disorder that causes tumors to form in many different organs. The brochure describes the physical and mental symptoms of TS. Skin lesions that occur in people who have TS include hypomelanotic macules, facial angiofibromas, shagreen patch, periungual fibromas, subungual fibromas, and forehead plaque. Brain lesions that are seen in people who have TS are cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. The most frequently observed neurologic problems in TS are epilepsy, mental disabilities, and psychiatric and behavioral problems. Tumors may also appear in the heart, the kidneys, the eyes, the lungs, and other organs. The brochure describes all of these clinical manifestations and discusses diagnostic screening and follow up. In addition, the brochure explains genetic counseling; identifies sources of general information, support, medical care, and special educational services; and lists sources of additional information.

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Treating Skin Disorders Associated With Tuberous Sclerosis Source: Tuberous Sclerosis Alliance. 2002. 2 p. Contact: Available from Tuberous Sclerosis Alliance. 801 Roeder Road, Suite 750, Silver Spring, MD 20110. (301) 562-9820 or (800) 225-6872. Fax: (301) 562-9870. Website: www.tsalliance.org. Summary: This fact sheet discusses treating the skin manifestations associated with tuberous sclerosis. Ash leaf spots are light areas of skin that look like ash tree leaves. The pigment-- producing cells in these spots are unable to produce sufficient pigment for a normal skin tone. Cosmetic products are available for covering these spots, and research is being conducted on treatments to stimulate pigment in the skin. Surgical excision or laser treatments are used to treat severe cases of shagreen patches and forehead plaques, lesions that contain excess fibrous tissue. Angiofibromas of the face are characterized by small, red spots on the cheeks, nose, and chin. A tunable dye laser destroys blood cells in the skin and is used in treating early forms of the condition. Surgical removal, laser resurfacing, and dermabrasion are used in well-devloped fibrous angiofibromas. Carbon dioxide or erbium:YAG skin resurfacing laser surgery is the best choice when large areas of the face are affected. Surgical excision is the most common technique for removing periungual fibromas of the fingernails and toenails and gingival fibromas of the gums of the mouth.

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Urinary Dysfunction and MS: A Guide for People with Multiple Sclerosis Source: New York, NY: National Multiple Sclerosis Society. 2001. 24 p. Contact: Available from National Multiple Sclerosis Society, Communications Department. 733 Third Avenue, New York, NY 10017-3288. (212) 986-3240 or (800) 3444867. Fax (212) 986-7981. Website: nationalmssociety.org. PRICE: $3.00 plus shipping and handling. Order number: ES6047. Summary: This guidebook helps readers with multiple sclerosis (MS) understand urinary incontinence and the clinical practice guidelines for their care. Advances in bladder management strategies are making it possible for people with MS to carry out their daily activities at home and at work with confidence, secure in the knowledge that they have their bladder function under control. These same advances have significantly decreased the incidence of bladder complications and the number of MS-related hospitalizations. Topics include normal bladder function; types of bladder dysfunction in MS, including dysfunction of storage, emptying, combined, and urinary tract infection; diagnosis and treatment; steps to diagnosis; the treatment process; and the impact of other factors (such as mobility problems) on bladder function. Two appendices offer a space for readers to list their medications and a brief resource on the types and effects of common medications prescribed for people with MS. A brief subject index is also included. The clinical practice guideline written for health care professionals can be obtained at www.pva.org (888-860-7244). 2 appendices. 4 figures. 2 tables.

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Tuberous Sclerosis and Your Baby Source: American Family Physician. 61(3): 710. February 1, 2000. Contact: American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237 or (913) 906-6000. E-mail: [email protected]. Website: www.aafp.org.

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Summary: This journal article uses a question and answer format to provide parents of children who have tuberous sclerosis with information on the causes and signs of this disorder that causes benign growths in the brain, eyes, heart, kidney, skin, or lungs. In about 50 percent of cases, tuberous sclerosis is inherited. However, in about the remaining 50 percent of cases, a normal gene mutates to the abnormal form that causes tuberous sclerosis. Signs of the disorder include cardiac rhabdomyomas (benign heart tumors), seizures, white spots on the skin, a rash on the face, or mental disability. The article includes information on the National Tuberous Sclerosis Association. •

Multiple Sclerosis and Incontinence Source: Olivette, MO: Home Delivery Incontinent Supplies, Inc. 1995. 2 p. Contact: Available from Home Delivery Incontinent Supplies, Inc. 1215 Dielman Industrial Court, Olivette, MO 63132. (800) 269-4663. PRICE: Single copy free. Summary: This patient education brochure provides information on multiple sclerosis (MS) and urinary incontinence. The brochure notes that because the urinary process requires coordination of voluntary and involuntary muscles, most individuals with MS experience some level of incontinence. Topics include the nervous system and its role in the urinary process, specific causes of incontinence, diagnosing the dysfunction, treatment options, and other urinary problems associated with MS. 2 figures. The National Guideline Clearinghouse™

The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “sclerosis” (or synonyms). The following was recently posted: •

ACR Appropriateness Criteriaâ„¢ for multiple sclerosis -- when and how to image Source: American College of Radiology - Medical Specialty Society; 1999; 16 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2447&nbr=1673&a mp;string=sclerosis

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Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force Source: American Academy of Neurology - Medical Specialty Society; 1999 April; 13 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2819&nbr=2045&a mp;string=sclerosis Healthfinder™

Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database:

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Amyotrophic Lateral Sclerosis Summary: A general overview of amyotrophic lateral sclerosis (ALS) that includes a description and information about treatment, prognosis and research. Source: National Institute of Neurological Disorders and Stroke, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=745

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Amyotrophic Lateral Sclerosis Fact Sheet Source: National Institute of Neurological Disorders and Stroke, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7227

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FAQ's About Tuberous Sclerosis Complex Summary: These are answers to questions about the prevalence, development, diagnosis, and treatment of tuberous sclerosis. Source: Tuberous Sclerosis Alliance http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7687

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Multiple Sclerosis Information Summary: A general overview of multiple sclerosis that includes a description of the disorder, and treatment, prognosis and research information. Source: National Institute of Neurological Disorders and Stroke, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=748

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Multiple Sclerosis: Hope Through Research Source: National Institute of Neurological Disorders and Stroke, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7228

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MultipleSclerosis.com Summary: The overall mission of multiplesclerosis. Source: Commercial Entity--Follow the Resource URL for More Information http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6690

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National Multiple Sclerosis Society--Southern California Chapter Summary: The National Multiple Sclerosis Society is dedicated to ending the devastating effects of multiple sclerosis. Source: National Multiple Sclerosis Society http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6447

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Questions and Answers about Lichen Sclerosis Summary: Lichen sclerosis (LIKE-in skler-O-sus) is a skin disorder that can affect men, women, or children, but is most common in women. Source: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6725

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Second Gene Responsible for Tuberous Sclerosis Complex Identified; TSC1 Finding on Chromosome 9 Follows 1993 Discovery of TSC2 Gene Summary: This press release reports on the identification of the second of two genes that cause tuberous sclerosis complex (TSC), a relatively common developmental disorder characterized by a number of Source: National Institute of Neurological Disorders and Stroke, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=2928

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Tuberous Sclerosis Fact Sheet Summary: This fact sheet on tuberous sclerosis outlines the causes, signs, symptoms, diagnosis, and treatment of tuberous sclerosis. Source: National Institute of Neurological Disorders and Stroke, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7243 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 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://search.nih.gov/index.html.

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Additional Web Sources

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

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

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

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

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

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

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

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WebMDHealth: http://my.webmd.com/health_topics

Associations and Sclerosis The following is a list of associations that provide information on and resources relating to sclerosis: •

ALD Family Support Trust Telephone: 020-7631-3336 Fax: 020-7631-3337 Email: [email protected] Web Site: www.aldfst.org.uk Background: The ALD Family Support Trust (ALDFST) is a not-for-profit organization dedicated to furthering medical research into Adrenoleukodystrophy (ALD); providing grants and allowances for the purposes of medical treatment and care of children with ALD; and educating the public about ALD. Adrenoleukodystrophy is a rare inherited metabolic disorder characterized by the loss of the protective fatty sheath around nerve fibers within the brain (cerebral demyelination) and progressive degeneration of the adrenal gland (adrenal atrophy), causing progressive mental deterioration, neuromuscular abnormalities, loss of the ability to speak, blindness, and life-threatening complications. Established in 1993 and consisting of approximately 57 members, the Trust also has a support group and provides networking opportunities to parents. Educational materials include pamphlets and a regular newsletter.

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American Autoimmune Related Diseases Association, Inc Telephone: (586) 776-3900 Fax: (586) 776-3903 Email: [email protected] Web Site: http://www.aarda.org/ Background: The American Autoimmune Related Diseases Association, Inc. (AARDA) is a national not-for-profit voluntary health agency dedicated to bringing a national focus to autoimmunity, a major cause of serious chronic diseases. The Association was founded for the purposes of supporting research to find a cure for autoimmune diseases

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and providing services to affected individuals. In addition, the Association s goals include increasing the public s awareness that autoimmunity is the cause of more than 80 serious chronic diseases; bringing national focus and collaborative effort among state and national voluntary health groups that represent autoimmune diseases; and serving as a national advocate for individuals and families affected by the physical, emotional, and financial effects of autoimmune disease. The American Autoimmune Related Diseases Association produces educational and support materials including fact sheets, brochures, pamphlets, and a newsletter entitled 'In Focus.'. •

Amyotrophic Lateral Sclerosis Association Telephone: (818) 880-9007 Toll-free: (800) 782-4747 Fax: (818) 880-9006 Email: [email protected] Web Site: http://www.alsa.org Background: The Amyotrophic Lateral Sclerosis Association (ALSA) is a national notfor-profit voluntary health organization dedicated to the fight against Amyotrophic Lateral Sclerosis (ALS). Amyotrophic Lateral Sclerosis, also known as 'Lou Gehrig s Disease,' is a rapidly progressive neuromuscular disease characterized by degeneration of the motor neurons responsible for transmitting electrical impulses from the brain to the voluntary muscles throughout the body. ALSA consists of a growing network of over 135 local volunteer chapters and support groups across the United States. The Association seeks to encourage, identify, fund, and monitor cutting-edge research into the cause, prevention, and possible cure of ALS. The organization also offers support on how to cope with the disease, provides referrals, and serves as the national information resource on ALS for medical professionals, affected individuals, and family members. The Information Center provides basic information about ALS and answers specific questions about the disease. ALSA also makes referrals to physicians, clinics, extended care facilities, home health agencies, visiting nurse agencies, transportation assistance, and medical equipment supplies. In addition, ALSA has a patient registry of individuals with the disease and distributes information on the latest research and clinical trials regarding ALS.

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Amyotrophic Lateral Sclerosis Society of Canada Telephone: 416-497-2267 Toll-free: (800) 267-4257 Fax: 416-497-1256 Email: [email protected] Web Site: http://www.als.ca Background: The Amyotrophic Lateral Sclerosis (ALS) Society of Canada is a national not-for-profit organization dedicated to providing information and support to individuals and family members affected by ALS and to promoting research to find a cure for the disorder. Amyotrophic Lateral Sclerosis (ALS), also known as 'Lou Gehrig s Disease,' is a rapidly progressive neuromuscular disease characterized by degeneration of the motor neurons responsible for transmitting electrical impulses from the brain to the voluntary muscles throughout the body. Established in 1977, the ALS Society, which operates in many locations across Canada, provides support and counseling for people with ALS, their families, and caregivers; raises funds to support research into the cause

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of and a potential cure for ALS; engages in patient advocacy; offers networking services; and provides equipment such as wheelchairs. •

Behcet s Organisation Worldwide (BOW) Telephone: 07713 220303 Toll-free: 999-999-9999 Fax: 999-999-9999 Email: [email protected] Web Site: http://www.behcets.org Background: The Behcet s Organisation Worldwide (BOW) is a voluntary, not-for-profit, self-help organization, whose aims and objectives are to assist patients and physicians by providing information about Behcet s disease and to advance public education into the causes and treatment of this disease and its associated conditions. Behcet s is a rare multisystem inflammatory disorder affecting the skin, eyes, and, in some instances, joints, blood vessels, central nervous system and/or digestive tract. The exact cause is unknown. Through its Books Into Local Libraries project, the BOW is creating an informational booklet about Behcet s, to be placed in local libraries and translated into several languages. The BOW is global in its approach, with coordinators in several countries and headquarters in the United Kingdom. It provides written material in English, Spanish, Portuguese, German, French, Italian and Arabic.

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Consortium of Multiple Sclerosis Centers Telephone: (201) 837-0727 Fax: (201) 837-8504 Email: [email protected] Web Site: http://mscare.org Background: The Consortium of Multiple Sclerosis Centers is a not-for-profit voluntary professional organization dedicated to the development and dissemination of scientifically-based knowledge regarding multiple sclerosis clinical care in order to improve the lives of those affected by multiple sclerosis. Multiple sclerosis (MS) is a chronic disorder of the central nervous system (CNS) that causes the destruction of the protective covering (myelin sheath) of certain nerves. Symptoms, which vary greatly from case to case, may include visual impairment (including blind spots); double vision (diplopia); involuntary rhythmic movements of the eyes (nystagmus); impairment of speech; numbness or tingling sensation in the limbs; difficulty walking; and dysfunction of the bladder and bowel. Established in 1986 through a grant from the Mellon Foundation, the organization, which consists of 50 members centers, is dedicated to improving the care of individuals with MS; being the principal organization of MS professionals; conducting clinical research and education; and sharing information and knowledge among members, individuals with MS, and health care professionals. The Consortium conducts an annual education conference, conferences for the health professionals, roundtable discussions, and the North American Research Consortium on MS (NARCOMS). The Consortium s educational materials include a newsletter for professional members entitled 'Consort,' a patient-oriented newsletter entitled 'Companion,' and a directory of all member centers. The Consortium partners with the National MS Society for educational and outreach projects and with NASA to seek applications of space technology to help people with MS.

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Dana Alliance for Brain Initiatives Telephone: (212) 223-4040 Fax: (212) 593-7623 Email: [email protected] Web Site: http://www.dana.org Background: The Dana Alliance for Brain Initiatives, a nonprofit organization supported by the Charles A. Dana Foundation, was established as an alliance of neuroscientists dedicated to providing information and promoting understanding concerning the personal and public benefits of brain research. (The Charles A. Dana Foundation is a private philanthropic foundation with grant programs in health and education.) According to the Alliance, approximately one in five Americans is affected by a brain disease or disorder, ranging from learning disabilities to Parkinson s Disease from epilepsy to spinal cord injuries. The Dana Alliance for Brain Initiatives is dedicated to answering questions concerning brain-related research and providing information concerning new developments. The Alliance offers a variety of periodicals, newsletters, reports, reference works, and books.

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Disabled Sports USA Telephone: (301) 217-0960 Fax: (301) 217-0968 Email: [email protected] Web Site: http://www.dsusa.org/~dsusa/dsusa.html Background: Disabled Sports USA (DS/USA) is a not-for-profit organization dedicated to ensuring that disabled people have access to sports, recreation, and physical education programs from preschool through college to elite sports levels. Established in 1967 by disabled Vietnam veterans, DS/USA serves people with physical disabilities that restrict mobility, including amputations, weakness or paralysis of both legs (paraplegia), paralysis of all four limbs (quadriplegia), cerebral palsy, head injury, multiple sclerosis, muscular dystrophy, spina bifida, stroke, and visual impairment. DS/USA consists of more than 60,000 members and 80 chapters around the United States. Educational materials include a general information packet, a newsletter entitled 'Disabled Sports USA Update,' and a sports magazine entitled 'Challenge.' Program activities include sporting activities and events, patient education (e.g., workshops), and patient networking.

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Eastern Paralyzed Veterans Association Telephone: (718) 803-3782 Toll-free: (800) 444-0120 Fax: (718) 803-0414 Email: [email protected] Web Site: http://www.epva.org Background: The Eastern Paralyzed Veterans Association (EPVA) is a not-for-profit organization dedicated to enhancing the lives of veterans with a spinal cord injury or disease. EPVA strives to assure quality health care, promote research, and advocate for civil rights and independence. Founded in 1946, EPVA has operated programs from benefits counseling to wheelchair sports, participated in drafting parts of the Americans with Disabilities Act (ADA) and the Fair Housing Amendments Act, and ensured

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compliance with these laws. EPVA's numerous programs include social services, wheelchair repair, architecture, library and information services, public affairs, benefits, government relations, legal affairs, and assistive technology programs. EPVA produces a variety of educational materials including brochures, pamphlets, booklets, reports, videos, and newsletters. •

Harvard Brain Tissue Resource Center Telephone: (617) 855-2400 Toll-free: (800) 272-4622 Fax: (617) 855-3199 Email: [email protected] Web Site: http://www.brainbank.mclean.org:8080 Background: The Harvard Brain Tissue Resource Center is a federally funded, not-forprofit organization, dedicated to serving as a national resource for the collection and distribution of postmortem brain tissues for medical research into the causes of neurological and psychiatric disorders. The Brain Bank is interested in the study of Huntington s, Alzheimer s, and Parkinson s diseases, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), Tourette and Rett syndromes, and autism, as well as schizophrenia and manic depressive illnesses. The Center distributes brain tissue samples, at no charge, to qualified investigators in the United States who are involved in studying the neurobiology of these disorders.

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Hunter's Hope Foundation, Inc Telephone: (716) 667-1200 Toll-free: (877) 984-4673 Fax: (716) 667-1212 Email: [email protected] Web Site: http://www.huntershope.org Background: The mission of the Hunter s Hope Foundation, Inc., is to foster public awareness of Krabbe disease and other leukodystrophies in order to increase the likelihood of early detection, to provide information and service linkages to families of children with leukodystrophies, to fund research aimed at identifying new therapies, and, ultimately, to seek a cure. Leukodystrophy is the name given to a group of very rare, progressive, metabolic diseases that affect the brain, spinal cord and, often, the peripheral nerves. Krabbe disease is one type of leukodystrophy. A not-for-profit organization, the Hunter s Hope Foundation serves an international audience, providing educational materials for patients, families, health professionals, and the public. It also provides advocacy, referrals, and a registry. Representatives of the Foundation are working with staff members at the State University of New York at Buffalo to develop a resource library, which will also be available online.

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International Alliance of ALS/MND Associations Telephone: 44 1604 611821 Fax: 44 1604 11852 Email: [email protected] Web Site: http://www.alsmndalliance.org

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Background: The International Alliance of ALS/MND Associations was founded in November 1992 to provide a forum for support and the exchange of information between the worldwide associations. More than 50 national patient support and advocacy groups from over 40 countries worldwide have joined together to form the International Alliance. Amyotrophic lateral sclerosis, or motor neurone disease, is a muscle wasting condition which affects individuals and those who care for them across the world. To help people with the disease, groups of people have come together to form associations. •

Les Turner Amyotrophic Lateral Sclerosis Foundation, Ltd Telephone: (847) 679-3311 Toll-free: (888) 257-1107 Fax: (847) 679-9109 Email: [email protected] Web Site: http://www.lesturnerals.org Background: The Les Turner Amyotrophic Lateral Sclerosis Foundation is a voluntary health organization dedicated to raising funds for ALS research, patient services, and public awareness. Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's Disease, is a progressive neurological disease that causes impaired breathing, speaking, and swallowing, as well as muscle weakness and eventually total paralysis. Intellectual function remains unaffected and there is no known cure. The Les Turner ALS Foundation was established in 1977 and provides educational materials for affected individuals and family members, health care professionals, and the general public. Program services include referrals and counseling, audio-visual aids, and a periodic newsletters entitled 'ALS Today.' Consisting of over 1,000 members, the organization offers support groups and patient networking to affected individuals, family members, and caregivers.

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March of Dimes Birth Defects Foundation Telephone: (914) 428-7100 Toll-free: (888) 663-4637 Fax: (914) 997-4763 Email: [email protected] Web Site: http://www.marchofdimes.com Background: The March of Dimes Birth Defects Foundation is a national not-for-profit organization that was established in 1938. The mission of the Foundation is to improve the health of babies by preventing birth defects and infant mortality. The March of Dimes funds programs of research, community services, education, and advocacy. Educational programs that seek to prevent birth defects are important to the Foundation and to that end it also produces a wide variety of printed informational materials and videos. The Pregnancy and Newborn Health Education Center staffs trained health information specialists who provide researched information on pregnancy issues, complications and risks, newborn care, birth defects, genetic diseases and related topics as well as referrals to relevant organizations and support groups.

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Motor Neurone Disease Association Telephone: 44 1604 250505 Fax: 44 1604 62476

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Email: [email protected] Web Site: http://www.mndassociation.org Background: The Motor Neurone Disease (MND) Association is a unique authority on MND. It is an independent charity and the only national organisation in England, Wales and Northern Ireland dedicated to supporting people with MND. The MND Association works to ensure that people affected by MND can secure the care and support they need. It also promotes and funds research into causes of, and a cure for, the disease. Other services include a national telephone Helpline, a network of Regional Care Advisers, a range of literature on all aspects of the disease, free loan of specialist equipment and limited financial support. The Association has a national office in Northampton, and over 85 branches nationwide. The MND Association relies entirely on donations and receives no government funding. •

Multiple Sclerosis International Federation Telephone: +44 (0)20 7620 1911 Fax: +44 (0)20 7620 1922 Email: [email protected] Web Site: http://www.msif.org Background: The Multiple Sclerosis International Federation (MSIF, formerly IFMSS) is an international not-for-profit federation of 42 national multiple sclerosis societies throughout the world. Multiple sclerosis (MS) is a progressive disease characterized by loss of myelin from nerve fibers within the brain and spinal cord (central nervous system). Myelin is a fatty substance that forms a protective, insulating sheath around certain nerve fibers, serving as an electrical insulator. The severity of MS may vary from case to case. Associated symptoms may include numbness, tingling, weakness, incoordination, visual abnormalities, and speech disturbances. Established in 1967, MSIF links the work of national MS Societies worldwide. We are committed to working together and with the international research community to eliminate MS and its devastating effects. We also speak out on a global level for those affected by MS. Our priorities are: Stimulating global research; Stimulating the active exchange of information; Providing support for the development of new and existing MS Societies All our work is carried out with the close involvement of people living with MS. The Federation's ultimate goal is helping to eradicate multiple sclerosis. The Federation also conducts international conferences, provides educational publications on various aspects of MS, and maintains a website that offers understandable information on MS in several different languages.

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Multiple Sclerosis Society of Canada Telephone: (416) 922-6065 Fax: (416) 922-7538 Email: [email protected] Web Site: http://www.mssoc.ca/ Background: The Multiple Sclerosis Society of Canada is a national not-for-profit voluntary organization that was founded in 1948 by a small group of volunteers in Montreal. The Society is a member of the International Federation of Multiple Sclerosis Societies (IFMSS). Multiple sclerosis (MS) is a progressive disease characterized by loss of myelin from nerve fibers within the brain and spinal cord (central nervous system).

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Myelin is a fatty substance that forms a protective, insulating sheath around certain nerve fibers, serving as an electrical insulator. The severity of MS may vary from case to case. Associated symptoms may include numbness, tingling, weakness, incoordination, visual abnormalities, and speech disturbances. The mission of the MS Society of Canada is to be a leader in finding a cure for MS and enabling affected individuals to enhance their quality of life. The Society provides a variety of services for affected individuals and their families including supportive counseling, referrals, self-help groups, the 'ASK MS Information System,' and educational workshops. The Society also offers an equipment program for affected individuals, conducts social and recreational activities, provides information about MS for health care professionals, and has a network of specialized MS clinics across Canada. The national office of the MS Society coordinates research, individual and family services, social action, and public education. The Society's divisions, chapters, and units across Canada provide direct services, conduct social activities, and promote public awareness. Services may vary across Canada depending upon the provincial government and community programs available. The MS Society of Canada also offers a variety of educational publications including newsletters and research summaries. •

Multiple Sclerosis Society of Great Britain and Northern Ireland Telephone: 020 84 38 0700 Fax: 020 84 38 0701 Email: [email protected] Web Site: http://www.mssociety.org.uk Background: The Multiple Sclerosis Society of Great Britain and Northern Ireland is a not-for-profit organization dedicated to offering local and national services to individuals whose lives have been affected by multiple sclerosis (MS) and promoting and funding MS research. Multiple sclerosis is a progressive disease characterized by loss of myelin from nerve fibers within the brain and spinal cord (central nervous system). Myelin is a fatty substance that forms a protective, insulating sheath around certain nerve fibers, serving as an electrical insulator. The severity of MS may vary from case to case. Associated symptoms may include numbness, tingling, weakness, incoordination, visual abnormalities, and speech disturbances. The MS Society was established in 1953 and currently consists of approximately 370 UK branches, and 45,000 members across Great Britain and Northern Ireland. The Society offers a variety of services and programs including telephone counseling, financial assistance for affected individuals, respite and holiday centers, residential and day centers, and transportation assistance. In addition, the MS Society is committed to regularly funding biomedical research; supporting applied research to improve the lives of affected individuals; working with other charities that serve people with MS; lobbying for equitable prescribing and funding of therapies; and improving statutory services by educating professionals about MS.

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Muscular Dystrophy Association Telephone: (520) 529-2000 Toll-free: (800) 572-1717 Fax: (520) 529-5300 Email: [email protected] Web Site: http://www.mdausa.org

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Background: Established in 1950, the Muscular Dystrophy Association (MDA) is a nonprofit, voluntary health agency dedicated to providing comprehensive medical services to individuals affected by over 40 neuromuscular diseases. MDA provides these services at some 230 hospital-affiliated clinics across the United States. The Association's worldwide research program allocates more than $28 million a year, seeking cures and treatments for neuromuscular disorders. MDA funds some 400 individual scientific investigations each year at a cost of $57 a minute, around the clock. This represents the largest single initiative to advance current knowledge of neuromuscular diseases and to find cures and treatments for this group of diseases. •

Muscular Dystrophy Association (Australia) Telephone: 61 3 9320 9555 Toll-free: 1 800 656 632 Fax: 61 3 9320 9595 Email: [email protected] Web Site: http://www.mda.org.au Background: The Muscular Dystrophy Association (MDA) is a not-for-profit organization in Australia that was founded in the early 1970s by a group of people affected by muscular dystrophy (MD). Muscular dystrophy refers to a group of genetic disorders characterized by progressive degeneration of muscle fibers, resulting in associated weakness, disability, and deformity. The different forms of muscular dystrophy may be categorized based upon age at onset, specific muscle groups affected, rate of disease progression, and mode of inheritance. The Muscular Dystrophy Association is committed to improving the quality of life of individuals with muscular dystrophy and other neuromuscular diseases. To fulfill its mission and objectives, the Association provides a variety of educational materials, conducts MDA camps for children and adults with neuromuscular disorders, and promotes and supports research. The Association's materials include information sheets on different forms of muscular dystrophy, parents guides, glossaries, and materials discussing the various aspects of these disorders. The Association also maintains a web site on the Internet that provides understandable information on muscular dystrophy, a FAQ ('frequently asked questions') area, a guestbook area for online visitors, and links to additional sources of information and support. In 1985, the Association established the Muscular Dystrophy Research Foundation to help ensure sufficient funding to accelerate research and to provide funds required for treatment programs. The MDA, in association with St. Vincents Hospital and the Department of Medicine, Melbourne University, is also affiliated with the Melbourne Neuromuscular Research Centre, and sponsors scientific research seminars and conferences.

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National Brain Tumor Foundation Telephone: (510) 839-9777 Toll-free: (800) 934-2873 Fax: (510) 839-9779 Email: [email protected] Web Site: http://www.braintumor.org Background: The National Brain Tumor Foundation is a national not-for-profit voluntary organization that serves as a comprehensive center for information regarding resources and support services for people whose lives are affected by brain tumor disease. Established in 1981, the National Brain Tumor Foundation also provides

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financial support for investigational studies into the causes, prevention, and treatments of brain tumors. To these ends, the National Brain Tumor Foundation has funded basic and applied laboratory research and clinical trials of new treatments at major institutions in the United States. The organization has also supported research into quality of life issues that regularly confront people with brain tumors. A comprehensive guide is available for affected individuals and their families who want to learn more about brain tumors. The National Brain Tumor Foundation also produces a variety of educational materials including a newsletter entitled 'Search.' Affected individuals and family members may also receive referrals to a network of support groups throughout the United States. •

National Foundation of Dentistry For the Handicapped Telephone: (303) 534-5360 Fax: (303) 534-5290 Email: [email protected] Web Site: www.nfdh.org Background: National Foundation of Dentistry for the Handicapped (NFDH), is a national charitable organization solely dedicated to meeting the needs of citizens with physical, medical, and mental disabilities. Our country's standard of dental care is one of the highest in the world, yet those Americans most desperately in need often go unserved. They may be children or adults that are mentally or physically disabled. They suffer from cerebral palsy, multiple sclerosis, mental illness, and many other disabilities.The Foundation was established in 1974 and is an affiliate of the American Dental Association and state and local dental associations. Disabled, elderly, and mentally compromised patients are linked with dentists in their communities to receive free comprehensive dental treatment, including prosthetics. There is also a program to provide training to help parents and professionals caring for developmentally disable persons to provide appropriate oral hygiene.

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National Hospice and Palliative Care Organization Telephone: (703) 837-1500 Toll-free: (800) 658-8898 Fax: (703) 837-1233 Email: [email protected] Web Site: http://www.nhpco.org Background: The National Hospice and Palliative Care Organization is the oldest and largest nonprofit membership organization representing hospice and palliative care programs and professionals in the United States. The organization is committed to improving end-of-life care and expanding access to hospice care with the goal of profoundly enhancing quality of life for people dying in America and their loved ones. NHPCO collaborates with other end-of-life organizations. NHPCO offers memberships to hospices, palliative care programs, grief/bereavement centers, education and research organizations, foundations, home health agencies, companion services, medical supply companies, pharmaceutical organizations, staffing agencies, software vendors, and healthcare consultants. NHPCO has knowledge of 3,240 operational or planned hospices operating in all 50 states, the District of Columbia, the Virgin Islands, Puerto Rico, and Guam. NHPCO represents over 80 percent of hospices nationwide. NHPCO estimates

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that almost 800,000 patients were served by hospice in 2001. Over 90 percent of the patients served were provided hospice care by NHPCO members. •

National Multiple Sclerosis Society Telephone: (212) 476-0436 Toll-free: (800) 344-4867 Fax: (212) 986-7981 Email: [email protected] Web Site: http://www.nationalmssociety.org Background: The National Multiple Sclerosis Society is a voluntary not-for-profit health organization dedicated to ending the devastating effects of MS by advancing the cure, prevention and treatment of multiple sclerosis and by improving the lives of affected individuals. Multiple sclerosis is a chronic disorder of the central nervous system that causes the destruction of the insulation (myelin sheath) surrounding the nerve fibers in the brain and spinal cord as well as the nerve fibers themselves. Established in 1946, the National MS Society funds MS research, offers services for people with MS and provides professional education programs. Through its home office and 50-state network of chapters,the Society serves more than a million people each year. The National MS Society also produces a wide variety of educational materials including a quarterly magazine, brochures, pamphlets, and video aids.

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Rothberg Institute, Inc Telephone: (203) 458-7100 Fax: (203) 458-2514 Email: [email protected] Web Site: www.childhooddiseases.org Background: The Rothberg Institute for Childhood Diseases is a non-profit research institution devoted to discovering, developing and commercializing novel chemical and biological entities for the treatment of tuberous sclerosis and other orphan childhood diseases. It applies innovative drug discovery strategies, operating at the intersection of modern biology, computer science, and chemistry.

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Scleroderma Foundation, Inc Telephone: (978) 463-5843 Toll-free: (800) 722-4673 Fax: (978) 463-5809 Email: [email protected] Web Site: http://www.scleroderma.org Background: The Scleroderma Foundation, Inc. (SF) is a not-for-profit organization dedicated to providing educational and emotional support for people with scleroderma and their families; increasing awareness of scleroderma; and supporting research to determine the disorder's cause, treatment, and cure. The Scleroderma Foundation testifies before Congress concerning the needs of people with scleroderma and works to increase public awareness through all forms of media. The organization raises research funding; institutes research grants; and conducts an annual conference. The Foundation also networks with other national health agencies on common concerns; assists people

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with scleroderma in securing Social Security and Disability benefits; and works with the medical community to promote better care and treatment. •

Scleroderma Research Foundation Telephone: (805) 563-9133 Toll-free: (800) 441-2873 Fax: (805) 563-2402 Email: [email protected] Web Site: http://www.srfcure.org Background: The Scleroderma Research Foundation is a voluntary research non-profit organization dedicated to finding a cure for scleroderma by funding and facilitating ongoing medical research. The Foundation also seeks to increase public awareness and understanding of this disorder. Established in 1987, the Scleroderma Research Foundation created a team of scientific and biomedical advisors to identify and address key issues that may lead to a cure. The efforts of the Foundation and its advisory team have led to the opening of the Bay Area Scleroderma Research Center in San Francisco and the East Coast Scleroderma Research Center in Baltimore, both cross-institutional, multi-disciplinary research facilities. With participation of the National Institutes of Health (NIH) and several institutes and universities, the Foundation has also assisted in the creation of clinical laboratory tests that provide for the early diagnosis of several forms of scleroderma. The provides a variety of educational materials to affected individuals, family members, health care and research professionals, and the general public.

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Scottish Motor Neurone Disease Association Telephone: 0(141) 945-1077 Toll-free: (800) 934-2873 Fax: 0(141) 945-2578 Email: [email protected] Web Site: http://www.scotmnd.org.uk Background: The Scottish Motor Neurone Disease Association offers care and support to anyone living anywhere in Scotland who is diagnosed with motor neurone disease, also known as amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease. This is a serious and progressively disabling muscle-wasting condition for which there is currently no cure. The Scottish MND Association provides information on the disorder and promotes and funds research. It was established in 1981.

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The Arc (a national organization on mental retardation) Telephone: (301) 565-3842 Toll-free: (800) 433-5255 Fax: (301) 565-3843 Email: [email protected] Web Site: http://thearc.org/ Background: The Arc is the largest organization in the United States that is solely devoted to improving the lives of all children and adults with mental retardation. The organization offers support to families affected by mental retardation and fosters research and educational programs on the prevention of mental retardation. The Arc is committed to securing opportunities for all people with mental retardation. To this end,

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the organization emphasizes personal opportunities for choice in education, housing, employment, and entertainment. The Arc is further committed to reducing the incidence and limiting the consequences of mental retardation through research, advocacy, and mutual support. The Arc provides leadership in the field of mental retardation and develops necessary human and financial resources to attain its goals. In addition, the Arc provides a wide variety of educational materials for parents, teachers, health care professionals, and others, including a regular newsletter, handbooks, instruction packets, reports, booklets, audio-visual aids, posters, and brochures. Many materials are available in Spanish. •

Tuberous Sclerosis Alliance Telephone: (301) 562-9890 Toll-free: (800) 225-6872 Fax: (301) 562-9870 Email: [email protected] Web Site: http://www.tsalliance.org Background: Tuberous Sclerosis Alliance, formerly the National Tuberous Sclerosis Association, is a voluntary not-for-profit organization dedicated to improving the quality of life of individuals and families affected by tuberous sclerosis. This hereditary disorder is characterized by benign, tumor-like nodules of the brain and/or retinas, skin lesions, seizures, and/or mental retardation. TSC (tuberous sclerosis complex) is a genetic disease, inherited as an autosomal dominant genetic condition. TSC can be sporadic, or occur for the first time in a family. Sporadic occurrences are the result of a new genetic mutation and account for approximately 60 percent of TSC diagnoses. Established in 1974, TS Alliance is committed to promoting and sponsoring medical research related to the diagnosis, cause, management, and cure of tuberous sclerosis and ensuring that affected individuals and families have access to appropriate medical services, support services, and resource information. It is involved in the development of public and professional educational programs aimed at increasing awareness of tuberous sclerosis and prompting early diagnosis and effective treatment. Tuberous Sclerosis Alliance also provides support groups and other services; promotes patient legislation beneficial to affected individuals; and conducts international symposia on tuberous sclerosis.

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Tuberous Sclerosis Association (UK) Telephone: 01527 871898 Fax: 01527 577390 Email: [email protected] Web Site: http://www.tuberous-sclerosis.org Background: The Tuberous Sclerosis Association (TSA), an international self-help organization located in the United Kingdom, was established in 1977 by a group of parents and interested physicians dedicated to providing support to individuals with Tuberous Sclerosis (TS) and their families, increasing awareness of the disorder, and promoting fundraising to support research. Tuberous Sclerosis, a rare genetic disorder that affects the skin and nervous system, may be characterized by the development of white skin patches, red or brown birthmarks, and/or a characteristic facial rash across the cheeks and nose; developmental delays; episodes of uncontrolled electrical disturbances in the brain that cause convulsive seizures (epilepsy); mental retardation in

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some cases; and/or the development of benign tumors, particularly of the brain, retina, kidney, heart, and skin. The Tuberous Sclerosis Association has helped to establish specialist, multidisciplinary TS clinics in Leeds, Bath, Cambridge, Northern Ireland (Craigavon), and Scotland (Edinburgh) that offer advice on diagnosis, management, and genetic counseling and work closely with local medical staff involved with the individuals and family members in question. The TSA also supports and promotes research into the causes and management of TS through its Education and Research Fund; is in touch with over 1,000 affected families across the world as well as interested professionals from the medical, social support, and education fields; offers networking opportunities to affected families that enable them to exchange information, support, and resources; and provides support to affected individuals, family members, and caregivers through visits and telephone support. In addition, the Association advises on where to obtain assistance concerning social services, benefits, and educational concerns and has a Family Care Worker who engages in patient and family advocacy. •

United Leukodystrophy Foundation Telephone: (815) 895-3211 Toll-free: (800) 728-5483 Fax: (815) 895-2432 Email: [email protected] Web Site: http://www.ulf.org/ Background: The United Leukodystrophy Foundation (ULF) is a voluntary not-forprofit organization dedicated to helping children and adults with leukodystrophy and assisting the family members, caregivers, and professionals who serve them. Leukodystrophy is a group of rare, progressive diseases that affect the white matter of the brain. Established in 1982, the United Leukodystrophy Foundation is committed to the identification, treatment, and cure of all leukodystrophies through programs of education, advocacy, research, and service. The Foundation also provides appropriate referrals, including to support groups; promotes professional and patient education; and offers a variety of educational and support materials. These include a regular newsletter, brochures, and audiovisual aids.

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to sclerosis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with 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 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.

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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://www.sis.nlm.nih.gov/Dir/DirMain.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. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “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://www.sis.nlm.nih.gov/hotlines/. 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 Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “sclerosis”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “sclerosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. 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 “sclerosis” (or a synonym) into the search box, and click “Submit Query.”

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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.27

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

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Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)28: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

28

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries 541

•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

542 Sclerosis

•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

Finding Medical Libraries 543

•

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

544 Sclerosis

•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

545

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/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

547

SCLEROSIS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abducens: A striated, extrinsic muscle of the eyeball that originates from the annulus of Zinn. [NIH] Abducens Nerve: The 6th cranial nerve. The abducens nerve originates in the abducens nucleus of the pons and sends motor fibers to the lateral rectus muscles of the eye. Damage to the nerve or its nucleus disrupts horizontal eye movement control. [NIH] Abducens Nerve Diseases: Diseases of the sixth cranial (abducens) nerve or its nucleus in the pons. The nerve may be injured along its course in the pons, intracranially as it travels along the base of the brain, in the cavernous sinus, or at the level of superior orbital fissure or orbit. Dysfunction of the nerve causes lateral rectus muscle weakness, resulting in horizontal diplopia that is maximal when the affected eye is abducted and esotropia. Common conditions associated with nerve injury include intracranial hypertension; craniocerebral trauma; ischemia; and infratentorial neoplasms. [NIH] Abductor: A muscle that draws a part away from the median line. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablate: In surgery, is to remove. [NIH] Ablation: The removal of an organ by surgery. [NIH] Abscess: Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. [NIH] Acantholysis: Separation of the prickle cells of the stratum spinosum of the epidermis, resulting in atrophy of the prickle cell layer. It is seen in diseases such as pemphigus vulgaris (see pemphigus) and keratosis follicularis. [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] Acetylcarnitine: An acetic acid ester of carnitine that facilitates movement of acetyl CoA into the matrices of mammalian mitochondria during the oxidation of fatty acids. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcysteine: The N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. [NIH] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an

548 Sclerosis

increase in hydrogen ion concentration. [EU] 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] Acuity: Clarity or clearness, especially of the vision. [EU] Acyl: Chemical signal used by bacteria to communicate. [NIH] Acylation: The addition of an organic acid radical into a molecule. [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] Adenopathy: Large or swollen lymph glands. [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] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a wound. [NIH] Adjunctive Therapy: Another treatment used together with the primary treatment. Its purpose is to assist the primary treatment. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a

Dictionary 549

synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]

Aetiology: Study of the causes of disease. [EU] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age Distribution: The frequency of different ages or age groups in a given population. The distribution may refer to either how many or what proportion of the group. The population is usually patients with a specific disease but the concept is not restricted to humans and is not restricted to medicine. [NIH] Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Agoraphobia: Obsessive, persistent, intense fear of open places. [NIH] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and

550 Sclerosis

renal disease. [EU] Albuterol: A racemic mixture with a 1:1 ratio of the r-isomer, levalbuterol, and s-albuterol. It is a short-acting beta 2-adrenergic agonist with its main clinical use in asthma. [NIH] Alcoholic Intoxication: An acute brain syndrome which results from the excessive ingestion of ethanol or alcoholic beverages. [NIH] Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]

Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allo: A female hormone. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Aloe: A genus of the family Liliaceae containing anthraquinone glycosides such as aloinemodin or aloe-emodin (emodin). [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] 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] Alveolar Process: The thickest and spongiest part of the maxilla and mandible hollowed out into deep cavities for the teeth. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Alveolitis: Inflammation of an alveolus. Called also odontobothritis. [EU] Amantadine: An antiviral that is used in the prophylactic or symptomatic treatment of Influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not

Dictionary 551

well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake. [NIH] Amebiasis: Infection with any of various amebae. It is an asymptomatic carrier state in most individuals, but diseases ranging from chronic, mild diarrhea to fulminant dysentery may occur. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] 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] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amnestic: Nominal aphasia; a difficulty in finding the right name for an object. [NIH] Amphetamine: A powerful central nervous system stimulant and sympathomimetic. Amphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulation of release of monamines, and inhibiting monoamine oxidase. Amphetamine is also a drug of abuse and a psychotomimetic. The l- and the d,l-forms are included here. The l-form has less central nervous system activity but stronger cardiovascular effects. The d-form is dextroamphetamine. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amygdala: Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the brain, within the temporal lobe. The amygdala is part of the limbic system. [NIH]

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] Anaesthetic: 1. Pertaining to, characterized by, or producing anaesthesia. 2. A drug or agent that is used to abolish the sensation of pain. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH]

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Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analysis of Variance: A statistical technique that isolates and assesses the contributions of categorical independent variables to variation in the mean of a continuous dependent variable. [NIH] Anaphylactic: Pertaining to anaphylaxis. [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] Anaphylaxis: An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. [NIH] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] 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] Anergy: Absence of immune response to particular substances. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Anginal: Pertaining to or characteristic of angina. [EU] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Angiotensin I: The decapeptide precursor of angiotensin II, generated by the action of renin on angiotensinogen. It has limited pharmacologic activity. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH]

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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] Anisotropy: A physical property showing different values in relation to the direction in or along which the measurement is made. The physical property may be with regard to thermal or electric conductivity or light refraction. In crystallography, it describes crystals whose index of refraction varies with the direction of the incident light. It is also called acolotropy and colotropy. The opposite of anisotropy is isotropy wherein the same values characterize the object when measured along axes in all directions. [NIH] Anode: Electrode held at a positive potential with respect to a cathode. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antecedent: Existing or occurring before in time or order often with consequential effects. [EU]

Anterior Horn Cells: Motor neurons in the anterior (ventral) horn of the spinal cord which project to skeletal muscles. [NIH] Anthraquinones: An anthracene ring which contains two ketone moieties in any position. Can be substituted in any position except on the ketone groups. [NIH] Antiallergic: Counteracting allergy or allergic conditions. [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]

Antibiotic Prophylaxis: Use of antibiotics before, during, or after a diagnostic, therapeutic, or surgical procedure to prevent infectious complications. [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] Antibody-Dependent Cell Cytotoxicity: The phenomenon of antibody-mediated target cell destruction by non-sensitized effector cells. The identity of the target cell varies, but it must possess surface IgG whose Fc portion is intact. The effector cell is a "killer" cell possessing Fc receptors. It may be a lymphocyte lacking conventional B- or T-cell markers, or a monocyte, macrophage, or polynuclear leukocyte, depending on the identity of the target cell. The reaction is complement-independent. [NIH] Anticholinergic: An agent that blocks the parasympathetic nerves. Called also

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parasympatholytic. [EU] 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] Antidepressant: A drug used to treat depression. [NIH] Antidote: A remedy for counteracting a poison. [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] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]

Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH] Antitussive: An agent that relieves or prevents cough. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Anxiety Disorders: Disorders in which anxiety (persistent feelings of apprehension, tension, or uneasiness) is the predominant disturbance. [NIH] Anxiolytic: An anxiolytic or antianxiety agent. [EU] Aorta: The main trunk of the systemic arteries. [NIH] Aortic Valve: The valve between the left ventricle and the ascending aorta which prevents

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backflow into the left ventricle. [NIH] Apathy: Lack of feeling or emotion; indifference. [EU] Apheresis: Components plateletpheresis. [NIH]

being

separated

out,

as

leukapheresis,

plasmapheresis,

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] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [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] Arginase: A ureahydrolase that catalyzes the hydrolysis of arginine or canavanine to yield L-ORNITHINE and urea. Deficiency of this enzyme causes hyperargininemia. EC 3.5.3.1. [NIH]

Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatic: Having a spicy odour. [EU] 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] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriosus: Circle composed of anastomosing arteries derived from two long posterior ciliary and seven anterior ciliary arteries, located in the ciliary body about the root of the iris. [NIH]

Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Articular: Of or pertaining to a joint. [EU] Articulation: The relationship of two bodies by means of a moveable joint. [NIH] Asbestos: Fibrous incombustible mineral composed of magnesium and calcium silicates with or without other elements. It is relatively inert chemically and used in thermal insulation and fireproofing. Inhalation of dust causes asbestosis and later lung and gastrointestinal neoplasms. [NIH] Asbestosis: A lung disorder caused by constant inhalation of asbestos particles. [NIH] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [NIH]

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Aseptic: Free from infection or septic material; sterile. [EU] Aspartate: A synthetic amino acid. [NIH] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Asphyxia: A pathological condition caused by lack of oxygen, manifested in impending or actual cessation of life. [NIH] Aspiration: The act of inhaling. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asthenia: Clinical sign or symptom manifested as debility, or lack or loss of strength and energy. [NIH] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, star-shaped cells called astrocytes. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atmospheric Pressure: The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. [NIH] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrioventricular Node: A small nodular mass of specialized muscle fibers located in the interatrial septum near the opening of the coronary sinus. It gives rise to the atrioventricular bundle of the conduction system of the heart. [NIH] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH]

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Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Audiometry: The testing of the acuity of the sense of hearing to determine the thresholds of the lowest intensity levels at which an individual can hear a set of tones. The frequencies between 125 and 8000 Hz are used to test air conduction thresholds, and the frequencies between 250 and 4000 Hz are used to test bone conduction thresholds. [NIH] Audiovisual Aids: Auditory and visual instructional materials. [NIH] Auditory: Pertaining to the sense of hearing. [EU] Auditory nerve: The eight cranial nerve; also called vestibulocochlear nerve or acoustic nerve. [NIH] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autoclave: Apparatus using superheated steam under pressure. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored, and then given back to the person after intensive treatment. [NIH] Autonomic: Self-controlling; functionally independent. [EU] 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] Autopsy: Postmortem examination of the body. [NIH] Avidity: The strength of the interaction of an antiserum with a multivalent antigen. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]

Axillary Artery: The continuation of the subclavian artery; it distributes over the upper limb, axilla, chest and shoulder. [NIH] Axonal: Condition associated with metabolic derangement of the entire neuron and is manifest by degeneration of the distal portion of the nerve fiber. [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] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [NIH]

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Baclofen: A GABA derivative that is a specific agonist at GABA-B receptors. It is used in the treatment of spasticity, especially that due to spinal cord damage. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission. [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] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacteriuria: The presence of bacteria in the urine with or without consequent urinary tract infection. Since bacteriuria is a clinical entity, the term does not preclude the use of urine/microbiology for technical discussions on the isolation and segregation of bacteria in the urine. [NIH] Basal cell carcinoma: A type of skin cancer that arises from the basal cells, small round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [NIH] Basal cells: Small, round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basilar Artery: The artery formed by the union of the right and left vertebral arteries; it runs from the lower to the upper border of the pons, where it bifurcates into the two posterior cerebral arteries. [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] Baths: The immersion or washing of the body or any of its parts in water or other medium for cleansing or medical treatment. It includes bathing for personal hygiene as well as for medical purposes with the addition of therapeutic agents, such as alkalines, antiseptics, oil, etc. [NIH] Batroxobin: A proteolytic enzyme obtained from the venom of fer-de-lance (Bothrops atrox). It is used as a plasma clotting agent for fibrinogen and for the detection of fibrinogen

Dictionary 559

degradation products. The presence of heparin does not interfere with the clotting test. Hemocoagulase is a mixture containing batroxobin and factor X activator. EC 3.4.21.-. [NIH] Behavioral Medicine: The interdisciplinary field concerned with the development and integration of behavioral and biomedical science, knowledge, and techniques relevant to health and illness and the application of this knowledge and these techniques to prevention, diagnosis, treatment, and rehabilitation. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benign tumor: A noncancerous growth that does not invade nearby tissue or spread to other parts of the body. [NIH] Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Bereavement: Refers to the whole process of grieving and mourning and is associated with a deep sense of loss and sadness. [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] Bicarbonates: Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the pH of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. [NIH] Bifida: A defect in development of the vertebral column in which there is a central deficiency of the vertebral lamina. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile Ducts: Tubes that carry bile from the liver to the gallbladder for storage and to the small intestine for use in digestion. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: 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]

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Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological Assay: A method of measuring the effects of a biologically active substance using an intermediate in vivo or in vitro tissue or cell model under controlled conditions. It includes virulence studies in animal fetuses in utero, mouse convulsion bioassay of insulin, quantitation of tumor-initiator systems in mouse skin, calculation of potentiating effects of a hormonal factor in an isolated strip of contracting stomach muscle, etc. [NIH] Biological Factors: Compounds made by living organisms that contribute to or influence a phenomenon or process. They have biological or physiological activities. [NIH] Biological Markers: Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biomedical Technology: The application of technology to the solution of medical problems. [NIH]

Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH]

Dictionary 561

Biphasic: Having two phases; having both a sporophytic and a gametophytic phase in the life cycle. [EU] Bladder: The organ that stores urine. [NIH] Blebs: Cysts on or near the surface of the lungs. [NIH] Blind spot: (1) A small area of the retina where the optic nerve enters the eye; occurs normally in all eyes.(2) Any gap in the visual field corresponding to an area of the retina where no visual cells are present; associated with eye disease. [NIH] Blister: Visible accumulations of fluid within or beneath the epidermis. [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 vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blotting and transferred to strips of nitrocellulose paper. The blots are then detected by radiolabeled antibody probes. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bone Conduction: Sound transmission through the bones of the skull to the inner ear. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small

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amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Artery: The continuation of the axillary artery; it branches into the radial and ulnar arteries. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [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 Ischemia: Localized reduction of blood flow to brain tissue due to arterial obtruction or systemic hypoperfusion. This frequently occurs in conjuction with brain hypoxia. Prolonged ischemia is associated with brain infarction. [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] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchiolitis: Inflammation of the bronchioles. [NIH] Bronchiolitis Obliterans: Inflammation of the bronchioles with obstruction by fibrous granulation tissue or bronchial exudate. It may follow inhalation of irritating gases or foreign bodies and it complicates pneumonia. [NIH] Bronchiolitis Obliterans Organizing Pneumonia: Inflammation of the bronchioles. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchodilator: A drug that relaxes the smooth muscles in the constricted airway. [NIH] 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]

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Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcifediol: The major circulating metabolite of vitamin D3 produced in the liver and the best indicator of the body's vitamin D stores. It is effective in the treatment of rickets and osteomalacia, both in azotemic and non-azotemic patients. Calcifediol also has mineralizing properties. [NIH] Calcinosis: Pathologic deposition of calcium salts in tissues. [NIH] Calcitriol: The physiologically active form of vitamin D. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium channel blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools. Since they are inducers of vascular and other smooth muscle relaxation, they are used in the drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms. [NIH] Calcium Channels: Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue. [NIH] Calcium Hydroxide: Ca(OH)2. A white powder that has many therapeutic uses. Because of its ability to stimulate mineralization, it is found in many dental formulations. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Calpain: Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including neuropeptides, cytoskeletal proteins, proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. [NIH] Camptothecin: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca

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acuminata. This compound selectively inhibits the nuclear enzyme DNA topoisomerase. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity. [NIH] Cannabidiol: Compound isolated from Cannabis sativa extract. [NIH] Cannabinoids: Compounds extracted from Cannabis sativa L. and metabolites having the cannabinoid structure. The most active constituents are tetrahydrocannabinol, cannabinol, and cannabidiol. [NIH] Cannabinol: A physiologically inactive constituent of Cannabis sativa L. [NIH] Cannabis: The hemp plant Cannabis sativa. Products prepared from the dried flowering tops of the plant include marijuana, hashish, bhang, and ganja. [NIH] Cannula: A tube for insertion into a duct or cavity; during insertion its lumen is usually occupied by a trocar. [EU] 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] Capsular: Cataract which is initiated by an opacification at the surface of the lens. [NIH] Carbamazepine: An anticonvulsant used to control grand mal and psychomotor or focal seizures. Its mode of action is not fully understood, but some of its actions resemble those of phenytoin; although there is little chemical resemblance between the two compounds, their three-dimensional structure is similar. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiotoxicity: Toxicity that affects 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] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH]

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Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] 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] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalyse: To speed up a chemical reaction. [EU] Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction. [NIH] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [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] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] 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] 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 Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Adhesion Molecules: Surface ligands, usually glycoproteins, that mediate cell-to-cell adhesion. Their functions include the assembly and interconnection of various vertebrate systems, as well as maintenance of tissue integration, wound healing, morphogenic movements, cellular migrations, and metastasis. [NIH]

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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 Cycle Proteins: Proteins that control the cell division cycle. This family of proteins includes a wide variety of classes, including cyclin-dependent kinases, mitogen-activated kinases, cyclins, and phosphoprotein phosphatases (phosphoprotein phosphatase) as well as their putative substrates such as chromatin-associated proteins, cytoskeletal proteins, and transcription factors. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell motility: The ability of a cell to move. [NIH] Cell 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 Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Cellular metabolism: The sum of all chemical changes that take place in a cell through which energy and basic components are provided for essential processes, including the synthesis of new molecules and the breakdown and removal of others. [NIH] Cellular Structures: Components of a cell. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellar Diseases: Diseases that affect the structure or function of the cerebellum. Cardinal manifestations of cerebellar dysfunction include dysmetria, gait ataxia, and muscle hypotonia. [NIH] 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]

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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 Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrovascular Disorders: A broad category of disorders characterized by impairment of blood flow in the arteries and veins which supply the brain. These include cerebral infarction; brain ischemia; hypoxia, brain; intracranial embolism and thrombosis; intracranial arteriovenous malformations; and vasculitis, central nervous system. In common usage, the term cerebrovascular disorders is not limited to conditions that affect the cerebrum, but refers to vascular disorders of the entire brain including the diencephalon; brain stem; and cerebellum. [NIH] 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] Charities: Social welfare organizations with programs designed to assist individuals in times of need. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] 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 immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotaxis: The movement of cells or organisms toward or away from a substance in response to its concentration gradient. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chimera: An individual that contains cell populations derived from different zygotes. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that

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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] Chiropractic: A system of treating bodily disorders by manipulation of the spine and other parts, based on the belief that the cause is the abnormal functioning of a nerve. [NIH] Chlamydia: A genus of the family Chlamydiaceae whose species cause a variety of diseases in vertebrates including humans, mice, and swine. Chlamydia species are gram-negative and produce glycogen. The type species is Chlamydia trachomatis. [NIH] Chlorambucil: An anticancer drug that belongs to the family of drugs called alkylating agents. [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] Cholangitis: Inflammation of a bile duct. [NIH] Cholecystectomy: Surgical removal of the gallbladder. [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] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Cholinesterase Inhibitors: Drugs that inhibit cholinesterases. The neurotransmitter acetylcholine is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system. [NIH] Chondroitin sulfate: The major glycosaminoglycan (a type of sugar molecule) in cartilage. [NIH]

Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic Fatigue Syndrome: Fatigue caused by the combined effects of different types of prolonged fatigue. [NIH] Chronic lymphocytic leukemia: A slowly progressing disease in which too many white

Dictionary 569

blood cells (called lymphocytes) are found in the body. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chymotrypsin: A serine endopeptidase secreted by the pancreas as its zymogen, chymotrypsinogen and carried in the pancreatic juice to the duodenum where it is activated by trypsin. It selectively cleaves aromatic amino acids on the carboxyl side. [NIH] Cicatrix: The formation of new tissue in the process of wound healing. [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] Cimetidine: A histamine congener, it competitively inhibits histamine binding to H2 receptors. Cimetidine has a range of pharmacological actions. It inhibits gastric acid secretion, as well as pepsin and gastrin output. It also blocks the activity of cytochrome P450. [NIH] 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] Civil Rights: Legal guarantee protecting the individual from attack on personal liberties, right to fair trial, right to vote, and freedom from discrimination on the basis of race, religion, national origin, age, or gender. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clonal Deletion: Removal, via cell death, of immature lymphocytes that interact with antigens during maturation. For T-lymphocytes this occurs in the thymus and ensures that mature T-lymphocytes are self tolerant. B-lymphocytes may also undergo clonal deletion. [NIH]

Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [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] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods

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attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used as a measure of platelet function. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cochlea: The part of the internal ear that is concerned with hearing. It forms the anterior part of the labyrinth, is conical, and is placed almost horizontally anterior to the vestibule. [NIH]

Codeine: An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. [NIH] Codons: Any triplet of nucleotides (coding unit) in DNA or RNA (if RNA is the carrier of primary genetic information as in some viruses) that codes for particular amino acid or signals the beginning or end of the message. [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Cognitive restructuring: A method of identifying and replacing fear-promoting, irrational beliefs with more realistic and functional ones. [NIH] Cohort Effect: Variation in health status arising from different causal factors to which each birth cohort in a population is exposed as environment and society change. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collagen disease: A term previously used to describe chronic diseases of the connective tissue (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU]

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Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Common Bile Duct: The largest biliary duct. It is formed by the junction of the cystic duct and the hepatic duct. [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [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

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biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computer Systems: Systems composed of a computer or computers, peripheral equipment, such as disks, printers, and terminals, and telecommunications capabilities. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Concentric: Having a common center of curvature or symmetry. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [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] Continence: The ability to hold in a bowel movement or urine. [NIH]

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Contractility: Capacity for becoming short in response to a suitable stimulus. [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] Contrast Sensitivity: The ability to detect sharp boundaries (stimuli) and to detect slight changes in luminance at regions without distinct contours. Psychophysical measurements of this visual function are used to evaluate visual acuity and to detect eye disease. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Conus: A large, circular, white patch around the optic disk due to the exposing of the sclera as a result of degenerative change or congenital abnormality in the choroid and retina. [NIH] Convulsion: A violent involuntary contraction or series of contractions of the voluntary muscles. [EU] Convulsive: Relating or referring to spasm; affected with spasm; characterized by a spasm or spasms. [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] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneum: The superficial layer of the epidermis containing keratinized 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 Circulation: The circulation of blood through the coronary vessels of the heart. [NIH]

Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or

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clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Coronavirus: A genus of the family Coronaviridae which causes respiratory or gastrointestinal disease in a variety of vertebrates. [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] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cost Savings: Reductions in all or any portion of the costs of providing goods or services. Savings may be incurred by the provider or the consumer. [NIH] Cowpox: A mild, eruptive skin disease of milk cows caused by cowpox virus, with lesions occurring principally on the udder and teats. Human infection may occur while milking an infected animal. [NIH] Cowpox Virus: A species of orthopoxvirus that is the etiologic agent of cowpox. It is closely related to but antigenically different from vaccina virus. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Creatine: An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. [NIH]

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] Criterion: A standard by which something may be judged. [EU] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which

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are followed over a period of time. [NIH] Crystallization: The formation of crystals; conversion to a crystalline form. [EU] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Cuprizone: Copper chelator that inhibits monoamine oxidase and causes liver and brain damage. [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] Cyclin A: A 33-kD protein identical to adenovirus E1A-associated protein p60. Cyclin A regulates p33cdk2 and p34cdc2, and is necessary for progression through the S phase of the cell cycle. [NIH] Cyclin-Dependent Kinases: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with cyclins to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events. [NIH]

Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystic Duct: The tube that carries bile from the gallbladder into the common bile duct and the small intestine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU]

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Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]

Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Death Certificates: Official records of individual deaths including the cause of death certified by a physician, and any other required identifying information. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decision Making: The process of making a selective intellectual judgment when presented with several complex alternatives consisting of several variables, and usually defining a course of action or an idea. [NIH] Decompression: Decompression external to the body, most often the slow lessening of external pressure on the whole body (especially in caisson workers, deep sea divers, and persons who ascend to great heights) to prevent decompression sickness. It includes also sudden accidental decompression, but not surgical (local) decompression or decompression applied through body openings. [NIH] Decompression Sickness: A condition occurring as a result of exposure to a rapid fall in ambient pressure. Gases, nitrogen in particular, come out of solution and form bubbles in body fluid and blood. These gas bubbles accumulate in joint spaces and the peripheral circulation impairing tissue oxygenation causing disorientation, severe pain, and potentially death. [NIH]

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Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] 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] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [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] Demyelinating Diseases: Diseases characterized by loss or dysfunction of myelin in the central or peripheral nervous system. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]

Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Amalgam: An alloy used in restorative dentistry that contains mercury, silver, tin, copper, and possibly zinc. [NIH] Dental Care: The total of dental diagnostic, preventive, and restorative services provided to meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] Dental Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [NIH]

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] Dentists: Individuals licensed to practice dentistry. [NIH] Dentition: The teeth in the dental arch; ordinarily used to designate the natural teeth in position in their alveoli. [EU] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU]

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Deprenyl: Substance that blocks the breakdown of dopamine, thus preserving its availability in the striatum. [NIH] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermal: Pertaining to or coming from the skin. [NIH] Dermatologist: A doctor who specializes in the diagnosis and treatment of skin problems. [NIH]

DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desipramine: A tricyclic dibenzazepine compound that potentiates neurotransmission. Desipramine selectively blocks reuptake of norepinephrine from the neural synapse, and also appears to impair serotonin transport. This compound also possesses minor anticholingeric activity, through its affinity to muscarinic receptors. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Dexterity: Ability to move the hands easily and skillfully. [NIH] Dextroamphetamine: The d-form of amphetamine. It is a central nervous system stimulant and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. [NIH] Dextromethorphan: The d-isomer of the codeine analog of levorphanol. Dextromethorphan shows high affinity binding to several regions of the brain, including the medullary cough center. This compound is a NMDA receptor antagonist (receptors, N-methyl-D-aspartate) and acts as a non-competitive channel blocker. It is used widely as an antitussive agent, and is also used to study the involvement of glutamate receptors in neurotoxicity. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic Imaging: Any visual display of structural or functional patterns of organs or tissues for diagnostic evaluation. It includes measuring physiologic and metabolic responses to physical and chemical stimuli, as well as ultramicroscopy. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diaphragm: The musculofibrous partition that separates the thoracic cavity from the abdominal cavity. Contraction of the diaphragm increases the volume of the thoracic cavity aiding inspiration. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastolic: Of or pertaining to the diastole. [EU] Diastolic blood pressure: The minimum pressure that remains within the artery when the heart is at rest. [NIH] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus,

Dictionary 579

hypothalamus, epithalamus, and subthalamus are derived. [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] Difluoromethylornithine: DFMO. An anticancer drug that has been shown to reduce the risk of cancer in animals. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Diploid: Having two sets of chromosomes. [NIH] Diplopia: A visual symptom in which a single object is perceived by the visual cortex as two objects rather than one. Disorders associated with this condition include refractive errors; strabismus; oculomotor nerve diseases; trochlear nerve diseases; abducens nerve diseases; and diseases of the brain stem and occipital lobe. [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] Disease Susceptibility: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the individual more than usually susceptible to certain diseases. [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

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consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Distemper: A name for several highly contagious viral diseases of animals, especially canine distemper. In dogs, it is caused by the canine distemper virus (distemper virus, canine). It is characterized by a diphasic fever, leukopenia, gastrointestinal and respiratory inflammation and sometimes, neurologic complications. In cats it is known as feline panleukopenia. [NIH] Distemper Virus, Canine: A species of morbillivirus causing distemper in dogs, wolves, foxes, raccoons, and ferrets. [NIH] Distention: The state of being distended or enlarged; the act of distending. [EU] Diuresis: Increased excretion of urine. [EU] Diuretic: A drug that increases the production of urine. [NIH] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] DNA Topoisomerase: An enzyme catalyzing ATP-independent breakage of single-stranded DNA, followed by passage and rejoining of another single-stranded DNA. This enzyme class brings about the conversion of one topological isomer of DNA into another, e.g., the relaxation of superhelical turns in DNA, the interconversion of simple and knotted rings of single-stranded DNA, and the intertwisting of single-stranded rings of complementary sequences. (From Enzyme Nomenclature, 1992) EC 5.99.1.2. [NIH] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Donepezil: A drug used in the treatment of Alzheimer's disease. It belongs to the family of drugs called cholinesterase inhibitors. It is being studied as a treatment for side effects caused by radiation therapy to the brain. [NIH] Dopa: The racemic or DL form of DOPA, an amino acid found in various legumes. The dextro form has little physiologic activity but the levo form (levodopa) is a very important physiologic mediator and precursor and pharmacological agent. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. [NIH] 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] Drive: A state of internal activity of an organism that is a necessary condition before a given

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stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Evaluation: Any process by which toxicity, metabolism, absorption, elimination, preferred route of administration, safe dosage range, etc., for a drug or group of drugs is determined through clinical assessment in humans or veterinary animals. [NIH] Drug Evaluation, Preclinical: Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [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] 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] Dysphonia: Difficulty or pain in speaking; impairment of the voice. [NIH] Dysphoric: A feeling of unpleasantness and discomfort. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystonia: Disordered tonicity of muscle. [EU] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Ejection fraction: A measure of ventricular contractility, equal to normally 65 8 per cent;

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lower values indicate ventricular dysfunction. [EU] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electric Conductivity: The ability of a substrate to allow the passage of electrons. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electromagnetic Fields: Fields representing the joint interplay of electric and magnetic forces. [NIH] 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]

Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Electroporation: A technique in which electric pulses of intensity in kilovolts per centimeter and of microsecond-to-millisecond duration cause a temporary loss of the semipermeability of cell membranes, thus leading to ion leakage, escape of metabolites, and increased uptake by cells of drugs, molecular probes, and DNA. Some applications of electroporation include introduction of plasmids or foreign DNA into living cells for transfection, fusion of cells to prepare hybridomas, and insertion of proteins into cell membranes. [NIH] Electroshock: Induction of a stress reaction in experimental subjects by means of an electrical shock; applies to either convulsive or non-convulsive states. [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] Emodin: Purgative anthraquinone found in several plants, especially Rhamnus frangula. It was formerly used as a laxative, but is now used mainly as tool in toxicity studies. [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of

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a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [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] Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord, often used to indicate an infectious process, but also applicable to a variety of autoimmune and toxic-metabolic conditions. There is significant overlap regarding the usage of this term and encephalitis in the literature. [NIH] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [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] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endorphin: Opioid peptides derived from beta-lipotropin. Endorphin is the most potent naturally occurring analgesic agent. It is present in pituitary, brain, and peripheral tissues. [NIH]

Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the body. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood

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capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]

Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epistasis: The degree of dominance exerted by one gene on the expression of a non-allelic gene. [NIH]

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Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

Epoprostenol: A prostaglandin that is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. It is a potent inhibitor of platelet aggregation. The sodium salt has been also used to treat primary pulmonary hypertension. [NIH] Erbium: Erbium. An element of the rare earth family of metals. It has the atomic symbol Er, atomic number 68, and atomic weight 167.26. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythrocyte Volume: Volume of circulating erythrocytes. It is usually measured by radioisotope dilution technique. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estriol: (16 alpha,17 beta)-Estra-1,3,5(10)-triene-3,16,17-triol. A metabolite of estradiol and usually the predominant estrogenic metabolite in urine. During pregnancy, large amounts of estriol are produced by the placenta. It has also been obtained from plant sources. The 16 beta-isomer has also been isolated from the urine of pregnant women. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Evaluation Studies: Studies determining the effectiveness or value of processes, personnel, and equipment, or the material on conducting such studies. For drugs and devices, clinical trials, drug evaluation, and drug evaluation, preclinical are available. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH]

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Evoked Potentials: The electric response evoked in the central nervous system by stimulation of sensory receptors or some point on the sensory pathway leading from the receptor to the cortex. The evoked stimulus can be auditory, somatosensory, or visual, although other modalities have been reported. Event-related potentials is sometimes used synonymously with evoked potentials but is often associated with the execution of a motor, cognitive, or psychophysiological task, as well as with the response to a stimulus. [NIH] Excipient: Any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; a vehicle. [EU] 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] Exercise Therapy: Motion of the body or its parts to relieve symptoms or to improve function, leading to physical fitness, but not physical education and training. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Expiration: The act of breathing out, or expelling air from the lungs. [EU] 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-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external 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

Dictionary 587

to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] Eye Abnormalities: Congenital absence of or defects in structures of the eye; may also be hereditary. [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] Facial: Of or pertaining to the face. [EU] Facial Nerve: The 7th cranial nerve. The facial nerve has two parts, the larger motor root which may be called the facial nerve proper, and the smaller intermediate or sensory root. Together they provide efferent innervation to the muscles of facial expression and to the lacrimal and salivary glands, and convey afferent information for taste from the anterior two-thirds of the tongue and for touch from the external ear. [NIH] Faecal: Pertaining to or of the nature of feces. [EU] Fallopian Tubes: Two long muscular tubes that transport ova from the ovaries to the uterus. They extend from the horn of the uterus to the ovaries and consist of an ampulla, an infundibulum, an isthmus, two ostia, and a pars uterina. The walls of the tubes are composed of three layers: mucosal, muscular, and serosal. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fasciculation: A small local contraction of muscles, visible through the skin, representing a spontaneous discharge of a number of fibres innervated by a single motor nerve filament. [EU]

Fat: Total lipids including phospholipids. [NIH] 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] Febrile: Pertaining to or characterized by fever. [EU] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Feline Panleukopenia: A highly contagious DNA virus infection of the cat family and of

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mink, characterized by fever, enteritis and bone marrow changes. It is also called feline ataxia, feline agranulocytosis, feline infectious enteritis, cat fever, cat plague, show fever. [NIH]

Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fetal Alcohol Syndrome: A disorder occurring in children born to alcoholic women who continue to drink heavily during pregnancy. Common abnormalities are growth deficiency (prenatal and postnatal), altered morphogenesis, mental deficiency, and characteristic facies - small eyes and flattened nasal bridge. Fine motor dysfunction and tremulousness are observed in the newborn. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] 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] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filgrastim: A colony-stimulating factor that stimulates the production of neutrophils (a type of white blood cell). It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. Also called granulocyte colony-stimulating factor (G-CSF). [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [NIH] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in

Dictionary 589

carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] 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] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Focus Groups: A method of data collection and a qualitative research tool in which a small group of individuals are brought together and allowed to interact in a discussion of their opinions about topics, issues, or questions. [NIH] Foetal: Of or pertaining to a fetus; pertaining to in utero development after the embryonic period. [EU] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH] Fovea: The central part of the macula that provides the sharpest vision. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [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]

Functional Residual Capacity: The volume of air remaining in the lungs at the end of a

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normal, quiet expiration. It is the sum of the residual volume and the expiratory reserve volume. Common abbreviation is FRC. [NIH] Fundus: The larger part of a hollow organ that is farthest away from the organ's opening. The bladder, gallbladder, stomach, uterus, eye, and cavity of the middle ear all have a fundus. [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Furosemide: A sulfamyl saluretic and diuretic. It has a fast onset and short duration of action and is used in edema and chronic renal insufficiency. [NIH] Gadolinium: An element of the rare earth family of metals. It has the atomic symbol Gd, atomic number 64, and atomic weight 157.25. Its oxide is used in the control rods of some nuclear reactors. [NIH] Gait: Manner or style of walking. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gangliosides: Protein kinase C's inhibitor which reduces ischemia-related brain damage. [NIH]

Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Acid: Hydrochloric acid present in gastric juice. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastritis: Inflammation of the stomach. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal Neoplasms: Tumors or cancer of the gastrointestinal system. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH]

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Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gelatinase A: A secreted endopeptidase homologous with interstitial collagenase, but which possesses an additional fibronectin-like domain. EC 3.4.24.24. [NIH] Gemcitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [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 Rearrangement: The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development. [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] General practitioner: A medical practitioner who does not specialize in a particular branch of medicine or limit his practice to a specific class of diseases. [NIH] 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 Counseling: Advising families of the risks involved pertaining to birth defects, in order that they may make an informed decision on current or future pregnancies. [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] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genistein: An isoflavonoid derived from soy products. It inhibits protein-tyrosine kinase and topoisomerase-ii (dna topoisomerase (atp-hydrolysing)) activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 phase arrest in human and murine cell lines. [NIH] 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] Germanium: A rare metal element with a blue-gray appearance and atomic symbol Ge, atomic number 32, and atomic weight 72.59. [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] Giant Cell Tumors: Tumors of bone tissue or synovial or other soft tissue characterized by the presence of giant cells. The most common are giant cell tumor of tendon sheath and giant cell tumor of bone. [NIH] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated

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with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. [NIH] Giardiasis: An infection of the small intestine caused by the flagellated protozoan Giardia lamblia. It is spread via contaminated food and water and by direct person-to-person contact. [NIH] Gingival Hypertrophy: Abnormal enlargement or overgrowth of the gingivae brought about by enlargement of existing cells. [NIH] Ginkgo biloba: Exclusive species of the genus Ginkgo, family Ginkgoacea. It produces extracts of medicinal interest. Ginkgo may refer to the genus or species. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioblastoma: A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. They may arise in any region of the central nervous system, with a predilection for the cerebral hemispheres, basal ganglia, and commissural pathways. Clinical presentation most frequently occurs in the fifth or sixth decade of life with focal neurologic signs or seizures. [NIH] Glioblastoma multiforme: A type of brain tumor that forms from glial (supportive) tissue of the brain. It grows very quickly and has cells that look very different from normal cells. Also called grade IV astrocytoma. [NIH] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH] Gliosis: The production of a dense fibrous network of neuroglia; includes astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomeruli: Plural of glomerulus. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and kidney failure. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Gluconeogenesis: The process by which glucose is formed from a non-carbohydrate source. [NIH]

Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen

Dictionary 593

frequently in diabetes mellitus but also occurs with other diseases. [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]

Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycols: A generic grouping for dihydric alcohols with the hydroxy groups (-OH) located on different carbon atoms. They are viscous liquids with high boiling points for their molecular weights. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycan: A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [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] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [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] Grading: A system for classifying cancer cells in terms of how abnormal they appear when examined under a microscope. The objective of a grading system is to provide information about the probable growth rate of the tumor and its tendency to spread. The systems used to grade tumors vary with each type of cancer. Grading plays a role in treatment decisions. [NIH]

Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the

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recipient. [NIH] Graft Survival: The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-Negative Bacteria: Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. [NIH] Granulation Tissue: A vascular connective tissue formed on the surface of a healing wound, ulcer, or inflamed tissue. It consists of new capillaries and an infiltrate containing lymphoid cells, macrophages, and plasma cells. [NIH] Granule: A small pill made from sucrose. [EU] Granulocyte Colony-Stimulating Factor: A glycoprotein of MW 25 kDa containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [NIH] Gravis: Eruption of watery blisters on the skin among those handling animals and animal products. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [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] Guanfacine: A centrally acting antihypertensive agent. The drug lowers both systolic and diastolic blood pressure by activating the central nervous system alpha-2 adrenoreceptors, which results in reduced sympathetic outflow leading to reduced vascular tone. Its adverse reactions include dry mouth, sedation, and constipation. [NIH] Guanidine: A strong organic base existing primarily as guanidium ions at physiological pH. It is found in the urine as a normal product of protein metabolism. It is also used in laboratory research as a protein denaturant. (From Martindale, the Extra Pharmacopoeia, 30th ed and Merck Index, 12th ed) It is also used in the treatment of myasthenia and as a fluorescent probe in HPLC. [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] Guinea Pigs: A common name used for the family Caviidae. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. [NIH]

Habitual: Of the nature of a habit; according to habit; established by or repeated by force of

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habit, customary. [EU] Haematoma: A localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel. [EU] Haemorrhage: The escape of blood from the vessels; bleeding. Small haemorrhages are classified according to size as petechiae (very small), purpura (up to 1 cm), and ecchymoses (larger). The massive accumulation of blood within a tissue is called a haematoma. [EU] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [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] Handicap: A handicap occurs as a result of disability, but disability does not always constitute a handicap. A handicap may be said to exist when a disability causes a substantial and continuing reduction in a person's capacity to function socially and vocationally. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Health Care Costs: The actual costs of providing services related to the delivery of health care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Health Education: Education that increases the awareness and favorably influences the attitudes and knowledge relating to the improvement of health on a personal or community basis. [NIH] Health Expenditures: The amounts spent by individuals, groups, nations, or private or public organizations for total health care and/or its various components. These amounts may or may not be equivalent to the actual costs (health care costs) and may or may not be shared among the patient, insurers, and/or employers. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Hematopoietic Stem Cell Transplantation: The transference of stem cells from one animal or human to another (allogeneic), or within the same individual (autologous). The source for the stem cells may be the bone marrow or peripheral blood. Stem cell transplantation has been used as an alternative to autologous bone marrow transplantation in the treatment of a variety of neoplasms. [NIH]

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Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemiparesis: The weakness or paralysis affecting one side of the body. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [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]

Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocyte: A liver cell. [NIH] Hepatocyte Growth Factor: Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is proto-oncogene protein C-met. [NIH] 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] Heritability: The proportion of observed variation in a particular trait that can be attributed to inherited genetic factors in contrast to environmental ones. [NIH] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes virus: A member of the herpes family of viruses. [NIH]

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Herpes Zoster: Acute vesicular inflammation. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

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] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Histocompatibility Antigens: A group of antigens that includes both the major and minor histocompatibility antigens. The former are genetically determined by the major histocompatibility complex. They determine tissue type for transplantation and cause allograft rejections. The latter are systems of allelic alloantigens that can cause weak transplant rejection. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeobox: Distinctive sequence of DNA bases. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]

Homogenate: A suspension of animal tissue that is ground in the all-glass "homogenizer" described by Potter and Elvehjem in 1936. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Hospice: Institution dedicated to caring for the terminally ill. [NIH] Hospital Records: Compilations of data on hospital activities and programs; excludes patient medical records. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Human growth hormone: A protein hormone, secreted by the anterior lobe of the pituitary, which promotes growth of the whole body by stimulating protein synthesis. The human gene has already been cloned and successfully expressed in bacteria. [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]

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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] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydrochloric Acid: A strong corrosive acid that is commonly used as a laboratory reagent. It is formed by dissolving hydrogen chloride in water. Gastric acid is the hydrochloric acid component of gastric juice. [NIH] Hydrocortisone: The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] 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] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxides: Inorganic compounds that contain the OH- group. [NIH] Hydroxyl Radical: The univalent radical OH that is present in hydroxides, alcohols, phenols, glycols. [NIH] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] 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]

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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] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperlipoproteinemia: Metabolic disease characterized by elevated plasma cholesterol and/or triglyceride levels. The inherited form is attributed to a single gene mechanism. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] 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] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypesthesia: Absent or reduced sensitivity to cutaneous stimulation. [NIH] Hypnotherapy: Sleeping-cure. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] 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 conditions. [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypotensive: Characterized by or causing diminished tension or pressure, as abnormally low blood pressure. [EU] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypothermia: Lower than normal body temperature, especially in warm-blooded animals; in man usually accidental or unintentional. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH]

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Idiocy: Is the most severe degree of mental defect. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Iloprost: An eicosanoid, derived from the cyclooxygenase pathway of arachidonic acid metabolism. It is a stable and synthetic analog of epoprostenol, but with a longer half-life than the parent compound. Its actions are similar to prostacyclin. Iloprost produces vasodilation and inhibits platelet aggregation. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Imipramine: The prototypical tricyclic antidepressant. It has been used in major depression, dysthymia, bipolar depression, attention-deficit disorders, agoraphobia, and panic disorders. It has less sedative effect than some other members of this therapeutic group. [NIH]

Immersion: The placing of a body or a part thereof into a liquid. [NIH] Immune Complex Diseases: Group of diseases mediated by the deposition of large soluble complexes of antigen and antibody with resultant damage to tissue. Besides serum sickness and the arthus reaction, evidence supports a pathogenic role for immune complexes in many other systemic immunologic diseases including glomerulonephritis, systemic lupus erythematosus and polyarteritis nodosa. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immune Tolerance: The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunoblotting: Immunologic methods for isolating and quantitatively measuring immunoreactive substances. When used with immune reagents such as monoclonal antibodies, the process is known generically as western blot analysis (blotting, western). [NIH]

Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH]

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Immunodominant Epitopes: Subunits of the antigenic determinant that are most easily recognized by the immune system and thus most influence the specificity of the induced antibody. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenetics: A branch of genetics which deals with the genetic basis of the immune response. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [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] Immunophilins: Members of a family of highly conserved proteins which are all cis-trans peptidyl-prolyl isomerases (peptidylprolyl isomerase). They bind the immunosuppressant drugs cyclosporine; tacrolimus and sirolimus. They possess rotomase activity, which is inhibited by the immunosuppressant drugs that bind to them. EC 5.2.1.- [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH]

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Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [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] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] 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] Induration: 1. The quality of being hard; the process of hardening. 2. An abnormally hard spot or place. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant Mortality: Perinatal, neonatal, and infant deaths in a given population. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]

Information Systems: Integrated set of files, procedures, and equipment for the storage, manipulation, and retrieval of information. [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]

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Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inoculum: The spores or tissues of a pathogen that serve to initiate disease in a plant. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inositol Phosphates: Phosphoric acid esters of inositol. They include mono- and polyphosphoric acid esters, with the exception of inositol hexaphosphate which is phytic acid. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Inspiratory Capacity: The maximum volume of air that can be inspired after reaching the end of a normal, quiet expiration. It is the sum of the tidal volume and the inspiratory reserve volume. Common abbreviation is IC. [NIH] Inspiratory Reserve Volume: The extra volume of air that can be inspired with maximal effort after reaching the end of a normal, quiet inspiration. Common abbreviation is IRV. [NIH]

Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Intention tremor: A tremor which arises or which is intensified when a voluntary, coordinated movement is attempted. [EU] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the

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laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interferon-beta: One of the type I interferons produced by fibroblasts in response to stimulation by live or inactivated virus or by double-stranded RNA. It is a cytokine with antiviral, antiproliferative, and immunomodulating activity. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-10: Factor that is a coregulator of mast cell growth. It is produced by T-cells and B-cells and shows extensive homology with the Epstein-Barr virus BCRFI gene. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-4: Soluble factor produced by activated T-lymphocytes that causes proliferation and differentiation of B-cells. Interleukin-4 induces the expression of class II major histocompatibility complex and Fc receptors on B-cells. It also acts on T-lymphocytes, mast cell lines, and several other hematopoietic lineage cells including granulocyte, megakaryocyte, and erythroid precursors, as well as macrophages. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] 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] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [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] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Interstitial Collagenase: A member of the metalloproteinase family of enzymes that is principally responsible for cleaving fibrillar collagen. It can degrade interstitial collagens, types I, II and III. EC 3.4.24.7. [NIH]

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Intervertebral: Situated between two contiguous vertebrae. [EU] Intervertebral Disk Displacement: An intervertebral disk in which the nucleus pulposus has protruded through surrounding fibrocartilage. This occurs most frequently in the lower lumbar region. [NIH] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracranial Embolism: The sudden obstruction of a blood vessel by an embolus. [NIH] Intracranial Embolism and Thrombosis: Embolism or thrombosis involving blood vessels which supply intracranial structures. Emboli may originate from extracranial or intracranial sources. Thrombosis may occur in arterial or venous structures. [NIH] Intrahepatic: Within the liver. [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] Intravesical: Within the bladder. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Introns: Non-coding, intervening sequences of DNA that are transcribed, but are removed from within the primary gene transcript and rapidly degraded during maturation of messenger RNA. Most genes in the nuclei of eukaryotes contain introns, as do mitochondrial and chloroplast genes. [NIH] Intubation: Introduction of a tube into a hollow organ to restore or maintain patency if obstructed. It is differentiated from catheterization in that the insertion of a catheter is usually performed for the introducing or withdrawing of fluids from the body. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Exchange: Reversible chemical reaction between a solid, often an ION exchange resin, and a fluid whereby ions may be exchanged from one substance to another. This technique is used in water purification, in research, and in industry. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a

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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] Iontophoresis: Therapeutic introduction of ions of soluble salts into tissues by means of electric current. In medical literature it is commonly used to indicate the process of increasing the penetration of drugs into surface tissues by the application of electric current. It has nothing to do with ion exchange, air ionization nor phonophoresis, none of which requires current. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] 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] Islet: Cell producing insulin in pancreas. [NIH] Isoelectric: Separation of amphoteric substances, dissolved in water, based on their isoelectric behavior. The amphoteric substances are a mixture of proteins to be separated and of auxiliary "carrier ampholytes". [NIH] Isoelectric Point: The pH in solutions of proteins and related compounds at which the dipolar ions are at a maximum. [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] Isoflavones: 3-Phenylchromones. Isomeric form of flavones in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position. [NIH] Isoflurane: A stable, non-explosive inhalation anesthetic, relatively free from significant side effects. [NIH] Isomerases: A class of enzymes that catalyze geometric or structural changes within a molecule to form a single product. The reactions do not involve a net change in the concentrations of compounds other than the substrate and the product.(from Dorland, 28th ed) EC 5. [NIH] Isometric Contraction: Muscular contractions characterized by increase in tension without change in length. [NIH]

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Isoproterenol: Isopropyl analog of epinephrine; beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract, etc. It is used mainly as bronchodilator and heart stimulant. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kainate: Glutamate receptor. [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] Keloid: A sharply elevated, irregularly shaped, progressively enlarging scar resulting from formation of excessive amounts of collagen in the dermis during connective tissue repair. It is differentiated from a hypertrophic scar (cicatrix, hypertrophic) in that the former does not spread to surrounding tissues. [NIH] Keratolytic: An agent that promotes keratolysis. [EU] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] 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] Killer Cells: Lymphocyte-like effector cells which mediate antibody-dependent cell cytotoxicity. They kill antibody-coated target cells which they bind with their Fc receptors. [NIH]

Kinetic: Pertaining to or producing motion. [EU] Kynurenic Acid: A broad-spectrum excitatory amino acid antagonist used as a research tool. [NIH]

Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an

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osseous and a membranous portion. [NIH] Laceration: 1. The act of tearing. 2. A torn, ragged, mangled wound. [EU] Lacrimal: Pertaining to the tears. [EU] Lactation: The period of the secretion of milk. [EU] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] 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] Laser Surgery: The use of a laser either to vaporize surface lesions or to make bloodless cuts in tissue. It does not include the coagulation of tissue by laser. [NIH] Laser therapy: The use of an intensely powerful beam of light to kill cancer cells. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Latent period: A seemingly inactive period, as that between exposure of tissue to an injurious agent and the manifestation of response, or that between the instant of stimulation and the beginning of response. [EU] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

Lectins: Protein or glycoprotein substances, usually of plant origin, that bind to sugar moieties in cell walls or membranes and thereby change the physiology of the membrane to cause agglutination, mitosis, or other biochemical changes in the cell. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] 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]

Leucovorin: The active metabolite of folic acid. Leucovorin is used principally as its calcium salt as an antidote to folic acid antagonists which block the conversion of folic acid to folinic acid. [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

Dictionary 609

of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [NIH] Levodopa: The naturally occurring form of dopa and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonism and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. [NIH] Levorphanol: A narcotic analgesic that may be habit-forming. It is nearly as effective orally as by injection. [NIH] Lewy Body Disease: Abnormal structure present in the surviving neurons of Parkinson's patients. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Limbic System: A set of forebrain structures common to all mammals that is defined functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival behaviors (feeding, mating, emotion). For most authors, it includes the amygdala, epithalamus, gyrus cinguli, hippocampal formation (see hippocampus), hypothalamus, parahippocampal gyrus, septal nuclei, anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] 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]

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Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [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 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] Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] 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] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Lobectomy: The removal of a lobe. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Lofepramine: A psychotropic imipramine derivative that acts as a tricyclic antidepressant and possesses few anticholinergic properties. It is metabolized to desipramine. [NIH] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Loss of Heterozygosity: The loss of one allele at a specific locus, caused by a deletion mutation; or loss of a chromosome from a chromosome pair. It is detected when heterozygous markers for a locus appear monomorphic because one of the alleles was deleted. When this occurs at a tumor suppressor gene locus where one of the alleles is already abnormal, it can result in neoplastic transformation. [NIH] Lovastatin: A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. [NIH] Low Back Pain: Acute or chronic pain in the lumbar or sacral regions, which may be associated with musculo-ligamentous sprains and strains; intervertebral disk displacement; and other conditions. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH]

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Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lumbar puncture: A procedure in which a needle is put into the lower part of the spinal column to collect cerebrospinal fluid or to give anticancer drugs intrathecally. Also called a spinal tap. [NIH] Lumen: The cavity or channel within a tube or tubular organ. [EU] Lung Transplantation: The transference of either one or both of the lungs from one human or animal to another. [NIH] Lung volume: The amount of air the lungs hold. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocyte Count: A count of the number of lymphocytes in the blood. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokines: Soluble protein factors generated by activated lymphocytes that affect other cells, primarily those involved in cellular immunity. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macrophage Activation: The process of altering the morphology and functional activity of macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (MAF) and the macrophage migration-inhibitory factor (MMIF), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. [NIH] Magnesium Hydroxide: Magnesium hydroxide (Mg(OH)2). An inorganic compound that occurs in nature as the mineral brucite. It acts as an antacid with cathartic effects. [NIH]

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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] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Malondialdehyde: The dialdehyde of malonic acid. [NIH] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [NIH] Mania: Excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behaviour, and elevation of mood. [EU] Manic: Affected with mania. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mastication: The act and process of chewing and grinding food in the mouth. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Measles Virus: The type species of morbillivirus and the cause of the highly infectious human disease measles, which affects mostly children. [NIH] Meatus: A canal running from the internal auditory foramen through the petrous portion of the temporal bone. It gives passage to the facial and auditory nerves together with the auditory branch of the basilar artery and the internal auditory veins. [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] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH]

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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] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Memory Disorders: Disturbances in registering an impression, in the retention of an acquired impression, or in the recall of an impression. Memory impairments are associated with dementia; craniocerebraltrauma; encephalitis; alcoholism (see also alcohol amnestic disorder); schizophrenia; and other conditions. [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] Menopause: Permanent cessation of menstruation. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental deficiency: A condition of arrested or incomplete development of mind from

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inherent causes or induced by disease or injury. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] 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] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methoxsalen: A naturally occurring furocoumarin compound found in several species of plants, including Psoralea corylifolia. It is a photoactive substance that forms DNA adducts in the presence of ultraviolet A irradiation. [NIH] Methylphenidate: A central nervous system stimulant used most commonly in the treatment of attention-deficit disorders in children and for narcolepsy. Its mechanisms appear to be similar to those of dextroamphetamine. [NIH] Metronidazole: Antiprotozoal used in amebiasis, trichomoniasis, giardiasis, and as treponemacide in livestock. It has also been proposed as a radiation sensitizer for hypoxic cells. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985, p133), this substance may reasonably be anticipated to be a carcinogen (Merck, 11th ed). [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH]

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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] Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [NIH] Micronuclei: Nuclei, separate from and additional to the main nucleus of a cell, produced during the telophase of mitosis or meiosis by lagging chromosomes or chromosome fragments derived from spontaneous or experimentally induced chromosomal structural changes. This concept also includes the smaller, reproductive nuclei found in multinucleate protozoans. [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] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [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 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] Microwaves: That portion of the electromagnetic spectrum lying between UHF (ultrahigh frequency) radio waves and heat (infrared) waves. Microwaves are used to generate heat, especially in some types of diathermy. They may cause heat damage to tissues. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mineralization: The action of mineralizing; the state of being mineralized. [EU] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] Minocycline: A semisynthetic staphylococcus infections. [NIH]

antibiotic

effective

against

tetracycline-resistant

Minor Histocompatibility Antigens: Allelic alloantigens often responsible for weak graft rejection in cases when (major) histocompatibility has been established by standard tests. In the mouse they are coded by more than 500 genes at up to 30 minor histocompatibility loci. The most well-known minor histocompatibility antigen in mammals is the H-Y antigen. [NIH]

Minor Histocompatibility Loci: Genetic loci responsible for the encoding of histocompatibility antigens other than those encoded by the major histocompatibility complex. The antigens encoded by these genes are often responsible for graft rejection in cases where histocompatibility has been established by standard tests. The location of some of these loci on the X and Y chromosomes explains why grafts from males to females may be

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rejected while grafts from females to males are accepted. In the mouse roughly 30 minor histocompatibility loci have been recognized, comprising more than 500 genes. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mitoxantrone: An anthracenedione-derived antineoplastic agent. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [NIH] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Mollicutes: A class of gram-negative bacteria consisting of cells bounded by a plasma membrane. Its organisms differ from other bacteria in that they are devoid of cell walls. It contains a single order, Mycoplasmatales. [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] Monoamine: Enzyme that breaks down dopamine in the astrocytes and microglia. [NIH] Monoamine Oxidase: An enzyme that catalyzes the oxidative deamination of naturally occurring monoamines. It is a flavin-containing enzyme that is localized in mitochondrial membranes, whether in nerve terminals, the liver, or other organs. Monoamine oxidase is important in regulating the metabolic degradation of catecholamines and serotonin in neural or target tissues. Hepatic monoamine oxidase has a crucial defensive role in inactivating circulating monoamines or those, such as tyramine, that originate in the gut and are absorbed into the portal circulation. (From Goodman and Gilman's, The Pharmacological

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Basis of Therapeutics, 8th ed, p415) EC 1.4.3.4. [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] Monocular: Diplopia identified with one eye only; it may be induced with a double prism, or it may occur either as a result of double imagery due to an optical defect in the eye, or as a result of simultaneous use of normal and anomalous retinal correspondence. [NIH] Monocyte: A type of white blood cell. [NIH] Monocyte Chemoattractant Protein-1: A chemokine that is a chemoattractant for human monocytes and may also cause cellular activation of specific functions related to host defense. It is produced by leukocytes of both monocyte and lymphocyte lineage and by fibroblasts during tissue injury. [NIH] Monogenic: A human disease caused by a mutation in a single gene. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morbillivirus: A genus of the family Paramyxoviridae (subfamily Paramyxovirinae) where all the virions have hemagglutinin but not neuraminidase activity. All members produce both cytoplasmic and intranuclear inclusion bodies. MEASLES VIRUS is the type species. [NIH]

Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]

Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Motor Activity: The physical activity of an organism as a behavioral phenomenon. [NIH] 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] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU]

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Mucosa: A mucous membrane, or tunica mucosa. [EU] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [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] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [NIH] Muscle Denervation: The resection or removal of the innervation of a muscle or muscle tissue. [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] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [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] Mutagenic: Inducing genetic mutation. [EU] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myasthenia: Muscular debility; any constitutional anomaly of muscle. [EU] Mycosis: Any disease caused by a fungus. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelin Proteins: Proteins found in the myelin sheath. The major proteins of central nervous system myelin include: myelin proteolipid protein, myelin basic proteins, and myelinassociated glycoprotein. The major proteins of peripheral nervous system myelin include: myelin basic proteins (myelin p1 protein and myelin p2 protein), myelin p0 protein, and myelin-associated glycoprotein. [NIH] Myelin Sheath: The lipid-rich sheath investing many axons in both the central and peripheral nervous systems. The myelin sheath is an electrical insulator and allows faster and more energetically efficient conduction of impulses. The sheath is formed by the cell membranes of glial cells (Schwann cells in the peripheral and oligodendroglia in the central

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nervous system). Deterioration of the sheath in demyelinating diseases is a serious clinical problem. [NIH] Myelitis: Inflammation of the spinal cord. Relatively common etiologies include infections; autoimmune diseases; spinal cord; and ischemia (see also spinal cord vascular diseases). Clinical features generally include weakness, sensory loss, localized pain, incontinence, and other signs of autonomic dysfunction. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myofibrils: Highly organized bundles of actin, myosin, and other proteins in the cytoplasm of skeletal and cardiac muscle cells that contract by a sliding filament mechanism. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. [NIH] Naltrexone: Derivative of noroxymorphone that is the N-cyclopropylmethyl congener of naloxone. It is a narcotic antagonist that is effective orally, longer lasting and more potent than naloxone, and has been proposed for the treatment of heroin addiction. The FDA has approved naltrexone for the treatment of alcohol dependence. [NIH]

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Narcolepsy: A condition of unknown cause characterized by a periodic uncontrollable tendency to fall asleep. [NIH] Narcosis: A general and nonspecific reversible depression of neuronal excitability, produced by a number of physical and chemical aspects, usually resulting in stupor. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Nasal Polyps: Focal accumulations of edema fluid in the nasal mucosa accompanied by hyperplasia of the associated submucosal connective tissue. Polyps may be neoplasms, foci of inflammation, degenerative lesions, or malformations. [NIH] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [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] Neck Pain: Discomfort or more intense forms of pain that are localized to the cervical region. This term generally refers to pain in the posterior or lateral regions of the neck. [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] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Needs Assessment: Systematic identification of a population's needs or the assessment of individuals to determine the proper level of services needed. [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] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephrectomy: Surgery to remove a kidney. Radical nephrectomy removes the kidney, the adrenal gland, nearby lymph nodes, and other surrounding tissue. Simple nephrectomy removes only the kidney. Partial nephrectomy removes the tumor but not the entire kidney. [NIH]

Nephrology: A subspecialty of internal medicine concerned with the anatomy, physiology, and pathology of the kidney. [NIH] Nephron: A tiny part of the kidneys. Each kidney is made up of about 1 million nephrons, which are the working units of the kidneys, removing wastes and extra fluids from the blood. [NIH]

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Nephropathy: Disease of the kidneys. [EU] Nephrosis: Descriptive histopathologic term for renal disease without an inflammatory component. [NIH] Nephrotic: Pertaining to, resembling, or caused by nephrosis. [EU] Nephrotic Syndrome: Clinical association of heavy proteinuria, hypoalbuminemia, and generalized edema. [NIH] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [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 Endings: Specialized terminations of peripheral neurons. Nerve endings include neuroeffector junction(s) by which neurons activate target organs and sensory receptors which transduce information from the various sensory modalities and send it centrally in the nervous system. Presynaptic nerve endings are presynaptic terminals. [NIH] Nerve Fibers: Slender processes of neurons, especially the prolonged axons that conduct nerve impulses. [NIH] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural Pathways: Neural tracts connecting one part of the nervous system with another. [NIH]

Neuralgia: Intense or aching pain that occurs along the course or distribution of a peripheral or cranial nerve. [NIH] Neuritis: A general term indicating inflammation of a peripheral or cranial nerve. Clinical manifestation may include pain; paresthesias; paresis; or hypesthesia. [NIH] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurofibrillary Tangles: Abnormal structures located in various parts of the brain and composed of dense arrays of paired helical filaments (neurofilaments and microtubules).

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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] Neuroglia: The non-neuronal cells of the nervous system. They are divided into macroglia (astrocytes, oligodendroglia, and schwann cells) and microglia. They not only provide physical support, but also respond to injury, regulate the ionic and chemical composition of the extracellular milieu, participate in the blood-brain and blood-retina barriers, form the myelin insulation of nervous pathways, guide neuronal migration during development, and exchange metabolites with neurons. Neuroglia have high-affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitters, but their role in signaling (as in many other functions) is unclear. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurologic Manifestations: Clinical signs and symptoms caused by nervous system injury or dysfunction. [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] 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] Neuropsychological Tests: Tests designed to assess neurological function associated with certain behaviors. They are used in diagnosing brain dysfunction or damage and central

Dictionary 623

nervous system disorders or injury. [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]

Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH] Neurotrophins: A nerve growth factor. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophil: A type of white blood cell. [NIH] 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] Nifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful antianginal agent that also lowers blood pressure. The use of nifedipine as a tocolytic is being investigated. [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] Nitrogen Dioxide: Nitrogen oxide (NO2). A highly poisonous gas. Exposure produces inflammation of lungs that may only cause slight pain or pass unnoticed, but resulting edema several days later may cause death. (From Merck, 11th ed) It is a major atmospheric pollutant that is able to absorb UV light that does not reach the earth's surface. [NIH] Nitrous Oxide: Nitrogen oxide (N2O). A colorless, odorless gas that is used as an anesthetic and analgesic. High concentrations cause a narcotic effect and may replace oxygen, causing death by asphyxia. It is also used as a food aerosol in the preparation of whipping cream. [NIH]

Nocturia: Excessive urination at night. [EU]

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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] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nystagmus: Rhythmical oscillation of the eyeballs, either pendular or jerky. [NIH] Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Occipital Lobe: Posterior part of the cerebral hemisphere. [NIH] Occult: Obscure; concealed from observation, difficult to understand. [EU] Occupational Therapy: The field concerned with utilizing craft or work activities in the rehabilitation of patients. Occupational therapy can also refer to the activities themselves. [NIH]

Octreotide: A potent, long-acting somatostatin octapeptide analog which has a wide range of physiological actions. It inhibits growth hormone secretion, is effective in the treatment of hormone-secreting tumors from various organs, and has beneficial effects in the management of many pathological states including diabetes mellitus, orthostatic hypertension, hyperinsulinism, hypergastrinemia, and small bowel fistula. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Oculomotor: Cranial nerve III. It originate from the lower ventral surface of the midbrain and is classified as a motor nerve. [NIH] Oculomotor Nerve: The 3d cranial nerve. The oculomotor nerve sends motor fibers to the levator muscles of the eyelid and to the superior rectus, inferior rectus, and inferior oblique muscles of the eye. It also sends parasympathetic efferents (via the ciliary ganglion) to the muscles controlling pupillary constriction and accommodation. The motor fibers originate in the oculomotor nuclei of the midbrain. [NIH] Oedema: The presence of abnormally large amounts of fluid in the intercellular tissue spaces of the body; usually applied to demonstrable accumulation of excessive fluid in the

Dictionary 625

subcutaneous tissues. Edema may be localized, due to venous or lymphatic obstruction or to increased vascular permeability, or it may be systemic due to heart failure or renal disease. Collections of edema fluid are designated according to the site, e.g. ascites (peritoneal cavity), hydrothorax (pleural cavity), and hydropericardium (pericardial sac). Massive generalized edema is called anasarca. [EU] Olfaction: Function of the olfactory apparatus to perceive and discriminate between the molecules that reach it, in gas form from an external environment, directly or indirectly via the nose. [NIH] Oligodendroglia: A class of neuroglial (macroglial) cells in the central nervous system. Oligodendroglia may be called interfascicular, perivascular, or perineuronal satellite cells according to their location. The most important recognized function of these cells is the formation of the insulating myelin sheaths of axons in the central nervous system. [NIH] Oligodendroglial: A cell that lays down myelin. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Opacity: Degree of density (area most dense taken for reading). [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] Ophthalmology: A surgical specialty concerned with the structure and function of the eye and the medical and surgical treatment of its defects and diseases. [NIH] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]

Optic disc: The circular area (disc) where the optic nerve connects to the retina. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Optic Neuritis: Inflammation of the optic nerve. Commonly associated conditions include autoimmune disorders such as multiple sclerosis, infections, and granulomatous diseases. Clinical features include retro-orbital pain that is aggravated by eye movement, loss of color vision, and contrast sensitivity that may progress to severe visual loss, an afferent pupillary

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defect (Marcus-Gunn pupil), and in some instances optic disc hyperemia and swelling. Inflammation may occur in the portion of the nerve within the globe (neuropapillitis or anterior optic neuritis) or the portion behind the globe (retrobulbar neuritis or posterior optic neuritis). [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Hygiene: The practice of personal hygiene of the mouth. It includes the maintenance of oral cleanliness, tissue tone, and general preservation of oral health. [NIH] Oral Manifestations: Disorders of the mouth attendant upon non-oral disease or injury. [NIH]

Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU] 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] Ornithine: An amino acid produced in the urea cycle by the splitting off of urea from arginine. [NIH] Ornithine Decarboxylase: A pyridoxal-phosphate protein, believed to be the rate-limiting compound in the biosynthesis of polyamines. It catalyzes the decarboxylation of ornithine to form putrescine, which is then linked to a propylamine moiety of decarboxylated Sadenosylmethionine to form spermidine. EC 4.1.1.17. [NIH] Orofacial: Of or relating to the mouth and face. [EU] Orthostatic: Pertaining to or caused by standing erect. [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Otitis: Inflammation of the ear, which may be marked by pain, fever, abnormalities of hearing, hearing loss, tinnitus, and vertigo. [EU] Otitis Media: Inflammation of the middle ear. [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] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous

Dictionary 627

antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [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]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] 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] Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH] Panic Disorder: A type of anxiety disorder characterized by unexpected panic attacks that last minutes or, rarely, hours. Panic attacks begin with intense apprehension, fear or terror and, often, a feeling of impending doom. Symptoms experienced during a panic attack include dyspnea or sensations of being smothered; dizziness, loss of balance or faintness; choking sensations; palpitations or accelerated heart rate; shakiness; sweating; nausea or other form of abdominal distress; depersonalization or derealization; paresthesias; hot flashes or chills; chest discomfort or pain; fear of dying and fear of not being in control of oneself or going crazy. Agoraphobia may also develop. Similar to other anxiety disorders, it may be inherited as an autosomal dominant trait. [NIH] Papilla: A small nipple-shaped elevation. [NIH]

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Papillary: Pertaining to or resembling papilla, or nipple. [EU] Paraesthesia: Morbid or perverted sensation; an abnormal sensation, as burning, prickling, formication, etc. [EU] Paralysis: Loss of ability to move all or part of the body. [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] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH] Parenchyma: The essential elements of an organ; used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework, or stroma. [EU] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paresis: A general term referring to a mild to moderate degree of muscular weakness, occasionally used as a synonym for paralysis (severe or complete loss of motor function). In the older literature, paresis often referred specifically to paretic neurosyphilis. "General paresis" and "general paralysis" may still carry that connotation. Bilateral lower extremity paresis is referred to as paraparesis. [NIH] Paresthesia: Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. [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] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Parturition: The act or process of given birth to a child. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Dictionary 629

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Advocacy: Promotion and protection of the rights of patients, frequently through a legal process. [NIH] Patient Compliance: Voluntary cooperation of the patient in following a prescribed regimen. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Pedigree: A record of one's ancestors, offspring, siblings, and their offspring that may be used to determine the pattern of certain genes or disease inheritance within a family. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pemoline: A central nervous system stimulant used in fatigue and depressive states and to treat hyperkinetic disorders in children. [NIH] Pemphigus: Group of chronic blistering diseases characterized histologically by acantholysis and blister formation within the epidermis. [NIH] Penicillamine: 3-Mercapto-D-valine. The most characteristic degradation product of the penicillin antibiotics. It is used as an antirheumatic and as a chelating agent in Wilson's disease. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Pepsin A: Formed from pig pepsinogen by cleavage of one peptide bond. The enzyme is a single polypeptide chain and is inhibited by methyl 2-diaazoacetamidohexanoate. It cleaves peptides preferentially at the carbonyl linkages of phenylalanine or leucine and acts as the principal digestive enzyme of gastric juice. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Fragments: Partial proteins formed by partial hydrolysis of complete proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [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

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multiple sets of these or other symbols such as geometric figures. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perennial: Lasting through the year of for several years. [EU] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [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] Peripheral stem cell transplantation: A method of replacing blood-forming cells destroyed by cancer treatment. Immature blood cells (stem cells) in the circulating blood that are similar to those in the bone marrow are given after treatment to help the bone marrow recover and continue producing healthy blood cells. Transplantation may be autologous (an individual's own blood cells saved earlier), allogeneic (blood cells donated by someone else), or syngeneic (blood cells donated by an identical twin). Also called peripheral stem cell support. [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Peripheral vision: Side vision; ability to see objects and movement outside of the direct line of vision. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH]

Dictionary 631

Peritoneal Dialysis: Dialysis fluid being introduced into and removed from the peritoneal cavity as either a continuous or an intermittent procedure. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] 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] Perspiration: Sweating; the functional secretion of sweat. [EU] Petechiae: Pinpoint, unraised, round red spots under the skin caused by bleeding. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Phallic: Pertaining to the phallus, or penis. [EU] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phonophoresis: Use of ultrasound to increase the percutaneous adsorption of drugs. [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] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphoprotein Phosphatase: A group of enzymes removing the serine- or threoninebound phosphate groups from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. (Enzyme Nomenclature, 1992) EC 3.1.3.16. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a

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terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylates: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Phototherapy: Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physical Fitness: A state of well-being in which performance is optimal, often as a result of physical conditioning which may be prescribed for disease therapy. [NIH] Physical Therapy: The restoration of function and the prevention of disability following disease or injury with the use of light, heat, cold, water, electricity, ultrasound, and exercise. [NIH]

Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Phytic Acid: Complexing agent for removal of traces of heavy metal ions. It acts also as a hypocalcemic agent. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Piloerection: Involuntary erection or bristling of hairs. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pineal Body: A small conical midline body attached to the posterior part of the third ventricle and lying between the superior colliculi, below the splenium of the corpus callosum. [NIH] Pineal gland: A tiny organ located in the cerebrum that produces melatonin. Also called pineal body or pineal organ. [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]

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Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma Exchange: Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (PPF), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasma Volume: Volume of plasma in the circulation. It is usually measured by indicator dilution techniques. [NIH] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [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] Platelet-Derived Growth Factor: Mitogenic peptide growth hormone carried in the alpha-

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granules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. [NIH] Plateletpheresis: The preparation of platelet concentrates with the return of red cells and platelet-poor plasma to the donor. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pleura: The thin serous membrane enveloping the lungs and lining the thoracic cavity. [NIH] Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Pleural cavity: A space enclosed by the pleura (thin tissue covering the lungs and lining the interior wall of the chest cavity). It is bound by thin membranes. [NIH] Ploidy: The number of sets of chromosomes in a cell or an organism. For example, haploid means one set and diploid means two sets. [NIH] Pneumoconiosis: Condition characterized by permanent deposition of substantial amounts of particulate matter in the lungs, usually of occupational or environmental origin, and by the tissue reaction to its presence. [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] Point System: A way to plan meals that uses points to rate food. The foods are placed in four classes: calories, carbohydrates, proteins, and fats. Each food is given a point value within its class. A person with a planned diet for the day can choose foods in the same class that have the same point values for meals and snacks. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polyarteritis Nodosa: A form of necrotizing vasculitis involving small- and medium-sized arteries. The signs and symptoms result from infarction and scarring of the affected organ system. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] 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] Polyploid: An organism with more than two chromosome sets in its vegetative cells. [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polytherapy: A therapy which uses more than one drug. [EU] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from

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plants, including safflower, sunflower, corn, and soybean oils. [NIH] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] Postal Service: The functions and activities carried out by the U.S. Postal Service, foreign postal services, and private postal services such as Federal Express. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postherpetic Neuralgia: Variety of neuralgia associated with migraine in which pain is felt in or behind the eye. [NIH] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] 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] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium hydroxide: A toxic and highly corrosive chemical used to make soap, in bleaching, and as a paint remover. It is used in small amounts as a food additive and in the preparatrion of some drugs. [NIH] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiating: 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] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [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] Predisposition: A latent susceptibility to disease which may be activated under certain

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conditions, as by stress. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Prefrontal Cortex: The rostral part of the frontal lobe, bounded by the inferior precentral fissure in humans, which receives projection fibers from the mediodorsal nucleus of the thalamus. The prefrontal cortex receives afferent fibers from numerous structures of the diencephalon, mesencephalon, and limbic system as well as cortical afferents of visual, auditory, and somatic origin. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prenatal Diagnosis: Determination of the nature of a pathological condition or disease in the postimplantation embryo, fetus, or pregnant female before birth. [NIH] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prion: Small proteinaceous infectious particles that resist inactivation by procedures modifying nucleic acids and contain an abnormal isoform of a cellular protein which is a major and necessary component. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] 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] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [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 Bulbar Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH] 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] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [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]

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Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prosthesis: An artificial replacement of a part of the body. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent. [NIH]

Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-

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binding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Folding: A rapid biochemical reaction involved in the formation of proteins. It begins even before a protein has been completely synthesized and proceeds through discrete intermediates (primary, secondary, and tertiary structures) before the final structure (quaternary structure) is developed. [NIH] Protein 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 Subunits: Single chains of amino acids that are the units of a multimeric protein. They can be identical or non-identical subunits. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Protein-Tyrosine Kinase: An enzyme that catalyzes the phosphorylation of tyrosine residues in proteins with ATP or other nucleotides as phosphate donors. EC 2.7.1.112. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycans: Glycoproteins which have a very high polysaccharide content. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]

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] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH]

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Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychotomimetic: Psychosis miming. [NIH] Psychotropic: Exerting an effect upon the mind; capable of modifying mental activity; usually applied to drugs that effect the mental state. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Fibrosis: Chronic inflammation and progressive fibrosis of the pulmonary alveolar walls, with steadily progressive dyspnea, resulting finally in death from oxygen lack or right heart failure. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] 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]

Pupil: The aperture in the iris through which light passes. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Putrescine: A toxic diamine formed by putrefaction from the decarboxylation of arginine and ornithine. [NIH] Pyramidal Cells: Projection neurons in the cerebral cortex and the hippocampus. Pyramidal cells have a pyramid-shaped soma with the apex and an apical dendrite pointed toward the pial surface and other dendrites and an axon emerging from the base. The axons may have local collaterals but also project outside their cortical region. [NIH] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Quadriplegia: Severe or complete loss of motor function in all four limbs which may result from brain diseases; spinal cord diseases; peripheral nervous system diseases; neuromuscular diseases; or rarely muscular diseases. The locked-in syndrome is characterized by quadriplegia in combination with cranial muscle paralysis. Consciousness

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is spared and the only retained voluntary motor activity may be limited eye movements. This condition is usually caused by a lesion in the upper brain stem which injures the descending cortico-spinal and cortico-bulbar tracts. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Quiescent: Marked by a state of inactivity or repose. [EU] Quinidine: An optical isomer of quinine, extracted from the bark of the Cinchona tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular action potential, and decreases automaticity. Quinidine also blocks muscarinic and alphaadrenergic neurotransmission. [NIH] Quinine: An alkaloid derived from the bark of the cinchona tree. It is used as an antimalarial drug, and is the active ingredient in extracts of the cinchona that have been used for that purpose since before 1633. Quinine is also a mild antipyretic and analgesic and has been used in common cold preparations for that purpose. It was used commonly and as a bitter and flavoring agent, and is still useful for the treatment of babesiosis. Quinine is also useful in some muscular disorders, especially nocturnal leg cramps and myotonia congenita, because of its direct effects on muscle membrane and sodium channels. The mechanisms of its antimalarial effects are not well understood. [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] Radio Waves: That portion of the electromagnetic spectrum beyond the microwaves, with wavelengths as high as 30 KM. They are used in communications, including television. Short Wave or HF (high frequency), UHF (ultrahigh frequency) and VHF (very high frequency) waves are used in citizen's band communication. [NIH] Radioactive: Giving off radiation. [NIH] Radioimmunoassay: Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Nonimmunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire.

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Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [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] Radiolabeled: Any compound that has been joined with a radioactive substance. [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] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] 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] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reaction Time: The time from the onset of a stimulus until the organism responds. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] 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

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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] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [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] Reductase: Enzyme converting testosterone to dihydrotestosterone. [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] Refractive Errors: Deviations from the average or standard indices of refraction of the eye through its dioptric or refractive apparatus. [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] 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] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Relaxin: Hormone produced by the ovaries during pregnancy that loosens ligaments that hold the hip bones together. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH]

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Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Repopulation: The replacement of functional cells, usually by proliferation, following or during irradiation. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Reproductive system: In women, this system includes the ovaries, the fallopian tubes, the uterus (womb), the cervix, and the vagina (birth canal). The reproductive system in men includes the prostate, the testes, and the penis. [NIH] Research Design: A plan for collecting and utilizing data so that desired information can be obtained with sufficient precision or so that an hypothesis can be tested properly. [NIH] Resected: Surgical removal of part of an organ. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Residual Volume: The volume of air remaining in the lungs at the end of a maximal expiration. Common abbreviation is RV. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respirator: A mechanical device that helps a patient breathe; a mechanical ventilator. [NIH] Respiratory Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines

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with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retrobulbar: Behind the pons. [EU] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] Retrospective: Looking back at events that have already taken place. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rheumatic Diseases: Disorders of connective tissue, especially the joints and related structures, characterized by inflammation, degeneration, or metabolic derangement. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] 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] Rods: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide side vision and the ability to see objects in dim light (night vision). [NIH]

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Rolipram: A phosphodiesterase inhibitor with antidepressant properties. [NIH] Saimiri: A genus of the family Cebidae consisting of four species: S. boliviensis, S. orstedii (red-backed squirrel monkey), S. sciureus (common squirrel monkey), and S. ustus. They inhabit tropical rain forests in Central and South America. S. sciureus is used extensively in research studies. [NIH] Saline: A solution of salt and water. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] 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] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Satellite: Applied to a vein which closely accompanies an artery for some distance; in cytogenetics, a chromosomal agent separated by a secondary constriction from the main body of the chromosome. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] 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] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Sclerotic: Pertaining to the outer coat of the eye; the sclera; hard, indurated or sclerosed. [NIH]

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Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sedentary: 1. Sitting habitually; of inactive habits. 2. Pertaining to a sitting posture. [EU] 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] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selegiline: A selective, irreversible inhibitor of Type B monoamine oxidase. It is used in newly diagnosed patients with Parkinson's disease. It may slow progression of the clinical disease and delay the requirement for levodopa therapy. It also may be given with levodopa upon onset of disability. (From AMA Drug Evaluations Annual, 1994, p385) The compound without isomeric designation is Deprenyl. [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] Self-Help Groups: Organizations which provide an environment encouraging social interactions through group activities or individual relationships especially for the purpose of rehabilitating or supporting patients, individuals with common health problems, or the elderly. They include therapeutic social clubs. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semicircular canal: Three long canals of the bony labyrinth of the ear, forming loops and opening into the vestibule by five openings. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensibility: The ability to receive, feel and appreciate sensations and impressions; the quality of being sensitive; the extend to which a method gives results that are free from false

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negatives. [NIH] Sensory loss: A disease of the nerves whereby the myelin or insulating sheath of myelin on the nerves does not stay intact and the messages from the brain to the muscles through the nerves are not carried properly. [NIH] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Sexually Transmitted Diseases: Diseases due to or propagated by sexual contact. [NIH] Sharpness: The apparent blurring of the border between two adjacent areas of a radiograph having different optical densities. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an

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activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Silicon: A trace element that constitutes about 27.6% of the earth's crust in the form of silicon dioxide. It does not occur free in nature. Silicon has the atomic symbol Si, atomic number 14, and atomic weight 28.09. [NIH] Silicon Dioxide: Silica. Transparent, tasteless crystals found in nature as agate, amethyst, chalcedony, cristobalite, flint, sand, quartz, and tridymite. The compound is insoluble in water or acids except hydrofluoric acid. [NIH] Single Person: The unmarried man or woman. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin Manifestations: Dermatologic disorders attendant upon non-dermatologic disease or injury. [NIH] Skin Tests: Epicutaneous or intradermal application of a sensitizer for demonstration of either delayed or immediate hypersensitivity. Used in diagnosis of hypersensitivity or as a test for cellular immunity. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep Paralysis: A state experienced by a person while going to sleep or on waking: consciousness is present but muscular movement is lost as well as the ability to speak. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smallpox: A generalized virus infection with a vesicular rash. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [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

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extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solitary Nucleus: Gray matter located in the dorsomedial part of the medulla oblongata associated with the solitary tract. The solitary nucleus receives inputs from most organ systems including the terminations of the facial, glossopharyngeal, and vagus nerves. It is a major coordinator of autonomic nervous system regulation of cardiovascular, respiratory, gustatory, gastrointestinal, and chemoreceptive aspects of homeostasis. The solitary nucleus is also notable for the large number of neurotransmitters which are found therein. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. [NIH] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [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] Soybean Oil: Oil from soybean or soybean plant. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [NIH] Spasmodic: Of the nature of a spasm. [EU] 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] Spatial disorientation: Loss of orientation in space where person does not know which way is up. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters

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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] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Speech 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] Spermidine: A polyamine formed from putrescine. It is found in almost all tissues in association with nucleic acids. It is found as a cation at all pH values, and is thought to help stabilize some membranes and nucleic acid structures. It is a precursor of spermine. [NIH] Sphincter: A ringlike band of muscle fibres that constricts a passage or closes a natural orifice; called also musculus sphincter. [EU] Spina bifida: A defect in development of the vertebral column in which there is a central deficiency of the vertebral lamina. [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 Cord Injuries: Penetrating and non-penetrating injuries to the spinal cord resulting from traumatic external forces (e.g., wounds, gunshot; whiplash injuries; etc.). [NIH] Spinal Cord Vascular Diseases: Hypoxic-ischemic and hemorrhagic disorders of the spinal cord. Arteriosclerosis, emboli, and vascular malformations are potential causes of these conditions. [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] Spinal tap: A procedure in which a needle is put into the lower part of the spinal column to collect cerebrospinal fluid or to give anticancer drugs intrathecally. Also called a lumbar puncture. [NIH] Spirochete: Lyme disease. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Spondylitis: Inflammation of the vertebrae. [EU] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated

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manner. [EU] Sprains and Strains: A collective term for muscle and ligament injuries without dislocation or fracture. A sprain is a joint injury in which some of the fibers of a supporting ligament are ruptured but the continuity of the ligament remains intact. A strain is an overstretching or overexertion of some part of the musculature. [NIH] Squamous: Scaly, or platelike. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] 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] Status Epilepticus: Repeated and prolonged epileptic seizures without recovery of consciousness between attacks. [NIH] Stem cell transplantation: A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells. [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] Sterile: Unable to produce children. [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] Steroid therapy: Treatment with corticosteroid drugs to reduce swelling, pain, and other symptoms of inflammation. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strabismus: Deviation of the eye which the patient cannot overcome. The visual axes assume a position relative to each other different from that required by the physiological conditions. The various forms of strabismus are spoken of as tropias, their direction being indicated by the appropriate prefix, as cyclo tropia, esotropia, exotropia, hypertropia, and hypotropia. Called also cast, heterotropia, manifest deviation, and squint. [EU]

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Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptavidin: A 60kD extracellular protein of Streptomyces avidinii with four high-affinity biotin binding sites. Unlike AVIDIN, streptavidin has a near neutral isoelectric point and is free of carbohydrate side chains. [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] Stress management: A set of techniques used to help an individual cope more effectively with difficult situations in order to feel better emotionally, improve behavioral skills, and often to enhance feelings of control. Stress management may include relaxation exercises, assertiveness training, cognitive restructuring, time management, and social support. It can be delivered either on a one-to-one basis or in a group format. [NIH] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stupor: Partial or nearly complete unconsciousness, manifested by the subject's responding only to vigorous stimulation. Also, in psychiatry, a disorder marked by reduced responsiveness. [EU] 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] Subculture: A culture derived from another culture or the aseptic division and transfer of a culture or a portion of that culture (inoculum) to fresh nutrient medium. [NIH] Subcutaneous: Beneath the skin. [NIH] 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] Subungual: Beneath a nail. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] 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]

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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] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Supraspinal: Above the spinal column or any spine. [NIH] Supraventricular: Situated or occurring above the ventricles, especially in an atrium or atrioventricular node. [EU] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sweat Glands: Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. [NIH] 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 nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of disease. [NIH] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic discussion of symptoms. 2. The combined symptoms of a disease. [EU] Synapses: Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate through direct electrical connections which are sometimes called electrical synapses; these are not included here but rather in gap junctions. [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

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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] Synaptosomes: Pinched-off nerve endings and their contents of vesicles and cytoplasm together with the attached subsynaptic area of the membrane of the post-synaptic cell. They are largely artificial structures produced by fractionation after selective centrifugation of nervous tissue homogenates. [NIH] Syncytium: A living nucleated tissue without apparent cellular structure; a tissue composed of a mass of nucleated protoplasm without cell boundaries. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synovial: Of pertaining to, or secreting synovia. [EU] Syphilis: A contagious venereal disease caused by the spirochete Treponema pallidum. [NIH]

Syringomyelia: The presence in the spinal cord of elongated central fluid containing cavities surrounded by gliosis. [NIH] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Systolic pressure: The highest pressure to which blood pressure rises with the contraction of the ventricles. [NIH] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telecommunications: Transmission of information over distances via electronic means. [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] Telophase: The final phase of cell division, in which two daughter nuclei are formed, the

Dictionary 655

cytoplasm divides, and the chromosomes lose their distinctness and are transformed into chromatin networks. [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] Temporal Lobe: Lower lateral part of the cerebral hemisphere. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Terbutaline: A selective beta-2 adrenergic agonist used as a bronchodilator and tocolytic. [NIH]

Terminal disease: Disease that cannot be cured and will cause death. [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 generalized form. [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] Tetrahydrocannabinol: A psychoactive compound extracted from the resin of Cannabis sativa (marihuana, hashish). The isomer delta-9-tetrahydrocannabinol (THC) is considered the most active form, producing characteristic mood and perceptual changes associated with this compound. Dronabinol is a synthetic form of delta-9-THC. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Thalamus: Paired bodies containing mostly gray substance and forming part of the lateral wall of the third ventricle of the brain. The thalamus represents the major portion of the diencephalon and is commonly divided into cellular aggregates known as nuclear groups. [NIH]

Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thermography: Measurement of the regional temperature of the body or an organ by infrared sensing devices, based on self-emanating infrared radiation. [NIH] Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH]

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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] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] 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]

Thrombopoietin: A humoral factor that controls blood platelet production through stimulation of megakaryocyte populations. Bone marrow megakaryocytes increase in both size and number in response to exposure to thrombopoietin. [NIH] Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thymidylate Synthase: An enzyme of the transferase class that catalyzes the reaction 5,10methylenetetrahydrofolate and dUMP to dihydrofolate and dTMP in the synthesis of thymidine triphosphate. (From Dorland, 27th ed) EC 2.1.1.45. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thymus Gland: A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. [NIH] Thymus Hormones: Humoral factors secreted by the thymus gland. They participate in the development of the lymphoid system and the maturation of the cellular immune response. [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] Thyroiditis: Inflammation of the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tic: An involuntary compulsive, repetitive, stereotyped movement, resembling a purposeful

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movement because it is coordinated and involves muscles in their normal synergistic relationships; tics usually involve the face and shoulders. [EU] Tidal Volume: The volume of air inspired or expired during each normal, quiet respiratory cycle. Common abbreviations are TV or V with subscript T. [NIH] Time Management: Planning and control of time to improve efficiency and effectiveness. [NIH]

Tin: A trace element that is required in bone formation. It has the atomic symbol Sn, atomic number 50, and atomic weight 118.71. [NIH] Tinnitus: Sounds that are perceived in the absence of any external noise source which may take the form of buzzing, ringing, clicking, pulsations, and other noises. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. [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] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tissue Plasminogen Activator: A proteolytic enzyme in the serine protease family found in many tissues which converts plasminogen to plasmin. It has fibrin-binding activity and is immunologically different from urinary plasminogen activator. The primary sequence, composed of 527 amino acids, is identical in both the naturally occurring and synthetic proteases. EC 3.4.21.68. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tome: A zone produced by a number of irregular spaces contained in the outermost layer of denture of the root of a tooth. [NIH] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] 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] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Total Lung Capacity: The volume of air contained in the lungs at the end of a maximal inspiration. It is the equivalent to each of the following sums: vital capacity plus residual volume; inspiratory capacity plus functional residual capacity; tidal volume plus inspiratory reserve volume plus functional residual capacity; tidal volume plus inspiratory reserve volume plus expiratory reserve volume plus residual volume. [NIH]

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Total-body irradiation: Radiation therapy to the entire body. Usually followed by bone marrow or peripheral stem cell transplantation. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [NIH] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Toxoid: The material resulting from the treatment of toxin in such a way that the toxic properties are inactivated whilst the antigenic potency remains intact. [NIH] 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] Tracheostomy: Surgical formation of an opening into the trachea through the neck, or the opening so created. [NIH] Transaminase: Aminotransferase (= a subclass of enzymes of the transferase class that catalyse the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally 2-keto acid). Most of these enzymes are pyridoxal-phosphate-proteins. [EU]

Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transcutaneous: Transdermal. [EU] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] 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]

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Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGFbeta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. [NIH]

Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]

Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [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] Triamcinolone Acetonide: An esterified form of triamcinolone. It is an anti-inflammatory glucocorticoid used topically in the treatment of various skin disorders. Intralesional, intramuscular, and intra-articular injections are also administered under certain conditions. [NIH]

Trichomoniasis: An infection with the protozoan parasite Trichomonas vaginalis. [NIH] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU] Trigeminal: Cranial nerve V. It is sensory for the eyeball, the conjunctiva, the eyebrow, the skin of face and scalp, the teeth, the mucous membranes in the mouth and nose, and is motor to the muscles of mastication. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Trochlear Nerve: The 4th cranial nerve. The trochlear nerve carries the motor innervation of the superior oblique muscles of the eye. [NIH] Trochlear Nerve Diseases: Diseases of the fourth cranial (trochlear) nerve or its nucleus in the midbrain. The nerve crosses as it exits the midbrain dorsally and may be injured along its course through the intracranial space, cavernous sinus, superior orbital fissure, or orbit. Clinical manifestations include weakness of the superior oblique muscle which causes

660 Sclerosis

vertical diplopia that is maximal when the affected eye is adducted and directed inferiorly. Head tilt may be seen as a compensatory mechanism for diplopia and rotation of the visual axis. Common etiologies include craniocerebral trauma and infratentorial neoplasms. [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] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tuberculin: A sterile liquid containing the growth products of, or specific substances extracted from, the tubercle bacillus; used in various forms in the diagnosis of tuberculosis. [NIH]

Tuberculin Test: One of several skin tests to determine past or present tuberculosis infection. A purified protein derivative of the tubercle bacilli, called tuberculin, is introduced into the skin by scratch, puncture, or interdermal injection. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] 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 Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tympanic membrane: A thin, tense membrane forming the greater part of the outer wall of the tympanic cavity and separating it from the external auditory meatus; it constitutes the boundary between the external and middle ear. [NIH] Tyramine: An indirect sympathomimetic. Tyramine does not directly activate adrenergic receptors, but it can serve as a substrate for adrenergic uptake systems and monoamine oxidase so it prolongs the actions of adrenergic transmitters. It also provokes transmitter release from adrenergic terminals. Tyramine may be a neurotransmitter in some invertebrate nervous systems. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH]

Dictionary 661

Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [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] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Univalent: Pertaining to an unpaired chromosome during the zygotene stage of prophase to first metaphase in meiosis. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] 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 Plasminogen Activator: A proteolytic enzyme that converts plasminogen to plasmin where the preferential cleavage is between arginine and valine. It was isolated originally from human urine, but is found in most tissues of most vertebrates. EC 3.4.21.73. [NIH]

Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]

Urinary urgency: Inability to delay urination. [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] Urodynamic: Measures of the bladder's ability to hold and release urine. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Urogenital Diseases: Diseases of the urogenital tract. [NIH] Urologic Diseases: Diseases of the urinary tract in both male and female. It does not include the male genitalia for which urogenital diseases is used for general discussions of diseases of both the urinary tract and the genitalia. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Uvea: The middle coat of the eyeball, consisting of the choroid in the back of the eye and the ciliary body and iris in the front of the eye. [NIH]

662 Sclerosis

Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [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] Vaccinia: The cutaneous and occasional systemic reactions associated with vaccination using smallpox (variola) vaccine. [NIH] Vaccinia Virus: The type species of Orthopoxvirus, related to cowpox virus, but whose true origin is unknown. It has been used as a live vaccine against smallpox. It is also used as a vector for inserting foreign DNA into animals. Rabbitpox virus is a subspecies of vaccinia virus. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] 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]

Variola: A generalized virus infection with a vesicular rash. [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] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasogenic: Acute peripheral circulatory failure due to loss of capillary tone associated with a reduced circulating blood volume. [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] Vegetative: 1. Concerned with growth and with nutrition. 2. Functioning involuntarily or unconsciously, as the vegetative nervous system. 3. Resting; denoting the portion of a cell cycle during which the cell is not involved in replication. 4. Of, pertaining to, or characteristic of plants. [EU] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venereal: Pertaining or related to or transmitted by sexual contact. [EU] Venlafaxine: An antidepressant drug that is being evaluated for the treatment of hot flashes in women who have breast cancer. [NIH]

Dictionary 663

Venom: That produced by the poison glands of the mouth and injected by the fangs of poisonous snakes. [NIH] Venous: Of or pertaining to the veins. [EU] Venous Thrombosis: The formation or presence of a thrombus within a vein. [NIH] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventilator: A breathing machine that is used to treat respiratory failure by promoting ventilation; also called a respirator. [NIH] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Dysfunction: A condition in which the ventricles of the heart exhibit a decreased functionality. [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] Vertebral: Of or pertaining to a vertebra. [EU] Vertigo: An illusion of movement; a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective vertigo). The term is sometimes erroneously used to mean any form of dizziness. [EU] Vestibular: Pertaining to or toward a vestibule. In dental anatomy, used to refer to the tooth surface directed toward the vestibule of the mouth. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] 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] Virus Replication: The process of intracellular viral multiplication, consisting of the synthesis of proteins, nucleic acids, and sometimes lipids, and their assembly into a new infectious particle. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH]

664 Sclerosis

Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Afferents: The sensory fibers innervating the viscera. [NIH] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Visual Acuity: Acuteness or clearness of vision, especially of form vision, which is dependent mainly on the sharpness of the retinal focus. [NIH] Visual Cortex: Area of the occipital lobe concerned with vision. [NIH] Visual field: The entire area that can be seen when the eye is forward, including peripheral vision. [NIH] Vital Capacity: The volume of air that is exhaled by a maximal expiration following a maximal inspiration. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Voice Quality: Voice quality is that component of speech which gives the primary distinction to a given speaker's voice when pitch and loudness are excluded. It involves both phonatory and resonatory characteristics. Some of the descriptions of voice quality are harshness, breathiness and nasality. [NIH] Volition: Voluntary activity without external compulsion. [NIH] Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [NIH] Wakefulness: A state in which there is an enhanced potential for sensitivity and an efficient responsiveness to external stimuli. [NIH] Wheelchairs: Chairs mounted on wheels and designed to be propelled by the occupant. [NIH]

White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] 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] Wounds, Gunshot: Disruption of structural continuity of the body as a result of the

Dictionary 665

discharge of firearms. [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] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [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] 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]

667

INDEX A Abdomen, 547, 562, 584, 605, 610, 627, 630, 650, 651, 655, 663 Abdominal, 193, 221, 547, 578, 627, 630, 631 Abducens, 547, 579 Abducens Nerve, 547, 579 Abducens Nerve Diseases, 547, 579 Abductor, 4, 547 Aberrant, 38, 54, 67, 77, 90, 135, 140, 207, 438, 547 Ablate, 67, 547, 582 Ablation, 67, 107, 547 Abscess, 547, 647 Acantholysis, 547, 629 Acceptor, 547, 609, 627, 658 Acetylcarnitine, 178, 547 Acetylcholine, 283, 399, 547, 568, 623 Acetylcysteine, 224, 288, 336, 547 Acidosis, 412, 547 Acoustic, 34, 74, 548, 557 Actin, 548, 619, 622 Action Potentials, 46, 548 Acuity, 134, 341, 548, 557 Acyl, 92, 548 Acylation, 92, 548 Adaptability, 548, 566 Adaptation, 218, 345, 465, 548, 633 Adenine, 426, 548, 639 Adenopathy, 266, 548 Adenosine, 403, 548, 556, 563, 631 Adenovirus, 108, 548, 575 Adenylate Cyclase, 403, 548 Adhesions, 390, 548 Adjunctive Therapy, 309, 428, 548 Adjustment, 265, 341, 343, 344, 548 Adjuvant, 132, 427, 548, 591 Adolescence, 61, 380, 410, 433, 548, 629 Adoptive Transfer, 47, 65, 548 Adrenal Cortex, 548, 574, 585, 598, 636 Adrenergic, 548, 550, 580, 584, 640, 653, 655, 660 Adverse Effect, 51, 549, 647 Aerobic, 51, 549, 616 Aerosol, 549, 623 Aetiology, 385, 438, 549 Afferent, 549, 587, 625, 636

Affinity, 93, 100, 103, 124, 230, 374, 549, 556, 578, 622, 648, 652 Agar, 549, 575, 633 Age Distribution, 25, 549 Age Groups, 549 Age of Onset, 16, 61, 380, 383, 388, 401, 411, 422, 432, 549 Agonist, 103, 549, 550, 558, 580, 619, 655 Agoraphobia, 549, 600, 627 Alanine, 127, 421, 450, 549 Albumin, 549, 633 Albuterol, 358, 550 Alcoholic Intoxication, 396, 550 Aldehydes, 384, 444, 550 Alertness, 364, 550, 563 Algorithms, 85, 550, 560 Alimentary, 550, 607, 628 Alkaline, 547, 550, 551, 563 Alkaloid, 550, 563, 617, 640 Alkylating Agents, 480, 550, 568 Alleles, 10, 15, 17, 21, 51, 60, 63, 71, 72, 79, 154, 158, 241, 282, 550, 609, 610 Allo, 397, 550 Allogeneic, 284, 550, 593, 595, 630 Allograft, 550, 597 Aloe, 428, 550 Alopecia, 550, 575 Alpha Particles, 550, 640 Alpha-1, 94, 550, 632 Alternative medicine, 321, 491, 550 Alveolar Process, 550, 643 Alveoli, 550, 577, 663 Alveolitis, 170, 204, 261, 550 Amantadine, 152, 329, 391, 496, 550 Amebiasis, 551, 614 Ameliorating, 44, 86, 389, 452, 453, 551 Amine, 551, 597 Amino Acid Sequence, 385, 411, 446, 551, 553, 586, 591 Aminolevulinic Acid, 152, 551 Ammonia, 551, 653, 661 Amnestic, 551, 613 Amphetamine, 551, 578 Amplification, 53, 164, 551 Amygdala, 551, 558, 609, 655 Anaesthesia, 6, 419, 420, 551, 602 Anaesthetic, 425, 551 Anal, 551, 584, 588, 610

668 Sclerosis

Analgesic, 551, 570, 583, 609, 617, 623, 625, 640 Analog, 135, 369, 388, 392, 453, 551, 578, 600, 607, 624 Analogous, 17, 64, 129, 139, 552, 658 Analysis of Variance, 134, 552 Anaphylactic, 396, 552 Anaphylatoxins, 552, 571 Anaphylaxis, 552 Anaplasia, 552 Anatomical, 103, 354, 381, 433, 552, 556, 567, 572, 579, 583, 601, 628, 645 Androgens, 548, 552, 574 Anemia, 327, 430, 512, 552, 589, 618 Anergy, 75, 552 Anesthesia, 6, 153, 246, 379, 431, 552, 583 Aneurysm, 552, 662 Angina, 325, 386, 552 Angina Pectoris, 386, 552 Anginal, 552, 623 Angiogenesis, 354, 481, 552, 612 Angioplasty, 386, 552, 619 Angiotensin I, 115, 552 Angiotensinogen, 552, 642 Anions, 384, 435, 549, 553, 606, 647, 652 Anisotropy, 166, 553 Anode, 553 Anorexia, 396, 430, 553 Antagonism, 553, 563 Antecedent, 87, 553 Anterior Horn Cells, 16, 188, 553 Anthraquinones, 428, 553 Antiallergic, 553, 574 Antibacterial, 553, 650 Antibiotic, 69, 348, 352, 507, 553, 562, 565, 615, 629, 650, 655 Antibiotic Prophylaxis, 507, 553 Antibody-Dependent Cell Cytotoxicity, 553, 607 Anticholinergic, 553, 610 Anticoagulant, 554, 638 Anticonvulsant, 54, 375, 425, 554, 564, 644 Antidepressant, 381, 419, 420, 428, 431, 434, 554, 600, 610, 645, 662 Antidote, 554, 608 Antigen-Antibody Complex, 554, 571 Antigen-presenting cell, 93, 409, 554, 577 Antihypertensive, 480, 554, 594 Anti-infective, 428, 554, 598 Anti-inflammatory, 102, 122, 124, 374, 428, 554, 574, 592, 636, 659 Anti-Inflammatory Agents, 102, 554, 574

Antimicrobial, 554, 580 Antineoplastic, 550, 554, 564, 574, 575, 591, 616 Antineoplastic Agents, 550, 554 Antioxidant, 26, 117, 218, 287, 306, 358, 554, 627 Antiproliferative, 76, 451, 452, 453, 554, 604 Antiserum, 384, 554, 557 Antitussive, 554, 578, 625 Antiviral, 76, 547, 550, 554, 604, 629 Anuria, 554, 607 Anxiety, 51, 73, 155, 301, 381, 433, 554, 627 Anxiety Disorders, 381, 433, 554, 627 Anxiolytic, 425, 431, 554 Aorta, 554, 663 Aortic Valve, 237, 245, 340, 460, 554 Apathy, 18, 555 Apheresis, 359, 555 Apoptosis, 19, 41, 52, 57, 65, 79, 93, 100, 104, 162, 220, 251, 273, 276, 308, 437, 555, 565 Applicability, 88, 123, 555 Aqueous, 392, 555, 558, 576, 583, 598, 608 Arachidonic Acid, 555, 600, 637 Arginase, 19, 555 Arginine, 19, 107, 318, 330, 413, 552, 555, 623, 626, 639, 660, 661 Aromatic, 555, 569, 631 Arterial, 13, 107, 184, 200, 385, 386, 479, 555, 562, 567, 573, 599, 605, 638, 654 Arterioles, 555, 561, 564, 619 Arteriosclerosis, 325, 555, 599, 619, 650 Arteriosus, 555, 639 Arteriovenous, 555, 567 Articular, 555, 626, 659 Articulation, 555, 581 Asbestos, 390, 555 Asbestosis, 555 Ascites, 399, 555, 625 Aseptic, 556, 626, 651, 652 Aspartate, 110, 119, 126, 147, 446, 556, 578 Aspartic, 23, 556, 586 Aspartic Acid, 23, 556 Asphyxia, 556, 623 Aspiration, 40, 171, 482, 556 Assay, 22, 27, 54, 96, 136, 377, 408, 411, 438, 556, 600, 640 Asthenia, 425, 556 Astrocytes, 19, 39, 54, 57, 71, 77, 113, 142, 149, 250, 448, 556, 592, 616, 622 Astrocytoma, 264, 556, 592

Index 669

Asymptomatic, 62, 87, 156, 222, 262, 551, 556 Ataxia, 384, 398, 512, 556, 566, 588, 655 Atmospheric Pressure, 556, 598, 599 ATP, 92, 403, 548, 556, 574, 580, 591, 631, 638, 658 Atrioventricular, 556, 573, 653 Atrioventricular Node, 556, 653 Atrium, 556, 573, 653, 663 Attenuated, 310, 448, 556, 579 Atypical, 258, 274, 388, 557 Audiometry, 8, 557 Audiovisual Aids, 537, 557 Auditory, 74, 114, 279, 280, 301, 302, 323, 349, 478, 557, 586, 612, 636, 660 Auditory nerve, 557, 612 Autoantibodies, 8, 20, 58, 131, 136, 156, 157, 193, 230, 262, 353, 398, 438, 492, 557 Autoantigens, 20, 21, 44, 58, 63, 68, 82, 131, 389, 420, 426, 557 Autoclave, 392, 557 Autoimmune disease, 13, 20, 21, 38, 44, 48, 53, 55, 56, 64, 65, 72, 78, 79, 86, 87, 89, 92, 94, 103, 105, 120, 121, 124, 128, 129, 132, 134, 175, 267, 358, 362, 363, 398, 420, 422, 423, 435, 436, 438, 441, 448, 449, 450, 451, 452, 524, 557, 618, 619, 633 Autologous, 56, 163, 202, 212, 284, 306, 310, 349, 355, 368, 448, 450, 557, 595, 630 Autologous bone marrow transplantation, 557, 595 Autonomic, 25, 120, 162, 547, 557, 619, 624, 630, 649, 653 Autonomic Nervous System, 120, 557, 630, 649, 653 Autopsy, 23, 91, 126, 232, 245, 263, 557 Avidity, 22, 47, 557 Axillary, 557, 562 Axillary Artery, 557, 562 Axonal, 22, 23, 60, 69, 90, 110, 125, 157, 159, 176, 187, 284, 367, 441, 443, 479, 557 Axotomy, 83, 557 B Bacillus, 557, 660 Baclofen, 330, 496, 498, 499, 558 Bacterial Physiology, 548, 558 Bacteriophage, 558, 633, 658 Bacteriuria, 507, 558 Basal cell carcinoma, 252, 558 Basal cells, 558 Basal Ganglia, 207, 556, 558, 562, 581, 592, 599, 609, 618

Basal Ganglia Diseases, 556, 558, 581, 599, 618 Base, 179, 375, 547, 548, 558, 577, 591, 594, 607, 634, 639, 655 Basement Membrane, 558, 586 Basilar Artery, 558, 612 Basophils, 558, 594, 609 Baths, 307, 558 Batroxobin, 386, 558 Behavioral Medicine, 25, 559 Benign, 57, 61, 83, 87, 99, 130, 193, 231, 422, 519, 521, 536, 537, 559, 595, 620, 641 Benign tumor, 57, 83, 87, 130, 537, 559 Benzene, 559, 606 Bereavement, 483, 533, 559 Beta Rays, 559, 582 Bicarbonates, 397, 559 Bifida, 559 Bilateral, 8, 37, 185, 231, 266, 350, 559, 628 Bile, 11, 559, 568, 575, 590, 598, 607, 610, 651 Bile Acids, 559, 651 Bile Acids and Salts, 559 Bile Ducts, 559, 590 Bile Pigments, 559, 607 Biliary, 20, 107, 559, 571 Bilirubin, 549, 559, 590, 599 Binding Sites, 135, 559, 652 Bioassay, 559, 560 Biological Assay, 86, 560 Biological Factors, 25, 560 Biological Markers, 360, 560 Biological response modifier, 560, 603 Biological therapy, 560, 594 Biological Transport, 560, 579 Biomedical Technology, 90, 560 Biopsy, 7, 64, 115, 358, 399, 480, 560, 630 Biopsy specimen, 8, 560 Biosynthesis, 555, 560, 610, 626, 647 Biotechnology, 76, 89, 136, 146, 478, 491, 505, 509, 511, 512, 513, 560 Biotin, 560, 652 Biotransformation, 560 Biphasic, 412, 561 Blebs, 132, 561 Blind spot, 526, 561 Blister, 561, 629 Blood Coagulation, 561, 563, 656 Blood Glucose, 412, 561, 596, 603 Blood Platelets, 561, 613, 647, 656 Blood pressure, 10, 210, 266, 480, 554, 561, 564, 599, 616, 623, 639, 649, 654

670 Sclerosis

Blood Volume, 354, 561, 662 Blood-Brain Barrier, 13, 98, 287, 354, 389, 443, 561, 609 Blot, 561, 600 Blotting, Western, 561, 600 Body Fluids, 561, 581, 649 Bolus, 416, 561 Bolus infusion, 561 Bone Conduction, 557, 561 Bone Marrow Transplantation, 66, 306, 308, 561 Bone Resorption, 5, 561, 563 Bone scan, 561, 645 Bowel, 92, 133, 160, 315, 391, 443, 526, 551, 562, 572, 579, 602, 605, 608, 624, 631, 651 Bowel Movement, 562, 572, 579, 651 Brachial, 156, 160, 562 Brachial Artery, 156, 562 Brachytherapy, 562, 604, 606, 640, 665 Bradykinin, 562, 623, 633 Brain Diseases, 562, 628, 639 Brain Ischemia, 562, 567 Brain Stem, 479, 562, 566, 567, 579, 622, 640 Branch, 11, 543, 562, 576, 582, 591, 601, 611, 612, 629, 639, 649, 653, 655 Broad-spectrum, 562, 565, 607 Bronchi, 562, 584, 607, 658 Bronchial, 562, 597 Bronchioles, 550, 562 Bronchiolitis, 251, 562 Bronchiolitis Obliterans, 251, 562 Bronchiolitis Obliterans Organizing Pneumonia, 251, 562 Bronchitis, 562, 569 Bronchodilator, 562, 607, 655 Buccal, 42, 562, 611 Bulbar, 388, 425, 562, 640 C Caffeine, 11, 393, 563, 639 Calcifediol, 563 Calcinosis, 273, 563 Calcitriol, 238, 563 Calcium channel blocker, 480, 563 Calcium Channel Blockers, 480, 563 Calcium Channels, 141, 283, 563 Calcium Hydroxide, 397, 563 Calmodulin, 43, 563 Calpain, 28, 137, 563 Camptothecin, 145, 320, 563 Cannabidiol, 564

Cannabinoids, 28, 162, 282, 287, 302, 310, 564 Cannabinol, 564 Cannabis, 302, 314, 321, 460, 564, 655 Cannula, 379, 564 Capillary, 7, 16, 79, 105, 481, 562, 564, 662, 663 Capsular, 238, 564 Carbamazepine, 146, 564 Carbohydrate, 24, 564, 574, 592, 593, 634, 647, 652 Carbon Dioxide, 354, 564, 576, 589, 590, 632, 643 Carboplatin, 177, 564 Carcinogen, 564, 614 Carcinogenic, 550, 559, 564, 603, 625, 637, 651 Carcinoma, 144, 221, 254, 380, 401, 432, 519, 564 Cardiotoxicity, 250, 564 Cardiovascular, 103, 125, 156, 325, 426, 551, 563, 564, 647, 649 Cardiovascular disease, 156, 564 Carnitine, 292, 547, 564 Carotene, 330, 337, 564, 643 Carrier Proteins, 26, 565, 633, 640 Case report, 3, 6, 142, 171, 199, 201, 218, 239, 241, 250, 274, 300, 565, 569 Case series, 565, 569 Caspase, 17, 24, 102, 138, 162, 178, 565 Catabolism, 90, 565 Catalyse, 565, 658 Catalytic Domain, 99, 565 Cataract, 106, 564, 565 Catecholamine, 565, 580 Catheterization, 5, 11, 507, 552, 565, 605, 619 Cathode, 553, 559, 565, 582 Cations, 565, 606 Caudal, 565, 578, 599, 635 Causal, 115, 378, 382, 385, 407, 409, 414, 415, 416, 417, 430, 565, 570, 584, 655 Cause of Death, 507, 565, 576 Ceftriaxone, 352, 565 Cell Adhesion, 54, 122, 274, 565 Cell Adhesion Molecules, 54, 565 Cell Cycle, 43, 62, 79, 110, 566, 575, 662 Cell Cycle Proteins, 79, 566 Cell Differentiation, 134, 566, 648 Cell Division, 33, 88, 424, 511, 558, 566, 576, 594, 613, 616, 632, 637, 646, 654

Index 671

Cell membrane, 455, 560, 563, 565, 566, 577, 582, 590, 618, 631 Cell motility, 566, 596 Cell proliferation, 28, 43, 63, 90, 100, 104, 112, 133, 447, 452, 453, 555, 566, 604, 648 Cell Respiration, 566, 616, 643 Cell Size, 112, 566, 589 Cell Survival, 28, 41, 566, 594 Cell Transplantation, 234, 368, 566 Cellular metabolism, 351, 566 Cellular Structures, 97, 566, 616 Centrifugation, 566, 654 Cerebellar, 74, 141, 374, 411, 419, 420, 431, 510, 556, 566, 642, 659 Cerebellar Diseases, 556, 566, 659 Cerebellum, 66, 562, 566, 567, 635, 642 Cerebral hemispheres, 558, 562, 567, 592, 654 Cerebral Infarction, 567 Cerebral Palsy, 464, 482, 507, 527, 533, 567, 649 Cerebrospinal fluid, 13, 30, 60, 77, 121, 154, 155, 162, 168, 172, 174, 178, 187, 188, 215, 230, 235, 267, 302, 352, 367, 384, 439, 455, 567, 611, 650 Cerebrovascular, 376, 425, 507, 558, 563, 564, 567, 655 Cerebrovascular Disorders, 425, 567, 655 Cerebrum, 228, 566, 567, 632, 654, 660 Cervical, 239, 567, 620 Cervix, 567, 589, 643 Character, 552, 567, 577 Charities, 531, 567 Chemokines, 31, 38, 92, 98, 104, 113, 125, 133, 165, 342, 442, 567 Chemotactic Factors, 567, 571 Chemotaxis, 93, 567 Chemotherapy, 210, 284, 287, 306, 316, 349, 357, 423, 567 Chimera, 47, 91, 567 Chin, 153, 207, 300, 520, 567 Chiropractic, 299, 568 Chlamydia, 15, 139, 142, 165, 206, 211, 340, 348, 460, 568 Chlorambucil, 492, 568 Chlorine, 568, 599 Cholangitis, 107, 568 Cholecystectomy, 379, 568 Cholesterol, 160, 172, 325, 326, 331, 486, 490, 559, 568, 574, 590, 599, 610, 651 Choline, 13, 86, 293, 568 Cholinergic, 382, 568

Cholinesterase Inhibitors, 568, 580 Chondroitin sulfate, 288, 568 Choroid, 568, 573, 643, 661 Chromatin, 555, 566, 568, 584, 655 Chromosomal, 17, 57, 60, 139, 551, 568, 615, 633, 644, 645 Chronic Disease, 16, 53, 55, 321, 352, 396, 524, 568, 570, 608 Chronic Fatigue Syndrome, 396, 568 Chronic lymphocytic leukemia, 106, 568 Chronic Obstructive Pulmonary Disease, 325, 390, 569 Chronic renal, 569, 590, 634 Chymotrypsin, 452, 569 Cicatrix, 569, 607 Ciliary, 165, 389, 499, 555, 569, 624, 661 Ciliary Neurotrophic Factor, 389, 569 Cimetidine, 416, 569 CIS, 49, 59, 397, 569, 601, 643 Civil Rights, 527, 569 Clear cell carcinoma, 569, 578 Clinical Medicine, 477, 569, 635 Clinical study, 316, 569, 573 Clinical trial, 12, 14, 20, 35, 41, 44, 69, 70, 71, 74, 86, 101, 102, 106, 122, 123, 128, 134, 157, 347, 350, 370, 411, 420, 492, 505, 525, 533, 569, 573, 575, 585, 618, 638, 641 Clonal Deletion, 72, 569 Clone, 34, 569 Cloning, 61, 75, 112, 128, 130, 424, 560, 569 Clot Retraction, 569, 633 Coagulation, 160, 481, 561, 570, 596, 608, 633, 656 Cochlea, 570, 603 Codeine, 392, 570, 578, 625 Codons, 570, 591, 625 Coenzyme, 331, 570, 610 Cofactor, 570, 638, 656 Cognition, 9, 18, 85, 178, 342, 344, 481, 570 Cognitive restructuring, 570, 652 Cohort Effect, 160, 570 Cohort Studies, 570, 584 Colitis, 570, 602 Collagen disease, 376, 570, 598 Collapse, 379, 552, 562, 570 Colloidal, 331, 549, 570, 582, 647 Combination Therapy, 35, 181, 351, 571 Combinatorial, 93, 123, 571 Common Bile Duct, 571, 575 Comorbidity, 237, 381, 433, 571

672 Sclerosis

Complement, 22, 39, 132, 289, 305, 398, 410, 552, 553, 571, 591, 612, 633 Complementary and alternative medicine, 299, 300, 311, 338, 571 Complementary medicine, 299, 300, 571 Complementation, 112, 571 Complete remission, 571, 642 Computational Biology, 505, 509, 571 Computed tomography, 10, 239, 572, 645 Computer Systems, 123, 572 Computerized axial tomography, 572, 645 Computerized tomography, 572 Concentric, 133, 157, 305, 361, 572 Conception, 468, 572, 588, 649, 651 Concomitant, 51, 89, 282, 430, 572 Conduction, 89, 324, 437, 438, 447, 556, 557, 572, 618 Cones, 572, 644 Conjugated, 332, 559, 572, 575, 644 Conjunctiva, 572, 659 Connective Tissue Cells, 572 Consciousness, 551, 572, 577, 580, 639, 648, 651 Constipation, 308, 572, 594 Constitutional, 424, 572, 618 Constriction, 572, 606, 624, 645, 662 Constriction, Pathologic, 572, 662 Consultation, 7, 572 Contamination, 12, 572 Continence, 11, 572 Contractility, 573, 581 Contraindications, ii, 573 Contrast Sensitivity, 134, 573, 625 Control group, 6, 134, 353, 364, 573, 641 Controlled clinical trial, 35, 182, 573 Controlled study, 102, 221, 280, 283, 317, 573 Conus, 573, 639 Convulsion, 210, 560, 573 Convulsive, 536, 573, 582 Coordination, 208, 363, 447, 521, 566, 573, 618 Cor, 573 Cornea, 430, 573, 593, 645, 652, 662 Corneum, 194, 573, 584 Coronary, 174, 326, 552, 556, 564, 573, 574, 614, 619 Coronary Circulation, 552, 573 Coronary heart disease, 564, 573 Coronary Thrombosis, 574, 614, 619 Coronavirus, 36, 574 Corticosteroid, 173, 410, 574, 636, 651

Cortisone, 574, 636 Cost Savings, 76, 574 Cowpox, 574, 662 Cowpox Virus, 574, 662 Cranial, 62, 64, 118, 168, 185, 511, 547, 557, 566, 574, 587, 595, 621, 624, 625, 630, 639, 659 Creatine Kinase, 210, 317, 574 Creatinine, 574, 607 Criterion, 376, 574 Crossing-over, 574, 642 Cross-Sectional Studies, 574, 584 Crystallization, 121, 575 Culture Media, 399, 549, 575 Cultured cells, 48, 81, 575 Cuprizone, 78, 575 Curative, 64, 66, 575, 623, 655 Cutaneous, 10, 72, 132, 201, 220, 238, 242, 243, 251, 252, 273, 440, 575, 599, 611, 628, 662 Cyclic, 283, 393, 548, 563, 575, 594, 623, 631, 637 Cyclin, 63, 79, 111, 142, 566, 575 Cyclin A, 79, 575 Cyclin-Dependent Kinases, 566, 575 Cyclophosphamide, 66, 170, 182, 202, 355, 360, 368, 389, 410, 480, 492, 496, 575 Cyclosporine, 4, 480, 492, 575, 601 Cysteine, 127, 181, 388, 547, 563, 567, 575, 652 Cystic Duct, 379, 571, 575 Cystine, 111, 575 Cytochrome, 42, 569, 575 Cytogenetics, 576, 645 Cytomegalovirus, 133, 576 Cytoplasm, 19, 555, 558, 566, 576, 584, 594, 619, 622, 644, 654, 655 Cytoskeletal Proteins, 563, 566, 576 Cytoskeleton, 441, 576, 615 Cytotoxic, 68, 89, 107, 132, 410, 412, 423, 427, 454, 455, 576, 601, 640, 641, 648 Cytotoxicity, 139, 140, 448, 455, 576 D Data Collection, 37, 123, 576, 589 Databases, Bibliographic, 505, 576 De novo, 92, 317, 576 Deamination, 576, 616, 661 Death Certificates, 150, 576 Decarboxylation, 576, 597, 626, 639 Decision Making, 255, 270, 576 Decompression, 227, 576 Decompression Sickness, 227, 576

Index 673

Defense Mechanisms, 97, 577 Deletion, 26, 42, 43, 91, 555, 569, 577, 610 Delivery of Health Care, 577, 595 Denaturation, 124, 577 Dendrites, 577, 622, 639 Dendritic, 93, 163, 225, 577, 613, 644 Dendritic cell, 93, 163, 225, 577 Density, 46, 52, 106, 566, 577, 589, 625, 649 Dental Amalgam, 302, 577 Dental Care, 533, 577 Dental Caries, 7, 577 Dentate Gyrus, 32, 577, 597 Dentists, 4, 533, 577 Dentition, 6, 577 Depolarization, 577, 648 Deprenyl, 391, 404, 439, 578, 646 Depressive Disorder, 40, 285, 312, 578 Deprivation, 19, 101, 126, 388, 578 Dermal, 210, 266, 276, 578 Dermatologist, 358, 578 DES, 93, 552, 578 Desipramine, 381, 433, 578, 610 Deuterium, 578, 598 Dexterity, 4, 578 Dextroamphetamine, 381, 433, 551, 578, 614 Dextromethorphan, 370, 389, 392, 393, 578 Diabetes Mellitus, 20, 27, 33, 204, 240, 326, 510, 578, 592, 593, 596, 624 Diagnostic Imaging, 166, 578 Diagnostic procedure, 373, 491, 578 Diaphragm, 578, 634 Diarrhea, 6, 7, 551, 578 Diarrhoea, 412, 578 Diastolic, 578, 594, 599 Diastolic blood pressure, 578, 594 Diencephalon, 567, 578, 599, 622, 636, 654, 655 Diffusion, 45, 96, 100, 110, 155, 177, 236, 248, 560, 579, 602 Difluoromethylornithine, 452, 579 Digestion, 550, 559, 562, 579, 605, 610, 651, 662 Digestive system, 371, 579 Digestive tract, 526, 579, 648 Dilatation, 156, 552, 579, 636, 662 Dilatation, Pathologic, 579, 662 Dilation, 562, 579, 662 Dilution, 120, 121, 579, 585, 633 Dimethyl, 391, 404, 418, 439, 579 Diploid, 571, 579, 632, 634 Diplopia, 246, 438, 526, 547, 579, 617, 660

Discrimination, 96, 569, 579 Disease Susceptibility, 21, 89, 579 Disorientation, 576, 579 Dissociation, 178, 549, 579, 605 Distal, 23, 110, 123, 510, 557, 580, 582, 630, 638 Distemper, 42, 417, 580 Distemper Virus, Canine, 580 Distention, 239, 580 Diuresis, 563, 580 Diuretic, 580, 590 Dizziness, 55, 377, 408, 580, 627, 663 DNA Topoisomerase, 580, 591 Domesticated, 580, 594 Dominance, 580, 584 Donepezil, 353, 580 Dopa, 580, 609 Dopamine, 381, 382, 404, 433, 439, 551, 578, 580, 609, 616, 631 Dorsal, 580, 635, 650 Dose-limiting, 107, 580 Doxycycline, 126, 427, 455, 580 Drive, ii, vi, 4, 8, 12, 33, 63, 64, 175, 281, 442, 444, 580 Drug Evaluation, 581, 585, 646 Drug Evaluation, Preclinical, 581, 585 Drug Interactions, 497, 581 Drug Tolerance, 581, 657 Duct, 11, 379, 564, 565, 568, 571, 581, 586, 645, 653 Duodenum, 239, 559, 569, 581, 627, 651 Dura mater, 581, 613, 627 Dysarthria, 34, 74, 344, 481, 581 Dyskinesias, 558, 581, 617 Dysphagia, 40, 581 Dysphonia, 3, 581 Dysphoric, 18, 578, 581 Dysplasia, 54, 75, 90, 179, 192, 213, 273, 314, 512, 581 Dyspnea, 581, 627, 639 Dystonia, 238, 402, 581 Dystrophy, 7, 350, 470, 512, 527, 531, 532, 581 E Echocardiography, 10, 153, 361, 581 Edema, 480, 581, 590, 619, 620, 621, 623, 625 Effector cell, 73, 94, 120, 129, 134, 553, 581, 607, 623 Ejection fraction, 171, 361, 581 Elastin, 570, 582, 587 Elective, 144, 258, 582

674 Sclerosis

Electric Conductivity, 553, 582 Electrocoagulation, 379, 570, 582 Electrode, 375, 553, 565, 582 Electrolysis, 553, 565, 582 Electrolyte, 394, 395, 574, 582, 607, 615, 635, 649 Electromagnetic Fields, 301, 317, 322, 582 Electromyography, 210, 582 Electrons, 100, 554, 558, 559, 565, 582, 605, 606, 612, 626, 627, 640, 641 Electrophoresis, 105, 124, 582 Electrophysiological, 32, 46, 48, 91, 96, 182, 184, 582 Electroporation, 47, 130, 582 Electroshock, 375, 582 Elementary Particles, 582, 612, 623, 638 Embryo, 566, 582, 602, 636, 661 Emodin, 428, 550, 582 Emphysema, 569, 582 Emulsion, 582, 589 Enamel, 6, 577, 583 Encephalitis, 67, 98, 140, 175, 342, 583, 613 Encephalitis, Viral, 583 Encephalomyelitis, 21, 29, 36, 44, 45, 47, 50, 53, 59, 63, 64, 65, 67, 68, 71, 78, 86, 88, 89, 94, 103, 104, 105, 111, 113, 122, 126, 128, 129, 130, 132, 134, 136, 138, 144, 145, 146, 165, 171, 196, 270, 361, 367, 383, 409, 420, 421, 426, 427, 434, 437, 439, 461, 462, 464, 477, 583 Encephalopathy, 29, 175, 176, 583 Endarterectomy, 552, 583 Endemic, 87, 583, 650 Endocrine System, 583, 621 Endorphin, 159, 583 Endoscopy, 379, 583 Endothelial cell, 31, 47, 104, 113, 209, 403, 561, 583, 588, 656 Endothelium, 16, 113, 156, 223, 481, 583, 584, 623, 633 Endothelium, Lymphatic, 583 Endothelium, Vascular, 583 Endothelium-derived, 584, 623 Endotoxin, 584, 660 End-stage renal, 33, 569, 584, 634 Enhancer, 52, 584 Enteropeptidase, 584, 660 Entorhinal Cortex, 97, 584, 597 Environmental Exposure, 15, 560, 584, 625 Environmental Health, 59, 152, 504, 506, 584

Enzymatic, 130, 563, 564, 565, 571, 575, 577, 584, 588, 597, 643 Enzyme Inhibitors, 92, 102, 584, 633 Eosinophils, 584, 594, 609 Epidemic, 16, 417, 584, 650 Epidemiologic Studies, 106, 560, 584 Epidemiological, 50, 69, 184, 210, 217, 388, 584 Epidermis, 547, 558, 561, 573, 584, 629, 639 Epigastric, 584, 627 Epinephrine, 548, 580, 584, 607, 624, 660 Epistasis, 63, 584 Epithelial, 78, 107, 252, 272, 560, 585, 596 Epithelial Cells, 107, 252, 585, 596 Epithelium, 107, 558, 583, 585, 606 Epitope, 22, 28, 29, 30, 45, 56, 58, 71, 94, 120, 132, 140, 185, 585 Epoprostenol, 585, 600 Erbium, 520, 585 Erection, 585, 632 Erythrocyte Volume, 561, 585 Erythrocytes, 430, 552, 561, 563, 585, 642 Esophagus, 579, 585, 651 Essential Tremor, 512, 585 Estradiol, 585 Estriol, 435, 585 Estrogen, 15, 43, 49, 103, 217, 237, 342, 435, 585, 636 Estrogen receptor, 49, 103, 217, 237, 435, 585 Ethanol, 550, 585 Ethnic Groups, 33, 585 Eukaryotic Cells, 576, 585, 601, 626, 661 Evacuation, 572, 585, 608 Evaluation Studies, 131, 585 Evoke, 324, 585, 651 Evoked Potentials, 96, 169, 259, 279, 302, 313, 586 Excipient, 446, 586 Excitability, 32, 48, 311, 586, 620, 640 Excitation, 388, 586, 589 Excitatory, 32, 77, 187, 393, 558, 586, 593, 607 Excitatory Amino Acids, 393, 586 Excitotoxicity, 17, 32, 48, 77, 88, 102, 131, 251, 275, 286, 350, 586 Excrete, 554, 586, 607 Exercise Therapy, 51, 586 Exocrine, 586, 627 Exogenous, 153, 364, 378, 382, 388, 390, 407, 409, 417, 430, 560, 586, 591, 637 Exon, 75, 77, 126, 170, 586

Index 675

Expiration, 586, 590, 603, 643, 664 Expiratory, 586, 590, 657 Extensor, 586, 638 External-beam radiation, 586, 606, 640, 665 Extracellular Matrix, 39, 49, 81, 288, 394, 572, 586, 588, 612 Extracellular Matrix Proteins, 586, 612 Extracellular Space, 586, 587, 615 Extraction, 6, 106, 587 Extrapyramidal, 550, 580, 587 Extravasation, 113, 587 Extremity, 32, 350, 486, 587, 628 Exudate, 428, 562, 587, 625 Eye Abnormalities, 75, 587 Eye Infections, 548, 587 Eye Movements, 587, 640 F Facial, 4, 5, 14, 17, 118, 222, 258, 380, 401, 432, 519, 536, 587, 612, 649 Facial Nerve, 17, 587 Faecal, 308, 578, 587 Fallopian Tubes, 587, 643 Family Planning, 87, 505, 587 Fasciculation, 402, 587, 622 Fatty acids, 92, 306, 367, 384, 547, 549, 587, 593, 637 Febrile, 191, 193, 210, 256, 307, 507, 587 Feces, 572, 587, 651 Feline Panleukopenia, 580, 587 Ferritin, 97, 588 Fetal Alcohol Syndrome, 158, 588 Fetus, 156, 588, 589, 600, 632, 636, 661 Fibrin, 561, 570, 588, 633, 656, 657 Fibrinogen, 558, 588, 633, 656 Fibrinolysis, 115, 160, 208, 481, 588 Fibroblast Growth Factor, 99, 588 Fibroblasts, 145, 266, 269, 276, 320, 368, 572, 588, 604, 617 Fibronectin, 588, 591 Fibrosis, 5, 7, 10, 73, 108, 162, 225, 286, 363, 392, 403, 479, 492, 512, 588, 639, 645 Filgrastim, 368, 588 Fissure, 547, 577, 588, 636, 659 Fistula, 588, 624 Fixation, 3, 588 Flatus, 589, 590 Flexion, 37, 350, 589 Flow Cytometry, 31, 54, 139, 589 Fluorescence, 26, 124, 589 Fluorescent Dyes, 589 Focus Groups, 231, 589

Foetal, 217, 589 Fold, 3, 588, 589 Folic Acid, 290, 291, 589, 608 Foramen, 568, 589, 612, 630 Forearm, 561, 589 Fossa, 566, 589 Fovea, 589 Fractionation, 589, 654 Frontal Lobe, 381, 433, 567, 589, 617, 636 Functional magnetic resonance imaging, 179, 589 Functional Residual Capacity, 589, 657 Fundus, 379, 589, 590 Fungus, 590, 618 Furosemide, 480, 590 G Gadolinium, 13, 119, 195, 259, 272, 354, 355, 356, 359, 367, 590 Gait, 7, 17, 53, 132, 376, 566, 590 Gallbladder, 379, 547, 559, 568, 575, 579, 590 Gallstones, 379, 559, 590 Gamma Rays, 590, 640, 641 Ganglia, 547, 558, 590, 621, 630, 653 Gangliosides, 152, 209, 590 Gap Junctions, 590, 653, 654 Gas, 95, 193, 551, 564, 568, 576, 579, 589, 590, 598, 623, 625, 662, 663 Gas exchange, 590, 663 Gastric, 275, 392, 564, 569, 590, 597, 598, 629 Gastric Acid, 569, 590 Gastrin, 569, 590, 597 Gastritis, 211, 590 Gastrointestinal Neoplasms, 555, 590 Gastrointestinal tract, 392, 568, 585, 590, 647, 649 Gelatin, 575, 591, 593, 656 Gelatinase A, 210, 591 Gemcitabine, 177, 591 Gene Expression, 25, 28, 33, 38, 55, 63, 118, 130, 249, 255, 513, 591 Gene Rearrangement, 353, 591 Gene Targeting, 90, 591 General practitioner, 480, 591 Genetic Code, 591, 624 Genetic Counseling, 519, 537, 591 Genetic Engineering, 560, 569, 591 Genetics, 36, 49, 52, 60, 75, 90, 148, 158, 182, 186, 192, 197, 204, 205, 207, 234, 245, 258, 266, 275, 278, 358, 519, 576, 580, 591, 601, 616

676 Sclerosis

Genistein, 103, 307, 591 Genomics, 118, 197, 591 Genotype, 42, 50, 52, 61, 82, 87, 165, 591, 631 Germanium, 418, 591 Germline mutation, 99, 591, 596 Giant Cell Tumors, 177, 591 Giant Cells, 54, 179, 591 Giardiasis, 592, 614 Gingival Hypertrophy, 6, 592 Ginkgo biloba, 334, 367, 425, 426, 592 Ginseng, 337, 592 Gland, 8, 524, 548, 574, 592, 611, 620, 627, 628, 632, 637, 646, 651, 653, 656 Glioblastoma, 317, 592 Glioblastoma multiforme, 317, 592 Glioma, 199, 276, 592 Gliosis, 69, 86, 244, 398, 447, 592, 654 Glomerular, 9, 28, 33, 49, 78, 81, 137, 192, 269, 480, 511, 592, 607 Glomeruli, 9, 49, 81, 592 Glomerulosclerosis, 9, 33, 48, 79, 81, 115, 305, 480, 592 Glomerulus, 9, 480, 592 Glucocorticoid, 592, 598, 636, 659 Gluconeogenesis, 592 Glucose, 33, 104, 381, 433, 512, 561, 578, 592, 593, 596, 603, 632, 645 Glucose Intolerance, 578, 592 Glutamic Acid, 334, 421, 450, 589, 593, 636 Glutathione Peroxidase, 97, 593, 646 Glycerol, 593, 631 Glycerophospholipids, 593, 631 Glycine, 107, 551, 559, 593, 647 Glycogen, 568, 593, 632 Glycols, 593, 598 Glycosaminoglycan, 568, 593 Glycosylation, 62, 106, 593 Gonadal, 593, 651 Governing Board, 593, 635 Gp120, 593, 629 Grade, 276, 592, 593 Grading, 106, 593 Graft, 73, 105, 133, 451, 593, 594, 597, 601, 615, 619 Graft Rejection, 593, 601, 615 Graft Survival, 133, 594 Graft-versus-host disease, 451, 594 Gram-negative, 412, 568, 594, 616 Gram-Negative Bacteria, 594, 616 Granulation Tissue, 562, 594 Granule, 577, 594, 644

Granulocyte Colony-Stimulating Factor, 588, 594 Granulocytes, 594, 608, 648, 664 Granuloma, 486, 594 Gravis, 196, 398, 435, 594 Growth factors, 23, 54, 76, 100, 117, 594 Guanfacine, 381, 434, 594 Guanidine, 416, 594 Guanylate Cyclase, 594, 623 Guinea Pigs, 387, 594 H Habitual, 34, 567, 594 Haematoma, 595 Haemorrhage, 424, 595 Hair follicles, 595, 664 Half-Life, 565, 595, 600 Handicap, 227, 595 Haploid, 595, 632, 634 Haplotypes, 52, 56, 68, 595 Haptens, 549, 595, 640 Headache, 563, 595 Health Care Costs, 285, 312, 595 Health Education, 108, 529, 595 Health Expenditures, 595 Health Status, 7, 174, 570, 595 Heart attack, 564, 595 Heart failure, 259, 279, 595, 625, 639 Hematopoietic Stem Cell Transplantation, 212, 595 Heme, 551, 559, 575, 596 Hemiparesis, 227, 596 Hemodialysis, 596, 607 Hemoglobin, 552, 585, 596 Hemoglobinuria, 512, 596 Hemorrhage, 229, 582, 595, 596, 619, 639, 652 Hemostasis, 596, 647 Heparin, 559, 596 Hepatic, 101, 107, 126, 242, 549, 571, 596, 616 Hepatitis, 39, 98, 100, 180, 201, 596 Hepatocyte, 188, 448, 596 Hepatocyte Growth Factor, 188, 448, 596 Hereditary, 52, 58, 99, 357, 367, 536, 587, 591, 596, 617, 621, 631, 644 Hereditary mutation, 591, 596 Heredity, 591, 596 Heritability, 46, 596 Herpes, 15, 57, 69, 140, 205, 211, 396, 596, 597 Herpes virus, 15, 205, 211, 396, 596 Herpes Zoster, 596, 597

Index 677

Heterogeneity, 33, 50, 70, 141, 201, 380, 402, 411, 432, 442, 549, 597 Hippocampus, 32, 97, 155, 193, 382, 577, 597, 609, 622, 639, 652 Histamine, 322, 393, 552, 569, 597 Histidine, 597 Histocompatibility, 79, 438, 597, 615 Histocompatibility Antigens, 79, 597, 615 Histology, 37, 597, 622 Homeobox, 63, 597 Homeostasis, 26, 75, 135, 178, 232, 273, 597, 649 Homodimer, 597, 659 Homogenate, 421, 597 Homologous, 353, 410, 550, 574, 591, 597, 618, 646, 653 Hormonal, 105, 120, 395, 440, 556, 560, 574, 597 Hormone, 43, 53, 59, 103, 105, 382, 383, 395, 410, 418, 428, 434, 440, 550, 559, 560, 563, 574, 578, 584, 585, 590, 597, 603, 613, 624, 633, 636, 642, 644, 648, 649, 656, 659 Hormone therapy, 395, 440, 597 Hospice, 40, 533, 597 Hospital Records, 42, 597 Human growth hormone, 395, 440, 597, 649 Humoral, 24, 58, 73, 86, 101, 145, 215, 382, 426, 439, 455, 460, 593, 597, 656 Humour, 597, 598 Hybrid, 57, 58, 62, 139, 140, 569, 598 Hybridization, 130, 598, 616 Hybridomas, 377, 408, 582, 598, 604 Hydrochloric Acid, 397, 598 Hydrocortisone, 78, 598 Hydrogen Bonding, 598, 624 Hydrogen Peroxide, 97, 124, 135, 136, 183, 593, 598, 609, 652 Hydrolysis, 397, 446, 555, 556, 560, 598, 629, 631, 634, 638, 660 Hydrophobic, 439, 593, 598 Hydroxides, 598 Hydroxyl Radical, 97, 140, 144, 598 Hydroxylation, 97, 563, 598 Hydroxylysine, 570, 598 Hydroxyproline, 570, 598 Hyperbaric, 206, 309, 313, 322, 323, 598, 599 Hyperbaric oxygen, 206, 309, 313, 322, 598, 599 Hyperbilirubinemia, 599, 607

Hypercholesterolemia, 326, 480, 599 Hyperlipoproteinemia, 599 Hyperplasia, 11, 272, 599, 620 Hypersensitivity, 116, 390, 552, 599, 644, 648 Hyperthermia, 307, 599 Hypertriglyceridemia, 480, 599 Hypertrophy, 34, 79, 573, 599 Hypesthesia, 599, 621 Hypnotherapy, 313, 599 Hypnotic, 425, 599 Hypochlorous Acid, 107, 599 Hypokinesia, 599, 628 Hypoplasia, 510, 519, 599 Hypotensive, 412, 599 Hypothalamic, 120, 207, 599 Hypothalamus, 120, 256, 380, 433, 557, 562, 579, 599, 609, 632, 649, 655 Hypothermia, 302, 599 Hypoxia, 148, 207, 562, 567, 599, 655 I Id, 289, 324, 407, 521, 524, 542, 544, 599 Idiocy, 479, 600 Idiopathic, 11, 97, 208, 480, 600 Iloprost, 282, 283, 287, 369, 492, 600 Imaging procedures, 600, 658 Imidazole, 416, 560, 597, 600 Imipramine, 381, 433, 600, 610 Immersion, 558, 600 Immune Complex Diseases, 554, 600, 633 Immune function, 38, 120, 389, 396, 442, 600, 601, 659 Immune Sera, 600 Immune Tolerance, 44, 89, 132, 421, 600 Immunization, 55, 89, 122, 409, 427, 548, 600, 601 Immunoassay, 384, 387, 600 Immunoblotting, 95, 600 Immunodeficiency, 66, 146, 512, 600 Immunodominant Epitopes, 151, 601 Immunofluorescence, 95, 492, 601 Immunogenetics, 68, 601 Immunogenic, 28, 601, 640 Immunoglobulin, 29, 56, 182, 203, 343, 385, 439, 454, 455, 553, 601, 617 Immunohistochemistry, 36, 601 Immunophilins, 146, 601 Immunosuppressant, 550, 601 Immunosuppressive, 9, 110, 203, 255, 308, 409, 414, 423, 492, 575, 592, 601, 654 Immunosuppressive Agents, 9, 492, 601

678 Sclerosis

Immunosuppressive therapy, 203, 308, 409, 601 Immunotherapy, 21, 70, 128, 449, 548, 560, 601 Implant radiation, 601, 604, 606, 640, 665 Impotence, 482, 601 In situ, 36, 61, 80, 601 In Situ Hybridization, 36, 61, 601 Incision, 601, 605 Incontinence, 5, 11, 92, 303, 308, 309, 327, 328, 356, 419, 420, 431, 483, 520, 521, 602, 619 Incubated, 92, 602 Incubation, 602, 608 Incubation period, 602, 608 Indicative, 24, 104, 458, 602, 629, 662 Induration, 378, 602 Infancy, 602 Infant Mortality, 529, 602 Infantile, 48, 62, 511, 602 Infarction, 327, 562, 567, 602, 634, 643 Infertility, 483, 602 Infiltration, 31, 63, 113, 120, 214, 389, 438, 447, 602 Inflammatory bowel disease, 6, 104, 602 Information Systems, 84, 602 Informed Consent, 36, 349, 602 Infusion, 107, 349, 359, 603, 619 Ingestion, 100, 212, 421, 550, 603, 634 Inhalation, 355, 421, 549, 555, 562, 603, 606, 634 Initiation, 23, 38, 45, 53, 60, 82, 90, 123, 269, 603, 610, 658 Initiator, 91, 560, 603 Inner ear, 8, 561, 565, 603 Innervation, 226, 587, 603, 618, 659 Inoculum, 603, 652 Inorganic, 559, 598, 603, 611 Inositol, 13, 397, 603, 614 Inositol Phosphates, 397, 603 Inotropic, 580, 603 Insight, 14, 36, 43, 52, 53, 75, 90, 94, 95, 96, 100, 116, 132, 603 Inspiratory Capacity, 603, 657 Inspiratory Reserve Volume, 603, 657 Insulator, 530, 531, 603, 618 Insulin, 21, 62, 193, 251, 327, 353, 364, 389, 398, 424, 499, 560, 603, 606 Insulin-dependent diabetes mellitus, 603 Insulin-like, 193, 251, 353, 389, 424, 499, 603 Intention tremor, 407, 603

Interferon-alpha, 603, 604 Interferon-beta, 84, 151, 158, 180, 189, 207, 217, 218, 248, 251, 273, 287, 341, 359, 410, 443, 446, 604 Interleukin-1, 101, 193, 207, 210, 214, 221, 604 Interleukin-10, 193, 214, 221, 604 Interleukin-2, 28, 359, 604 Interleukin-4, 383, 434, 604 Interleukin-6, 215, 235, 604 Interleukins, 601, 604 Intermediate Filaments, 604, 622 Intermittent, 5, 7, 11, 327, 507, 604, 631 Internal Medicine, 154, 227, 237, 244, 283, 284, 285, 287, 402, 407, 604, 620 Internal radiation, 604, 606, 640, 665 Interneurons, 32, 604 Interstitial, 10, 214, 236, 562, 587, 591, 604, 606, 665 Interstitial Collagenase, 591, 604 Intervertebral, 605, 610 Intervertebral Disk Displacement, 605, 610 Intestinal, 193, 392, 563, 564, 584, 605, 612 Intestine, 559, 562, 605, 608 Intoxication, 388, 605, 664 Intracranial Embolism, 567, 605 Intracranial Embolism and Thrombosis, 567, 605 Intrahepatic, 107, 605 Intramuscular, 47, 180, 276, 351, 605, 628, 659 Intrathecal, 57, 138, 182, 215, 605 Intravenous, 86, 149, 203, 311, 320, 351, 359, 360, 361, 453, 454, 480, 496, 603, 605, 628 Intravesical, 36, 605 Intrinsic, 20, 30, 62, 72, 93, 549, 558, 605 Introns, 15, 605 Intubation, 565, 605 Invasive, 32, 40, 360, 379, 438, 455, 600, 605, 612 Involuntary, 521, 526, 558, 573, 581, 585, 605, 619, 632, 642, 649, 656 Ion Channels, 556, 605, 622, 623, 654 Ion Exchange, 605, 606 Ionization, 93, 105, 605, 606 Ionizing, 550, 584, 605, 641 Ions, 91, 117, 135, 395, 403, 558, 559, 563, 579, 582, 594, 598, 605, 606, 616, 632, 638 Iontophoresis, 183, 605, 606 Iris, 555, 573, 606, 639, 661

Index 679

Irradiation, 48, 355, 368, 410, 606, 614, 643, 665 Ischemia, 131, 547, 556, 562, 590, 606, 619, 643 Ischemic stroke, 41, 606 Islet, 21, 606 Isoelectric, 606, 652 Isoelectric Point, 606, 652 Isoenzyme, 574, 606 Isoflavones, 103, 606 Isoflurane, 6, 606 Isomerases, 601, 606 Isometric Contraction, 37, 606 Isoproterenol, 34, 607 J Jaundice, 396, 599, 607 Joint, 7, 212, 300, 366, 398, 469, 555, 576, 582, 607, 626, 651, 653, 654 K Kainate, 32, 607 Kb, 218, 504, 607 Keloid, 194, 607 Keratolytic, 577, 607 Keto, 418, 607, 658 Kidney Disease, 49, 126, 242, 249, 371, 390, 480, 483, 504, 511, 512, 607 Kidney Failure, 78, 118, 584, 592, 607 Kidney Failure, Acute, 607 Kidney Failure, Chronic, 607 Kidney stone, 607, 661 Killer Cells, 132, 607 Kinetic, 70, 113, 394, 605, 607 Kynurenic Acid, 172, 183, 607 L Labile, 571, 607 Labyrinth, 570, 603, 607, 646, 663 Laceration, 608, 655 Lacrimal, 587, 608 Lactation, 608, 636 Large Intestine, 579, 605, 608, 642, 648 Laryngeal, 3, 142, 608 Larynx, 3, 608, 658 Laser Surgery, 520, 608 Laser therapy, 493, 608 Latency, 73, 96, 301, 312, 608 Latent, 50, 353, 438, 608, 635 Latent period, 438, 608 Laxative, 549, 582, 608 Lectins, 374, 608 Lens, 106, 511, 564, 565, 608, 664 Lentivirus, 57, 608 Lethal, 32, 76, 126, 131, 350, 454, 608

Leucocyte, 221, 550, 608, 609 Leucovorin, 351, 454, 608 Leukaemia, 272, 608 Leukapheresis, 349, 352, 356, 555, 609 Leukemia, 87, 150, 272, 316, 511, 609 Leukocytes, 45, 113, 308, 399, 437, 558, 561, 567, 584, 594, 604, 609, 617, 631, 660 Leukopenia, 580, 609 Levodopa, 381, 404, 434, 439, 580, 609, 646 Levorphanol, 392, 578, 609 Lewy Body Disease, 402, 609 Library Services, 542, 609 Life cycle, 561, 609 Life Expectancy, 26, 609 Ligament, 609, 637, 651 Ligands, 47, 104, 111, 113, 123, 132, 133, 138, 565, 609 Limbic, 551, 609, 636 Limbic System, 551, 609, 636 Linkage, 33, 51, 56, 60, 61, 75, 88, 130, 165, 197, 198, 218, 236, 380, 402, 432, 609 Linkage Disequilibrium, 60, 609 Lip, 5, 192, 218, 609 Lipid Peroxidation, 45, 97, 287, 609, 627 Lipopolysaccharide, 412, 594, 610 Liposomes, 100, 610 Liver scan, 610, 645 Loading dose, 37, 610 Lobe, 32, 96, 246, 267, 567, 597, 610, 628 Lobectomy, 267, 610 Localization, 19, 38, 117, 139, 165, 601, 610, 621 Lofepramine, 419, 610 Longitudinal Studies, 119, 574, 610 Longitudinal study, 25, 59, 110, 219, 610 Loss of Heterozygosity, 43, 48, 82, 610 Lovastatin, 272, 610 Low Back Pain, 482, 610 Low-density lipoprotein, 610 Lumbar, 352, 356, 359, 605, 610, 611, 650 Lumbar puncture, 352, 356, 359, 611, 650 Lumen, 564, 583, 611 Lung Transplantation, 43, 611 Lung volume, 10, 611 Lupus, 45, 217, 328, 398, 451, 463, 611, 654 Lutein Cells, 611, 636 Lymph, 92, 128, 383, 434, 548, 557, 567, 583, 598, 611, 620 Lymph node, 92, 128, 383, 434, 557, 567, 611, 620 Lymphatic, 583, 602, 611, 614, 625, 649, 650, 656

680 Sclerosis

Lymphatic system, 611, 649, 650, 656 Lymphocyte, 68, 103, 144, 154, 182, 214, 229, 355, 422, 423, 553, 554, 607, 611, 612, 613, 617 Lymphocyte Count, 422, 611 Lymphocytic, 611 Lymphoid, 65, 92, 410, 553, 594, 608, 611, 656 Lymphokines, 71, 611 Lymphoma, 210, 272, 284, 306, 312, 316, 319, 322, 511, 611 Lysine, 174, 283, 405, 413, 421, 444, 450, 598, 611, 660 Lytic, 611, 647 M Macrophage, 93, 104, 130, 188, 409, 449, 553, 604, 611 Macrophage Activation, 104, 611 Magnesium Hydroxide, 397, 611 Magnetic Resonance Spectroscopy, 109, 119, 219, 276, 285, 465, 612 Major Histocompatibility Complex, 31, 49, 56, 71, 105, 129, 595, 597, 604, 612, 615 Malabsorption, 512, 612 Malignancy, 87, 612 Malignant, 61, 67, 99, 249, 399, 512, 519, 554, 592, 612, 618, 620, 641, 645 Malignant tumor, 612, 618 Malnutrition, 549, 556, 612, 618 Malondialdehyde, 97, 612 Mandible, 239, 550, 567, 612, 643 Mania, 612 Manic, 528, 612 Manifest, 7, 72, 91, 399, 557, 612, 651 Mastication, 612, 659 Matrix metalloproteinase, 18, 49, 113, 151, 193, 222, 225, 269, 442, 612 Maximum Tolerated Dose, 355, 581, 612 Measles Virus, 24, 417, 612 Meatus, 379, 612, 660 Mechanical ventilation, 40, 612 Medial, 375, 555, 612, 625 Mediate, 19, 31, 79, 94, 97, 113, 118, 342, 403, 423, 450, 565, 580, 607, 613 Mediator, 225, 270, 580, 604, 613, 647 Medical Records, 15, 105, 597, 613 Medical Staff, 368, 537, 613 Medicament, 386, 393, 425, 426, 613 MEDLINE, 505, 509, 512, 613 Medullary, 376, 578, 613 Megakaryocytes, 613, 656

Meiosis, 613, 615, 618, 653, 661 Melanin, 606, 613, 631, 660 Melanocytes, 613 Melanoma, 105, 512, 613 Membrane Proteins, 610, 613 Memory Disorders, 115, 613 Meninges, 565, 566, 581, 613, 650 Meningitis, 27, 140, 613 Menopause, 49, 327, 613, 635 Menstruation, 613 Mental deficiency, 588, 613 Mental Disorders, 371, 599, 614, 638 Mental Health, iv, 12, 25, 40, 51, 265, 371, 504, 508, 614, 639 Mental Retardation, 11, 48, 54, 61, 82, 87, 118, 130, 158, 380, 401, 432, 513, 535, 536, 614 Mentors, 30, 75, 614 Mercury, 577, 589, 614 Mesenchymal, 57, 614 Meta-Analysis, 182, 614 Metabolic disorder, 524, 614 Metabolite, 110, 161, 235, 252, 287, 560, 563, 579, 585, 608, 610, 614 Metabotropic, 152, 614 Metastasis, 221, 565, 612, 614 Methionine, 116, 335, 579, 614, 652 Methoxsalen, 499, 614 Methylphenidate, 381, 433, 614 Metronidazole, 416, 614 MI, 16, 66, 81, 107, 183, 286, 451, 486, 545, 614 Microbe, 615, 658 Microbiology, 14, 98, 124, 174, 548, 557, 558, 615 Microdialysis, 32, 615 Micronuclei, 263, 615 Microorganism, 570, 615, 628, 664 Micro-organism, 577, 615 Microscopy, 8, 23, 26, 43, 58, 81, 95, 96, 124, 141, 558, 615 Microtubule-Associated Proteins, 615, 622 Microtubules, 62, 604, 615, 621 Microwaves, 615, 640 Mineralization, 563, 615 Mineralocorticoids, 548, 574, 615 Minocycline, 102, 273, 285, 347, 427, 455, 615 Minor Histocompatibility Antigens, 105, 597, 615 Minor Histocompatibility Loci, 615

Index 681

Mitochondria, 19, 42, 59, 80, 93, 275, 547, 616, 619, 626 Mitochondrial Swelling, 616, 620 Mitosis, 62, 555, 608, 615, 616 Mitotic, 62, 111, 112, 616 Mitoxantrone, 70, 150, 182, 224, 230, 250, 272, 410, 496, 500, 616 Mobility, 4, 5, 9, 53, 143, 323, 363, 422, 486, 520, 527, 616 Mobilization, 93, 368, 616 Modeling, 25, 85, 96, 250, 616 Modification, 45, 56, 61, 92, 481, 591, 616, 640 Molecular Probes, 582, 616 Molecular Structure, 403, 616, 659 Mollicutes, 168, 616 Monitor, 53, 60, 124, 356, 400, 525, 574, 616, 624 Monoamine, 381, 391, 404, 419, 434, 439, 551, 575, 578, 616, 646, 660 Monoamine Oxidase, 381, 391, 404, 419, 434, 439, 551, 575, 578, 616, 646, 660 Monoclonal antibodies, 95, 141, 377, 408, 418, 454, 600, 617 Monocular, 205, 617 Monocyte, 65, 73, 98, 113, 225, 226, 242, 553, 617 Monocyte Chemoattractant Protein-1, 242, 617 Monogenic, 51, 617 Morbillivirus, 580, 612, 617 Morphine, 286, 570, 617, 620, 625 Morphogenesis, 62, 588, 617 Morphological, 48, 91, 582, 590, 613, 617 Morphology, 37, 124, 252, 565, 611, 617 Motility, 80, 617, 647 Motion Sickness, 617, 620 Motor Activity, 381, 433, 617, 640 Motor Cortex, 13, 17, 62, 77, 164, 176, 232, 367, 617, 642 Motor nerve, 102, 122, 587, 617, 624, 630 Motor Neurons, 14, 17, 19, 32, 37, 42, 58, 62, 76, 80, 83, 90, 91, 100, 102, 116, 117, 122, 137, 141, 193, 216, 383, 388, 402, 442, 455, 525, 617 Movement Disorders, 3, 169, 240, 550, 581, 617, 655 Mucins, 617, 645 Mucolytic, 547, 617 Mucosa, 611, 618, 636 Multicenter study, 200, 353, 618 Multiple Myeloma, 285, 313, 618

Multivalent, 121, 557, 618 Muscle Denervation, 17, 618 Muscle Fibers, 532, 556, 618 Muscle Hypertonia, 618, 622 Muscular Atrophy, 61, 62, 122, 383, 510, 512, 618 Muscular Diseases, 618, 622, 628, 639 Muscular Dystrophies, 581, 618 Musculature, 4, 455, 599, 618, 651 Mutagenesis, 26, 618 Mutagenic, 550, 618 Mutagens, 618 Myasthenia, 196, 398, 594, 618 Mycosis, 396, 618 Myelin Proteins, 56, 262, 449, 618 Myelitis, 174, 361, 619 Myelogenous, 150, 272, 619 Myeloma, 385, 619 Myocardial infarction, 386, 574, 614, 619 Myocardial Ischemia, 552, 619 Myocardial Reperfusion, 619, 643 Myocardial Reperfusion Injury, 619, 643 Myocardium, 34, 552, 614, 619 Myofibrils, 563, 619 Myotonic Dystrophy, 512, 619 N Naive, 31, 130, 619 Naloxone, 396, 619 Naltrexone, 396, 397, 619 Narcolepsy, 510, 578, 614, 620 Narcosis, 620 Narcotic, 396, 397, 609, 617, 619, 620, 623 Nasal Mucosa, 620 Nasal Polyps, 390, 620 Natural selection, 25, 620 Nausea, 6, 7, 287, 620, 627, 661 NCI, 1, 111, 370, 503, 569, 620 Neck Pain, 7, 620 Necrosis, 177, 317, 389, 412, 434, 555, 567, 592, 602, 614, 619, 620, 643 Needs Assessment, 166, 340, 620 Neocortex, 620, 622 Neonatal, 126, 240, 602, 620 Neoplasia, 5, 110, 512, 620 Neoplasm, 620, 645, 660 Neoplastic, 57, 357, 454, 552, 598, 610, 611, 620 Nephrectomy, 115, 620 Nephrology, 9, 192, 286, 324, 480, 620 Nephron, 27, 231, 592, 620 Nephropathy, 33, 78, 510, 607, 621 Nephrosis, 621

682 Sclerosis

Nephrotic, 9, 251, 511, 621 Nephrotic Syndrome, 251, 511, 621 Nerve Degeneration, 621 Nerve Endings, 621, 654 Nerve Fibers, 189, 358, 363, 377, 408, 437, 524, 530, 531, 534, 621 Nerve Growth Factor, 621, 623 Networks, 534, 621, 655 Neural Pathways, 621 Neuralgia, 4, 7, 195, 224, 271, 323, 621, 635 Neuritis, 202, 238, 391, 621, 626 Neuroblastoma, 81, 117, 621 Neurodegenerative Diseases, 41, 97, 116, 125, 131, 402, 452, 453, 558, 621 Neuroendocrine, 25, 53, 621 Neurofibrillary Tangles, 97, 159, 621 Neurofilaments, 23, 90, 137, 621, 622 Neurogenic, 51, 485, 507, 622 Neuroglia, 592, 622 Neurologic Manifestations, 232, 622 Neurologist, 74, 105, 224, 381, 434, 622 Neuromuscular, 32, 61, 142, 309, 350, 351, 387, 399, 464, 524, 525, 532, 547, 622, 628, 639 Neuromuscular Diseases, 351, 532, 622, 628, 639 Neuromuscular Junction, 142, 387, 399, 547, 622 Neuropathy, 4, 157, 376, 431, 622, 630 Neuropeptide, 446, 622 Neurophysiology, 31, 162, 176, 203, 207, 213, 216, 241, 259, 262, 279, 303, 312, 323, 577, 621, 622 Neuropsychological Tests, 109, 366, 622 Neurotoxic, 88, 623 Neurotoxicity, 578, 623 Neurotransmitters, 586, 622, 623, 649 Neurotrophins, 41, 116, 183, 623 Neutrons, 550, 606, 623, 640 Neutropenia, 157, 623 Neutrophil, 261, 623 Niacin, 623, 660 Nifedipine, 282, 623 Nitric Oxide, 19, 45, 77, 92, 100, 107, 125, 137, 142, 144, 158, 181, 199, 202, 235, 270, 367, 623 Nitrogen, 45, 92, 125, 550, 551, 552, 575, 576, 586, 589, 607, 623, 660 Nitrogen Dioxide, 45, 623 Nitrous Oxide, 6, 623 Nocturia, 11, 623 Norepinephrine, 548, 578, 580, 624

Nuclear, 28, 106, 367, 383, 403, 434, 511, 558, 564, 582, 585, 590, 592, 609, 620, 624, 644, 655 Nuclei, 19, 62, 288, 550, 551, 582, 591, 605, 609, 612, 615, 616, 623, 624, 625, 638, 654 Nucleic acid, 381, 437, 446, 591, 598, 601, 618, 623, 624, 636, 639, 644, 650, 663 Nucleic Acid Hybridization, 381, 598, 624 Nystagmus, 239, 407, 419, 420, 431, 526, 624 O Observational study, 143, 287, 624 Occipital Lobe, 579, 624, 664 Occult, 221, 236, 624 Occupational Therapy, 243, 474, 624 Octreotide, 193, 624 Ocular, 106, 229, 237, 238, 377, 408, 510, 624 Oculomotor, 579, 624 Oculomotor Nerve, 579, 624 Oedema, 176, 624 Olfaction, 95, 625 Oligodendroglia, 46, 618, 622, 625 Oligodendroglial, 443, 625 Oliguria, 607, 625 Oncogene, 274, 512, 596, 625 Oncogenic, 608, 625 Opacity, 565, 577, 625 Open Reading Frames, 410, 608, 625 Ophthalmology, 106, 157, 202, 214, 238, 239, 589, 625 Opium, 617, 625 Opsin, 625, 643 Optic Chiasm, 599, 625 Optic disc, 625, 626 Optic Nerve, 96, 398, 419, 420, 431, 561, 625, 627, 643, 644, 645 Optic Neuritis, 202, 242, 419, 420, 431, 438, 625 Oral Health, 626 Oral Hygiene, 4, 5, 533, 626 Oral Manifestations, 7, 274, 626 Orbital, 547, 625, 626, 659 Organ Culture, 626, 657 Organelles, 94, 566, 576, 613, 626, 633 Ornithine, 452, 453, 626, 639 Ornithine Decarboxylase, 452, 453, 626 Orofacial, 4, 7, 626 Orthostatic, 624, 626 Osteoarthritis, 53, 626 Osteoporosis, 158, 327, 626 Otitis, 486, 626

Index 683

Otitis Media, 486, 626 Outpatient, 181, 349, 626 Ovaries, 587, 626, 642, 643, 647 Overdose, 396, 626 Ovum, 609, 626, 636, 664 Oxidants, 367, 626 Oxidation, 97, 116, 131, 218, 239, 547, 554, 560, 575, 593, 609, 626, 627 Oxidation-Reduction, 560, 626, 627 Oxidative Stress, 16, 42, 62, 77, 97, 100, 116, 232, 283, 627 Oxygen Consumption, 627, 643 Oxygenation, 576, 627 P Pachymeningitis, 613, 627 Palliative, 40, 302, 474, 533, 627, 655 Palsy, 4, 18, 377, 402, 408, 528, 627 Pancreas, 128, 398, 413, 547, 560, 569, 579, 603, 606, 627, 649, 660 Pancreatic, 128, 512, 564, 569, 627 Pancreatic cancer, 512, 627 Pancreatic Juice, 569, 627 Panic, 600, 627 Panic Disorder, 600, 627 Papilla, 627, 628 Papillary, 221, 628 Paraesthesia, 419, 420, 628 Paraplegia, 367, 398, 527, 628 Parasite, 628, 659 Parasitic, 430, 628 Parathyroid, 563, 628 Parathyroid hormone, 563, 628 Parenchyma, 40, 80, 109, 365, 628 Parenteral, 368, 392, 398, 496, 628 Paresis, 621, 628 Paresthesia, 426, 431, 628 Parietal, 628, 631, 634 Parkinsonism, 16, 97, 159, 190, 216, 232, 240, 262, 282, 382, 510, 609, 628 Paroxysmal, 185, 240, 285, 312, 316, 512, 552, 628 Partial remission, 628, 642 Particle, 628, 649, 658, 663 Parturition, 628, 636 Patch, 11, 393, 493, 519, 573, 628, 658 Pathogen, 39, 64, 381, 407, 602, 603, 628 Pathologic Processes, 363, 555, 629 Pathologies, 74, 258, 429, 629 Pathophysiology, 66, 73, 78, 84, 102, 119, 191, 315, 472, 477, 629 Patient Advocacy, 526, 629 Patient Compliance, 47, 76, 629

Patient Education, 469, 481, 518, 519, 521, 527, 537, 540, 542, 545, 629 Pediatrics, 26, 66, 75, 381, 434, 629 Pedigree, 61, 629 Pelvic, 313, 629, 637 Pemoline, 381, 433, 629 Pemphigus, 79, 547, 629 Penicillamine, 243, 492, 629 Penicillin, 553, 629, 662 Penis, 629, 631, 643 Pepsin, 569, 629 Pepsin A, 569, 629 Peptide Fragments, 394, 629 Peptide T, 83, 94, 411, 412, 629 Perception, 375, 376, 407, 629, 645 Percutaneous, 271, 379, 386, 630, 631 Perennial, 428, 630 Perforation, 193, 589, 630 Perfusion, 13, 110, 161, 263, 354, 599, 630, 657 Pericardium, 630, 654 Periodontal disease, 7, 299, 390, 630 Periodontitis, 5, 390, 630 Peripheral Nerves, 419, 420, 431, 528, 630, 650 Peripheral Nervous System, 412, 577, 581, 618, 621, 622, 627, 628, 630, 636, 639, 649, 652 Peripheral Nervous System Diseases, 622, 628, 630, 639 Peripheral Neuropathy, 61, 431, 630 Peripheral stem cell transplantation, 630, 658 Peripheral stem cells, 594, 630 Peripheral vision, 630, 664 Peritoneal, 191, 202, 244, 256, 308, 315, 316, 555, 625, 630, 631 Peritoneal Cavity, 555, 625, 630, 631 Peritoneal Dialysis, 191, 202, 308, 316, 631 Peritoneum, 630, 631 Perivascular, 31, 39, 113, 163, 394, 625, 631 Peroxidase, 308, 609, 631 Peroxide, 97, 631 Perspiration, 430, 631 Petechiae, 595, 631 Phagocyte, 626, 631 Phagocytosis, 16, 631 Phallic, 588, 631 Pharmacokinetic, 631 Pharmacologic, 100, 552, 595, 631, 657, 658 Phenotype, 21, 39, 44, 46, 48, 50, 53, 58, 61, 77, 79, 82, 86, 89, 100, 104, 111, 112, 113,

684 Sclerosis

126, 127, 132, 143, 165, 169, 240, 438, 560, 571, 631 Phenylalanine, 336, 381, 419, 420, 434, 629, 631, 660 Phonophoresis, 606, 631 Phosphodiesterase, 393, 631, 645 Phospholipases, 631, 648 Phospholipids, 418, 587, 603, 631 Phosphoprotein Phosphatase, 566, 631 Phosphorus, 383, 434, 563, 631, 632 Phosphorylase, 563, 631 Phosphorylated, 23, 164, 570, 631, 632 Phosphorylates, 269, 632 Phosphorylation, 43, 106, 110, 220, 288, 575, 632, 638 Photocoagulation, 570, 632 Phototherapy, 137, 269, 632 Physical Examination, 8, 352, 376, 632 Physical Fitness, 586, 632 Physical Therapy, 307, 458, 632 Physiologic, 99, 123, 164, 549, 560, 578, 580, 595, 599, 613, 632, 637, 641, 643, 659 Physiology, 32, 53, 60, 92, 97, 557, 560, 582, 608, 620, 622, 632 Phytic Acid, 397, 430, 603, 632 Pigment, 493, 520, 559, 613, 632 Piloerection, 412, 632 Pilot study, 13, 95, 114, 122, 149, 227, 268, 275, 282, 305, 313, 314, 320, 632 Pineal Body, 632 Pineal gland, 309, 632 Pitch, 632, 664 Pituitary Gland, 574, 588, 632 Placenta, 585, 632, 636, 661 Plants, 550, 556, 564, 568, 582, 592, 614, 617, 624, 632, 635, 645, 658, 660, 662 Plasma cells, 16, 439, 553, 594, 618, 619, 633 Plasma Exchange, 259, 361, 423, 633 Plasma protein, 394, 395, 549, 583, 633, 638, 647 Plasma Volume, 561, 615, 633 Plasmapheresis, 555, 633 Plasmid, 44, 47, 633, 662 Plasmin, 115, 242, 633, 657, 661 Plasminogen, 115, 140, 633, 657, 661 Plasminogen Activators, 633 Plasticity, 104, 179, 633 Plastids, 626, 633 Platelet Activation, 481, 633, 648 Platelet Aggregation, 552, 585, 600, 623, 633

Platelet-Derived Growth Factor, 99, 194, 386, 633 Plateletpheresis, 555, 634 Platelets, 116, 356, 357, 563, 623, 633, 634, 656 Pleura, 634 Pleural, 399, 625, 634 Pleural cavity, 625, 634 Ploidy, 112, 634 Pneumoconiosis, 390, 634 Point Mutation, 62, 112, 190, 437, 634 Point System, 10, 634 Poisoning, 311, 605, 614, 620, 634 Polyarteritis Nodosa, 461, 600, 634 Polycystic, 126, 242, 390, 511, 512, 634 Polymerase, 492, 634 Polymorphic, 21, 56, 75, 577, 634 Polymorphism, 56, 137, 193, 215, 237, 634 Polyploid, 112, 634 Polysaccharide, 554, 593, 634, 638 Polytherapy, 54, 634 Polyunsaturated fat, 305, 634 Pons, 547, 558, 562, 635, 644 Postal Service, 42, 635 Posterior, 380, 433, 551, 555, 556, 558, 566, 568, 580, 606, 620, 624, 626, 627, 632, 635, 645 Postherpetic Neuralgia, 550, 635 Postmenopausal, 49, 237, 626, 635 Postnatal, 588, 635, 651 Postsynaptic, 635, 648, 653, 654 Post-synaptic, 635, 654 Post-translational, 45, 92, 635 Post-traumatic, 617, 635 Potassium, 397, 615, 635, 640 Potassium hydroxide, 397, 635 Potentiate, 404, 439, 635 Potentiating, 396, 560, 635 Potentiation, 568, 635, 648 Practicability, 635, 659 Practice Guidelines, 508, 520, 521, 635 Preclinical, 44, 110, 130, 375, 581, 635 Predisposition, 144, 353, 388, 635 Prednisolone, 182, 636 Prednisone, 66, 181, 410, 418, 423, 428, 636 Prefrontal Cortex, 18, 636 Prenatal, 87, 162, 241, 582, 588, 636 Prenatal Diagnosis, 87, 162, 241, 636 Presynaptic, 621, 636, 653, 654 Prion, 93, 172, 636 Probe, 97, 594, 615, 636 Progesterone, 336, 636, 651

Index 685

Prognostic factor, 163, 215, 245, 255, 636 Progressive Bulbar Palsy, 383, 636 Progressive disease, 109, 361, 377, 401, 408, 411, 530, 531, 537, 636 Projection, 577, 604, 624, 625, 636, 639, 642 Prolactin, 246, 636 Proline, 570, 598, 636 Promoter, 33, 49, 127, 137, 193, 637 Prone, 27, 33, 49, 124, 637 Prophase, 618, 637, 653, 661 Prophylaxis, 385, 386, 436, 507, 637, 662 Prospective Studies, 41, 637 Prospective study, 40, 145, 232, 259, 610, 637 Prostaglandin, 107, 246, 284, 585, 637 Prostaglandins A, 637 Prostate, 430, 446, 512, 637, 643 Prosthesis, 212, 637 Protease, 82, 122, 131, 452, 571, 637, 657 Protective Agents, 563, 637 Protein Binding, 637, 657 Protein C, 29, 47, 62, 93, 97, 267, 302, 405, 444, 452, 462, 549, 551, 558, 588, 638, 661 Protein Conformation, 551, 638 Protein Folding, 90, 638 Protein S, 56, 369, 374, 478, 512, 513, 560, 591, 597, 638, 644, 655 Protein Subunits, 374, 638 Protein-Tyrosine Kinase, 591, 638 Proteinuria, 9, 78, 480, 592, 618, 621, 638 Proteoglycans, 288, 558, 587, 638 Proteolytic, 82, 117, 137, 550, 558, 571, 584, 588, 633, 638, 657, 661 Prothrombin, 638, 656 Protocol, 6, 30, 35, 47, 69, 74, 126, 300, 638 Protons, 397, 550, 598, 605, 612, 638, 640 Proximal, 23, 123, 580, 636, 638, 647 Psoriasis, 128, 266, 390, 638 Psychiatric, 288, 381, 433, 517, 519, 528, 560, 614, 638 Psychic, 639, 646 Psychomotor, 564, 639 Psychotomimetic, 551, 578, 639 Psychotropic, 28, 610, 639 Public Health, 17, 41, 42, 119, 479, 508, 639 Public Policy, 505, 639 Publishing, 3, 5, 136, 236, 477, 480, 482, 639 Pulmonary Artery, 10, 561, 639, 663 Pulmonary Edema, 568, 607, 639 Pulmonary Fibrosis, 83, 390, 639

Pulmonary hypertension, 10, 242, 243, 247, 286, 573, 585, 639 Pulse, 110, 170, 616, 639 Pupil, 573, 579, 626, 639 Purines, 403, 639, 647 Purpura, 595, 639 Putrefaction, 639 Putrescine, 452, 453, 626, 639, 650 Pyramidal Cells, 577, 639 Pyridoxal, 626, 639, 658 Q Quadriplegia, 527, 639 Quaternary, 418, 638, 640 Quiescent, 79, 640 Quinidine, 370, 640 Quinine, 640 R Race, 186, 550, 569, 580, 615, 640 Radiation therapy, 312, 316, 580, 586, 589, 599, 604, 606, 640, 658, 665 Radio Waves, 352, 354, 356, 615, 640 Radioactive, 562, 595, 598, 601, 604, 605, 606, 610, 616, 617, 624, 625, 640, 641, 645, 665 Radioimmunoassay, 384, 640 Radioimmunotherapy, 640, 641 Radioisotope, 585, 641, 658 Radiolabeled, 82, 561, 606, 640, 641, 665 Radiological, 159, 166, 630, 641 Radiology, 12, 84, 109, 119, 253, 256, 276, 285, 287, 521, 641 Radiotherapy, 166, 284, 306, 322, 366, 412, 562, 606, 640, 641, 665 Random Allocation, 641 Randomization, 348, 350, 641 Randomized clinical trial, 147, 149, 641 Reaction Time, 364, 641 Reactivation, 490, 641 Reactive Oxygen Species, 97, 641 Reagent, 70, 406, 413, 568, 598, 641 Receptors, Serotonin, 641, 647 Recombinant, 24, 47, 76, 94, 133, 147, 251, 368, 412, 498, 499, 641, 662 Recombination, 112, 126, 591, 642 Reconstitution, 70, 642 Rectum, 562, 579, 589, 590, 602, 608, 637, 642 Recur, 389, 398, 642 Recurrence, 9, 642 Red blood cells, 135, 357, 585, 642, 645 Red Nucleus, 556, 642 Reductase, 610, 642

686 Sclerosis

Refer, 1, 506, 549, 562, 571, 580, 588, 592, 596, 604, 610, 619, 623, 624, 641, 642, 663 Reflex, 315, 316, 317, 587, 642 Refraction, 553, 642, 650 Refractive Errors, 579, 642 Refractory, 32, 54, 320, 361, 582, 642 Regeneration, 63, 65, 588, 642 Regimen, 44, 107, 170, 322, 360, 367, 368, 381, 395, 434, 440, 581, 629, 642 Rehabilitative, 19, 642 Relapse, 28, 47, 101, 139, 159, 182, 193, 219, 245, 273, 359, 411, 419, 420, 431, 449, 642 Relaxin, 368, 499, 642 Reliability, 167, 254, 267, 277, 642 Remission, 9, 28, 96, 376, 378, 389, 391, 411, 426, 438, 443, 446, 480, 642 Renin, 115, 552, 642 Reperfusion, 131, 619, 643 Reperfusion Injury, 132, 643 Repopulation, 99, 643 Reproductive cells, 591, 596, 643 Reproductive system, 103, 643 Research Design, 19, 643 Resected, 66, 91, 643 Resection, 54, 255, 618, 643 Residual Volume, 590, 643, 657 Resorption, 5, 643 Respiration, 26, 116, 564, 616, 643 Respirator, 612, 643, 663 Respiratory Physiology, 643, 663 Response rate, 277, 643 Restoration, 619, 632, 641, 642, 643, 664 Retina, 80, 537, 561, 568, 572, 573, 608, 622, 625, 643, 644, 662, 664 Retinal, 11, 251, 255, 426, 617, 625, 643, 644, 664 Retinal Ganglion Cells, 625, 644 Retinoblastoma, 512, 644 Retinoid, 255, 644 Retinol, 255, 643, 644 Retrobulbar, 626, 644 Retrograde, 108, 644 Retrospective, 200, 210, 644 Retroviral vector, 56, 644 Retrovirus, 57, 87, 143, 154, 229, 385, 413, 417, 644 Rheumatism, 10, 153, 154, 156, 160, 164, 168, 175, 182, 197, 207, 225, 243, 244, 266, 392, 644 Ribonucleic acid, 644 Ribonucleoproteins, 398, 644 Ribose, 548, 644

Ribosome, 644, 659 Rigidity, 628, 632, 644 Riluzole, 153, 209, 220, 256, 268, 272, 284, 312, 389, 424, 425, 426, 496, 499, 644 Risk factor, 16, 41, 50, 153, 245, 249, 256, 308, 388, 507, 584, 637, 644 Rods, 590, 643, 644 Rolipram, 355, 374, 645 S Saimiri, 264, 645 Saline, 633, 645 Saliva, 4, 150, 482, 645 Salivary, 7, 576, 579, 587, 627, 645 Salivary glands, 576, 579, 587, 645 Saponins, 645, 651 Sarcoma, 413, 645 Satellite, 462, 486, 625, 645 Scans, 51, 69, 86, 111, 119, 126, 194, 348, 354, 355, 359, 360, 645 Schizoid, 645, 664 Schizophrenia, 141, 425, 460, 528, 613, 645, 664 Schizotypal Personality Disorder, 645, 664 Sclera, 568, 572, 573, 645, 662 Sclerotic, 5, 32, 49, 384, 443, 447, 645 Sebaceous, 646, 664 Secondary tumor, 614, 646 Secretion, 7, 18, 54, 121, 130, 342, 343, 569, 574, 597, 598, 603, 604, 608, 615, 617, 624, 631, 646, 659, 662 Secretory, 646, 653, 654 Sedative, 570, 600, 646 Sedentary, 51, 646 Segmental, 9, 78, 192, 258, 324, 480, 592, 646 Segmentation, 13, 266, 646 Segregation, 56, 558, 642, 646 Selegiline, 381, 404, 434, 439, 646 Selenium, 293, 308, 367, 646 Self-Help Groups, 531, 646 Semen, 637, 646 Semicircular canal, 603, 646 Semisynthetic, 564, 615, 646 Senile, 626, 646 Sensibility, 551, 646 Sensory loss, 619, 647, 655 Septal, 11, 382, 609, 647 Septic, 412, 556, 647 Sequence Analysis, 105, 121, 647 Sequence Homology, 629, 647 Sequencing, 15, 20, 58, 124, 647 Serine, 127, 452, 569, 631, 647, 657, 660

Index 687

Serologic, 156, 457, 600, 647 Serotonin, 66, 381, 419, 431, 434, 578, 616, 641, 647, 660 Serous, 583, 634, 647 Serum Albumin, 640, 647 Sex Characteristics, 430, 548, 552, 647 Sex Determination, 512, 647 Sexually Transmitted Diseases, 483, 647 Sharpness, 647, 664 Shock, 139, 396, 412, 552, 582, 598, 647, 659 Signal Transduction, 80, 389, 403, 603, 647 Signs and Symptoms, 7, 23, 389, 622, 634, 642, 648 Silicon, 418, 648 Silicon Dioxide, 648 Single Person, 10, 648 Skeletal, 42, 75, 216, 261, 275, 387, 552, 553, 568, 574, 607, 618, 619, 640, 648, 649 Skeleton, 424, 548, 607, 637, 648 Skin Manifestations, 520, 648 Skin Tests, 359, 648, 660 Skull, 561, 648, 655 Sleep Paralysis, 317, 648 Small intestine, 559, 575, 581, 592, 597, 605, 648, 660 Smallpox, 648, 662 Smooth muscle, 43, 82, 133, 386, 403, 552, 562, 563, 572, 597, 617, 618, 648, 649, 652 Social Environment, 640, 648 Social Support, 537, 648, 652 Sodium, 145, 397, 585, 615, 640, 648, 653 Soft tissue, 7, 561, 591, 648, 649 Solid tumor, 552, 649 Solitary Nucleus, 557, 649 Solvent, 207, 559, 585, 593, 649 Soma, 406, 639, 649 Somatic, 18, 24, 54, 83, 424, 548, 597, 609, 613, 616, 630, 636, 649 Somatic cells, 613, 616, 649 Somatic mutations, 24, 424, 649 Somatostatin, 624, 649 Sound wave, 572, 649 Soybean Oil, 635, 649 Spasm, 391, 443, 573, 622, 649 Spasmodic, 3, 649 Spastic, 58, 87, 132, 348, 367, 649 Spatial disorientation, 580, 649 Specialist, 212, 236, 530, 537, 579, 649 Spectrometer, 105, 650 Spectrum, 18, 87, 106, 232, 517, 615, 640, 650 Speech Disorders, 482, 486, 650

Speech Intelligibility, 74, 650 Sperm, 552, 568, 591, 596, 643, 649, 650, 660 Spermidine, 626, 650 Sphincter, 40, 608, 650 Spina bifida, 483, 527, 650 Spinal Cord Diseases, 628, 639, 650 Spinal Cord Injuries, 83, 527, 650 Spinal Cord Vascular Diseases, 619, 650 Spinal Nerves, 412, 630, 650 Spinal tap, 352, 356, 359, 611, 650 Spirochete, 650, 654 Spleen, 430, 576, 611, 650 Spondylitis, 79, 106, 650 Sprains and Strains, 610, 651 Squamous, 252, 651 Staging, 481, 486, 645, 651 Standard therapy, 66, 149, 651 Staphylococcus, 615, 651 Status Epilepticus, 317, 651 Stem cell transplantation, 163, 200, 202, 205, 284, 306, 310, 357, 492, 595, 651 Stem Cells, 349, 357, 595, 630, 651, 661 Sterile, 392, 556, 628, 651, 660 Sterility, 575, 602, 651 Steroid, 9, 43, 149, 361, 383, 434, 435, 480, 559, 574, 645, 651 Steroid therapy, 9, 361, 480, 651 Stimulant, 381, 434, 551, 563, 578, 597, 607, 614, 629, 651, 662 Stimulus, 113, 573, 581, 582, 586, 603, 605, 608, 641, 642, 651, 656 Stomach, 547, 560, 579, 585, 590, 597, 620, 629, 630, 648, 650, 651 Stool, 602, 608, 651 Strabismus, 579, 651 Strand, 56, 243, 249, 481, 634, 652 Streptavidin, 121, 652 Stress management, 13, 652 Striatum, 382, 578, 652 Stroma, 606, 628, 652 Stupor, 620, 652 Subacute, 7, 24, 176, 376, 602, 652 Subclinical, 46, 64, 166, 602, 646, 652 Subculture, 414, 415, 652 Subcutaneous, 209, 392, 581, 625, 628, 652 Subiculum, 597, 652 Subspecies, 649, 652, 662 Substance P, 614, 642, 646, 652 Substrate, 131, 388, 565, 582, 584, 606, 652, 660 Subungual, 380, 401, 432, 519, 652

688 Sclerosis

Sulfur, 586, 614, 652 Supplementation, 13, 43, 49, 134, 304, 305, 308, 310, 318, 652 Support group, 319, 483, 506, 524, 525, 529, 533, 536, 537, 653 Supportive care, 458, 653 Suppression, 57, 65, 70, 103, 136, 145, 375, 414, 416, 477, 574, 653 Suppressive, 66, 450, 653 Supraspinal, 558, 653 Supraventricular, 240, 653 Sweat, 430, 631, 653 Sweat Glands, 653 Sympathetic Nervous System, 557, 623, 653 Sympathomimetic, 551, 578, 580, 584, 607, 624, 653, 660 Symphysis, 568, 637, 653 Symptomatic, 5, 27, 62, 152, 266, 288, 319, 476, 550, 653 Symptomatic treatment, 152, 288, 550, 653 Symptomatology, 16, 29, 400, 653 Synapses, 381, 433, 568, 623, 653, 654 Synapsis, 653 Synaptic, 145, 393, 648, 653, 654 Synaptic Transmission, 393, 653 Synaptic Vesicles, 653, 654 Synaptosomes, 81, 654 Syncytium, 592, 654 Synergistic, 128, 447, 636, 654, 657 Synovial, 591, 654 Syphilis, 376, 390, 654 Syringomyelia, 376, 654 Systemic disease, 82, 654 Systemic lupus erythematosus, 20, 45, 55, 246, 390, 461, 570, 600, 654 Systolic, 10, 594, 599, 654 Systolic pressure, 10, 654 T Tachycardia, 240, 654 Tacrolimus, 601, 654 Telangiectasia, 8, 512, 654 Telecommunications, 572, 654 Telencephalon, 558, 654 Telophase, 615, 654 Temporal, 9, 26, 31, 71, 85, 95, 103, 126, 127, 164, 175, 182, 189, 191, 198, 203, 210, 216, 222, 223, 246, 257, 258, 263, 267, 307, 310, 314, 324, 551, 597, 612, 655 Temporal Lobe, 9, 31, 95, 164, 175, 210, 222, 246, 257, 258, 307, 310, 314, 551, 655 Teratogenic, 550, 655

Terbutaline, 238, 655 Terminal disease, 40, 655 Tetani, 655 Tetanic, 655 Tetanus, 86, 655 Tetracycline, 57, 427, 455, 580, 615, 655 Tetrahydrocannabinol, 28, 564, 655 Thalamic, 169, 556, 655 Thalamic Diseases, 556, 655 Thalamus, 66, 562, 578, 609, 636, 655 Therapeutics, 17, 18, 94, 100, 130, 147, 198, 302, 363, 409, 466, 469, 497, 617, 655 Thermal, 553, 555, 579, 623, 655 Thermography, 320, 655 Third Ventricle, 599, 632, 655 Thorax, 547, 611, 655 Threonine, 498, 629, 631, 647, 656 Threshold, 586, 599, 656 Thrombin, 80, 588, 633, 638, 656 Thrombocytes, 634, 656 Thrombocytopenia, 154, 656 Thrombolytic, 633, 656 Thrombomodulin, 638, 656 Thrombopoietin, 154, 656 Thrombosis, 605, 638, 652, 656 Thrombus, 574, 602, 606, 619, 633, 656, 663 Thymidine, 656 Thymidylate Synthase, 107, 656 Thymus, 389, 395, 440, 569, 600, 611, 656 Thymus Gland, 656 Thymus Hormones, 395, 440, 656 Thyroid, 177, 218, 221, 228, 244, 246, 395, 440, 628, 656, 660 Thyroid Gland, 628, 656 Thyroid Hormones, 246, 656, 660 Thyroiditis, 244, 435, 656 Thyroxine, 549, 631, 656 Tic, 261, 656 Tidal Volume, 603, 657 Time Management, 652, 657 Tin, 391, 426, 443, 526, 530, 531, 577, 628, 630, 657 Tinnitus, 626, 657 Tissue Culture, 24, 113, 341, 382, 657 Tissue Distribution, 103, 657 Tissue Plasminogen Activator, 208, 657 Tolerance, 56, 67, 89, 112, 128, 143, 369, 378, 381, 398, 420, 433, 436, 448, 548, 592, 657 Tome, 331, 657 Tomography, 66, 177, 285, 303, 311, 381, 433, 612, 657

Index 689

Tonicity, 581, 657 Tooth Preparation, 548, 657 Topical, 288, 335, 585, 598, 657 Torsion, 402, 602, 657 Total Lung Capacity, 10, 657 Total-body irradiation, 368, 658 Toxicokinetics, 658 Toxicology, 282, 306, 308, 459, 506, 658 Toxins, 29, 388, 390, 554, 563, 583, 602, 617, 640, 658 Toxoid, 86, 658 Trace element, 26, 184, 430, 648, 657, 658 Tracer, 66, 658 Trachea, 562, 608, 656, 658 Tracheostomy, 40, 389, 658 Transaminase, 425, 658 Transcriptase, 378, 382, 407, 408, 410, 417, 429, 644, 658 Transcription Factors, 54, 566, 658 Transcutaneous, 320, 375, 658 Transdermal, 322, 393, 398, 658 Transduction, 80, 108, 647, 658 Transfection, 38, 68, 560, 582, 658 Transfer Factor, 600, 658 Transferases, 593, 658 Transforming Growth Factor beta, 480, 498, 659 Transgenes, 52, 57, 62, 67, 126, 659 Translation, 15, 82, 110, 129, 659 Translational, 70, 89, 659 Transmitter, 547, 556, 580, 586, 605, 613, 622, 624, 653, 654, 659, 660 Trauma, 23, 55, 80, 547, 558, 595, 620, 655, 657, 659, 660 Treatment Outcome, 108, 659 Tremor, 384, 402, 422, 603, 628, 659 Triamcinolone Acetonide, 182, 659 Trichomoniasis, 614, 659 Tricyclic, 381, 419, 420, 433, 578, 600, 610, 659 Trigeminal, 4, 7, 195, 224, 271, 323, 659 Triglyceride, 599, 659 Trochlear Nerve, 579, 659 Trochlear Nerve Diseases, 579, 659 Trophic, 17, 41, 83, 100, 126, 388, 621, 660 Tropism, 40, 660 Trypsin, 452, 569, 584, 660 Tryptophan, 66, 419, 570, 647, 660 Tubercle, 660 Tuberculin, 359, 660 Tuberculin Test, 359, 660 Tuberculosis, 171, 390, 611, 660

Tubulin, 615, 660 Tumor Necrosis Factor, 104, 172, 221, 266, 374, 383, 409, 434, 660 Tumor suppressor gene, 57, 82, 99, 142, 242, 274, 380, 401, 432, 610, 660 Tumour, 317, 389, 412, 424, 660 Tympanic membrane, 288, 660 Tyramine, 404, 439, 616, 660 Tyrosine, 41, 46, 97, 100, 140, 194, 381, 419, 420, 421, 434, 437, 450, 580, 638, 660 U Ubiquitin, 62, 622, 661 Umbilical Arteries, 661 Umbilical Cord, 311, 661 Umbilical cord blood, 311, 661 Unconscious, 577, 599, 661 Univalent, 598, 627, 661 Urea, 17, 555, 607, 626, 653, 661 Uremia, 607, 661 Ureters, 607, 661 Urethra, 629, 637, 661 Uric, 146, 203, 259, 287, 358, 639, 661 Urinary Plasminogen Activator, 657, 661 Urinary tract, 12, 507, 520, 558, 565, 661 Urinary tract infection, 507, 520, 558, 661 Urinary urgency, 5, 661 Urodynamic, 5, 12, 260, 661 Urogenital, 661 Urogenital Diseases, 661 Urologic Diseases, 482, 661 Uterus, 567, 587, 589, 590, 613, 626, 636, 643, 661, 662 Uvea, 661, 662 Uveitis, 56, 214, 251, 328, 435, 662 V Vaccination, 21, 129, 267, 429, 662 Vaccine, 44, 175, 201, 272, 429, 448, 548, 638, 662 Vaccinia, 132, 662 Vaccinia Virus, 132, 662 Vacuoles, 626, 662 Vagina, 567, 578, 613, 643, 662 Valine, 629, 661, 662 Variola, 662 Vascular endothelial growth factor, 137, 662 Vasculitis, 201, 251, 348, 567, 634, 662 Vasoconstriction, 403, 584, 662 Vasodilation, 183, 398, 403, 600, 662 Vasodilator, 562, 580, 597, 619, 623, 662 Vasogenic, 176, 662 Vasomotor, 158, 662

690 Sclerosis

VE, 17, 201, 202, 235, 248, 366, 527, 662 Vector, 44, 47, 57, 108, 233, 658, 662 Vegetative, 634, 662 Vein, 11, 352, 354, 355, 356, 359, 552, 555, 605, 624, 645, 661, 662, 663 Venereal, 654, 662 Venlafaxine, 381, 434, 662 Venom, 486, 558, 663 Venous, 164, 555, 567, 605, 625, 638, 663 Venous Thrombosis, 164, 663 Ventilation, 40, 219, 663 Ventilator, 612, 643, 663 Ventral, 17, 479, 553, 599, 624, 635, 650, 663 Ventricle, 551, 554, 556, 573, 597, 639, 654, 655, 663 Ventricular, 171, 246, 278, 361, 573, 581, 619, 663 Ventricular Dysfunction, 582, 663 Venules, 443, 561, 564, 583, 663 Vertebrae, 356, 605, 650, 663 Vertebral, 376, 558, 559, 650, 663 Vertigo, 419, 420, 431, 626, 663 Vestibular, 278, 323, 324, 478, 663 Vestibule, 570, 603, 646, 663 Veterinary Medicine, 505, 663 Virulence, 556, 560, 658, 663 Virus, 24, 36, 39, 42, 50, 57, 64, 67, 68, 69, 71, 74, 87, 98, 100, 120, 132, 133, 140, 151, 180, 185, 226, 229, 233, 259, 348, 378, 381, 382, 396, 401, 407, 408, 410, 413, 414, 415, 416, 417, 429, 490, 558, 574, 580, 584, 587, 591, 592, 593, 604, 633, 644, 648, 658, 662, 663 Virus Replication, 36, 40, 663 Viscera, 649, 663, 664

Visceral, 5, 78, 557, 609, 631, 664 Visceral Afferents, 557, 664 Viscosity, 547, 664 Visual Acuity, 96, 134, 171, 376, 573, 664 Visual Cortex, 579, 664 Visual field, 134, 175, 561, 625, 664 Vital Capacity, 10, 32, 37, 102, 657, 664 Vitamin A, 290, 603, 644, 664 Vitreous Body, 643, 664 Vitro, 15, 21, 32, 34, 47, 49, 62, 65, 71, 73, 75, 76, 77, 78, 79, 80, 82, 83, 86, 93, 94, 95, 98, 99, 105, 111, 115, 117, 120, 129, 131, 132, 133, 134, 135, 170, 209, 260, 343, 374, 393, 414, 415, 416, 441, 560, 581, 596, 601, 654, 657, 664 Voice Quality, 74, 664 Volition, 605, 664 Vulgaris, 79, 547, 664 W Wakefulness, 380, 433, 664 Wheelchairs, 463, 526, 664 Windpipe, 656, 664 Withdrawal, 101, 480, 664 Womb, 643, 661, 664 Wound Healing, 63, 565, 569, 588, 612, 664 Wounds, Gunshot, 650, 664 X Xenograft, 553, 665 X-ray, 6, 135, 352, 354, 356, 565, 572, 589, 590, 606, 624, 640, 641, 645, 665 X-ray therapy, 606, 665 Y Yeasts, 590, 631, 665 Z Zymogen, 569, 638, 665

Index 691

692 Sclerosis