YELIN 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 2004 by ICON Group International, Inc. Copyright 2004 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., 1960Myelin: 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: 0-497-00733-9 1. Myelin-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on myelin. 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 MYELIN ..................................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Myelin........................................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 61 The National Library of Medicine: PubMed ................................................................................ 72 CHAPTER 2. NUTRITION AND MYELIN ......................................................................................... 121 Overview.................................................................................................................................... 121 Finding Nutrition Studies on Myelin........................................................................................ 121 Federal Resources on Nutrition ................................................................................................. 122 Additional Web Resources ......................................................................................................... 123 CHAPTER 3. ALTERNATIVE MEDICINE AND MYELIN ................................................................... 125 Overview.................................................................................................................................... 125 National Center for Complementary and Alternative Medicine................................................ 125 Additional Web Resources ......................................................................................................... 136 General References ..................................................................................................................... 137 CHAPTER 4. DISSERTATIONS ON MYELIN ..................................................................................... 139 Overview.................................................................................................................................... 139 Dissertations on Myelin ............................................................................................................ 139 Keeping Current ........................................................................................................................ 140 CHAPTER 5. PATENTS ON MYELIN ................................................................................................ 141 Overview.................................................................................................................................... 141 Patents on Myelin...................................................................................................................... 141 Patent Applications on Myelin .................................................................................................. 160 Keeping Current ........................................................................................................................ 183 CHAPTER 6. BOOKS ON MYELIN ................................................................................................... 185 Overview.................................................................................................................................... 185 Book Summaries: Online Booksellers......................................................................................... 185 Chapters on Myelin.................................................................................................................... 186 CHAPTER 7. PERIODICALS AND NEWS ON MYELIN...................................................................... 189 Overview.................................................................................................................................... 189 News Services and Press Releases.............................................................................................. 189 Academic Periodicals covering Myelin ...................................................................................... 191 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 193 Overview.................................................................................................................................... 193 U.S. Pharmacopeia..................................................................................................................... 193 Commercial Databases ............................................................................................................... 194 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 197 Overview.................................................................................................................................... 197 NIH Guidelines.......................................................................................................................... 197 NIH Databases........................................................................................................................... 199 Other Commercial Databases..................................................................................................... 201 APPENDIX B. PATIENT RESOURCES ............................................................................................... 203 Overview.................................................................................................................................... 203 Patient Guideline Sources.......................................................................................................... 203 Finding Associations.................................................................................................................. 205 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 207 Overview.................................................................................................................................... 207 Preparation................................................................................................................................. 207 Finding a Local Medical Library................................................................................................ 207
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Medical Libraries in the U.S. and Canada ................................................................................. 207 ONLINE GLOSSARIES................................................................................................................ 213 Online Dictionary Directories ................................................................................................... 214 MYELIN DICTIONARY ............................................................................................................... 215 INDEX .............................................................................................................................................. 293
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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 myelin is indexed in search engines, such as www.google.com or others, a nonsystematic 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 myelin, 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 myelin, 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 myelin. 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 myelin, 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 myelin. The Editors
1
From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON MYELIN Overview In this chapter, we will show you how to locate peer-reviewed references and studies on myelin.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and myelin, 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 “myelin” (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: •
University of Iowa Plays Crucial Role in Alzheimer's Research Source: Iowa Medicine. 76(10): 458-460. October 1986. Summary: This article reports on research into new diagnostic procedures for Alzheimer's disease such as computerized tomography scans, a neuropsychological test battery, and single photon emission tomography. It also reports on the reduction of glutamate, the destruction of myelin, and the preservation of motor skills in Alzheimer's patients.
•
For the Cortex, Neuron Loss May Be Less Than Thought Source: Science. 273: 48-50. July 5, 1996.
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Summary: This journal article discusses recent findings that challenge the belief that widespread cell death in the brain, especially in the neocortex, causes the cognitive changes of normal aging. This belief got its major impetus in 1955 when researchers at the State University of New York, Buffalo, published reports of extensive cell loss in a number of neocortical areas in aged brains. Subsequent studies in the 1980's suggest that the earlier findings may have been affected by the method used to prepare the brain tissue for microscopic examination, and that the earlier studies may have included brains with Alzheimer's disease or other dementias known to cause cell death. Since then, other studies with both animals and humans have found little or no loss of cortical neurons in normal aging. Imaging studies have shown that the brain shrinks with age. Some of these studies have found a loss of both gray matter and white matter, while others have found a loss of white matter only. Several lines of research suggest that other brain changes might contribute to the cognitive deficits associated with older age. Some of these changes under investigation include a decrease in the density of certain receptor proteins through which neurons respond to neurotransmitter signals, and a breakdown of the myelin sheath that insulates nerve fibers and facilitates their ability to transmit signals. If these findings are correct, they may have implications for developing drugs to prevent cognitive decline in older age.
Federally Funded Research on Myelin The U.S. Government supports a variety of research studies relating to myelin. 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 myelin. 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 myelin. The following is typical of the type of information found when searching the CRISP database for myelin: •
Project Title: A PHASE II TRIAL OF RITUXAN IN MULTIPLE SCLEROSIS Principal Investigator & Institution: Cross, Anne H.; Associate Professor; Neurology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2004; Project Start 03-FEB-2004; Project End 31-JAN-2008 Summary: (provided by applicant): Rituximab is a humanized monoclonal antibody (Ab) against CD20 on B cells that is FDA-approved for the therapy of non- Hodgkin's lymphoma. It depletes B cells and plasmablasts (early plasma cells that still express CD20) from the circulation. Our preliminary data in three patients indicates B cells and plasmablasts are depleted from the CSF by rituximab. This K24 mid-career application is
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
5
based upon a Phase II trial of rituximab in relapsing MS. Rituximab will be given at the standard dose of 4 intravenous doses of 375mg/m2. This regimen eliminates circulating cells expressing CD20 (B cells, plasmablasts) completely for 6-12 months. Circumstantial evidence strongly suggests that B cells and/or Ab are involved in the pathogenesis of MS. However, all data thus far are associative. To determine whether B cells truly play a role will require a controlled trial of their elimination to determine if the course of MS will be altered. We are undertaking a Phase II trial of the safety and MRI efficacy of Rituxan in 30 patients with active, relapsing MS, despite taking beta-interferon (BIFN) or glatiramer acetate (GA). All patients entering are volunteers and are fully informed of the risks involved and the alternatives. Patients continue taking BIFN or GA. To receive study drug, subjects must have at least one gadolinium-enhancing lesion on any of three pre-treatment brain MRIs, and must have had at least one clinical relapse in the 18 months prior to enrollment, despite being on a standard therapy (BIFN or GA). Endpoints are safety, in terms of toxicity and the possibility of worsening of MS, and efficacy based on MRI activity. The primary efficacy endpoint will be reduction in number of gadolinium-enhancing lesions on 3 brain MRIs performed post-treatment in comparison to the 3 MRIs performed pre-treatment. B cell and plasma cell numbers and activation status, level of immunoglobulin in the spinal fluid and serum will be measured pre- and post-treatment. Ab levels to several myelin antigens (human MOG, MBP, dilapidated and whole myelin) and MBP in CSF will be assayed pre- and posttreatment. The study takes place in the General Clinical Research Center at WUSM. Genentech is providing drug free-of-charge and some funding. The National MS Society has reviewed and approved this trial, and is funding the bulk of this trial, including MRI's, but the NMSS does not pay salaries of tenured faculty. PI spends 10 hrs per week seeing private outpatients, 2-6 hrs/week seeing inpatients, plus an additional 3-6 hrs/wk on dictations, disability forms, and dealing with phone calls related to private patients. PI also serves 2 mon/yr, on "service" as Neurology Ward or Consulting Attending and performs clinical trials Sponsored by pharmaceutical companies (reimbursement is better than for private patient care) in order to cover her salary. PI is applying for the K24 award to perform this trial, and to mentor junior persons as part of this and other research projects. With the K24, PI will decrease time devoted to private outpatients by 50%, will eliminate taking on any new private patients, and will transfer the care of many of her > 1,000 private patients to Drs. Parks and Naismith, and PI will be able to focus 30% more time on investigator-initiated trials and mentoring junior colleagues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: A WHOLE GENOME ADMIXTURE SCAN FOR MULTIPLE SCLEROSIS Principal Investigator & Institution: Reich, David E.; Genetics; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2004; Project Start 15-JUN-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Multiple sclerosis (MS) is an inflammatory disease of the CNS. It is thought that tissue injury occurs when activated, myelin-reactive T cells migrate into the CNS and cause damage to myelin, oligodendrocytes and axons. Ultimately, MS is a complex genetic disease as studies in twins, half-siblings, and adoptees indicate a strong family inheritability. However, large-scale studies attempting to identify genes affecting the disease have so far had limited success, calling for a more powerful search strategy. The classic method of finding genes--linkage mapping--works well for rare, single gene disorders that run simply in families. But linkage scans have
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failed to find the genes for more common, genetically complex diseases including MS. The approach most likely to work for gene discovery is the direct assessment of variation in populations and its association to disease. With present technology, the best-known way of doing this---haplotype mapping--is not practical because it requires studying too many sites in the genome. Because MS is significantly more common in Europeans than in Africans, a new approach, admixture mapping, may be a shortcut for using association studies to find disease genes. Specifically, we hypothesize that the intermediate genetic risk of MS in African Americans is derived almost entirely from their small percentage (10-40%) of European ancestry. By scanning along the genomes of African Americans with MS looking for regions of unusually high European ancestry, we can identify the 'European' gene segments that are likely to contain the genes that are related to MS risk. In this study, we propose to carry out the first whole-genome admixture scan for human disease genes, using 100-times fewer markers than a haplotype-based study. An admixture scan has the potential to rapidly identify disease regions especially for the subset of diseases that have different prevalences in two populations. The admixture mapping approach has only become feasible in the past year because of the large numbers of SNPs discovered with known frequencies in both African- and European-Americans. The SNP resources and novel analytical tools have now converged with large sample collections of African-American MS patients. The central aim of this project will be to carry out an admixture scan for MS genes in a sample of 1,000 African Americans with MS and 340well-matched controls. To followup all the genomic regions associated with disease, we will triple density of markers to increase statistical confidence in the results and refine the positions. We will then move to a targeted haplotype-based association study in the most interesting regions to clone new genes associated with MS. 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 2002; 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
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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: ADHESION AND GENE EXPRESSION IN CMT1B Principal Investigator & Institution: Shy, Michael E.; Associate Professor of Neurology; Neurology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 05-APR-2001; Project End 31-MAR-2005 Summary: (provided by applicant): Myelin is a multi-lamellar structure that surrounds axons in both the CNS and PNS facilitating nerve conduction. P0, a transmembrane glycoprotein of the immunoglobulin super family, is the major structural protein in PNS myelin, and is expressed exclusively in Sehwann cells, the myelinating glia. Human mutations in P0 give rise to peripheral demyelinating neuropathies. Our long range goal is to understand the role of P0 in myelination and disease. Several lines of evidence demonstrate that P0 acts as a homophilic adhesion molecule, suggesting that P0 mediates myelin compaction through homophilic interactions between adjacent membrane leaflets. Analysis of the crystal structure of the P0-extracelfular domain indicates that adjacent P0 molecules have the potential to interact in cis to form tetramers, and that these tetramers may further interact in trans to mediate homophilic adhesion. Furthermore, mutations of amino acid residues that the crystal structure identifies as critical to both cis and trans interactions cause a demyelinating peripheral neuropathy in patients. Mutations within the cytoplasmic domain of P0 are also found in patients with inherited demyelinating neuropathy and deletions within the cytoplasmic domain have been experimentally shown to result in loss of adhesive function. We have shown that point mutations of serine and threonine in a consensus Protein Kinase C binding site, as well as a second nearby serine, which corresponds to a human nonsense mutation giving rise to demyelinating neuropathy, are critical to adhesive function. Furthermore, our deletion analysis suggests that the juxtamembrane cytoplasmic region is also important for adhesive function. Thus both the extracellular and intracellular domains of P0 are necessary for homophilic adhesion in vitro and for myelination in vivoadhesion. P0 may also play a regulatory role during myelination. Complete loss of P0 in mice through homologous recombination not only produces a demyelinating peripheral neuropathy, but also markedly alters the pattern of myelinspecific gene expression in peripheral nerve. However, the relationship between adhesive function and this regulatory function is not known. In this proposal we will further define the regions and specific residues in the extracellular and intracellular domains that are essential for adhesive function through expression of mutated P0 in established cell lines and analysis of P0-mediated, as well as attempt to resolve the relationship between the seemingly separate P0 functions, adhesive and myelination. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: AN SCHIZOPHRENIA
INVESTIGATION
OF
OLIGODENDROGLIA
IN
Principal Investigator & Institution: Hof, Patrick R.; Professor; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Demyelinating diseases have long been known to be associated with behavioral disturbances. The expression levels of several myelin-related genes are consistently and substantially lower in brains obtained from schizophrenic patients than in control cases. Diffusion tensor imaging (DTI), an in vivo magnetic resonance imaging technique which assesses the coherence of white matter tracts, reveals a marked decrease in anisotropy in schizophrenic patients, indicating changes in the directionality and alignment of axons. Magnetic transfer imaging (MTI) further demonstrates reduction in myelin content in schizophrenia. An explanation for the decreased expression of myelin-related genes in schizophrenia and for the fact that these genes differentiate control from schizophrenic cases is that oligodendroglial cells are dysfunctional in schizophrenia. We propose a thorough quantitative analysis of oligodendroglial pathology in cortical and subcortical regions in brains obtained from schizophrenic patients, and a characterization of the possible repercussions of such disruption of specific axonal pathways on the morphology and function of neocortical neuron populations in genetically modified mouse models in which myelin-related genes have been knocked out. We will use rigorous stereologic analyses to assess possible changes in the numbers of oligodendrocytes in the cerebral cortex or the thalamus in schizophrenia. The 3-dimensional, spatial distribution of oligodendrocytes in these pathways may be consequently modified and may offer a quantitative neuropathological correlate of the changes in myelination. We will estimate this parameter using stereologic tessellation algorithms and relate these analyses to in vivo data obtained by DTI and MTI in other components of this Center. Finally, disruption of myelination resulting from knocking out specific myelin-related genes in mice will likely affect the organization of axonal pathways furnishing inputs to the neocortex. We will measure the degree of complexity of the dendritic arborization in reconstructed pyramidal neurons from such mice models. Changes in spine density, volume, and morphology, as well as ultrastructural changes in myelination will be quantified in these mice to assess how these parameters are modified by the myelination deficits. The human cases and the animal models studied within the context of this program offer an opportunity to analyze oligodendroglial changes that have a clinical impact and to determine the morphologic characteristics of the circuits whose alteration Ieads to the cortical and subcortical dysfunction that possibly underlies the pathogenesis of schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANTIGEN TARGETING TO DENDRITIC CELL Principal Investigator & Institution: Nussenzweig, Michel C.; Professor and Howard Hughes Investigator; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Description (provided by applicant): DCs are specialized antigen presenting cells found in lymphoid and epithelial tissues, which are uniquely potent inducers of primary immune responses in vitro and in vivo. In tissue culture experiments, DCs are typically two orders of magnitude more effective as antigen presenting cells than B cells or macrophages. In addition, during contact allergy and transplantation (two of the most
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9
powerful known stimuli of T cell immunity in vivo) DCs migrate from peripheral tissues to lymphoid organs, the sites for the induction of most types of primary immune responses. Based on these and similar experiments, it has been proposed that the principal function of DCs is to initiate T cell mediated immunity, but there is also indirect evidence from a number of different laboratories suggesting that DCs may play a role in maintaining peripheral tolerance. However, nearly all of these experiments involved DC purification and culture in vitro, both of which induce major alterations in the state of DC maturation and function. Thus, the physiologic role of DCs in the steady state in vivo has yet to be determined. To examine the function of DCs in vivo, we developed a method for antigen delivery to these cells using a monoclonal antibody to a DC restricted endocytic receptor, DEC-205. Our experiments show that antigen delivered to DCs is several orders of magnitude more efficient in inducing T cell activation than peptide in complete Freund's adjuvant. However, antigen delivered to DCs under physiological conditions fails to produce prolonged T cell activation, and, within 7-9 days, the number of antigen-specific T cells is reduced and residual T cells become anergic to further stimulation even by antigens delivered with strong adjuvants. The long-range goal of the proposed research is to understand the physiologic role of DCs in immunity and tolerance in vivo. The working hypothesis is that DCs maintain tolerance under steady state conditions but that they initiate immune responses when appropriately activated. The first part of the application will make use of the DEC-205mediated antigen delivery system to define the role of DCs in tolerance and immunity to a defined peptide. In the second part of the application, DEC-205-mediated antigen delivery will be used to examine the role of DC-mediated T cell tolerance and T cell activation in experimental allergic encephalomyelitis using a defined antigenic peptide from myelin basic protein. The third part of the Project aims to understand how DC activation regulates immunity in vivo. These studies have significant potential implication for understanding the role of the innate immune system in initiation of autoimmune diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AUTOIMMUNE ENCEPHALOMYELITIS AND C-REL Principal Investigator & Institution: Chen, Youhai H.; Associate Professor; Pathology and Lab Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-MAY-2006 Summary: (provided by applicant): The Rel/NF-KB family of transcription factors play pivotal roles in inflammation and immunity. The long-term goal of our research is to elucidate the mechanisms of Rel/NF-kB action in autoimmune diseases. This proposal is based on our recent discovery that c-Rel-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE), and are unable to develop a strong TH1 type response to self-myelin antigens. The goal of this proposal is to elucidate the mechanisms of c-Rel action in animal models of multiple sclerosis. A major challenge to study the roles of transcription factors in autoimmune diseases is that they are often expressed by a variety of cell types. In the case of c-Rel, it is expressed not only by cells of the immune system, but also by cells of target organs such as brain and spinal cord. The roles of c-Rel in different cell types must be established before a comprehensive understanding of c-Rel action in autoimmunity can be achieved. We hypothesize that cRel expressed by immune cells and neural cells may play different roles in EAE: c-Rel expressed by immune cells orchestrates the activation and effector function of inflammatory cells leading to tissue injury, whereas c-Rel expressed by neural cells
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protects them from inflammation-induced cell death, presumably by activating antiapoptotic genes. To test these hypotheses, we will study the roles of c-Rel in 1) activation of myelin-specific T cells, 2) formation of inflammatory lesions, and 3) death of inflammatory and neural cells in EAE. The roles of c-Rel expressed by different cell types will be dissected using transgenic adoptive transfer models and bone-marrow chimeric models. Information generated from these studies may not only help elucidate the mechanisms of c-Rel action in EAE but also aid in developing a general strategy to study the roles of transcription factors in autoimmune diseases. Novel strategies targeting Rel/NF-kB may then be developed to treat or prevent the autoimmune diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
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 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
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Project Title: AXONAL REGULATION OF SCHWANN CELLS--NOVEL ROLES OF NRG1 Principal Investigator & Institution: Salzer, James L.; Professor; Cell Biology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002; Project Start 01-MAR-1988; Project End 31-MAR-2006 Summary: (provided by applicant): Axons regulate the proliferation, survival and differentiation of Schwann cells. Neuregulin- I (NRG- 1), a family of neuronal growth factors, has an established and crucial role in the early events of Schwann cell development, promoting Schwann cell maturation, proliferation and survival. Neuregulin receptors, members of the erbB family of receptor tyrosine kinases, are expressed by Schwann cells. Following ligand binding, they undergo autophosphorylation and activate intracellular signaling pathways, notably investigator 3-kinase which we have shown is required for these early events. In this proposal, we will investigate whether NRG- 1 and the erbB receptors, exclusively mediate the initial interactions of axons and Schwann cells or whether they also mediate later interactions, including myelin and basal lamina (BL) and node of Ranvier formation. To investigate the role of NRG- 1 in these later events of development, we will coculture mature Schwann cells with neurons isolated from mice with either a conditional, neuronspecific knockout of NRG-1 or a knockout of the CRD-NRG-l isoform. We are particular interested in whether nrg- 1-I- neurons can still induce Schwann cell proliferation and survival and promote normal myelin and BL formation. We have recently found that erbB2 and several candidate interacting proteins, are enormously enriched in the Schwann cell microvilli which contact the nodal axolemma. To elucidate the signifance of this finding for local signaling and node organization, we will characterize the time course of its accumulation and its precise localization in the microvilli, determine whether erbB2 is complexed to and/or activates several candidate proteins in the microvilli and examine whether erbB2 regulates microvilli formation and nodal organization. Finally, we have found that MAP kinase and P1 3-kinase activation are activated not only during development, but also shortly after axotomy and NRGinduced demyelination. To investigate the role of MAP kinase and investigator 3-kinase activation during Wallerian degeneration and demyelination, we will examine whether activation of these pathways is a feature of demyelination in vivo, examine the effects of blocking their activation using pharmacologic inhibitors during Wallerian degeneration in vitro and determine whether the sequence of events during Wallenan degeneration is altered in cultures from NRG- 1 knockouts or in cultures treated with erbB2/e3rbB3-Fc, which inhibits NRG- 1 signaling. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BIOCHEMISTRY REGENERATION
OF
PROTEINS
RELATED
TO
NERVE
Principal Investigator & Institution: Perez-Ballestero, Rafael; Texas A&M UniversityKingsville Campus Box 104 Kingsville, Tx 78363 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006 Summary: The mammalian central nervous system (CNS) does not support nerve regeneration. On the other hand, cold-blooded vertebrates show successful nerve regeneration in their CNS. The study of the biochemistry of nerve regeneration in the CNS of cold-blooded vertebrates is of interest in basic research, as well as for the development of treatments for human conditions derived from pathological or traumatic damage to nervous tissues. Studies with the optic nerve system of teleost fish
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have identified several proteins related to nerve regeneration. The relevance of some of these proteins in axonal growth and pathfinding has already been reported in the scientific literature. Among the proteins induced during optic nerve regeneration, RICH proteins (Regeneration Induced CNPase Homotog proteins) were recently cloned (corresponding cDNAs) and showed to be homologous to mammalian CNPases. CNPases are enzymes (phosphodiesterases) present in the myelin sheath of mammals that are proposed to interact with membranes and the cytosketeton, but their specific function is not well defined yet. RICH proteins share similar catalytic properties with mammalian CNPases, but our knowledge of these proteins is still limited. In the current funding period of the proposal, the participation of three subdomains of RICH proteins in catalysis and intracellular localization has been studied by site directed mutagenesis. Currently, the effect of the deletion of individual subdomains in subcellular localization as well as in the morphology of eukaryotic ceils overexpressing these proteins is being investigated. This proposal is aimed at the continuation and extension of these studies. Cell lines of proneuronal phenotype and zebrafish retina explants will be transfected with constructs that express wild type RICH protein and the deletion mutants. Neurite growth properties will be monitored in the transfectants. Efforts at finding target proteins that interact with RICH in neuronal cells will be continued by multiple approaches, including overlay and two-hybrid library screenings. Finally, the participation of RICH protein in the development of the nervous system will be analyzed with studies in zebrafish embryos, using microinjection and RNA interference approaches. The proposed experhnents should extend our knowledge of RICH proteins, particularly in the understanding of their role in nerve regeneration and the development of the nervous system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOSYNTHESIS AND ASSEMBLY OF MYELIN MEMBRANE PROTEINS Principal Investigator & Institution: Colman, David R.; Penfield Professor and Director; Mc Gill University James Admin. Bldg., Room 429 Montreal, Pq H3a 2T5 Timing: Fiscal Year 2002; Project Start 30-SEP-1987; Project End 31-JUL-2007 Summary: (provided by applicant): Ultimately, we want to understand how the myelin sheath acquires its extraordinary morphology, and so provide the groundwork for understanding a wide variety of de- and dysmyelinating disease states, such as Multiple Sclerosis, Guillain-Barre Syndrome and the Charcot-Marie-Tooth Diseases. The mechanisms by which the myelin sheath is generated remain elusive. We will test during the next grant period the validity of a new model we have developed for the generation of the myelin spiral. This model anticipates that the first step in the myelination program occurs when a protein scaffold is laid down adhesively linking the myelinating cell with the axon, and forming a guide for new membrane addition. In order to test this model we must first accurately define the positions of certain key marker proteins, (some of which are newly discovered) when these molecules are expressed naturally (in terms of temporal and spatial distribution) in the myelin-axon protein scaffold. We also propose to uncover the actual pattern of new membrane addition to forming myelin, and observe the dynamical movements of protein, lipid and cytoplasmic compartments, using selected fluorescently-labeled myelin protein or axonal moieties as "reference markers." Our approach is to study living, actively myelinating cells directly observed by high resolution confocal and two photon microscopy, and we will define how initially completely segregated intracellular pathways ultimately converge to yield the myelin sheath. Accordingly, (I) we will
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engineer mice using bacterial artificial chromosomes (BAC cloning) to express, as naturally as possible, certain key neural cell proteins labeled in tandem with innocuous fluorescent moieties. The protein products of these artificial genes will be fluorescent, obviating the need for antibodies visualized by indirect methods. Furthermore, BAC methodologies yield protein products whose expression (temporal and spatial) is identical to the natural gene. These mice will be used as source material for in vitro myelination studies. (II) We will study fluorescent lipid incorporation into surface membranes of myelinating cells, and compare these data to the assembly parameters of the protein scaffold formed at the internodal ends, as ascertained in Aim I. Finally, (III) we will directly observe dynamical movements of the cytoplasmic channels that enclose non-compact myelin through the injection of fluorescent beads directly into premyelinating Schwann cells in culture, and examine the movement of these beads over time as myelination progresses. The studies we propose will allow a comprehensive analysis of the short and long term (several hours to weeks) continuous, relative contributions of proteins, membrane lipid and fluid cytoplasmic components to myelin formation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CD200 EXPRESSION ON APOPTOTIC DCS AND IMMUNE TOLERANCE Principal Investigator & Institution: Truitt, Robert L.; Professor; Pediatrics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2004; Project Start 01-AUG-2004; Project End 31-JUL-2006 Summary: (provided by applicant): During apoptotic cell death, biochemical processes, including the action of caspases, modify self-proteins and create potential autoantigens. To maintain a steady-state in the face of natural cell turnover, the immune system must have a mechanism to prevent or control responses to cell death-associated autoantigens or risk autoimmunity. CD200 is a transmembrane glycoprotein that shares sequence homology with the B7-family of T cell costimulatory molecules and is known to impart a T cell tolerogenic signal. We made the novel observation that CD200 mRNA and protein expression was increased in apoptotic murine dendritic cells (DCs). We identified functional p53-response elements within the CD200 gene. We identified both p53- and caspase-dependent pathways leading to increased expression of CD200 on apoptotic DCs. CD200 on apoptotic DCs significantly altered the rate of T cell proliferation and the cytokine profile in autologous MLR cultures. Furthermore, using CD200 knockout mice, we found that CD200 was essential for induction of UVB-mediated immune tolerance to haptenated proteins in contact hypersensitivity assays. Based on our mouse data, we hypothesize that CD200 expression on apoptotic DCs contributes to the induction of immune tolerance to caspase-generated self-peptides in vivo. We propose to test this hypothesis in vivo using an established mouse model of immune tolerance to hapten and to extend our studies to human DCs and immune responses to both caspasegenerated self-peptides and model autoantigens in vitro. Our Specific Aims are: (1) To determine whether CD200 on infused or resident DCs plays a role in the induction of immune tolerance to hapten using wild-type and CD200 knockout mice; (2) To assess the expression of CD200 mRNA and protein in subsets of human DCs and in cultures of primary keratinocytes with and without induction of apoptosis; and (3) To test the effect of blocking CD200/CD200R interaction on T cell responses to caspase-generated selfpeptides, nucleohistone and myelin basic protein using PBMC from normal individuals and multiple sclerosis patients. If the data support our hypothesis, we will have identified CD200 expression on apoptotic DCs as an important molecule in maintaining
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self-tolerance in humans and, perhaps, in limiting autoimmunity. These studies will also provide new insight into a novel molecular pathway that is a target for enhancement of antitumor immunity and for prevention of graft rejection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHARACTERIZATION OF LYMPHOCYTES THAT SUPPRESS EAE Principal Investigator & Institution: Lafaille, Juan J.; Assistant Professor; Skirball Institute; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2003; Project Start 01-APR-1998; Project End 31-MAR-2008 Summary: (provided by applicant): Experimental autoimmune encephalomyelitis is an inflammatory demyelinating disease of the central nervous system (CNS) studied as a model of multiple sclerosis. Mice which harbor a monoclonal myelin basic protein (MBP)-specific ab T cell compartment develop EAE spontaneously. EAE can be prevented in these mice by the administration of a small number of polyclonal CD4+ T cells (regulatory T cells or T-reg) belonging to either the CD4+CD25+ or the CD4+CD25T cell subpopulations. The biological impact of T-reg administration is large, and, therefore, so is its potential for clinical application, yet many important properties of Treg cells that control spontaneous EAE remain poorly understood. This application focuses on key events involved in immunoregulation of spontaneous EAE in MBPspecific T cell receptor transgenic mice. In Aim 1, we will assess the role of the cytokines, cytokine receptors and co-stimulatory molecules IL-2, CD25, IL-10, TGF-b and CD28 in the generation, survival and function of T-reg. A better knowledge of T-reg dependence on these cytokines and co-stimulatory signals may enhance the potential of in vivo manipulation of immunoregulatory T cells. In Aim 2, we will investigate the MHC restriction of regulatory T cells. The characteristics of MHC restriction of T-reg cells may help in the design of strategies to purify these cells out of the total CD4+ T cell compartment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CLONOTYPIC LYMPHOCYTES
REGULATION
OF
ENCEPHALITOGENIC
T
Principal Investigator & Institution: Offner, Halina; Professor; Neurology; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-JAN-1987; Project End 31-JUL-2006 Summary: (provided by applicant): Inflammatory T cells express receptors (TCR) that recognize foreign molecules, but may also be misdirected to react against self molecules, eg. myelin proteins, causing autoimmune diseases such as multiple sclerosis (MS). One natural regulatory mechanism that limits this process involves a second set of T cells that recognizes the TCR expressed by the inflammatory T cells. These regulatory "TCR reactive" T cells can be readily boosted in vivo with recombinant TCR proteins or peptides that correspond to variable (V) region genes that are over expressed by the pathogenic self reactive T cells. After activation with defined TCR sequences, TCR reactive T cells secrete inhibitory factors (cytokines) that can locally inhibit both the target pathogenic T cells as well as bystander inflammatory T cells that may express a different TCR directed at different myelin antigens. Treatment with TCR proteins has been shown to be highly effective at preventing and treating rodent models of MS, called experimental autoimmune encephalomyelitis (EAE). These studies have provided crucial data for treating patients with MS, where trials are currently in progress. Recent studies in mice that express a transgenic TCR BV chain for myelin basic protein (MBP)
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have demonstrated that TCR-reactive T cells develop through rearrangement of nontransgenic AV genes that pair mainly with the transgenic BV chain. Other groups have demonstrated the critical importance of newly rearranged CD4+ TCR alpha/beta+ regulatory T cells in preventing spontaneous EAE in TCR double transgenic mice that cannot produce regulatory T cells. It is thus hypothesized that TCR reactive T cells constitute the major portion of this important regulatory T cell population that thus far has not been characterized for antigen specificity. Two specific aims are proposed: Aim 1. Contribution of TCR-specific regulatory CD4+ T cells to EAE resistance. CD4+ T cells specific for TCR AV and BV determinants will be functionally evaluated in TCR double transgenic B10.PL mice specific for MBP-Ac1-11, where TCR-reactive T cells are naturally enriched, and in double transgenic mice backcrossed onto the RAG‑1/- background, where TCR-reactive T cells cannot be positively selected. Defined TCR reactive T cell populations will be used to transfer protection to recipient mice susceptible to spontaneous or induced EAE. Aim 2. Contribution of cytokines, chemokines, and chemokine receptors to TCR mechanism. Intact and knockout B6 mice with MOG-induced EAE will be vaccinated with BV8S2 protein to assess the role of selected cytokines, chemokines, and chemokine receptors that have been implicated in the protective TCR mechanism. In knockout mice where TCR protection is lost, wild type T cell populations will be added back to confirm efficacy. These proposed studies will provide new and definitive insights into the biological importance and function of TCR-reactive T ceils in preventing and treating spontaneous and induced EAE, and will guide further human studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONNEXIN32 MUTATIONS IN CHARCOT-MARIE-TOOTH-X DISEASE Principal Investigator & Institution: Musil, Linda S.; Assistant Scientist; None; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 05-FEB-2001; Project End 31-JAN-2005 Summary: (From the Applicant's Abstract): The X-linked form of type I Charcot-MarieTooth disease (CMTX) is the second most common hereditary peripheral neuropathy in humans. CMTX is caused by mutations in the gap junction channel protein connexin32 (Cx32) that are thought to affect its ability to mediate the radial diffusion of substances through the Schwann cell myelin sheath. CMTX is genetically as well as phenotypically heterogeneous: over 200 different defects in the coding region of the Cx32 gene have been found in CMTX patients, whose clinical symptoms range from very mild/asymptomatic to eventually becoming wheelchair-bound. Studies in transfected tissue culture cells and transgenic mice indicate that different mutations interfere with Cx32 function by distinct mechanisms: some mutants are translated inefficiently and/or degraded very quickly; others appear to affect channel function at the cell surface; and many are detected only intracellularly and act as dominant negative inhibitors of wildtype connexins. How different Cx32 mutations result in these diverse phenotypes is unknown. Our initial characterization of three CMTX-linked Cx32 point mutants in PCI2 cell transfectants revealed that each mutant was defective in folding and oligomeric assembly and underwent a distinct intracellular fate: E208K Cx32 accumulated in the endoplasmic reticulum whereas both the E186K and R142W mutants were transported to the Golgi region from which they trafficked either to lysosomes (RI42W Cx32) or back to the ER (EI86K Cx32). The goal of the proposed studies is to elucidate the molecular mechanisms by which CMTX-linked mutations affect the assembly, intracellular transport, and degradation of Cx32. These studies will be conducted in transfected
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tissue culture cells as well as in peripheral nerve tissue from mice expressing Cx32 mutants. Specifically, we will use molecular and cellular biological techniques to: (1) define the intracellular trafficking routes and molecular chaperone interactions of CMTX-linked Cx32 mutants; (2) identify, and test the correctability of, conformational defects in Cx32 induced by different CMTX-linked mutations; (3) elucidate the mechanisms whereby Cx32 mutants gain access to, and are degraded by, cytosolic proteasomes; and (4) determine the molecular basis for the dominant-negative activity of some CMTX-linked mutants and identify the in vivo target of this activity in myelinating Schwann cells. These studies will elucidate the causes of phenotypic diversity in CMTX as well as provide the first molecular insights into the quality control mechanisms that govern the fidelity of connexin assembly into gap junctional channels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTROL OF MHV INFECTION IN THE CENTRAL NERVOUS SYSTEM Principal Investigator & Institution: Buchmeier, Michael J.; Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 01-FEB-1998; Project End 31-JAN-2004 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: CYTOKINE REGULATION OF MATURE MYELIN-SPECIFIC T CELLS Principal Investigator & Institution: Segal, Benjamin M.; Professor; Neurology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-DEC-2005 Summary: Experimental autoimmune encephalomyelitis (EAE) is an autoimmune demyelinating disease of the central nervous system (CNS) induced by CD4+ T cells reactive with myelin antigens, including myelin basic protein (MBP). It is widely used as an animal model of multiple sclerosis (MS). There is growing evidence for a role of the Th1 polarizing monokine, IL-12, in the pathogenesis of EAE as well as MS. We have recently found that primed MBP-reactive CD4+ Th1 cells are prevented from inducing disease in naive syngeneic recipients when coinjected with a neutralizing antibody against IL-12. Spinal cords from the protected mice are free of infiltrates. In this proposal we plan to expand upon these findings to elucidate the mechanism of action of anti-IL12 in suppressing CNS inflammation. To do so, we will use an adoptive transfer protocol in which donor T cells can be identified since they express a congenic Thy marker. The goal of Aim 1 is to distinguish between two hypotheses: (i) anti- IL-12 blocks the passage of effector T cells across the blood- brain-barrier; or (ii) anti-IL-12 triggers the premature death of effector T cells. Based on the results of preliminary experiments, we will measure the effects of IL-12 on the expression of candidate adhesion and chemotactic molecules or pro- and anti-apoptotic mediators. In Aim2 we will assess the efficacy of anti-IL-12 therapy when initiated following the onset of clinical signs. These experiments will test the hypothesis that autoimmune effector cells depend on IL-12 to maintain their biological activities relatively late in the pathogenic process. We will assess whether anti-IL-12 suppresses the production of myelinotoxic molecules, such as TNFalpha or Lymphotoxinalpha, or induces the production of immunosuppressive factors, such as IL- 10 or TGFbeta, in the CNS. Furthermore, we will determine whether IL-12 neutralization blocks determinant spreading in the adoptive transfer recipients, thereby suppressing future relapses. These studies may have therapeutic relevance to MS as well as provide insights into the pathways by which IL-12 regulates differentiated effector T cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEMYELINATING 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 2003; Project Start 01-APR-1982; Project End 31-MAR-2008 Summary: (provided by applicant) The long-term goals of this program are an understanding of central nervous system (CNS) demyelinating disease. To this end, this program contains a multidisciplinary approach to defining mechanisms of myelin loss using a well defined rnurine model of 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 its natural host that result in demyelination during acute and persistent CNS infection. Although the host response is competent to control infectious virus, a persistent infection without detectable infectious virus is associated with chronic ongoing myelin loss, which has numerous similarities to multiple sclerosis, the most prevalent human demyelinating disease. This program is unique, offering a stable core of investigators addressing fundamental questions of viral persistence and immune responses, both as protective mechanisms and as inducers of demyelination. Funding is requested for continuation of Project 12 (Norman Marten),
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Project 2 (Stephen Stohlman) and Project 10 (Cornelia Bergmann) and for addition of a new project directed by Thomas Lane. Project 12 focuses on the initial events in CNS inflammation including the role of innate cytokines and neutrophils in shaping both the innate and adaptive CNS immune response, and an exciting new approach to understanding how T cells traffic through the CNS parenchyma. Project 2 continues an examination of the role of distinct CD8+ T cell effectors mechanisms in controlling virus replication in oligodendroglia and astrocytes, the mechanisms used by oligodendroglia to resist perforin mediated cytolysis and the negative co-receptors which limit T cell effector function leading to persistent infection. Project 10 analyzes the role of MHC and costimulatory molecule expression by individual CNS cell types in modulating both acute and chronic demyelination. Project 13 focuses on the role(s) of the chemokine IP10. Specifically, molecular regulation of IP-10 expression in JHMV infected astrocytes will be examined. In addition, the cellular basis for IP-10 mediated attraction of both T cells and macrophages into the CNS is determined. Data obtained from these projects will add to the basic understanding of viral pathogenesis within the CNS and importantly, provide valuable information on the interactions of specific CNS cells involved in viral persistence and demyelination with the cellular and soluble mediators of the host immune response. PROJECT 1 P.I.: Norman Marten Title: Regulation of CNS Inflammatory Cell Entry and Trafficking Description (provided by applicant) JHM virus (JHMV) infection induces an acute inflammatory response restricted to the CNS, which controls viral replication. However, it fails to fully clear virus, thereby setting the stage for a persistent CNS infection. Chronic JHMV infection is associated with persisting viral antigen and viral RNA in conjunction with ongoing demyelination. T cells play a distinct role in both viral clearances during acute infection as well as contributing to demyelination during chronic infection. Thus, rapid T cell infiltration during acute disease is crucial to controlling virus replication in order to limit subsequent immune mediated pathogenesis. The mechanisms, which govern the trafficking of inflammatory cells into the CNS during acute viral induced encephalomyelitis, are relatively unknown. The goals of this project are to identify the mechanisms governing inflammatory cell entry into the CNS. Aim 1 investigates the role of IFN-??? in mediating CNS inflammation. IFN-???R-/- mice will be compared to wt mice to determine the influence of IFN-???? in inducing pro and anti-inflammatory, genes, including cytokines, matrix metalloproteinases (MMPs) and tissue inhibiters of MMPs (TIMPs). The kinetics and quantity of inflammatory cell recruitment reveal the roles of IFN-???? in shaping both the innate and adaptive CNS responses to viral infection. Definition of the mechanisms of IFN-???? anti-viral activity are determined via analysis of mice deficient in the two major IFN induced anti-viral pathways. Aim 2 examines the contribution of neutrophils to regulating both the loss of blood brain barrier integrity and in shaping the overall inflammatory response within the CNS. Transient depletion of neutrophils results in dramatic reduction in CNS recruitment of inflammatory cells. CXCL2-/- mice, defective in neutrophil trafficking, will be used to characterize the proinflammatory role of neutrophils. JHMV infection is associated with induction of MMP-9 protein, a protease involved in breakdown of basement membranes. The factors which mediates initial neutrophil infiltration will be examined via infection of MMP-9-/- mice. Aim 3 investigates a novel model of impaired intraparenchymal inflammatory cell trafficking. Infection of mice doubly deficient in performing and IFN-? (PKO/GKO) results in accumulation of inflammatory cells in the subarachnoid and perivascular areas. By contrast, infection of these mice following reconstitution with CD8+T cells from normal donors, allows trafficking of the inflammatory cells into the CNS parenchyma. Infection of PKO/GKO mice is associated with increased expression of the MMP inhibitor TIMP-1. We will test the hypothesis that
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unregulated virus growth increases expression of TIMP-1, preventing MMP mediated leukocyte migration through the CNS parenchyma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EM CYTOPATHOLOGY OF AUTOIMMUNE DEMYELINATION Principal Investigator & Institution: Raine, Cedric S.; Professor; Pathology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-MAY-1977; Project End 31-MAR-2005 Summary: (adapted from applicant's abstract): Multiple sclerosis (MS) is a devastating inflammatory disease of the central nervous system (CNS) in which myelin and oligodendrocytes are depleted from large areas of white matter. The nature of the immunologic attack is not well understood and the relative contributions of T and B cells are debated. Recent work suggests that the process of myelin destruction in MS may vary among lesions. This proposal centers on the hypothesis that effector mechanisms leading to demyelination in MS lesions are heterogeneous. Four approaches will be investigated. The first will examine MS lesions at different stages of development for the involvement of antibodies in myelin destruction with a recentlydeveloped technique using conjugates of known peptides of myelin antigens coupled to gold to localize autoantibodies in situ in MS lesions. With a similar immunocytochemical technology, cytokine profiles in MS lesions will be evaluated. Whether cytokines localize to the same or different regions as antibodies in the lesion or are associated with particular stages of lesion development will be studied. The second area will study by immunocytochemistry, ISH, RPA and immunoblotting, the relative roles of immunoglobulin (Ig) and cytokines in a murine model of experimental autoimmune encephalomyelitis (EAE), in which a gene critical for B cell development (uMT) has been deleted and in which it has been shown that despite the lack of antibody, the mice develop CNS lesions similar to wild-type controls. This suggests either that heterogeneity in myelin destruction exists, that Ig is not needed for demyelination, or that the mouse (or the C57BL/6 strain) is different from other species (or strains). The third aim follows on using similar technologies to examine EAE in a susceptible strain, SJL, induced by active and by adoptive sensitization. The prediction is that antibody involvement will be the effector mechanism after active sensitization and that cytokines will be more prominent in the adoptive transfer model. The final area to be examined relates to mechanisms underlying the oligodendroglial survival response around active lesions in MS where remyelination is commonly seen. For this, localization and expression of molecules of the NFkappaB, c-Jun and Bcl-2 cascades will be investigated in well-characterized MS lesions. It is hypothesized that as with patterns of demyelination, heterogeneity also occurs in the oligodendrocyte response in MS. Understanding the variability in the above mechanisms in MS might lead to better monitoring of the disease and the patient, and should provide data readily translatable to the clinic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENCEPHALITOGENIC PREPARATION
NATURE
OF
ALTERED
BRAIN
Principal Investigator & Institution: Swanborg, Robert H.; Professor; Immunology and Microbiology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-SEP-1976; Project End 31-MAR-2005
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Summary: (adapted from applicant's abstract) The investigators recently reported that encephalitogenic myelin basic protein (MBP) peptide 63-81 elicits EAE in DA rats when given in incomplete Freund's adjuvant (IFA). The induction of this autoimmune disease without the use of Mycobacteria eliminates one of the more artificial aspects of the EAE model. This protocol elicits tolerance in most susceptible rodents, and our studies suggest that a defect in tolerance induction may exist in DA rats. However, autoimmune diseases do not develop spontaneously in DA rats, which suggests that this strain also possess potent immunoregulatory processes that maintain immunological homeostasis. In recent studies, we have found that DA rats have potent natural killer (NK) cell activity. We also reported in Lewis (LEW) rats, that the aspartic acid residue at position 82 of MBP73-86, the dominant encephalitogenic epitope of guinea pig MBP, is a T cell receptor (TCR) contact residue that is critical for the activation of encephalitogenic V, 88.2+ T cells and induction of EAE. Analogs of MBP73-86 with substitutions at position 82 are not encephalitogenic, but appear to protect against EAE. Three Specific Aims are proposed: Aim l. To test the hypothesis that a generalized defect in tolerance induction exists in uniquely EAE-susceptible DA rats. We will evaluate other tolerance induction protocols and ascertain the underlying mechanism. Aim 2. To determine whether NK cells maintain immunological homeostasis in autoimmune disease-susceptible DA rats. Aim 3. To determine how Thl cells specific for nonencephalitogenic peptide analogs of MBP suppress EAE in LEW rats. Our objective is to ascertain how the activation of autoreactive encephalitogenic T cells is controlled, and how they evade immunological homeostasis to become activated and elicit autoimmune disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENZYMATIC REGULATION OF VERY LONG CHAIN FATTY ACID Principal Investigator & Institution: Watkins, Paul A.; Associate Professor; Kennedy Krieger Research Institute, Inc. Baltimore, Md 21205 Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 31-DEC-2006 Summary: Elevated tissue levels of very long-chain fatty acids (VLCFA) are associated with human diseases such as X-linked adrenoleukodystrophy (X-ALD). Fibroblasts from X-ALD patients have impaired peroxisomal VLCFA beta-oxidation and reduced activity of peroxisomal very long-chain acyl-CoA synthetase (VLCS). An earlier hypothesis suggested that ALD, the protein defective in X-ALD, controlled VLCFA degradation by interacting with peroxisomal VLCS. New data indicate that ALDP may a more general role in VLCFA homeostasis. The former hypothesis implies a role of peroxisomal VLCS and the latter a role for extraperoxisomal VLCS. Irrespective of which hypothesis provides correct, enzymes with VLCS activity are necessary for activation and subsequent metabolism of VLCFA. We cloned cDNAs encoding several proteins with VLCS activity. We hypothesize that two of these enzymes play significant roles in VLCFA homeostasis and may be involved in X-ALD pathogenesis. In Aim 1 we will study the biochemical function of human and mouse BG, a primarily cytoplasmic enzyme first described in a Drosophila mutant ("bubblegum") with neurodegeneration and elevated VLCFA levels, and related enzymes. BG activates VLCFA and several essential brain fatty acids, and is expressed almost exclusively in tissues pathologically affected in X-ALD (brain, testis and adrenal gland). Elucidation of BG's function will be facilitated by producing a mouse knockout model in Aim 2. Because BG is primarily found in brain, we hypothesize that BG functions critically in other aspects of brain fatty acid homeostasis such as docosahexenoic acid synthesis and acylation of myelin proteolipid protein. In Aim 3, we will study a recently produced VLCS knockout mouse model. VLCS differs from BG in that the former is expressed primarily in liver and
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kidney and localizes to peroxisomes and endoplasmic reticulum. We will test hypothesis that VLCS as critical roles in VLCFA, beta-oxidation, complex lipid synthesis, branched-chain fatty acid catabolism and bile acid synthesis. In Aim 4, biochemical studies of lipid metabolism will be undertaken to probe the role(s) of BG, VLCS, ALDP (the peroxisomal membrane ABC transporter defective in X-ALD) and related peroxisomal ABC transporters in X-ALD patient fibroblasts and in double and triple-knockout animal models produced by mating mice form Aims 2 and 3 of this Project with those from other projects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EPHRINS IN MYELIN-BASED INHIBITION OF REGENERATION Principal Investigator & Institution: Benson, M Douglas.; Cell Biology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2007 Summary: (provided by applicant): The goal of this study is to understand the molecular basis of myelin's inhibitory effect on axonal regeneration. The specific hypothesis to be tested is whether ephrinB3, a known axon repellant during development, is a myelin-based inhibitor with respect to the regeneration of injured corticospinal tract (CST) axons that express the EphA4 receptor. Experiments in Aim 1 will employ an in vitro assay deteremine if ephrinB3 is, in fact, inhibitory to neurite outgrowth from postnatal cortical neurons, its potency as an inhibitor compared to other known myelin-based inhibitors and the contribution it makes to the overall inhibitory activity of myelin. Aim 2 will use site directed mutants of the EphA4 receptor tyrosine kinase (the receptor for ephrinB3 in CST development) in a neuronal cell culture system to determine which amino acids in the intracellular portion of the molecule are required for ephrin-induced repulsion/inhibition. Results from these experiments will, hopefully, lead to the identification of key signalling molecules involved in inhibition by ephrins of axonal regeneration. Studies in Aim 3 will seek to extend the findings of experiments in Aim 1 by examining a mouse model of chronic spinal cord injury coupled with genetic and pharmicological blockage of Eph/ephrin function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EPITOPE SPECIFIC T LYMPHOCYTES IN RELAPSING EAE Principal Investigator & Institution: Jones, Richard E.; Neurology; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (adapted from applicant's abstract): The long-term objective of the proposal is to understand the immune mechanisms responsible for the relapsing episodes of paralysis which occur in patients with multiple sclerosis (MS). The debilitating paralysis of MS results from damage initiated by certain white blood cells (myelin-specific T lymphocytes) that have become harmful within the spinal cord. Following an episode of paralysis, a patient with MS may experience temporary remission or recovery from paralysis, which may in turn be followed by a relapse or worsening of the paralysis. Such a remitting/relapsing clinical course is often associated with a progression of the severity of the disease. Currently, there are few effective treatments available to MS patients (over 300,000 Americans). Experimental autoimmune encephalomyelitis (EAE), is an experimental autoimmune disease in laboratory rats and mice that is similar to MS. Studies in EAE suggest that initial episodes of paralysis and subsequent relapses may involve distinct clones of T lymphocytes, each specific for a distinct target (epitope) in
22
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the CNS. However, requirements of distinct, multiple clones of epitope-specific T cells in relapsing EAE have not been tested experimentally. Such information would benefit efforts to develop effective, specific immunosuppressive therapies since treatments designed to inhibit distinct T cell populations or clones are likely to be the most effective in MS if the targeted cells are actually required for the disease. For this proposal, EAE will be induced in T cell-deficient mice with single or multiple clones of myelin epitopespecific SJL or [SJL X SCID]F1 mouse T cells in order to define requirements for single and multiple clones of T cells in relapsing EAE. In Aim 1, clones of myelin epitopespecific T cells will be generated and characterized. In Aim 2, requirements for epitopespecific T cells in relapsing EAE will be defined by examining the course of disease induced with single or multiple T cell clones in lymphocyte deficient (SJLXSCID) mice. In Aim 3, the in vivo function of T cells in the CNS will be assessed during disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ETHANOL EFFECTS ON PKC IN OLIGODENDROCYTES. Principal Investigator & Institution: Ellingson, John S.; Pathology, Anat/Cell Biology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2004; Project Start 10-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Ethanol (EtOH) is a potent teratogen for the developing nervous system and causes a variety of abnormal neurological effects in children born of alcoholic mothers, referred to as the fetal alcohol syndrome (FAS). One factor involved in the EtOH-caused neurological defects appears to be abnormal formation of myelin. We are identifying the regulatory processes affected by EtOH which result in dysmyelination by using the non-neoplastic continuous CG-4 line of oligodendrocytes (OLGs). CG-4 progenitors differentiate into OLGs in the virtual absence of supporting cells and are a good model to identify the effects of EtOH that directly affect signaling in OLGs. Exposure of differentiating CG-4 cells to relatively clinical levels of EtOH alters the temporal and quantitative expression of ethanolamine plasmalogen (EP1), a major lipid in myelin. EtOH inhibits the expression of myelin basic protein (MBP), but not that of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP). By using modulators of PKC, we showed that EtOH inhibited MBP expression by activating PKC without increasing the expression of any of the 9 PKC isozymes detected in CG4 0LGs. We are planning to use the same approach to identify which PKC isozyme is activated by EtOH to cause inhibited MBP expression by using isozyme-specific peptide inhibitors. We also plan to determine the isozyme involved by expanding our studies of treating OLGs with isozyme-specific antisense oligodeoxyribonucleotides to selectively inhibit the expression of specific PKC isozymes. We will use cell fractionation to determine which PKC isozyme(s)EtOH activates by increasing its distribution in the membrane fraction and which PKC classes display increased enzyme activity. By using immunocytochemical confocal microscopy we have found that the classical PKCs have unique subcellular localizations. We now will expand those preliminary studies to determine if EtOH affects PKC functions in OLGs by altering the subcellular localization of specific PKC isozymes, as it does in other cell types. We will study the effects of EtOH on MBP expression in primary cultures of OLGs. The proposed studies of identifying the role of specific PKC isozymes in cellular processes are of major interest to develop clinical isozyme-specific modulators to alleviate disease processes or correct pathology, such as demyelination or dysmyelination resulting from FAS, other pathological conditions, or trauma Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FACTORS AFFECTING REGENERATION THROUGHT THE GLIAL SCAR Principal Investigator & Institution: Silver, Jerry; Professor; Neurosciences; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-FEB-1988; Project End 31-JAN-2005 Summary: (Verbatim from the Applicant's Abstract) The dorsal column white matter tracts of the adult rat spinal cord have been tested in a novel way to learn whether the purportedly inhibitory glial scar or myelin can promote or hinder axonal regeneration of adult DRG's. This has been done by utilizing a microtransplantation technique which can introduce a small bolus of DRG cell bodies into either the unlesioned or prelesioned dorsal column white matter distal to the site of injury. This procedure allows for introduction of axotomized neurons without causing further inflammation and glial scarring at the site of implantation. The exciting results show that both normal as well as lesioned white matter away from an area of trauma are robustly permissive for long distance axon regrowth, at least for adult sensory axons. However, upon reaching the area of the forming scar, the rapidly regenerating growth cones halt abruptly and become dystrophic within a field of reactive glial matrix. It is suggested that these observations constitute compelling evidence that the glial scar and, hence, inhibitory factors such as proteoglycans at his locale, constitute the major environmental impediment to regeneration in the adult CNS. We propose to utilize the microtransplantation technique in a variety of interesting permutations of the preliminary experiments in order to explore the following questions. (1) Does a critical period exist for regeneration of adult DRG's into pre-degenerated dorsal column white matter? (2) What is the extent of reinnervation of the dorsal column nuclei or the dorsal horn grey matter by microtransplanted DRG's with increasing time after tract injury? (3) Can we develop a combinational strategy for stimulating dystrophic, transplanted DRG axons trapped within a scar, to regenerate through and beyond the glial scar? The long term goals of these experiments are to understand the basic biology that underlies the mechanisms of axon regrowth or its failure within adult white matter and to develop effective bridging strategies that allow adult axons to utilize the massive potential for regeneration which we now know exists beyond the glial scar. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FOLDING AND MISFOLDING OF PMP22 Principal Investigator & Institution: Sanders, Charles R.; Associate Professor; Biochemistry; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2004; Project Start 05-FEB-2004; Project End 31-JAN-2006 Summary: (provided by applicant): The common neuromuscular disorder CharcotMarie-Tooth Disease Type IA (CMTD) is caused by genetic defects associated with the gene encoding the tetraspan membrane protein peripheral myelin protein 22 (PMP22). These defects lead to changes in the level of functional PMP22 which is produced during myelination-- changes which sometimes result in severe myelin defects. One class of aberrations are dominant missense mutations which lead to PMP22 having an altered amino acid sequence. These seemingly minor changes in amino acid sequence typically result in misfolding/mistrafficking of the nascent PMP22 upon expression into the endoplasmic reticulum, such that the protein is unable to properly assemble and traffic to the cell membrane. While misfolding of PMP22 has been documented in elegant detail at the cell biological level, very little is known about the fundamental molecular structural and energetic factors which govern the partitioning of nascent PMP22 and
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other membrane proteins between productive folding/trafficking pathways versus terminally misfolded pathways. This project is designed to address this lack of knowledge by initiating studies of the folding and misfotding of wild type and diseaseassociated mutant forms of PMP22 using purified proteins, advanced biophysical methods, and well-controlled experimental conditions. The four mutants being chosen for study are those upon which available mouse models for CMTD are based. Wild type and mutant forms of PMP22 will be overexpressed, purified, and subjected to structural studies using various techniques. The stabilities of wild type and disease-associated mutants will be examined to see if protein instability is likely to be a factor related to the increased misfolding of the mutants. Folding kinetic studies will also be undertaken to elucidate rates and structural aspects of folding and misfolding pathways. Finally, the determination of the high resolution structure of wild type PMP22 will be pursued using high resolution NMR and X-ray crystallographic methods. These studies will shed light on the fundamental molecular basis for CMTD Type IA. Moreover, these studies may lead directly to the formulation of therapeutic strategies for CMTD which are based upon modulating the efficiency of productive PMP22 folding/trafficking. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTION MYELINATION
OF
QKI
RNA-BINDING
PROTEIN
IN
CNS
Principal Investigator & Institution: Feng, Yue; Assistant Professor of Pharmacology; Biochemistry; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): Accumulating evidence suggests that RNA-binding proteins play important roles in cell function and development. The goal of this application is to understand the function of the RNA-binding protein QKT in myelination. Diminished QKI expression in myelin-producing cells leads to severe dysmyelination in quakingviable (qkv) mice. QKI is a member of the Signal Transduction Activators of RNA (STARs), which carries a single RNA-binding domain as well as several Src-Homology 3 (SH3)-binding domains thus can interact with both RNA and signaling molecules. STAR proteins, upon phosphorylation in response to signaling cascades, are postulated to exert regulatory influences on cellular RNAs. Consistent with this view, we have found that QKI selectively interacts with the mRNA encoding the myelin basic protein (MBP), and tyrosine phosphorylation of QK1 dramatically reduces this interaction. The functional importance of this interaction is reinforced by our recent finding that MBP mRNA is severely destabilized and mislocalized in the qkv oligodendrocytes in which QKI is almost completely lost. These findings suggest that MBP mRNA is a functional target for QKI in myelination, and the interaction between QKI and the MBP mRNA is critical in controlling the normal posttranscriptional fate of the MBP mRNA. This application focuses on delineating the molecular mechanisms by which QKI regulates the metabolism of the MBP mRNA. Three specific aims are proposed: 1) To determine whether accelerated degradation of MBP mRNA occurs in the cytoplasm of qkt about/qkv oligodendrocytes, and whether elevated QKI expression prolongs the half-life of the MBP mRNA; 2) To define the MBP mRNA element required for interaction with QKI and to determine whether this element mediates QIU' s effect on mRNA stability; 3) To test whether tyrosinephosphorylation of QKI regulates its ability to bind and to stabilize mRNA. Answers to these questions should significantly advance our knowledge of fundamental mechanisms governing myelination and provide particular insights into how mRNA metabolism is controlled by protein-RNA interaction. This may ultimately lead to new
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therapeutic strategies against myelin disorders. In addition, understanding how QKI regulates its RNA targets during myelination may elucidate common mechanisms for other STARs in cell growth and tumorigenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTIONAL ORGANIZATION OF THE MYELIN MEMBRANE Principal Investigator & Institution: Taylor, Christopher M.; Neuroscience; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-DEC-2003 Summary: (provided by applicant): The specific aims of this proposal are to 1) establish a two-dimensional (2D) proteomic map of myelin proteins using high-resolution 2D gel electrophoresis, Western blotting, mass spectrometry, and bioinformatics, 2) establish a 2D proteomic map of proteins partitioned into myelin glycosphingolipid rafts and 3) investigate the role of galactocerebroside and sulfatide in myelin rafts by analyzing mutant mice lacking the enzymes cerebroside galactosyltransferase (CGT-nulI) and cerebroside sulfotransferase (CST-nulI). This project will 1) provide a comprehensive and invaluable database for the myelin biology community, 2) provide clues relating to the functional significance of galactocerebroside and sulfatide in forming rafts in myelin, 3) provide a more complete understanding of the organization of proteins and lipids in myelin as well as identify potential targets for the therapeutic intervention in many myelin related disorders/diseases Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GAP JUNCTIONS AND SCHWANN CELLS Principal Investigator & Institution: Spray, David C.; Professor; Neuroscience; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 05-FEB-1996; Project End 31-MAR-2003 Summary: The overall goal of these studies is to define the role that gap junctions play in the functions of myelinating, non-myelinating and proliferating Schwann cells in the peripheral nervous system. Because point mutations in Cx32 are responsible for the Xlinked form of Charcot-Marie-Tooth syndrome (CMTX), a demyelinating peripheral neuropathy, we are particularly interested in correlated changes in Cx32 expression with myelination in vivo and in culture and in properties of CMTX mutant channels. Because expression of other gap junction proteins (connexins) can be induced in myelinating Schwann cells by nerve injury, we are also interested in the nature of this induction and the changes in Schwann cell behavior when different connexin are expressed. We will apply a broadly based approach to the studies, taking advantage of recently developed animal models deficient in myelin proteins and making use of transfection technology in Schwann cells and cell lines. Specific Aim 1. To compare the functional properties of Schwann cells cultured from myelinated and nonmyelinated nerves of wildtype mice and transgenic mice in which connexin expression is altered. Specific Aim 2. To determine turnover dynamics and transport characteristics of the connexins and their mRNAs that are expressed in myelinating, nonmyelinating and proliferating Schwann cells in wildtype and connexin-altered transgenic mice. Specific Aim 3. To determine the impact of myelin-related genes on gap junction properties using transfected cell lines and Schwann cells cultured from transgenic mice in which myelin-related proteins are altered. Together, these studies should answer major questions regarding basic biology of Schwann cells and the role of gap junctions in physiological and pathophysiological conditions.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENDER DIFFERENCES IN IMMUNE RESPONSE IN MS Principal Investigator & Institution: Pelfrey, Clara M.; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2003 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 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
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Project Title: GENETIC CONTROL OF MYELINATION BY EGR2 AND NAB PROTEINS Principal Investigator & Institution: Svaren, John P.; Assistant Professor; Comparative Biosciences; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 15-JAN-2002; Project End 31-DEC-2006 Summary: (provided by the applicant): The myelin sheath that insulates peripheral nerve fibers is critical for efficient conduction of nerve signals through motor and sensory nerves. Myelin is produced by Schwann cells in a developmental process that is triggered by their association with developing axons. Several peripheral neuropathies-
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including Charcot-Marie-Tooth disease (CMT), Dejerine-Sottas Syndrome (DSS), and Congenital Hypomyelinating Neuropathy (CHN}-are caused by deficits in myelin formation and maintenance, and mutations in the gene coding for the EGR2 transactivator have recently been associated with these diseases. These results confirm previous work showing that the EGR2/Krox-20 is a critical regulator of myelin formation in mouse development. The goal of this application is to elucidate the mechanisms of transcriptional control that become altered in peripheral nerve diseases associated with EGR2 mutations. Several neuropathy-associated mutations inhibit DNA-binding by EGR2, but all of these mutations are dominant. This finding is surprising since only one functional allele of EGR2/Krox-20 is sufficient for myelin formation in mice. To understand the mechanism by which the dominant mutants cause peripheral neuropathies, microarray analysis will be used to identify genes that become deregulated by expression of dominant EGR2 mutants. The evidence suggests that the dominant mutants effectively sequester a critical cofactor of EGR2 activity, and studies of protein-protein interactions will be employed to identify this cofactor. Finally, one of the EGR2 mutations alters a domain that interacts with the NAB family of corepressor/coactivator proteins. This recessive mutation therefore strongly implicates the NAB proteins as important regulators of myelination, and microarray analysis will again be used to investigate how NAB proteins modify expression of the EGR2 gene network. Finally, expression of dominant negative NAB proteins will be used to investigate the functional role of NAB proteins in myelination of peripheral nerves. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GORDON CONFERENCE ON MYELIN Principal Investigator & Institution: Miller, Robert H.; Professor; Neurosciences; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2004; Project Start 27-MAY-2004; Project End 31-MAY-2005 Summary: (provided by applicant): In this application we are requesting support for the seventh Gordon conference on Myelin to be held in II Ciocci, Barga, Italy from May 2328, 2004. The field of myelin biology has seen significant advances since the last meeting including the characterization of transcription factors regulating critical steps in the development of myelinating cells, the identification of cellular mechanisms that control the behavior of remyelinating cells in diseases such as Multiple Sclerosis and the unraveling of the molecular complexes at axonal-glial junctions. The development of new animal models of demyelination promises to provide further critical insights into the normal function of myelin and its dysfunction in a variety of pathologies. The program for this 7th meeting has been developed to highlight these new advances in our understanding of the biology of myelin and myelinating cells and their role in disease. Care has been taken to minimize overlap in speakers with the previous meeting, or with related meetings in the same year and to expand the focus of the meeting beyond simply "myelin". The study of myelin and the biology of myelinating cells is; however, undergoing a period of expansion with the recruitment of scientists studying diverse aspects of membrane trafficking, cell signaling and cell migration. The program has been designed to attract scientists working both directly on myelin and its associated cells as well as in related areas of brain tumor biology and regeneration. This enhanced diversity will continue to increase the variety of myelin-associated scientist and provide for a dynamic and broad-spectrum meeting. To specifically encourage the participation of young investigators, registration and travel stipends will be offered as funds permit. All attendees will be expected to contribute to an oral presentation or present a poster. In addition to formal sessions, extensive poster sessions will encourage productive
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interactions between scientists with different expertise and in keeping with the goals of the Gordon Conference organization; such synergy will provide critical impetus and guidance to the field of myelin biology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IDENTIFYING A VIRAL CAUSE OF MULTIPLE SCLEROSIS Principal Investigator & Institution: Lipton, Howard L.; Professor; Evanston Northwestern Healthcare 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: IMMUNE RESPONSES IN PATIENTS WITH GBS AND CIDP Principal Investigator & Institution: Ilyas, Amjad A.; Associate Professor; Neurology and Neurosciences; Univ of Med/Dent Nj Newark Newark, Nj 07107 Timing: Fiscal Year 2002; Project Start 02-APR-1999; Project End 31-MAR-2004 Summary: Acute Guillain-Barr syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are acquired human demyelinating diseases of the unknown etiology and pathogenesis. Much evidence points to immunological mechanisms of tissue injury in these diseases often following an infectious trigger in
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GBS. The established therapeutic efficacy of plasmapheresis in GBS and CIDP suggests that autoantibodies or circulating immune factors are paramount in the pathogenesis of these disorders. Recent evidence indicates that major acidic glycolipids such as GM1, LM1, GD1a and GT1b are important antigens in about half of the patients with GBS. However, the antigenic specificity in most of the other GBS patients remains unknown. We have found that a proportion of patients with GBS react with GT1b, a minor ganglioside. We hypothesize that the antigens in the GBS patients not reactive with major gangliosides, are minor as yet not well characterized glycolipids or proteins/glycoproteins. The specific aim of this study is identify and characterize glycolipid and protein antigens in GBS patients that do not exhibit autoantibodies against major ganglioside antigens. We propose to test sera from a large number of patients with GBS, CIDP and controls, for autoantibodies to proteins and minor glycolipid antigens, and to purify and characterize the putative protein or glycolipid antigen(s). PAGE-Western blotting, enzyme linked immunosorbent assay (ELISA) and thin-layer chromatogram-immunostaining will be used to test for antineural antibodies. Early and serial serum specimens from GBS and CIDP patients will be examined to see whether autoantibody titers correlate with disease severity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INSULIN OLIGODENDROCYTE
LIKE
GROWTH
FACTOR
1
ACTIONS
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Principal Investigator & Institution: D'ercole, a Joseph.; Harry S. Andrews Professor of Pediatrics; Pediatrics; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 15-JUL-1999; Project End 31-MAR-2004 Summary: (Adapted from the applicant's abstract): Oligodendrocytes and the myelin sheaths that they produce are vulnerable to a variety of diseases and injuries, including multiple sclerosis (MS), undernutrition and ischemic insults. Prevention of oligodendrocyte death and promotion of remyelination are crucial to recovery. The object of this application is to determine the mechanisms by which insulin-like growth factor 1(IGF-1) protects cells of the oligodendrocyte lineage and myelin from damage and stimulates their recovery from injury. The investigator hypothesizes that IGF-1 protects oligodendrocytes and myelin from injury and promotes remyelination following injury. Furthermore, the investigator proposes that IGF-1 acts directly on cells of the oligodendrocyte lineage through mechanisms mediated by the type-1 IGF-1 receptor (IGFIR) and involving both inhibition of apoptosis signals and stimulation of growth and survival pathways. The applicant's hypotheses are supported by: (1) findings that demyelinating insults induce brain IGF-1 gene expression in a fashion temporospatially related to the injury; (2) the data showing that IGF-1 overexpressing transgenic mice exhibit marked increases in myelin and myelin-specific protein mRNA abundance as well as a significant increase in oligodendrocyte number; and (3) studies showing that IGF-1 protects cultured oligodendrocytes and myelin from the damage induced by tumor necrosis factor (TNF-alpha), a cytokine implicated in MS and other demyelinating disorders. To further understand IGF-1's actions and its mechanisms in protecting oligodendrocytes and myelin from damage the investigator proposes to: 1) determine the signaling pathways that mediate IGF-1's actions in protecting oligodendrocytes and myelin from injury caused by TNF-alpha 2) confirm that IGF-1 protects against TNF-alpha-induced oligodendrocyte and myelin injury in vivo by cross-breeding IGF-1transgenic mice to TNF-alpha transgenic mice and then evaluating oligodendrocyte survival and function; (3) determine IGF-1's actions on the
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oligodendrocytes and myelin recovery following injury by generating transgenic mice that conditionally express IGF-1 and evaluating the effects of induced IGF-1 overexpression on the oligodendrocyte lineage and myelin after injury; and (4) determine whether IGF-1 actions on oligodendrocytes and myelin are direct by studying mutant mice in whom IGF-IR expression is specifically ablated in oligodendrocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MAP KINASE REGULATION OF MICROGLIAL ACTIVATION Principal Investigator & Institution: Bhat, Narayan R.; Professor; Neurology; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 15-APR-2001; Project End 31-MAR-2005 Summary: Description (From the Applicant's Abstract): Microglia, the principal immune effector cells of the brain, play an important role in the regulation of the immunologic microenvironment within the CNS. They lie dormant until the integrity of the CNS is challenged by injury, infection or disease processes and when chronically activated, secrete a number of inflammatory mediators including cytokines and tissue damaging free radicals as part of the pathogenic mechanism common to a variety of CNS disorders including stroke, Alzheimer's Disease, AIDS dementia and demyelinating diseases such as multiple sclerosis. A mechanistic understanding of the process of microglial activation is, therefore, crucial for devising therapeutic strategies to suppress neuroinflammation. This project tests the hypothesis that signal transduction pathways mediated by members of the mitogen-activated protein kinase (MAPK) family play a key role in microgiial activation and the induction of inflammatory responses. Primary cultures of rat brain microglia wili be used as a model to accomplish the following objectives. The activities and the roles of MAPK cascades (i.e., extracellular signalregulated kinase or ERK, p38 MAPK and c-Jun N-terminal kinase or JNK) will be investigated in microglia activated in response to endotoxin and receptor (CD40) ligation. The effects of pharmacological inhibitors of MAPKs on the expression of microglial antigens (i.e., MHC class 11, B7 and CD40), cytokines (i.e., TNFa, IL-1, IL-6) and inducible nitric oxide synthase (iNOS) will be determined by immunochemical and RT-PCR techniques. Possible isoforrn-specific roles and down-stream targets of p38 MAPK and JNK in inducing cytokine and iNOS gene expression will be characterized in transient transfection studies using molecular mutants of the kinases along with iNOS and cytokine gene promoter constructs. The suppressive effects of the kinase inhibitors on activation-associated microglial functions; i.e., targeting of oligodendrocytes and myelin phagocytosis will be tested using in vitro models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISM AND SPECIFICITY OF MAP KINASES Principal Investigator & Institution: Dalby, Kevin N.; Associate Professor; Medicinal Chemistry; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Applicant's abstract): Mitogen-activated protein kinases (MAPKs) are extremely important enzymes in signal transduction. The consequence of a breakdown in the normal control of these enzymes can lead to many devastating diseases such as cancer. Three major subfamilies have been identified in humans and long-term goals are to identify methods of inhibiting specific members of each subfamily. To achieve this goal a solid chemical-biology approach is taken, where enzymology and molecular
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biology is combined to establish fundamental properties of the enzymes. The first focus is to define the kinetic mechanism of the extracellular signal-regulated kinase, ERK2, the first MAPK to be discovered, and to test the hypothesis that ADP release is rate-limiting. Sophisticated pre-steady state quench-flow and stopped-flow fluorescence techniques, and equilibrium binding studies, will be used to quantify and identify individual enzymatic steps. The second focus builds on the kinetic model and tests the hypothesis that protein-protein interactions modulate ERK2 activity. A structural analysis-will identify ERK2-substrate interactions and substrate-induced conformational transitions with myelin basic protein and the truncated protein substrates c-Myc(1-100) and Ets-1 (1-138), using trace-labeling experiments. A powerful combination of site-directed mutagenesis and pre-steady state kinetics will critically probe the mechanistic implications of protein-protein interactions mediated by ERK2, focusing on a recently discovered modular binding domain found in many ERK2 substrates. The third focus will use peptide phage display technology to epitope-map ERK2-protein interactions and to test the hypothesis that protein-protein interactions mediated by ERK2 are driven by the recognition of small modular binding sequences that have evolved to form transiently stable complexes. The specific aims during this period are: l) to define the kinetic mechanism of ERK2; 2) to perform structure-function studies to examine ERK2 substrate protein-protein interactions; and 3) to identify tight binding, modular peptide sequences by peptide phage display and contrast their function with wild type modular sequences. This will be the first comprehensive mechanistic study of ERK2 and the discovery of novel peptide inhibitors will set the scene for future structural and cell biology approaches aimed at understanding the breakdown in regulation of one of the primary enzymes in involved in human cancer and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS IN CNS MYELINATION: ROLE OF PD-IALPHA/ATX Principal Investigator & Institution: Fuss, Babette; Assistant Professor; Anatomy and Neurobiology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2007 Summary: (provided by applicant): The long-term goal of these studies is to gain insight into the role of counteradhesive molecules for oligodendrocyte function. Counteradhesion, mediated by the family of matricellular proteins, has been implicated in the transformation of cells into intermediate adhesive states that favor cellular functions related to locomotion. Despite of a variety of locomotive events during myelin sheath formation, the involvement of matricellular proteins has not been characterized. We hypothesize, based on our preliminary data, that phosphodiesterase-Ia/autotaxin [PD-Ia/ATX (NPP-2)] is released by oligodendrocytes as a hitherto uncharacterized matricellular component of the extracellular matrix that regulates the adhesive state of post-migratory oligodendrocytes and consequently determines their process remodeling capacity and thus the overall efficiency of myelin sheath formation. In, specific aim 1, we will investigate the role of metalloproteolytic activities in the generation of soluble, oligodendrocyte-derived PD-Ia/ATX, since it is the soluble form of this type II transmembrane protein that appears functionally active during myelination initiation. In specific aim 2, we will determine the extent to which cytoskeleton-related mechanisms, similar to the ones observed for other matricellular proteins, contribute to PD-Ia/ATX's counteradhesive effect toward oligodendrocytes. In these experiments, we will determine the involvement of functional active integrins, the redistribution of cytoskeletal proteins and the activation of Rho-GTPases for PD-Ia/ATX mediated counteradhesion. In the experiments to specific aim 3, we will determine the extent to
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which process outgrowth/remodeling and myelin membrane and sheath formation is directly dependent on PDIa/ATX expression levels. In these studies we will analyze PDIa/ATX over- and under-expressing oligodendrocytes for their capacity to generate complex process morphologies and myelin membrane structures in vitro and to myelinate axons in vivo in the brain of the dysmyelinating mouse mutant shiverer. In addition, we will characterize transgenic mice, in which oligodendrocytes over-express PD-la/ATX. These studies will provide novel insight into the molecular mechanisms that determine CNS myelination, and they may contribute to the development of novel therapeutic strategies designed to improve remyelination under pathological conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS OF OLIGODENDROCYTE DIFFERENTIATION Principal Investigator & Institution: Chao, Moses V.; Professor; Cell Biology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002; Project Start 05-FEB-2001; Project End 31-JAN-2005 Summary: (From the Applicant's Abstract): This application will investigate the mechanisms by which oligodendrocytes progress from a proliferating precursor cell to a fully myelinating cell. It is well established that oligodendrocytes can myelinate multiple axons in the central nervous system. The appearance of oligodendrocytes and their ability to undergo myelination in the CNS occur relatively late during development, after neurogenesis. A number of components of the myelin sheath have been identified, but the underlying molecular mechanisms that control myelin formation and oligodendroglial cells numbers are not fully understood. The specific aims will focus upon the contribution of the cell cycle machinery on the regulation of oligodendrocyte proliferation. In addition, signal transduction events through Fyn tyrosine phosphorylation have been found to be one of the earliest events during oligodendrocyte differentiation. The major objectives will be to define how cell cycle regulation leads to cell specification and how activation of tyrosine kinase activities promotes oligodendrocyte process formation and myelination. These studies may eventually lead to the identification of signals required for oligodendrocytes to form an insulating myelin sheet around axons in the nerve. This investigation will have a direct impact upon basic mechanisms affecting CNS regeneration, remyelination and demyelinating diseases, such as multiple sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MICROTUBULES AND MYELINATION IN A MUTANT RAT Principal Investigator & Institution: Duncan, Ian D.; Professor; Medical Sciences; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-JUL-1994; Project End 31-MAR-2003 Summary: Myelination of the central nervous system (CNS) is a complex developmental process, requiring exquisitely timed interactions between axons and the myelin forming cells, the oligodendrocyte, and the appropriate temporal expression of an array of myelin genes. The initial elaboration of the myelin sheath in the developing CNS, and the long-term maintenance of compact myelin, each place different demands on the myelin forming cell. However, both processes are likely to be influenced by the structural and transport properties of the oligodendrocyte cytoskeleton. This proposal will study a new and unique rat myelin mutant, the taiep rat, which develops a chronic progressive neurological disease as a consequence of a CNS myelin disorder, associated with a microtubular accumulation in oligodendrocyte. The long-term goals are to
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characterize this mutant and its molecular defect and use it to define the role of microtubule and associated proteins in myelin formation and maintenance. To achieve these long-term goals, five specific aims have been planned: 1) The phenotype of the mutant will be characterize using morphological and morphometric approaches to study gla, cell kinetics, myelin, and the onset of the microtubule accumulation. 2) To determine whether environmental factors in the taiep CNS play any role in the development of the microtubule accumulation, cross transplantation experiments will be carried out. These will study the structure and function of taiep oligodendrocyte transplanted into the CNS of other myelin mutants, and of normal cells transplanted into the taiep CNS. 3) The polarity, stability and organizing centers of microtubule in the taiep rat oligodendrocyte will be compared to normal cells to determine whether an abnormal organization of tubules might interfere with transport events within the cell. 4) The role of microtubule regulatory proteins in the taiep mutation will be studied using antibodies to these proteins by Western blots and immunolabelling. Absence, or an over-or under- expression, or ectopic expression, of such a protein will be determined. Messenger RNAs for these proteins will also be examined by Northern blots and in situ hybridization. Finally, 5) To study the effects of accumulation of microtubule in taiep oligodendrocyte, cultures of these cells will be immunolabelled for myelin proteins known to co-localize with the cytoskeleton, and myelin protein mRNAs will be localized by in situ hybridization. Similar experiments will be performed on normal oligodendrocyte in which the cytoskeleton has been pharmacologically manipulated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MODULATION OF AUTOREACTIVE T CELLS Principal Investigator & Institution: Zaghouani, Habib; Professor; Molecular Microbiol and Immun; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2002; Project Start 01-JAN-2000; Project End 31-DEC-2003 Summary: The immune system usually develops antibodies and T cells that attack microbes or tumors but not our own cells or organs. However, there are circumstances where the immune system generates T cells that react and assault our own antigens and tissues. This reactivity against self could evolve into an abrupt reaction and lead to severe autoimmune disease. The long term objective of this proposal is to develop a strategy to calm the autoaggressive T cells and reverse the disease. The model system to be used to test the strategy is experimental autoimmune encephalomyelitis (EAE), a T cell mediated inflammatory and demyelinating disease of the central nervous system (CNS) that is used as an animal model for human multiple sclerosis (MS). In both EAE and human MS T cells infiltrate the CNS and upon recognition of the myelin proteins within the brain produce protein hormones or cytokines that attract inflammatory cells capable of destroying the myelin sheath that covers and protects the axons. A logical approach to treat this disease is to inactivate or reprogram the myelin reactive T cells to halt production of inflammatory cytokines. Peripheral and non-activated antigen presenting cells (APCs) express minimal or no costimulatory molecules. In consequence presentation of antigen by such APCs leads to T cell unresponsiveness. The strategy of antigen injection in the absence of costimulatory activation is being considered as a useful approach to turn off autoreactive T cells involved in autoimmunity. In addition, since T cells are flexible in the way that they recognize antigens it is possible to slightly modify the composition of antigen to generate altered forms that are recognizable by the T cells but could shut off the cell or reprogram the cytokine production. In this application we propose to test a vehicle strategy to deliver self and altered- self peptides
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in a manner that could effectively modulate the autoreactive T cells and possibly improve the disease. In this strategy wild type and modified myelin peptides will be genetically incorporated into immunoglobulins (Igs) and the resulting Ig-myelin chimeras will be injected into sick mice without adjuvant (no costimulation) to test for amelioration of the disease. We have evidence that Igs function as an efficient peptide delivery system and are endowed with the capability to promote the modulator function of altered peptides. Therefore, our hypothesis is that delivery of self and altered self peptides by Igs maybe an efficient strategy to ameliorate T cell mediated autoimmune disease involving multiple autoantigens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR BASIS OF THE DEMYLINATING DISORDER ADLD Principal Investigator & Institution: Fu, Ying-Hui; Associate Professor; Neurology; University of California San Francisco 3333 California Street, Suite 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2002; Project Start 15-APR-2001; Project End 31-MAR-2004 Summary: (Investigator's abstract): Autosomal dominant leukodystrophy (ADLD) is a rare adult-onset demyelinating disorder. We have identified 6 families with this disorder. Two of these are large pedigrees for whom a tremendous amount of clinical, neuroradiological and neuropathological data has been collected. Although these patients share many clinical features with other white matter disorders, unique neuropathological findings suggest that the genesis of this disorder neither resides in defects of structural myelin proteins nor fatty acid metabolism in peroxisomes. ADLD is not an immune disease like multiple sclerosis (MS). We've demonstrated that lesions in ADLD brain have dramatic reduction in astrocyte number and that the surviving astrocytic cells are morphologically very abnormal. We hypothesize that ADLD results from a defect that interferes with a unique element in the myelination process and that understanding of this defect may provide novel insights into the process of myelin maintenance and turnover. We have localized the gene causing ADLD in these two large families to chromosome 5q3 1. Fine mapping has further narrowed the region and a complete physical map predicts the gene to reside within 3 megabases, much of which has already been sequenced. Candidate gene identification and testing are underway. Some genes in the region have already been eliminated using various mutation analysis strategies. Several plausible candidates are currently being tested including a novel gene with multiple EGF-like domains. This proposal outlines a strategy for identifying and characterizing the gene. Available patient material, physical mapping reagents and genomic sequence position us well for accomplishing this goal. In addition, experiments will be pursued toward preliminary characterization of both the wild-type and mutant ADLD protein. Understanding the cause of this demyelinating disorder may yield clues to genetic factors that modulate the expression of acquired leukodystrophies. Ultimately, discovery of a new element in the synthesis and maintenance of myelin may provide a novel target for compounds that may stimulate remyelination in more common disorders like MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOLECULAR MECHANISMS OF SCHWANN CELL MYELINATION Principal Investigator & Institution: Trapp, Bruce D.; Professor; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 01-MAR-1999; Project End 31-MAR-2006
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Summary: (provided by applicant): Myelin surrounds many of the axons in the central and peripheral nervous systems where it facilitates the rapid conduction of nerve impulses and provides an extrinsic trophic effect that promotes axonal maturation and survival. Dysmyelination and demyelination are major causes of neurological disability in humans and can be fatal. Historically, neurological deficits in these primary myelin diseases were thought to result from myelin pathology. However, recent studies have identified axonal degeneration in a number of primary myelin diseases. The most common causes of genetic myelin disease in humans are gene duplications that alter the dosage of myelin proteins. Much of what is known about the cellular and molecular aspects of normal myelination and the pathogenesis of inherited myelin diseases has been obtained from studies of rodents in which myelin protein genes are mutated, deleted or overexpressed. We have developed transgenic mouse models of PNS and CNS dysmyelination by overexpressing P0 protein, the major structural protein of PNS myelin in Schwann cells, and by expressing high levels of P0 protein in myelinating oligodendrocytes. The overall goal of this application is to understand how P0 overexpression causes myelin and axonal pathology. Schwann cells that overexpress P0 protein ensheath but fail to myelinate axons because they mistarget P0 to non-myelin surface membranes. Studies in Specific Aim 1 will investigate mechanisms responsible for P0 and MAG targeting in MDCK cells in vitro. Specific Aim 2 will investigate how dysmyelination in P0 overexpressing mice causes alteration in ion channel distribution in PNS axons and a distal axonopathy that consists of axonal withdrawal from the neuromuscular junction and subsequent axonal sprouting and neuromuscular junction reinnervation. We have also established that P0 expression by oligodendrocytes results in CNS dysmyelination and axonal degeneration. Specific Aim 3 will investigate molecular mechanisms responsible for these pathologies and determine if the phenotype is rescued by their breeding to PLP null mice. Collectively, these studies should provide novel information about the pathogenesis of dysmyelination, molecular mechanisms of normal myelination, and the mechanisms by which myelin-forming cells modulate the development and survival of axons. 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-2005 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
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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 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: MYELIN OLIGODENDROCYTES
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Principal Investigator & Institution: Larocca, Jorge N.; Neurology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2007 Summary: (provided by applicant): The goal of this project is to define the roles of rRab22b in the formation of myelin and of endocytic compartments. Myelin is a highly specialized multilamellar structure that surrounds axon segments. The integrity of the myelin sheath is essential for normal conduction. Disruptions of the myelin sheath that occur in several diseases, including multiple sclerosis and lysosomal disorders have irreparable consequences. Myelin biogenesis is a highly regulated process that requires coordination of numerous oligodendrocytic events involved in lipid and protein synthesis, intracellular trafficking of membranes, and changes in cell shape. Membrane trafficking is necessary both for delivery of structural myelin components and for movement of molecules that participate in the signaling mechanisms that regulate myelin biogenesis. Both exocytic and endocytic trafficking pathways play major roles in the formation and maintenance of myelin. The coordination.of these processes is required to preserve the structural and functional organization of oligodendrocytes. Rab proteins play a key role in the regulation of membrane trafficking. Our studies indicated that rRab22b, a novel Rab protein that is present in oligodendrocytes, regulates transport from the trans-Golgi network (TGN) to the endosomes. Other evidence suggests that membrane trafficking from the TGN to the endosomes plays essential roles in the biogenesis of endosomes and lysosomes and in the transport of proteins to myelin. We will determine whether Rab22b is involved in the transport of endosomal and lysosomal proteins from the TGN to the endosomes and whether myelin proteins are transported through this pathway before being targeted to myelin. The studies will be performed in living cells including Hela cells, HOG and primary cultures of rat oligodendrocytes. EYFP- tagged rRab22b will be co-expressed with ECFP-tagged endosomal proteins and lysosomal proteins. The organelles containing the EYFP-tagged and ECFP-tagged proteins will be visualized by double fluorescence microscopy. Timelapse experiments will carry out to visualize the budding from the TGN of vesicles containing the EFYP-tagged and ECFP-tagged proteins. The role of rRab22b in the
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transport of proteins from the TGN to the endosomes will be confirmed in experiments using rRab22b dominant negative mutant by analysis of how the transport of ECFP chimeric proteins is affected. Similar experiments will carried out expressing rRab22bEFYP and ECFP-tagged myelin proteins in HOG and oligodendrocytes. The participation of rRab22b in extension of oligodendrocyte processes and formation of membrane will be assessed by expressing rRab22b mutants in oligodendrocyte primary cultures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYELIN GENE PRODUCTS IN POST MORTEM TISSUE Principal Investigator & Institution: Buxbaum, Joseph D.; Associate Professor and Head; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): We have carried out microarray analyses in a welldefined schizophrenic cohort provided by the Brain Bank Core (Core C). We observed that there were significant decreases in the levels of expression of six myelin/oligodendrocyte-related genes. In addition, we observed that making use of the expression levels of these 6 genes and 29 additional myelin/oligodendrocyte-related genes, we could perfectly discriminate the schizophrenics from controls. This observation implicates myelin/oligodendrocyte abnormalities in schizophrenia, and is further supported by the imaging studies (Project 4, DTI/MTI; Project 5, MRS) and neuroanatomical studies (Project 1, Oligodendroglia) detailed elsewhere in the proposal. The overarching aims of the current project are to expand on our existing results by determining the generality of the decreased myelin/oligodendrocyte related gene expression in the prefrontal cortex of schizophrenics to other prominently implicated brain regions and other schizophrenia cohorts, as well as to begin to understand the mechanisms underlying the decreased gene expression. These general aims and hypotheses will be tested by the following specific aims. Specific Aim 1: Examine the expression levels of myelin/oligodendrocyte-related genes in additional brain areas. Specific Aim 2: Study the expression levels of myelin/oligodendrocyte-related genes in additional patient samples. Specific Aim 3: Determine the cellular basis for altered gene expression. Specific Aim 4: Determine the molecular basis for altered gene expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MYELIN PO GLYCOPROTEIN: STRUCTURE & ADHESIVE MECHANISMS Principal Investigator & Institution: Kirschner, Daniel A.; Professor; Biology; Boston College 140 Commonwealth Ave Newton, Ma 02467 Timing: Fiscal Year 2002; Project Start 15-JAN-2000; Project End 31-DEC-2003 Summary: (Applicant's abstract): The overall objective of this application is to define the molecular organization of myelin, the diverse adhesive mechanisms that stabilize its multilamellar sheath, and what defects in its organization and molecular constituents may lead to dysmyelination or demyelination such as occur in certain peripheral neuropathies and in multiple sclerosis. The approach is based on a correlation of results from X-ray crystallography and solution scattering, membrane diffraction, and electron microscopy. The specific aims, which are focused on the structure and role of the major transmembrane protein of peripheral nerve myelin (P0-glycoprotein) are: (1) to determine the three-dimensional structure of P0-glycoprotein for human and Xenopus. The proteins analyzed will include recombinant molecules having the native amino acid
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sequence, as well as those having specific sequence alterations known to occur in human peripheral neuropathies. These studies will inform about the atomic structure of P0 and about the crystal contacts or adhesion interfaces that may be responsible for the role of this protein in myelin formation and stability. (2) To characterize the protein-protein interactions between nearest-neighbor P0 molecules in a membrane mimetic environment using small-angle X-ray scattering. The membrane protein will be solubilized in aqueous solutions of detergents at very low concentration, and solution scattering will be undertaken using a synchrotron X-ray source. These studies will provide information about the interprotein molecular contacts that P0 molecules make in a milieu that more closely resembles its native environment (the lipid bilayer of the myelin membrane) than does a crystal. (3) To evaluate the membrane-membrane interactions in myelin of Xenopus peripheral nerves. Determining the pH- and ionic strength-dependence of membrane structure and packing in dissected peripheral nerves that have been incubated at different will provide strong constraints for testing hypotheses about the adhesion mechanisms of P0 at both the cytoplasmic and extracellular membrane appositions. This hierarchy of experimental objectives will allow the investigator to uniquely correlate structural data from the atomic to the molecular, to the membrane level, and thus contribute to an understanding of the structural biology of a membrane protein that figures significantly in both health and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYELINATION--ASSEMBLY OF LIPIDS AND PROTEINS Principal Investigator & Institution: Benjamins, Joyce A.; Professor; Neurology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-APR-1977; Project End 31-JUL-2004 Summary: Oligodendrocyte (OL) injury results in loss of myelin, failure of myelination, axonal damage and ultimately cell death. We have shown that increased intracellular Ca++ mediates damage in mature membrane sheet-bearing OLs. We hypothesize that the duration, magnitude and source of increased intracellular Ca++ are major determinants of the nature and outcome of OL damage. Specifically, we will ask whether a given mode of increasing Ca++ leads to membrane sheet retraction, OL death or both. We will compare Ca++-mediated injury elicited by thapsigargin to that elicited by the NO donor SNAP and by the glutamate receptor agonist kainate. In parallel with experiments on enriched OL cultures, we will utilize a myelinating co-culture system to examine the effects of axons on the responses of OLs to Ca++-mediated injury. Our long term objective is to identify strategies for protecting OLs from damage and optimizing myelin repair in white matter injury associated with diseases such as multiple sclerosis or with the sequelae of stroke or trauma. Specific Aim 1 utilizes laser cytometry to define the changes in Ca++ initiated in mature OLs by thapsigargin, NO and kainate. A range of doses will be compared for their effects on Ca++, membrane sheet retraction, and OL viability. Specific Aim 2 analyzes changes in cytoskeleton and rates of endocytosis which accompany Ca++-mediated retraction of OL membrane sheets, with focus on endocytosis of WGA receptors and proteolipid protein. Specific Aim 3 analyzes the role of increased Ca++ in the pathways leading to necrotic or apoptotic cell death. The contribution of each pathway will be assessed with various doses of the agents. Specific Aim 4 analyzes changes in gene expression accompanying OL responses to increased intracellular Ca++. Changes in message levels for myelin proteins (MBP, PLP, and DDM-20), relevant transcription factors (SCIP, GtX, and CREB) and immediate early genes (zif , c-fos, and c-jun) will be measured by nuclease protection assay or Northern
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blotting. In Specific Aim 5, the effects of axons on OL responses to increased OL Ca++ will be examined. Myelinated DRG-OL cultures will be exposed to thapsigargin, NO, or kainate. Cultures will be grown in a two-compartment system, so that agents can be applied to the axon-myelin-glia compartment, but not the neuronal cell bodies. Effects on myelin, OL viability, and axonal integrity will be evaluated by immunocytochemical staining. In situ hybridization and RT-PCR will assess changes in message levels. In the last four specific aims, the initial steps in signaling pathways that ultimately lead to Ca++-mediated injury will be examined by assessing the effects of Ca++ chelation at various times, and by determining whether cyclic AMP or calpains are involved. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEONATAL HYPOXIC-ISCHEMIC WHITE MATTER INJURY Principal Investigator & Institution: Silverstein, Faye S.; Professor; Pediatrics & Communicable Dis; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 15-APR-2001; Project End 31-MAR-2004 Summary: (PI's abstract) This application is submitted in response to PAS 99-080, "Exploratory Grants in Pediatric Brain Disorders: Integrating the Science." The proposal will lay the foundation for a new inter-institutional collaboration (Univ. Of Michigan and Wayne State Univ.) between clinician scientists with expertise in the pathogenesis of brain injury (Drs. Silverstein and Barks), and a neuroanatomist with expertise in oligodendroglial development (Dr. Skoff). The long-term goal of the proposed research is to develop novel approaches for understanding the pathogenesis of hypoxic-ischemic white matter injury in the immature brain. Studies of neonatal ischemic brain injury in experimental models have focused on mechanisms of neuronal injury and neuroprotection, and have largely neglected white matter injury. Yet, in human neonates and young infants the white matter, particularly in periventricular regions, is highly susceptible tp ischemic injury. In preliminary experiments, in situ hybridization and RT-PCR assays were developed to examine injury-induced changes in expression of 2 oligodendroglia (OL)-specific genes, proteolipid protein (PLP), and myelin basic protein (MBP); preliminary findings provide the impetus for this application. Experiments performed in immature rodent stroke models (in neonatal rats and mice) revealed that hypoxic ischemic injury results in acute disruption of OL gene expression within periventricular white matter; and also alters expression of OL-specific genes in cells in the sub-ventricular zone; in neonatal rats, intraventricular injection of the excitatory amino acid agonist AMPA results in a similar pattern of acute disruption of OL gene expression. This application proposes to build upon these finding to develop novel approaches for understanding mechanisms of OL injury in the immature brain. Aim 1 will: evaluate the influence of hypoxia-ischemia (HI) on PLP and MBP gene expression; determine whether acute HI induced suppression of OL-gene expression predicts the severity of chronic OL damage; and evaluate the impact of specific interventions that could exacerbate or attenuate HI-induced OL injury. Aim 2 will examine the influence of AMPA lesioning on PLP and MBP gene expression and OL injury. Aim 3 focuses upon the impact of HI on OL precursors in the ventricular and subventricular zones; and specifically will analyze whether these OL precursors undergo apoptosis, whether the loss of OL precursors is permanent, and whether mild HI insults can elicit a proliferative response in these cells. Taken together, results of these experiments will improve our understanding of the impact of HI on OL in the immature brain and enhance development of more effective therapeutic approaches to limit or prevent neonatal ischemic white matter injury.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEUROGLIAL INTERACTIONS AT THE NODE OF RANVIER Principal Investigator & Institution: Rasband, Matthew N.; Neuroscience; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The rapid and successful transmission of electrical signals in myelinated nerve fibers requires axoglial interaction and the proper subcellular distribution of ion channels. This fact is well illustrated by the high degree of regulation in Na+ channel localization, clustering, and isoform expression at nodes of Ranvier. Recent work suggests that this regulation is dependent on both myelin and specific neuroglial interactions at the paranode, the site where sequential layers of the myelin sheath terminate against the axon in septate like axoglial junctions. Diseases or injuries that result in demyelination (such as multiple sclerosis and spinal cord injury) result in conduction block not only through changes to the passive electrical properties of the nerve fiber, but also because the precise localization and clustering of ion channels is disrupted. This proposal aims to test the hypothesis that neuroglial interactions regulate the expression, clustering, and localization of Na+ channels at nodes of Ranvier. To do this, we will: 1. Identify and characterize new molecular components of the node and paranode by immunoaffinity purification of nodal and paranodal protein complexes; these purified proteins will be characterized by mass-spectrometry. Bona fide interactions with known proteins will be verified by co-immunoprecipitation and colocalization in native tissueand transfected cells. 2. Identify and characterize the antigens for a library of monoclonal antibodies wehave made against unknown nodal and paranodal proteins. The functions of newly identified antigens will be determined through a developmental analysis of expression at nodes of Ranvier, and by coimmunoprecipitation and colocalization with known proteins from/in brain and spinal cord. 3. Identify the function of the myelin sheath and paranode in regulating Na+ channel isoform expression at nodes of Ranvier by examining expression during chronic and acute demyelination, and in mutant mice with altered paranodal structure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OLIGODENDROCYTE GENERATION DURING IRON DEFICIENCY Principal Investigator & Institution: Mayer-Proschel, Margot; Assistant Professor; Biomedical Genetics; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The most prevalent nutrient deficiency in the world is a lack of iron. It has been estimated that 35 to 58% of women have some degree of iron deficiency. The occurrence of iron deficiency is particularly prevalent during pregnancy. It has been reported that for children under 2 years of age, the estimated prevalence of iron deficiency is 25%. While it is known that iron deficiency in children is associated with a number of neural defects including behavioral effects, alterations to the blood brain barrier, changes in fatty acid composition, and hypo-myelination, the cellular mechanisms leading to such defects are not well understood. For example, it has been hypothesized that iron deficiency leads to a failure of oligodendrocyte maturation or survival. Another possibility that has been discussed is a failure in the generation of oligodendrocytes from the precursor cells that give rise to them due to iron deficiency. These hypotheses are based on observations that there is a peak of iron availability in vivo that coincides precisely with peak periods of myelination and that normal
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myelination does not occur in the absence of sufficient iron. The vast majority of studies that try to decipher the specific role of iron in gliogenesis have focused on the postnatal stage of development, when oligodendrocytes form functional myelin in vivo. Our own studies, however, have indicated that a lack of iron has a severe impact on the very early glial precursor cells of the embryonic spinal cord. Embryonic glial precursor cells that grow in low iron seem to be impaired in their ability to divide and to differentiate. Thus, we now propose that the hypomyelination that is associated with iron deficiency is likely to be a late consequence of damage that occurred already during embryogenesis. We propose that iron interferes with the earliest developmental steps ancestral to oligodendrocyte generation and therefore disrupts the normal sequence of progressive lineage restriction that is required for proper generation of these myelin-producing cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OLIGODENDROCYTE REGULATION OF AXONAL MORPHOLOGY Principal Investigator & Institution: Strittmatter, Stephen M.; Professor; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): A major neurological complication in very low birth weight infants is the development of periventricular leukomalacia and ventriculomegaly, with subsequent cerebral palsy and cognitive impairment. The primary pathological hallmark of this condition is the loss of myelin and oligodendrocytes. Here we seek to explore the cellular and molecular consequences of oligodendrocyte loss during this stage of neurodevelopment. In particular, we hypothesize that oligodendrocyte loss will lead to secondary changes in axonal morphology and hence behavior. A rodent model for periventricular leukomalacia involving chronic sublethal hypoxia will be characterized in detail for alterations in oligodendrocyte/axon interaction and axonal morphology. These changes will be correlated with behavioral deficits. Preliminary data implicate suppression of the oligodendrocyte proteins Nogo and MAG during hypoxia in the development of ectopic axonal sprouting. To verify the role of these particular proteins, mice lacking Nogo, MAG or the NogoReceptor will be compared with those exposed to chronic sublethal hypoxia. Similarities between the mutant mice and the hypoxic mice will support the hypothesis that these proteins contribute to the pathophysiology of periventricular leukomalacia. In addition, the synergistic effects of hypoxia plus Nogo, MAG or Nogo receptor gene deletion will be analyzed. This may provide further support for the hypothesis that hypoxia-induced deficits in oligodendrocytes lead to maladaptive changes in axonal morphology. Together these studies should advance our current understanding of the interactions between oligodendrocytes and axons under conditions similar to those experienced by very low weight birth weight infants. Such knowledge may lead to the development of novel therapeutic approaches aimed at lessening the long-term neurological sequela of prematurity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OPIOIDS MODULATE OLIGODENDROCYTE DEVELOPMENT & FUNCTION Principal Investigator & Institution: Knapp, Pamela E.; Associate Professor; Anatomy and Neurobiology; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 31-JAN-2007
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Summary: (provided by applicant): Pre- and postnatal exposure to opioids can profoundly affect CNS development and function. Since the fastest growing population of opiate (heroin) abusers are young women of childbearing years, there is a public health interest in understanding how opioid signaling affects CNS development. Opioids given experimentally in vivo or to slice cultures during pre- or perinatal periods can alter survival and proliferation of neurons and astroglia, cause permanent changes in CNS structure and adversely affect learning and memory. Opiate exposure also reduces neurogenesis in adult hippocampus by 40 percent. Opioid effects are complex. Depending on the cell type or receptor (mu, delta or kappa) targeted, opioids can be toxic or protective and can have distinct effects on cell maturation. The survival of oligodendrocytes (OLs) and formation of myelin is critical for CNS function. Although opiate abuse can result in myelin pathology, essentially nothing is known about opioid effects on OLs either during neonatal or perinatal periods or in the adult. Our work has defined the existence of opioid signaling pathways in cultured OLs by showing that: (a) OLs express mu- and kappa-opioid receptors in a temporally specific pattern; (b) OLs have physiologic responses (survival, proliferation, myelin production) to selective manipulation of receptors; (c) OLs synthesize, process and probably secrete 2 classes of endogenous opioids (dynorphins, enkephalins). The central goals of this proposal are to determine the spatiotemporal expression patterns of opioid receptors and peptides within the developing and mature CNS, and to determine the role that opioids play in modulating the survival and function of OLs. Functional studies center on the role of dynorphin peptides since our findings show dynorphin mediates effects on the survival of OLs and neurons. A secondary goal is to determine whether manipulation of opioid signaling pathways can promote OL survival and myelination in clinical conditions with myelin pathology. Proposed studies use complementary in vivo and in vitro approaches employing mice deficient in opioid receptors and dynorphin to: (1) Identify spatiotemporal patterns of opioid receptor expression on OLs in the CNS; (2) Identify spatiotemporal patterns of dynorphin expression on OLs in the CNS and determine if dynorphin peptides are secreted; (3) Test the hypothesis that signaling through kappaopioid receptors promotes OL survival and activates the PI3-kinase/Aktl pathway; (4) Test the hypothesis that some dynorphin peptides have glutamatergic effects on OLs. Techniques used include cell culture, immunostaining, in situ hybridization, immunoblot, confocal microscopy and adenoviral transfection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: P0-MEDIATED SIGNALING AND MYELINATION Principal Investigator & Institution: Lilien, Jack E.; Professor; Biological Sciences; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Myelin is a multilamellar membrane that surrounds axons in both the central and peripheral nervous system P0, a member of the immunoglobulin family of adhesion molecules, is the most abundant protein in peripheral myelin and is thought to mediate adhesion between the multiple layers of myelin as they wrap around the axon. Consistent with an important role for P0 in myelination, mutations in both the extracellular and intracellular domains cause the human peripheral neuropathy Charcot-Marie-Tooth disease type 1B. Our long-range goals are to couple basic and clinical research to discover the molecular basis for P0 function in human myelination. We have recently discovered that point mutations in a Protein Kinase C (PKC) target motif - RSTK - in the cytoplasmic domain of P0 abolish its adhesive function, as does inhibition of PKC. We have also identified a CMT1B patient
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with a mutation in the RSTK motif (R to S), further indicating the importance of PKCmediated phosphorylation in myelination. The goals of this proposal are to determine the role of PKC-mediated phosphorylation in adhesion and myelination. 1) We have found that RACK1, the Receptor for Activated C Kinase is a component of the complex of proteins associated with the cytoplasmic domain of P0. We will determine if RACK1 or other adapters are needed to target PKC to the cytoplasmic domain of P0. We will further characterize the domains through which partners interact using deletion constructs in conjunction with the two-hybrid system and/or an in vitro binding assay 2. By analogy with other adhesion molecules, we hypothesize that phosphorylation creates a binding site for adaptors or effectors essential for the interaction of P0 with downstream targets. We have identified one protein whose interaction with P0 depends on phosphorylation of serine in the RSTK motif using the yeast two-hybrid system. We will characterize the binding of this component and downstream targets. 3) We will evaluate the role of each of the components identified in aims 1 and 2 using an in vitro myelination culture system by introducing dominant-negative and constitutively active constructs, as well as constructs coding for peptide competitors for critical proteinprotein interactions, into Schwann cells prior to co-culture with neurons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PATHOLOGY OF DYSMYELINATION AND DEMYELINATION Principal Investigator & Institution: Rosenbluth, Jack; Professor; Physiology and Neuroscience; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2003; Project Start 01-APR-1998; Project End 31-JAN-2006 Summary: (provided by applicant): The myelin sheath/axon complex in the vicinity of the node of Ranvier of myelinated fibers is a precisely organized structural unit believed to have evolved to optimize rapid and efficient nerve conduction. The principal components are a very large and uniquely structured axoglial junction, which separates nodal sodium channels from internodal potassium channels. Minor damage to this intricate nodal/paranodal complex could significantly affect nerve conduction and cause functional losses, even with changes subtle enough to escape detection by routine methods. In view of the potential functional significance of "subtle" pathological changes in this complex, we wish to define them more fully in experimental models in which the pathogenetic elements can be controlled and in which we can analyze the pathology using not only classical light microscopic and ultrastructural techniques but also ultrastructural immunocytochemistry in conjunction with freeze-fracture methodology. We will make use of mutations affecting myelinated nerve fibers to assess the effects of specific deficiencies on the integrity of the axoglial junction, on the density and distribution of the nodal and internodal ion channel aggregates, on nerve conduction and on axon damage. We will also use the in vivo model of focal antibodymediated dysmyelination and demyelination, which we have been working with, to determine whether equivalent abnormalities can be identified in this model of multiple sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PDGF SIGNALING IN OLIGODENDROCYTE DEVELOPMENT Principal Investigator & Institution: Mckinnon, Randall D.; Associate Professor; Surgery; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, Nj 088545635
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Timing: Fiscal Year 2002; Project Start 01-JUN-1997; Project End 31-MAY-2005 Summary: The long term goal of our studies is to elucidate the mechanisms whereby polypeptide growth factors regulate the development of oligodendrocytes, the myelin forming cell of the CNS. These issues are important in order to understand the mechanisms underlying disorders affecting CNS myelin, and for devising strategies for intervention including promoting regeneration by endogenous repair, or transplanting cells to supplement this repair. The specific focus of this proposal is to anlyze the functionally important domains of the Platelet Derived Growth Factor alpha-receptor (PDGFRalpha) that modulate the biological responses of oligodendrocytes to PDGF. The purpose of these experiments is to determine how oligodendrocytes generate diverse biological responses from a single growth factor. PDGF is one of at least seven ligands acting via receptors with tyrosine kinase activity that affect oligodendrocyte development, and has a diverse range of effects including the ability to modulate proliferation, migration, differentiation and survial. The fundamental question addressed in this proposal is whether specific domains of PDGFRalpha, associated with distinct signaling pathways, are linked to separate biological responses of oligodendrocyte progenitors to PDGD. This hypothesis will be addressed using a combination of in vitro and in vivo approaches. First, expression vectors encoding mutant versions of PDGFRalpha will be transfected into primary oligodendrocyte progenitors, which will then be examined for PDGFRalpha transgene-meditaed biological reponses in vitro. The PDGFRalpha transgenes are engineered to be specifically activated by a neutral ligand (hCSF-1) and include mutations in domains of PDGFRalpha that block activation of individual second messenger pathways. Second, mutated PDGFRalpha cDNAs will be introduced into progenitor cells isolated from PDGFRalpha-null mice, and the effects of specific mutations on oligodendrocyte development will be analyze after transplantation in vivo. Third signaling pathways activated by PDGF will be characterizing by RNA transcript analysis. These experiments should (I) identify the intra-cellular domains of PDGFRalpha, and signal transduction pathways associated with these domains, regulating the proliferation, migration, differentiation and survival of oligodendrocyte progenitors, and (ii) whether individual domains are associated with these specific biological responses, in vitro and in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHYSIOLOGY OF VOCALIZATION SEN IN AUDITORY CORTEX Principal Investigator & Institution: Tramo, Mark J.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2003 Summary: Deficits in speech perception and language acquisition with relative preservation of pure tone detection thresholds and other elementary psychoacoustic functions are common findings in diseases afflicting the auditory forebrain. Injury to the peripheral auditory system, especially early in development, often leads to central pathophysiological changes and perceptual impairments that cannot be overcome by prostheses or cochlear implants. The present application seeks to continue the development of our nonhuman primate model for analyzing the physiological response properties of auditory cortical neurons in relation to the acoustical features of communication sounds. Specifically, the timing and magnitude of neuronal excitation and inhibition evoked by species-specific vocalizations and synthetic stimuli will be analyzed in alert Macaca mulatta with respect to: 1) the spectral energy distribution and harmonic structure of the stimulus; 2) the temporal envelope of the stimulus waveform; 3) the temporal separation of stimulus events; 4) the temporal order of stimulus events;
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5) the acoustic and contextual categories of vocal stimuli; and 6) the spectrotemporal receptive field properties of the neuron. Microelectrode penetrations into posterior superior temporal cortex will be stereotaxically guided using magnetic resonance imaging; recording sites will be reconstructed histologically after terminal mapping experiments, and microanatomical correlates will be defined using acetylcholinesterase, cytochrome oxidase, parvalbumin, Nissl, and myelin staining methods. In the longer term, this experimental model could be developed to investigate central pathophysiological-functional correlates of acute and chronic peripheral disease and to compare cortical neuron responses to vocal communication sounds before and after cochlear implantation. The aim of research on the single-unit physiology of auditory cortex in relation to the psychophysics of vocal communication is to advance basic knowledge about auditory function in the hope of enhancing treatment strategies for communication disorders that utilize electrical stimulation, prostheses, and rehabilitation therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
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 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:
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(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: PROCESSING AND DEGRADATION OF PROTEOLIPID PROTEIN Principal Investigator & Institution: Skoff, Robert P.; Professor; Anatomy and Cell Biology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 15-FEB-1999; Project End 31-JAN-2005 Summary: Proteolipid protein (PLP) is a highly conserved, integral myelin protein of the central nervous system. Modest over expression of the normal protein is, puzzlingly, lethal in humans and in animals at early ages. But absence of this major myelin protein, surprisingly, produces a very mild phenotype in null mice and in humans with PLP gene deletions. Mutations of the protein, even conservative amino acid substitutions, are usually lethal in humans and animals. What are the cellular and molecular factors that produce these different phenotypes? At the cellular level, the severity of the disease in the PLP mutants correlates quite well with the number of dying oligodendrocyte (Ols). At the molecular level, it has been postulated that defective intracellular transport of the mutant PLPs proteins is the underlying factor that induces OL death but the molecular mechanism(s) and signals that induce OL death have not been investigated. We hypothesize that the ubiquity-proteasome complex is involved in the degradation of PLP. The ubiquitin-proteasome system then triggers the programmed cell death (PCD) cascade. We will investigate using the in vitro systems how mutant and normal PLP proteins are processed by the ubiquitin-proteasome system and how OL death is induced. In vivo studies of the PCD cascade in Ols will be performed correlated with the in vitro data to assure that tissue culture mechanisms are an accurate reflection of the in vivo processes. Specific Aim 1: Determine if mutations of PLP protein induce PCD and if mutations of DM20 protein (an alternative splice product of the PLP gene) are as lethal as PLP; determine if both proteins are modified with ubiquitin in the endoplasmic reticulum; study PCD cascade in Ols. Specific Aim 2: Determine why over expression of normal PLP and normal DM20 proteins induce PCD and if these proteins are modified by ubiquitin. Examine the transport of PLP to the cell membrane by DM20. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HORMONE
REGULATION
OF
BRAIN
DEVELOPMENT
BY
THYROID
Principal Investigator & Institution: Mariash, Cary N.; Professor; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 15-APR-2000; Project End 31-MAR-2004 Summary: Thyroid hormone deficiency during fetal and early childhood development is a major world-wide public health problem causing mental retardation and irreversible brain damage. The long term goal of this program is to understand the mechanism by which thyroid hormone (T3) regulates mammalian brain development. T3 regulates late brain development by activating several brain genes at a precise time. However, prior to this activation these genes are resistant to thyroid hormone despite the presence of T3 and thyroid hormone receptors. Thus, the loss of repression allows T3 to activate these genes at the appropriate time. To define the mechanism of this novel repressor effect we
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will study two different brain genes, Purkinje cell protein-2 (Pcp-2) and myelin basic protein (MBP), each expressed in two different cell types, cerebellar Purkinje cells and oligodenrocytes, respectively. We propose three specific aims: (1) to define the sequences within the Pcp-2 gene responsible for the repression of T3-dependent activation; (2) establish the role of the orphan receptor protein COUP-TF in repressing the response of Pcp-2 to T3; (3) determine the mechanism of repression for T3 induction of MBP gene in developing oligodendrocyte cultures. The first aim will utilize gel shift assays and DNAse I footprinting to localize the repressor sequence within an identified repressor region of the Pcp-2 gene. The identified sequence will be mutated and tested for loss of repressor action in transgenic mice using a Pcp-2 promoter construct shown to duplicate the in vivo developmental response of the Pcp-2 gene. Preliminary results suggest that the orphan nuclear receptor COUP-TF may be involved in the repressor activity. We will test the potential role of COUP- TFI by measuring Pcp-2 in mice deficient in this protein. Primary Purkinje cell cultures will be used to test the potential role of COUP- TFII in repressing the response to T3. We will use anti-sense technology to knockout the protein in culture and transient transfection assays to overexpress the protein. The third aim will be accomplished by examining the T3 response of other TREs to test if the MBP TRE is involved in repression of the T3 induction of MBP. We will determine if COUP-TF is the repressor protein that binds to the MBP TRE, and if not we will clone the repressor protein. These studies will provide critical information on the role of thyroid hormone in allowing synchronous development of the mammalian brain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATORY DEMYELINATION
CD4/CD8
T
CELLS
IN
AUTOIMMUNE
Principal Investigator & Institution: Kumar, Vipin; Torrey Pines Institute/Molecular Studies Molecular Studies San Diego, Ca 921211122 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Immune regulation plays a critical role in the control of mature self-reactive, potentially pathogenic T cells. Different cellular components and their interactions in regulatory mechanisms are not well understood. Here we will investigate how a dominant negative feedback mechanism controls myelin basic protein (MBP)-reactive Vbeta8.2+ T cells mediating experimental autoimmune encephalomyelitis in the H-2u mouse, a prototype for multiple sclerosis. This regulation is focused on the recognition of TCR peptide/MHC complexes in class I and II MHC contexts by regulatory CD8 and CD4 T cells (Treg) respectively. We have proposed (see Figure 1) that CD4 Treg provide help in the recruitment/activation of CD8 Treg, which ultimately induce apoptosis in activated Vbeta8.2+ Th1 cells. The depletion of pathogenic Th1 and expansion of non-pathogenic Th2 cells eventually leads to immune deviation of the anti-MBP response and protection from EAE. CD4 Treg are reactive to a framework 3-region peptide, BS, whereas CD8 Treg recognize the CDR1/2 region peptide, B3 or p41-50, from the TCR Vbeta8.2 chain. Using CDR3 length spectratyping, or immunoscope analysis and annexin-V staining of CFSE-labeled cells we will determine the fate of Vbeta8.2+ T cells following induced or physiological regulation in vivo. We will determine the role of type 1 and type 2 cytokines in the initial and late phases of regulation, respectively. CD8 Treg clones will be generated and characterized for their MHC-restriction, TCR-V gene usage and functional properties, including their cytolytic activity both in vitro and in vivo, and their ability to control disease upon adoptive transfer. We will determine the mechanism of killing by the CD8 Treg using B10.PL.lpr, B10.PL.gld and B10.PL.perforin-/- mice. Knowledge of the immune
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principles involved here is important not only for understanding the biology of immune regulation but also in the design of TCR-based therapeutic approaches for autoimmune conditions in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REPAIR AND REGENERATION OF CENTRAL VISUAL PATHWAYS Principal Investigator & Institution: Barres, Ben A.; Assistant Professor; Neurobiology; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2004; Project Start 22-JAN-1996; Project End 31-DEC-2006 Summary: (provided by applicant): We propose to investigate why central visual pathways fail to regenerate after injury and how their repair can be enhanced. Specifically, we will investigate why the axons of mature retinal ganglion cells (RGCs) fail to regenerate after axotomy. The regeneration of RGCs through the optic nerve has long served as a simple model system for study of CNS regenerative failure. The rat optic nerve consists primarily of RGC axons, astrocytes, and myelinating oligodendrocytes. We have developed methods to purity and culture rodent RGCs, optic nerve astrocytes and oligodendrocytes. Using these methods we will continue to investigate the molecular mechanisms that promote and inhibit RGC axon elongation in culture, and how we can apply this knowledge to enhance regeneration. In this proposal, we will investigate the molecular basis of 3 phenomena implicated in the failure of RGC axons to regenerate. Over the last grant period, we discovered that neonatal RGCs are signaled by amacrine cells to irreversibly lose their intrinsic competence to rapidly regenerate their axons. In the first aim, we will use gene profiling to investigate the molecular basis for this loss. In the second aim, we investigate the identity of myelin-associated inhibitors of regeneration in the optic nerve and the RGC receptors that they bind to by constructing bacteriophage display libraries of single chain antibodies and selecting antibodies that enhance RGC regeneration. In the third am, we will investigate why the clearance of myelin debris in Wallerian degeneration is so prolonged after optic nerve injury. We will specifically test the hypothesis that this is accounted for by the recent discovery that CNS microglia are immature myeloid precursor cells rather than quiescent phagocytes. Finally, we will apply what we learn in the first 3 aims to determine if we can enhance RGC regeneration after optic nerve injury in vivo. Our ultimate goal is to understand why RGCs fail to regenerate afar axotomy and to develop new treatments promote their regeneration after injury in ocular diseases including glaucoma, retinal ischemia, optic neuritis, and neuropathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SPROUTING & CNS PLASTICITY IN NOGO & NGR MUTANT MICE Principal Investigator & Institution: Mcgee, Aaron W.; Neurology; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2006 Summary: (provided by applicant): Nogo is a neuronal and myelin membrane protein that inhibits neurite outgrowth and impedes functional recovery after spinal cord injury. Examining the trafficking of nogo and the nogo-66 receptor (NgR) in neuronal cultures will address functions of nogo in regulating axon and dendritic spine formation. Mice lacking a functional gene for nogo display elongation and collateral sprouting of damaged axons, and improved locomotor activity following spinal cord injury (SCI). Understanding the physiological function(s) of nogo in contexts other than SCI may provide opportunities to develop rational interventions for promoting functional
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recovery from CNS injury. In mice lacking nogo, or NgR, analysis of afferent terminations from dorsal roots adjacent regions of the spinal cord denervated by rhizotomy will determine if nogo or NgR can increase the sprouting of uninjured neurons. The plasticity of the vibrissae (whisker) representations (barrels) in somatosensory cortex may be aberrant these mice. Comparing the pattern of barrels by staining, and neuronal structural plasticity with chronic imaging of cortical pyramidal neurons in these mutant mice may elucidate role of nogo and signaling through the NgR in regulating cortical plasticity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEM CELL PLASTICITY AFTER BLASTOCYST IMPLANTATION Principal Investigator & Institution: Recht, Lawrence D.; Professor; Neurology; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Several recent studies indicate that tissue-derived stem cells can not only differentiate into cells of the tissue from which they are obtained, but also those from other tissues. We have been interested in the range of differentiative capacity (which we term plasticity) of CNS derived stem cells and hypothesized that one way to assay this would be to implant these cells into blastocyts and assess incorporation into the resulting mice later in development. Our results indicate a robust incorporation of these cells into extraneural tissues including bone marrow, where they express lineage markers of differentiated hematopoietic cells, bone muscle and GI tract. We believe this model provides a unique insight into stem cell plasticity because of the high efficiency of implantation and production of apparently normal pups. We propose to follow-up our studies by addressing the following specific aims: 1) We will determine whether incorporation of stem cells into blastocysts varies as a function of stem cell subpopulation or type, we will create a retorviral library of neural stem cells to assess whether specific subpopulations exist as well as comparing neural stem cells with marrow stromal cells in their ability to incorporate into blastocysts; 2) We will determine whether incorporation of neural stem cells into other tissues renders them functional by performing bone marrow transplantation of cells obtained from chimeric pups into lethally irradiated mice and assessing whether neural stem cells can repair a embryonically lethal genetic defect in bone; and 3) We will assess whether neural stem cells retain their functional capacity to develop into olfactory interneurons after blastocyst transplantation and determine whether their implantation at the blastocyst stage can repair mice with an absence of myelin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURE/FUNCTION ANALYSIS OF LOW PL CONNEXIN ISOFORMS Principal Investigator & Institution: Hertzberg, Elliot L.; Professor; Neuroscience; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Gap junctions are assemblages of cell-cell channels occurring in regions of cell contact. These channels permit direct intercellular communication by passive diffusion of low molecular weight hydrophilic molecules, including calcium, cyclic nucleotides, inositol phosphates and other signaling molecules. Several gap junction proteins, termed connexins, serve prominent roles in the nervous system. Among these, Connexin43 (Cx43) is expressed at high levels in astrocytes where
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Myelin
they provide a mechanism of spatial buffering of ions and exert a modulatory influence on neuronal activity. Mutations of Cx32, found in myelin, lead to a progressive peripheral neuropathy termed X-linked Charcot-Marie-Tooth disease. Mutations in Cx26 underlie the most common forms of non-syndromic deafness. Interestingly, connexins are the only family of plasma membrane proteins that do not appear to be glycosylated. Preliminary studies of Cxs 43, 32 and 26 indicate that they are significantly more negatively charged than anticipated based upon their sequence and known covalent modifications. That these pI variants are indistinguishable by SDS-PAGE indicates that the molecular basis for acidic pI variants is of low molecular weight. The specific aims of this proposal are to (1) identify this modification and the altered amino acid residues and (2) determine its role in the assembly and functioning of gap junction channels. Our approach to determining the chemical basis of connexin will be biochemical, relying especially on mass spectrometry, and genetic engineering. The role of this modification will be assessed using pharmacology and site-direct mutagenesis. Identification of a low Mr anion covalently attached to connexins might provide the first target for pharmacological intervention in gap junction function. Knowledge of where charged residues exist will profoundly influence modeling studies of connexins and, likely, other membrane proteins, in which alterations of electrostatic interactions play a role in channel selectivity and gating. Many of the experiments will push experimental procedures for use in the study of membrane proteins. Establishing the basis of connexin charge alteration will introduce a new player in chemical modification of proteins and their properties. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SUB-VOXEL TISSUE CHARACTERIZATION WITH IN-VIVO MRI Principal Investigator & Institution: Does, Mark D.; Radiology & Radiological Scis; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2007 Summary: (provided by applicant): The overall aims of this project are to develop and implement novel methods for quantitative, in vivo characterization of tissue by magnetic resonance imaging (MRI). The microscopic compartition of water in tissues reflects potentially important structural properties that may be probed by diverse MRI measurements. In particular, water diffusion and nuclear magnetic resonance (NMR) relaxation cannot be described by single components in many tissues. With some limited success, multiple component characterization of these attributes has been proposed and studied in an attempt to extract specific information about the micro-anatomical water compartments from which they are derived. The further development of efficient and effective methods for acquiring and analyzing subvoxel characteristics promises to be useful for assessing structure and pathophysiology in various tissues, particularly nerve and muscle. The studies proposed herein will provide faster, more accurate, and more informative techniques for compartmental studies using MRI. Experimental studies on model tissues will establish comprehensive and quantitative in vivo descriptions of water diffusion, longitudinal relaxation and transverse relaxation, and how they correlate to each other and the physical compartments from which they are derived. These observations will then be used to design novel MRI methods, which are more specific for depicting tissue microstructure in vivo. One example, amongst others, is the aim to develop rapid and easily implemented MRI methods of visualizing and quantifying myelin content in the brain based on detailed compartmental models of relaxation and diffusion in white matter. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SYNTHESIS AND ASSEMBLY OF BASIC PROTEINS INTO MYELIN Principal Investigator & Institution: Campagnoni, Anthony T.; Professor; None; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-SEP-1985; Project End 31-MAR-2004 Summary: Description ( from the applicant's abstract): Recently, our conception of the two principal myelin protein genes, i.e. the myelin basic protein (MBP) and proteolipid protein (PLP) genes, has begun to change in view of new information about their structure, expression patterns and possible non-myelin related functions of their products. There is a considerable body of evidence to suggest that the PLP/DM20 gene plays roles other than that encoding the major myelin structural proteins in nonmyelinating cells. This could occur either through multiple activities of the "classic" PLP and DM20, or through the existence of other products of the gene that have not yet been identified. We have isolated two new srPLP/DM20 gene products and identified a new exon of the gene. These products are expressed in neurons as well as oligodendrocytes, and they are localized in the somata of oligodendrocytes and neurons and are absent from the myelin sheath. On the basis of these and other preliminary data, we propose the existence of other products of the PLP/DM20 gene in addition to the "classic" and srPLP/DM20 variants. The overall objective of this application is to isolate and identify these other variants of the PLP/DM20 gene and to examine possible non-myelin functions of the "classic" PLP and DM20 as well as the variant products of the gene. These include: (1) identifying and characterizing novel products of the PLP/DM20 gene and examining their cellular and regional localization in the developing nervous system; (2)[re-] evaluating the hypothesis that cell death in the jimpy mutant is due solely to toxic effects of the mutated protein by prepare cell lines stably transfected with normal and variant/mutant PLP/DM20 cDNAs and comparing levels of expression in conditionally-immortalized OL lines on cell survival; and (3) examining aspects of the non-myelin roles of PLP/DM20 gene products. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: T CELL DEMYELINATION
RECEPTORS
INVOLVED
IN
TMEV
INDUCED
Principal Investigator & Institution: Kim, Byung S.; Professor; Microbiology and Immunology; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-MAY-1994; Project End 31-MAR-2004 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 a relevant infectious animal model, an alternative to the experimental autoimmune encephalomyelitis (EAE) system, for studying human multiple sclerosis (MS) in light of the potential viral etiology and similarities in the progression of chronic demyelination. Previously, we have identified major Th epitopes accounting for greater than 85 percent of the Th response to TMEV. In addition, we have identified the Th epitopes (VP1233-250 and VP274-86, but not VP32437) involved in the pathogenesis of demyelination and their association to induce relatively high levels of Th responses. We have further observed that the Jbeta1 region polymorphism is associated with susceptibility to demyelination and that the susceptible H-2Ds MHC locus can override the resistant effect of the TCR beta-chain genotype. Furthermore, we have recently selected spontaneously arising nonpathogenic variant viruses containing a single amino acid substitution at position 244
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within the major Th1 epitope, VP1233-250, resulting in a switch to Th2 response. Moreover, the initial demyelination induced by TMEV infection leads to the development of autoimmune Th response to a major myelin component. Our recent preliminary studies for spectratyping and TCR CDR3 analyses of infiltrating T cells in the CNS indicate that clonal expansion of certain T cell populations is apparent as early as 7 d after viral infection. Some of the major population appear to be persistent throughout the disease course. In comparison with CDR3 sequences of hybridomas with known specificity, these T cells represent virus- and/or autoantigen-reactive populations. Based on these preliminary results, we propose to correlate the TCR repertoire in the CNS with the development of TMEV-induced demyelination. Three specific aims are proposed in this application: (1) Correlation of the TCR repertoire in the CNS with the pathogenesis of TMEV-induced demyelination; (2) Role of virusspecific and autoreactive T cells in the pathogenesis of demyelination; and (3) Influence of additional Vbeta or resistant MHC class I genes in the selection of TCR repertoire in the CNS. We believe that our proposed studies will yield important information on the role of infiltrating T cell populations and their expansion in the pathogenesis of virusinduced, T cell-mediated demyelination, leading to the eventual development of autoimmunity to CNS autoantigens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: T CELL RESPONSE TO MYELIN PROTEOLIPID PROTEIN Principal Investigator & Institution: Kuchroo, Vijay K.; Associate Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JUL-1992; Project End 31-MAR-2006 Summary: (provided by applicant): Proteolipid protein (PLP) is the major protein component of central nervous system (CNS) myelin and is now recognized as a major autoantigen involved in the development of experimental autoimmune encephalomyelitis (EAE), an experimental model for human multiple sclerosis (MS). Just as MS is known to occur in certain human populations at a higher frequency, it is also known that some strains of mice are susceptible (e.g. SJL) while others are resistant (e.g. B10.S), even though the mice are H-2 identical. PLP 139-151 (HSLGKWLGHPDKF) is the dominant antigen for the induction of EAE in SJL mice, and we have found that the number of PLP 139-151 reactive T cells in the naive SJL repertoire is very high (1:20,000). In spite of this the SJL mice do not develop spontaneous EAE. We believe this is because SJL mice possess two different repertoires, that both recognize PLP 139-151, but which differ in their fine specificity and function in that one is pathogenic and the other is protective. We have developed two T cell receptor (TcR) transgenic mice which are representative of each of these repertoires. The transgenic mice expressing a pathogenic TcR develop EAE, whereas the mice expressing a non-pathogenic TcR do not. We have also generated an IAS/PLP 139-151 tetramer which binds and stains pathogenic T cells in transgenic and non-transgenic SJL mice. In this grant we propose to study the role of the two repertoires in the induction and regulation of EAE. We propose to: 1) Study the selection, expansion, differentiation and interplay between the two PLP 139-151 specific T cell repertoires in susceptible and resistant mice. By using the tetramers we will determine a) how the PLP 139-151 specific T cells expand and differentiate and b) how the two PLP 139-151 specific repertoires function in the susceptible-SJL and resistant-B 10.S mice. 2) Determine the cellular basis for the difference in susceptibility to EAE in SJL and B1O.S mice. By using transgenic T cells from the SJL and B10.S mice that express pathogenic TcR we will a) study the role of T cells; b) the role of APCs and their critical molecules (like class II, B7 and IL- 12) in susceptibility/resistance to EAE. 3) Analyze the
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mechanism by which expression of the alternate T cell repertoire specific for PLP 139151 induces protection against EAE. Using the TcR transgenic mice that express the alternate TcR repertoire to PLP 139-151, we will a) determine whether these transgenic mice will develop EAE either spontaneously, of following immunization with the PLP 139-151 or other cross-reactive ligands; b) cross the two transgenic mice expressing pathogenic and protective TcRs and analyze the dual TcR transgenic mice for the development of EAE The results will provide basic information on the mechanism by which PLP specific T cells induce autoimmunity of the CNS and how different repertoires balance each other and regulate development of autoimmunity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: T-CELL FUNCTIONS IN THE INJURED SPINAL CORD Principal Investigator & Institution: Popovich, Phillip G.; Associate Professor; Molecular Virology, Immunology & Medical Genetics; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Spinal cord injury (SCI) triggers a neuroinflammatory reaction that can exacerbate tissue damage and promote repair of injured neurons and glia. Exploitation of immune-mediated repair mechanisms and antagonism of degradative immunological cascades has therapeutic value. Unfortunately, these mechanisms and cellular/humoral cascades remain enigmatic. To date, studies of neuroinflammation after SCI have focused largely on neutrophils, microglia and/or macrophages. However, T-lymphocytes also infiltrate the traumatized spinal cord; yet, their roles in processes of secondary degeneration and repair are poorly defined. Given that T-cells directly influence blood-brain barrier integrity, axonal conduction, extracellular matrix composition, macrophage/microglial function and neuronal/glial survival, activated T-cells undoubtedly affect recovery from SCI. We have demonstrated that SCI primes the activation (i.e., proliferation and cytokine production) of peripheral T-cells and that activated T-cells infiltrate the injury site. How and to what extent these cells influence recovery from SCI is not known. Studies in Aim 1 will evaluate T-cell influences on the normal progression of SCI pathology and functional recovery. A systematic manipulation of all T-cells will be accomplished using nude rats and antibody-mediated depletion of T-cells. In Aim 2, we will determine whether recovery from SCI can be improved by inhibiting CNS myelin-reactive T-cells -cells that we have previously shown exacerbate pathology and impair functional recovery after SCI. Selective depletion of myelin-reactive T-cells will be accomplished using a clinically feasible oral tolerance paradigm. Newer preliminary data has prompted us to also consider whether other (non-myelin reactive) T-cells can be exploited for therapeutic purposes. Accordingly, studies in Aim 3 will determine whether heat shock protein-reactive T-cells can convey neuroprotection and improve recovery from SCI by suppressing acute neuroinflammation. Studies in Aim 4 will explore a suspected mechanism of T-cell mediated injury after SCI, i.e., activation of recruited macrophages. This will be accomplished by macrophage depleting animals with enhanced myelin-reactive T-cell function. The primary hypothesis to be tested in this proposal is that T-cells exert pathological and neuroprotective effects within the injured spinal cord. This functional diversity depends on the phenotype and antigenspecificity of recruited T-cells as well as the cellular and biochemical milieu at the injury site. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE MECHANISMS OF AUTOIMMUNE RESPONSE INITIATION IN MS Principal Investigator & Institution: Markovic-Plese, Silva; Neurology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 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 co-stimulation requirements for the activation and growth characteristics of Tcells 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 ROLE OF B CELLS IN EAE PATHOGENESIS Principal Investigator & Institution: Cross, Dorothy A.; Neurology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Whether B cells, plasma cells and antibody (Ab) play a role in the pathogenesis of MS or its animal model, experimental autoimmune encephalomyelitis (EAE) is controversial. Myelin-specific T cells can transfer EAE to naive recipients, whereas neither B cells nor Abs can transfer EAE. Ab-producing cells are extremely numerous in most active MS lesions and increased amounts of Abs in the spinal fluid are a relatively diagnostic feature of MS. Our data indicate a critical role for B cells in EAE induced by active immunization with the extracellular 120 amino acids of myelin oligodendrocyte glycoprotein (rMOG), but not when disease is induced by a short encephalitogenic peptide (MOG35-55) in C57BL/6 (B6) mice. The hypothesis to be tested is that myelin-specific B cells and their products are critical in the pathogenesis of
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this model of CNS inflammatory demyelination via a role in antigen processing and presentation that focuses the immune response toward encephalitogenic epitopes of MOG. Our studies indicate that rMOG-primed wild-type (WT) B6 T cell lines do not induce EAE in B cell deficient (B-/-) B6 mice, nor do B-/- T cell lines initiated with rMOG-primed T cells transfer EAE to WT or B-/- recipients. These data suggest a complex role for B cells and their products during both the initiation and effector stages of disease. We will determine the mechanisms by which B cells act in rMOG-induced EAE, and whether B cells or Ab or both are involved. Our preliminary data indicate that B-/- mice have a broader response to rMOG, as they recognize an additional MOGepitope by proliferation and cytokine production that WT mice do not recognize. This seems to indicate that B cells or Abs affect MOG processing and presentation to T cells. Guided by these preliminary data, the foremost candidate mechanism to be tested is whether there is a differential processing of MOG by B cells vs other APCs, and whether B cells or their products focus the immune response toward encephalitogenic epitopes of MOG. Experiments will utilize WT B6 mice, B-/- mice on a B6 background, and mice with normal B cells that do not elaborate Ab ("B6/APC"). In Aim 1, the stage(s) of EAE in which B cells play a role will be fully determined. Whether B cells play a critical role in MOG processing and presentation to activate encephalitogenic T cells, using B cells specific for myelin or irrelevant antigens, will be examined in Aim 2a, and whether myelin-specific Abs or non-specific Abs alter MOG processing will be determined in Aim 2b. The remainder of Aim 2 will focus on effects of B cells on other APCs, especially dendritic cells, and on effects of B cells on cytokine and chemokine expression. Methods to alter in humans the number and function of B cells and Abs already exist, making our results potentially applicable to MS therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF IRON IN MYELINATION Principal Investigator & Institution: Connor, James R.; Professor; Neural and Behavioral Science; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2007 Summary: (provided by applicant) Although it is accepted as dogma that iron deficiency during development is associated with hypomyelination, the actual data that led to this concept are minimal. In addition, whether any change in myelin quantity or quality is directly or indirectly mediated by iron has not been established. In this proposal we unite the expertise of foreign investigator, Dr. Pasquini, in myelin analysis with the expertise in iron neurobiology of US investigator, Dr. Connor to address the significant clinical question of the role of iron in myelin production and maintenance. The World Health Organization has identified iron deficiency as the number one health disorder. Argentina, the foreign site in this application, has an incidence of iron deficiency in infants that reaches 60%. Iron deficiency is not only from dietary insufficiency, but also stems from the high incidence of parasitic infections in many Latin American children. Three novel animal models are presented in this proposal for analysis, each representing a unique defect in iron metabolism. There are three aims in the proposal. The working hypothesis that unites the three unique animal models is that inadequate iron availability is associated with a uniform decrease in all components of myelin. If the outcome is consistent with our hypothesis, the data will indicate that the role of iron in myelin production is to serve as a metabolic fuel to support the energy required to maintain myelin. If the data are inconsistent with our hypothesis and there are specific components of myelin that are affected relative to the others, the data will suggest a
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specific role for iron in the synthesis or processing of that component. The future directions would be to move to a cell culture model to directly test the effect of iron. The second aim will use the neonatal hypoxic/ischemic insult model to test the hypothesis that iron status of white matter affects the outcome of the insult. The third aim will test the hypothesis that intracranial injections of transferrin, the iron mobilization protein, will correct myelin deficits in the experimental models used in Aims 1 and 2. The data generated from the studies in this proposal will be novel and will lead to new insights into the specific role of iron in myelin production, maintenance and damage. The data could lead to a possible therapeutic strategy for dysmyelinating disorders. The proposed research will be primarily performed in Argentina through the University of Buenos Aries as an extension of NIH grants PO1 HD30704-08, P01 and HD39386-03. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE NEUROTROPHINS
TRAFFICKING
OF
MYELIN
PROTEINS
AND
Principal Investigator & Institution: Shooter, Eric M.; Neurobiology; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-DEC-1975; Project End 31-MAR-2004 Summary: (From the applicant's abstract): Neurons and glia, like other cells, have highly regulated mechanisms for ensuring that proteins, once synthesized, are correctly sorted, stored, inserted into membranes or released from the cell. When one or more of these mechanisms is faulty the cell is stressed and a disease may result. The two systems that will be studied are the intracellular transport and fate of a myelin protein, (PMP22), in Schwann cells and of neurotrophins in CNS neurons. Mutations in duplications or deletions in the PMP22 gene are the cause of peripheral neuropathies. Aberrant trafficking of neurotrophins may contribute to degeneration of CNS neurons. PMP22 is a homodimer that forms heterodimers with a mutant PMP22 found in the Trembler-J mouse, an animal model for Charcot-Marie-Tooth (CMT) disease. Whether heterodimer formation occurs with other PMP22 mutants and what are the consequences in terms of trafficking and insertion into myelin will be determined. What are mechanisms that divert mutant PMP22s from their normal pathways and where and how are these proteins degraded before or during myelination? The experiments on the trafficking of epitope tagged or untagged PMP22 will be analyzed in Schwann or COS cells in culture, in myelinating co-cultures and in Trembler-J nerves. The involvement of neurotrophins in CNS function suggests that they are released from neurons, at least in part by regulatable pathways. The sorting and secretion of epitope-tagged neurotrophins by constituivie or regulatable pathways will be examined in cortical, hippocampal and retinal ganglion neurons in culture using Adenovirus mediated gene transfer. The sorting and trafficking of neurotrophins will be followed in the hippocampal and entorhinal cortex and basal forebrain either in transgenic mice expressing epitopetagged neurotrophins or in tissue from animals stereotactically injected with Adeno- or Adneoassociated virus encoding the neurotrophins. The effect of short or long term exposure of hippocampal and cortical neuron dendrites to BDNF in vivo will be determined. Finally, whether NT-3 can promote axonal survival in two animal models of demyelination will be determined. Overexpression of NT-3 in muscle will be achieved through mating of a transgenic myo-NT-3 with either a PMP22-deficient mouse or the or the Trembler-J mouse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TOLERENCE INDUCED BY I.V. MBP IN EAE Principal Investigator & Institution: Rostami, Abdolmohamad; Professor and Chair; Neurology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-MAR-2003 Summary: adapted from applicant's abstract): Experimental allergic encephalomyelitis (EAE) is an autoimmune demyelinating disease that serves as a mo] -for the human disease Multiple Sclerosis. In EAE, the proinflammatory myelin-reactive T cells that mediate clinical disease represent the primary targets for therapeutic intervention. Intravenous administration of Myelin: Basic Protein prior to immunization or during ongoing EAE results in tolerance induction (i.v. tolerance) and diminished clinical disease manifestations. This tolerance is mediated by multiple mechanisms, including immune deviation (Thl - Th2 shift), induction of apoptotic cell death, and decreased trafficking of activated pro-inflammatory cells to the central nervous system (CNS). In the proposed studies, we will focus on the immunological outcome of i.v. tolerance in the CNS. Infiltrating mononuclear cells from the CNS of tolerized and nontolerized animals will be obtained and analyzed with multiparametric flow cytometric analysis. We will compare the activation profiles, expression of costimulatory ligands, apoptosis and the production of the various pro-inflammatory (TNF-oc, IL-2, and IFN- about) and anti-inflammatory cytokines by the defined mononuclear cell populations (CD4+, CD8+, CDllb+, CDl9+ or NKl.l+ populations) infiltrating the CNS of tolerized and nontolerized animals. In addition, we will compare CNS-derived cells to those obtained from the periphery (spleen and lymph nodes). Trafficking and activation of transgenic T cells specific for MBP, as well as apoptosis induction, in tolerized and nontolerized animals will also be assessed. Finally, we will assess the mechanism whereby i.v. tolerance regulates chemokines and chemokine receptors systemically and locally within the CNS. These studies will further elucidate the mechanisms by which i.v. MBP induces tolerance and suppresses clinical disease in EAE and will provide a novel method for analyzing the migration and functional status of infiltrating cells in the CNS in particular and in target organs of other autoimmune diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSDUCTION MECHANISMS IN GROWTH CONE GUIDANCE Principal Investigator & Institution: Poo, Mu-Ming; Professor; Molecular and Cell Biology; University of California Berkeley Berkeley, Ca 947205940 Timing: Fiscal Year 2002; Project Start 01-SEP-1988; Project End 31-MAY-2004 Summary: (Verbatim from the Applicant's Abstract): Diffusible or substrate-bound guidance molecules are responsible for guiding the growth of axons towards their target cells in the developing nervous system. Several families of guidance molecules and their receptors have been identified, but the signaling mechanisms in the neuronal cytoplasm are largely unknown. In this project, we propose to carry out in vitro studies of signal transduction events underlying the turning response of the growth cone of cultured Xenopus spinal neurons induced by microscopic gradients of three guidance molecules: netrin-1, brain-derived neurotrophic factor (BDNF), and a secreted form of myelinassociated glycoprotein (MAG). In part I, we will carry out quantitative analysis of the turning responses of the growth cone in gradients of these guidance molecules and the modulatory actions of extracellular matrix components and electrical activity. We will also examine the hypothesis that similar cellular mechanisms are used by the growth cone to detect gradients of guidance cues in either diffusible or substrate-bound form. In part II, we will examine the role of calcium and cAMP gradients within the growth cone
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cytoplasm in mediating the growth cone turning responses, and determine the relationship between calcium and cAMP signals induced by these guidance molecules. In part III, we will examine various stages of cytoplasmic signaling from receptor activation to cytoskeleton rearrangement. We will study the mechanisms linking receptor activation to cytoplasmic signaling, the role of the Rho-family of small GTPases, filopodial activity and the dynamics of actin filaments and microtubules during the early phase of the turning response. In part IV, we will characterize the phenomenon of adaptation and resensitization of the growth cone response during its pathfinding towards a source of netrin-1 or BDNF and examine potential underlying mechanisms. These studies offer a unique opportunity in elucidating the cellular transduction events underlying the action of three defined guidance molecules. The results will contribute to our understanding of the normal development of the nervous system and provide insights into potential therapeutic approaches in promoting nerve regeneration after injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TREATMENT OF MULTIPLE SCLEROSIS MODEL WITH RNA PADLOCKS Principal Investigator & Institution: Johnston, Brian H.; President and Ceo; Somagenics, Inc. Santa Cruz, Ca 95060 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2005 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 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
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Project Title: USING BIOCHEMICAL MARKERS TO DETECT ABUSIVE HEAD TRAUMA Principal Investigator & Institution: Berger, Rachel P.; Professor; Children's Hosp Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 152132583 Timing: Fiscal Year 2003; Project Start 14-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Child abuse is a leading cause of serious traumatic brain injury (TBI) in infants and young children. Proper diagnosis of abusive head trauma (AHT) is difficult even for experienced, astute physicians. Misdiagnosis is common and can have catastrophic medical consequences for patients. Aside from increased awareness, there are currently no established strategies or diagnostic tests to help physicians properly identify AHT. A screening test that could alert physicians to the possibility of AHT and thereby aid in proper and timely diagnosis, could have an enormous impact. Biochemical markers of brain injury are released from the brain after TBI and diffuse into cerebrospinal fluid (CSF) and/or serum, where their concentrations can be measured. CSF and serum concentrations of three of these biochemical markers -neuron-specific enolase (NSE), S100B, and myelin-basic protein (MBP) - are sensitive indicators of mild, moderate and severe TBI in adults and children. These markers may therefore have the potential to act as diagnostic adjuncts to complement physician acumen in properly diagnosing AHT. Specific Aim 1 is to determine the sensitivity and specificity of serum NSE concentrations for detecting AHT in infants at increased risk of AHT and to determine whether the use of a panel of NSE, S100B and MBP improves sensitivity or specificity when compared with NSE as a single marker. Specific Aim 2 is to determine whether increases in CSF and serum NSE, S100B and/or MBP are specific to TBI or whether their concentrations can be affected by four non-traumatic neurological insults: hypoxic-ischemic encephalopathy, meningitis, progressive encephalopathy and seizures. The candidate is a pediatrician at Children's Hospital of Pittsburgh (CHP). This Mentored Career Development Award will allow the candidate to pursue a unique and highly integrated mentored program in pediatric neurotrauma and child abuse. Pittsburgh is an ideal environment for this type of program because of the resources of CHP, the Safar Center for Resuscitation Research and The Child Advocacy Center. Dr. Patrick Kochanek, the primary mentor for this award, is internationally recognized for his work in the field of pediatric TBI, has served as a mentor on multiple K awards and is the PI of an NICHD-funded training grant (T32) in pediatric neurointensive care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: WHITE MATTER ABNORMALITIES IN SCHIZOPHRENIA Principal Investigator & Institution: Davis, Kenneth L.; Professor and Chairman; Psychiatry; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The proposed Mt. Sinai Conte Center for the Neuroscience of Mental Disorders (CCNMD) is designed to be a highly focused effort to elucidate the role of white matter, oligodendrocytes and myelin in schizophrenia. This proposal is informed by increasing evidence of white matter abnormalities in schizophrenia in a variety of areas of scientific exploration. A failure in connectivity has been demonstrated to have a role in schizophrenia. Myelination and those factors that affect myelination, such as the function of oligodendroglia, are critical processes that could profoundly affect neuronal connectivity, especially given the diffuse distribution
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of oligodendrocytes and the widespread distribution of brain regions that have been implicated in schizophrenia. Multiple lines of evidence now converge to implicate oligodendroglia and myelin in schizophrenia. Imaging and neurocytochemical evidence, similarities with demyelinating diseases, age-related changes in white matter, myelin-related gene abnormalities, and morphological abnormalities in the oligodendroglia demonstrated in schizophrenic brains, all contribute to a hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome (see overview and specific projects for detailed references). A broad set of methodologies and expertise will be brought to bear on the questions the CCNMD will pursue, including neuroanatomy, neuroimaging, molecular biology, molecular genetics, neuropsychology, phenomenology, statistics, and data management. The CCNMD is comprised of 4 Cores: Core A: Administrative; Core B: Clinical; Core C: Brain Bank; Core D: Data Management and Statistics. The projects of the CCNMD include: Project 1 which will quantify alterations in both numbers of and spatial distribution of oligodendroglia in the brains of schizophrenic patients, focusing on cortical, thalamic, and predominantly white matter areas. Project 2 is based on microarray findings by the laboratory of Dr. Buxbaum of decreased expression of 6 myelin-related genes in the dorsolateral prefrontal cortex of a subgroup of relatively treatment refractory patients. Project 3 examines genes involved in myelination for DNA sequence variation affecting protein sequence and expression in order to assess the possibility that some of these variants are involved in determining susceptibility to schizophrenia. Project 4 brings powerful neuroimaging techniques- diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI)- to the study of white matter in schizophrenia. Project 5 applies proton magnetic resonance spectroscopy (1 MRS) to white matter areas in the brains of schizophrenic patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: WHITE MATTER EXCITOTOXICITY Principal Investigator & Institution: Stys, Peter K.; Ottawa Health Research Institute 725 Parkdale Ave Ottawa, On Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2003 Summary: (Verbatim from the Applicant's Abstract) Axonal connections within the white matter of the central nervous system play the crucial role of transmitting electrical signals. Common and devastating diseases such as stroke, spinal cord injury and multiple sclerosis almost always cause damage to white matter structures, yet far less is known about the pathophysiology of white matter injury. Despite the lack of synaptic machinery in this tissue, early reports indicate that glutamate-dependent excitotoxic mechanisms play an important role in mediating white matter injury. This application aims to examine in greater detail how endogenous excitotoxins damage myelinated axons. Using the in vitro rat optic nerve and spinal dorsal columns as well studied models of isolated white matter, electrophysiology and immunchistochemistry for injury markers in myelin, axoplasm and glial cytoplasm will be used to examine the effects of exogenously applied excitotoxins such as glutamate, kainite, and ANIPA. Selective inhibitors will be applied to dissect out which subclass of ionotropic glutamate receptor(s) are responsible for injury. Abnormal fluxes of Na and Ca ions will be examined using ion-sensitive dyes and confocal microscopy to see which compartments (myelin, axon cylinder, glia) suffer excess accumulations as a result of glutamate receptor activation. Total (free + bound) elemental analysis of Na and Ca will be performed with electron probe x-ray microanalysis as the ionized fraction may
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underestimate the total amount of Na or Ca entry and may be a more reliable determinant of subsequent functional injury. The role of endogenous glutamate, released non-synaptically by in vitro anoxia or ischemia, will be studied using a simlar approach, with the goal of determining which sub cellular compartments suffer ionic overload and structural injury that is dependent on activation of glutamate receptors. Immunchistochemistry and high-resolution confocal microscopy, coupled with digital image processing techniques for resolution enhancement and 3-dimensional reconstruction, will be applied to examine the distribution of glutamate receptors in white matter using specific antisera. By elucidating glutamate-dependent injury mechanisms in CNS white matter, it is hoped that an important new avenue wil1 become available for pharmacological protection of this key tissue. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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 “myelin” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for myelin in the PubMed Central database: •
A developmentally regulated DNA-binding protein from mouse brain stimulates myelin basic protein gene expression. by Haas S, Gordon J, Khalili K.; 1993 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=359703
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A leucine-to-proline mutation in the putative first transmembrane domain of the 22kDa peripheral myelin protein in the trembler-J mouse. by Suter U, Moskow JJ, Welcher AA, Snipes GJ, Kosaras B, Sidman RL, Buchberg AM, Shooter EM.; 1992 May 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=49086
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A myelin protein is encoded by the homologue of a growth arrest-specific gene. by Welcher AA, Suter U, De Leon M, Snipes GJ, Shooter EM.; 1991 Aug 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=52260
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A single amino acid change in a myelin basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis. by Smilek DE, Wraith DC, Hodgkinson S, Dwivedy S, Steinman L, McDevitt HO.; 1991 Nov 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=52772
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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 small number of residues in the class II molecule I-Au confer the ability to bind the myelin basic protein peptide Ac1-11. by Pearson CI, Gautam AM, Rulifson IC, Liblau RS, McDevitt HO.; 1999 Jan 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15116
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A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens. by Nicholson LB, Murtaza A, Hafler BP, Sette A, Kuchroo VK.; 1997 Aug 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23155
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Abnormal compact myelin in the myelin-deficient rat: absence of proteolipid protein correlates with a defect in the intraperiod line. by Duncan ID, Hammang JP, Trapp BD.; 1987 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299056
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Alteration of lipid-phase behavior in multiple sclerosis myelin revealed by wideangle x-ray diffraction. by Chia LS, Thompson JE, Moscarello MA.; 1984 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=345024
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Amino acid incorporation into proteolipid of myelin in vitro. by Klee CB, Sokoloff L.; 1965 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=301364
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Amino Acid Sequence of the Basic Protein of the Myelin Membrane. by Eylar EH.; 1970 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=283369
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An Apical-Type Trafficking Pathway Is Present in Cultured Oligodendrocytes but the Sphingolipid-enriched Myelin Membrane Is the Target of a Basolateral-Type Pathway. by de Vries H, Schrage C, Hoekstra D.; 1998 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25288
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Analysis of the proximal transcriptional element of the myelin basic protein gene. by Devine-Beach K, Haas S, Khalili K.; 1992 Feb 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=310421
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Analysis of transcription control elements of the mouse myelin basic protein gene in HeLa cell extracts: demonstration of a strong NFI-binding motif in the upstream region. by Tamura T, Miura M, Ikenaka K, Mikoshiba K.; 1988 Dec 23; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=339057
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Antigen therapy eliminates T cell inflammation by apoptosis: Effective treatment of experimental autoimmune neuritis with recombinant myelin protein P2. by Weishaupt A, Gold R, Gaupp S, Giegerich G, Hartung HP, Toyka KV.; 1997 Feb 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19792
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Anti-peripheral myelin antibody in patients with demyelinating neuropathy: quantitative and kinetic determination of serum antibody by complement component 1 fixation. by Koski CL, Humphrey R, Shin ML.; 1985 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=397156
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Anti-peripheral nerve myelin antibodies in Guillain-Barre syndrome bind a neutral glycolipid of peripheral myelin and cross-react with Forssman antigen. by Koski CL, Chou DK, Jungalwala FB.; 1989 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303980
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Association of calnexin with mutant peripheral myelin protein-22 ex vivo: A basis for "gain-of-function" ER diseases. by Dickson KM, Bergeron JJ, Shames I, Colby J, Nguyen DT, Chevet E, Thomas DY, Snipes GJ.; 2002 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125041
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Association of JC Virus Large T Antigen with Myelin Basic Protein Transcription Factor (MEF-1/Pur[alpha]) in Hypomyelinated Brains of Mice Transgenically Expressing T Antigen. by Tretiakova A, Otte J, Croul SE, Kim JH, Johnson EM, Amini S, Khalili K.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112670
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Autoreactive CD8+ T-cell responses to human myelin protein-derived peptides. by Tsuchida T, Parker KC, Turner RV, McFarland HF, Coligan JE, Biddison WE.; 1994 Nov 8; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=45125
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Binding of myelin basic protein peptides to human histocompatibility leukocyte antigen class II molecules and their recognition by T cells from multiple sclerosis patients. by Valli A, Sette A, Kappos L, Oseroff C, Sidney J, Miescher G, Hochberger M, Albert ED, Adorini L.; 1993 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=287995
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Characterization of mouse myelin basic protein messenger RNAs with a myelin basic protein cDNA clone. by Zeller NK, Hunkeler MJ, Campagnoni AT, Sprague J, Lazzarini RA.; 1984 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=344601
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Characterization of myelin proteolipid mRNAs in normal and jimpy mice. by Gardinier MV, Macklin WB, Diniak AJ, Deininger PL.; 1986 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=367136
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Comparison of Weigert Stained Sections with Unfixed, Unstained Sections for Study of Myelin Sheaths. by Richter CP, Warner CL.; 1974 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=388058
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Components in multiple sclerosis cerebrospinal fluid that are detected by radioimmunoassay for myelin basic protein. by Carson JH, Barbarese E, Braun PE, McPherson TA.; 1978 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=392465
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Copolymer 1 acts against the immunodominant epitope 82 --100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. by Aharoni R, Teitelbaum D, Arnon R, Sela M.; 1999 Jan 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15188
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Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis. by Aharoni R, Teitelbaum D, Sela M, Arnon R.; 1997 Sep 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23498
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Cross-reactions and specificities of monoclonal antibodies against myelin basic protein and against the synthetic copolymer 1. by Teitelbaum D, Aharoni R, Sela M, Arnon R.; 1991 Nov 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=52751
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Degradation of basic protein in myelin by neutral proteases secreted by stimulated macrophages: A possible mechanism of inflammatory demyelination. by Cammer W, Bloom BR, Norton WT, Gordon S.; 1978 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=411512
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Density of sodium channels in mammalian myelinated nerve fibers and nature of the axonal membrane under the myelin sheath. by Ritchie JM, Rogart RB.; 1977 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=393228
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Development and maturation of central nervous system myelin: Comparison of immunohistochemical localization of proteolipid protein and basic protein in myelin and oligodendrocytes. by Hartman BK, Agrawal HC, Agrawal D, Kalmbach S.; 1982 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=346609
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Developmental regulation of myelin basic protein in dispersed cultures. by Barbarese E, Pfeiffer SE.; 1981 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=319254
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Differential aggregation of the Trembler and Trembler J mutants of peripheral myelin protein 22. by Tobler AR, Liu N, Mueller L, Shooter EM.; 2002 Jan 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117586
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Differential regulation of oligodendrocyte markers by glucocorticoids: posttranscriptional regulation of both proteolipid protein and myelin basic protein and transcriptional regulation of glycerol phosphate dehydrogenase. by Kumar S, Cole R, Chiappelli F, de Vellis J.; 1989 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=297935
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Differentiation-specific regulation of Schwann cell expression of the major myelin glycoprotein. by Poduslo JF, Windebank AJ.; 1985 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=390679
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Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells--specificity
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and promiscuity. by Fridkis-Hareli M, Teitelbaum D, Gurevich E, Pecht I, Brautbar C, Kwon OJ, Brenner T, Arnon R, Sela M.; 1994 May 24; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=43891 •
Disruption of the compacted myelin sheath of axons of the central nervous system in proteolipid protein-deficient mice. by Boison D, Stoffel W.; 1994 Nov 22; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=45301
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Dominant-Negative Action of the Jimpy Mutation in Mice Complemented with an Autosomal Transgene for Myelin Proteolipid Protein. by Schneider A, Griffiths IR, Readhead C, Nave K.; 1995 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41961
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Expression and crystallization of the complex of HLA-DR2 (DRA, DRB1*1501) and an immunodominant peptide of human myelin basic protein. by Gauthier L, Smith KJ, Pyrdol J, Kalandadze A, Strominger JL, Wiley DC, Wucherpfennig KW.; 1998 Sep 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21725
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Expression of specific mRNAs during adipose differentiation: identification of an mRNA encoding a homologue of myelin P2 protein. by Bernlohr DA, Angus CW, Lane MD, Bolanowski MA, Kelly TJ Jr.; 1984 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=391726
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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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Fulminant spontaneous autoimmunity of the central nervous system in mice transgenic for the myelin proteolipid protein-specific T cell receptor. by Waldner H, Whitters MJ, Sobel RA, Collins M, Kuchroo VK.; 2000 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16253
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Functional breakdown of the lipid bilayer of the myelin membrane in central and peripheral nervous system by disrupted galactocerebroside synthesis. by Bosio A, Binczek E, Stoffel W.; 1996 Nov 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24084
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Gene therapy in allergic encephalomyelitis using myelin basic protein-specific T cells engineered to express latent transforming growth factor-[beta]1. by Chen LZ, Hochwald GM, Huang C, Dakin G, Tao H, Cheng C, Simmons WJ, Dranoff G, Thorbecke GJ.; 1998 Oct 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22862
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Glucocorticoids and progestins signal the initiation and enhance the rate of myelin formation. by Chan JR, Phillips LJ II, Glaser M.; 1998 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27916
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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/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=44037
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Identification of a cDNA coding for a fifth form of myelin basic protein in mouse. by Newman S, Kitamura K, Campagnoni AT.; 1987 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=304321
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Identification of an Embryonic Isoform of Myelin Basic Protein That is Expressed Widely in the Mouse Embryo. by Mathisen PM, Pease S, Garvey J, Hood L, Readhead C.; 1993 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47726
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Identification of prelarge and presmall basic proteins in mouse myelin and their structural relationship to large and small basic proteins. by Barbarese E, Braun PE, Carson JH.; 1977 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=431560
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Identification of the gene encoding Brain Cell Membrane Protein 1 (BCMP1), a putative four-transmembrane protein distantly related to the Peripheral Myelin Protein 22 / Epithelial Membrane Proteins and the Claudins. by Christophe-Hobertus C, Szpirer C, Guyon R, Christophe D.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=35279
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Identification of three forms of human myelin basic protein by cDNA cloning. by Kamholz J, de Ferra F, Puckett C, Lazzarini R.; 1986 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=323864
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Immunocytochemical localization of rat peripheral nervous system myelin proteins: P2 protein is not a component of all peripheral nervous system myelin sheaths. by Trapp BD, McIntyre LJ, Quarles RH, Sternberger NH, Webster HD.; 1979 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=383866
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Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia. by Becker KJ, McCarron RM, Ruetzler C, Laban O, Sternberg E, Flanders KC, Hallenbeck JM.; 1997 Sep 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23514
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Individual exons encode the integral membrane domains of human myelin proteolipid protein. by Diehl HJ, Schaich M, Budzinski RM, Stoffel W.; 1986 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=387231
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Infection with Mycobacterium bovis BCG Diverts Traffic of Myelin Oligodendroglial Glycoprotein Autoantigen-Specific T Cells Away from the Central Nervous System and Ameliorates Experimental Autoimmune Encephalomyelitis. by Sewell DL, Reinke EK, Co DO, Hogan LH, Fritz RB, Sandor M, Fabry Z.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164279
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Integral membrane proteins significantly decrease the molecular motion in lipid bilayers: a deuteron NMR relaxation study of membranes containing myelin proteolipid apoprotein. by Meier P, Sachse JH, Brophy PJ, Marsh D, Kothe G.; 1987 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=304944
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Interactions of dicyclohexylcarbodiimide with myelin proteolipid. by Lin LF, Lees MB.; 1982 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=345869
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Involvement of distinct murine T-cell receptors in the autoimmune encephalitogenic response to nested epitopes of myelin basic protein. by Sakai K, Sinha AA, Mitchell DJ, Zamvil SS, Rothbard JB, McDevitt HO, Steinman L.; 1988 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282508
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Jimpy mutant mouse: a 74-base deletion in the mRNA for myelin proteolipid protein and evidence for a primary defect in RNA splicing. by Nave KA, Lai C, Bloom FE, Milner RJ.; 1986 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=387116
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Metabolism of peripheral nerve myelin in experimental diabetes. by Spritz N, Singh H, Marinan B.; 1975 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=301851
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Molecular basis for heterosis for myelin basic protein content in mice. by Miskimins R, Ebato H, Seyfried TN, Yu RK.; 1986 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=323111
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Molecular characterization of antibody specificities against myelin /oligodendrocyte glycoprotein in autoimmune demyelination. by von Budingen HC, Hauser SL, Fuhrmann A, Nabavi CB, Lee JI, Genain CP.; 2002 Jun 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123046
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Monoclonal antibody specific for myelin glycoprotein P0: derivation and characterization. by Franko MC, Koski CL, Gibbs CJ Jr, McFarlin DE, Gajdusek DC.; 1982 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=346474
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Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder. by Hudson LD, Puckett C, Berndt J, Chan J, Gencic S.; 1989 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=298228
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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; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=54873
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Myelin basic protein demonstrated immunocytochemically in oligodendroglia prior to myelin sheath formation. by Sternberger NH, Itoyama Y, Kies MW, Webster HD.; 1978 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=392586
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Myelin-associated glycoprotein demonstrated immunocytochemically in myelin and myelin-forming cells of developing rat. by Sternberger NH, Quarles RH, Itoyama Y, Webster HD.; 1979 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=383284
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Nuclear proteins in mouse brain cells bind specifically to the myelin basic protein regulatory region. by Lashgari MS, Devine-Beach K, Haas S, Khalili K.; 1990 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296918
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Oral Tolerance in Myelin Basic Protein T-Cell Receptor Transgenic Mice: Suppression of Autoimmune Encephalomyelitis and Dose-Dependent Induction of Regulatory Cells. by Chen Y, Inobe J, Kuchroo VK, Baron JL, Janeway CA, Weiner HL.; 1996 Jan 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40243
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Pelizaeus-Merzbacher disease: a valine to phenylalanine point mutation in a putative extracellular loop of myelin proteolipid. by Pham-Dinh D, Popot JL, Boespflug-Tanguy O, Landrieu P, Deleuze JF, Boue J, Jolles P, Dautigny A.; 1991 Sep 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=52341
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Peripheral myelin protein 22 is a constituent of intercellular junctions in epithelia. by Notterpek L, Roux KJ, Amici SA, Yazdanpour A, Rahner C, Fletcher BS.; 2001 Dec 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64694
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Plasma cell dyscrasia and peripheral neuropathy: identification of the myelin antigens that react with human paraproteins. by Latov N, Braun PE, Gross RB, Sherman WH, Penn AS, Chess L.; 1981 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=349211
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Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. by Hauben E, Agranov E, Gothilf A, Nevo U, Cohen A, Smirnov I, Steinman L, Schwartz M.; 2001 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=209402
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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/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=52672
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Production of Tumor Necrosis Factor and Other Proinflammatory Cytokines by Human Mononuclear Phagocytes Stimulated with Myelin P2 Protein. by Baron P, Constantin G, D'Andrea A, Ponzin D, Scarpini E, Scarlato G, Trinchieri G, Rossi F, Cassatella MA.; 1993 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46521
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Progesterone Synthesized by Schwann Cells during Myelin Formation Regulates Neuronal Gene Expression. by Chan JR, Rodriguez-Waitkus PM, Ng BK, Liang P, Glaser M.; 2000 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14919
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Rapid and Transient Activation of a Myelin Basic Protein Kinase in Tobacco Leaves Treated with Harpin from Erwinia amylovora. by Adam AL, Pike S, Hoyos ME, Stone JM, Walker JC, Novacky A.; 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=158546
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Rapid preimplantation detection of mutant (shiverer) and normal alleles of the mouse myelin basic protein gene allowing selective implantation and birth of live young. by Gomez CM, Muggleton-Harris AL, Whittingham DG, Hood LE, Readhead C.; 1990 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=54139
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Reactivity to myelin antigens in multiple sclerosis. Peripheral blood lymphocytes respond predominantly to myelin oligodendrocyte glycoprotein. by Kerlero de Rosbo N, Milo R, Lees MB, Burger D, Bernard CC, Ben-Nun A.; 1993 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=288456
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Recombination within the myelin basic protein gene created the dysmyelinating shiverer mouse mutation. by Molineaux SM, Engh H, de Ferra F, Hudson L, Lazzarini RA.; 1986 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=386755
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Regulatory CD8+ T cells fine-tune the myelin basic protein-reactive T cell receptor V[beta] repertoire during experimental autoimmune encephalomyelitis. by Jiang H, Curran S, Ruiz-Vazquez E, Liang B, Winchester R, Chess L.; 2003 Jul 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166237
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Restoration of myelin formation by a single type of myelin basic protein in transgenic shiverer mice. by Kimura M, Sato M, Akatsuka A, Nozawa-Kimura S, Takahashi R, Yokoyama M, Nomura T, Katsuki M.; 1989 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=297684
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Restricted T-cell receptor V beta gene usage by myelin basic protein-specific T-cell clones in multiple sclerosis: predominant genes vary in individuals. by Ben-Nun A, Liblau RS, Cohen L, Lehmann D, Tournier-Lasserve E, Rosenzweig A, Zhang JW, Raus JC, Bach MA.; 1991 Mar 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=51253
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Schwann cell expression of a major myelin glycoprotein in the absence of myelin assembly. by Poduslo JF, Berg CT, Dyck PJ.; 1984 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=345022
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Schwann-cell differentiation in clonal cultures of the neural crest, as evidenced by the anti-Schwann cell myelin protein monoclonal antibody. by Dupin E, Baroffio A, Dulac C, Cameron-Curry P, Le Douarin NM.; 1990 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=53422
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Short-Lived Complexes between Myelin Basic Protein Peptides and IAk. by Mason K, McConnell HM.; 1994 Dec 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45458
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Small basic proteins of myelin from central and peripheral nervous systems are encoded by the same gene. by Mentaberry A, Adesnik M, Atchison M, Norgard EM, Alvarez F, Sabatini DD, Colman DR.; 1986 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=323021
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Specific Binding of Peroxidase-Labeled Myelin Basic Protein in Allergic Encephalomyelitis. by Johnson AB, Wisniewski HM, Raine CS, Eylar EH, Terry RD.; 1971 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=389503
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Specific inhibition of the T-cell response to myelin basic protein by the synthetic copolymer Cop 1. by Teitelbaum D, Aharoni R, Arnon R, Sela M.; 1988 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282850
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Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein. by Breithaupt C, Schubart A, Zander H, Skerra A, Huber R, Linington C, Jacob U.; 2003 Aug 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=170938
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Structure of Human T-Cell Receptors Specific for an Immunodominant Myelin Basic Protein Peptide: Positioning of T-Cell Receptors on HLA-DR2/Peptide Complexes. by Wucherpfennig KW, Hafler DA, Strominger JL.; 1995 Sep 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41074
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Study of the expression of myelin proteolipid protein (lipophilin) using a cloned complementary DNA. by Naismith AL, Hoffman-Chudzik E, Tsui LC, Riordan JR.; 1985 Oct 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=322052
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Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigen-specific triggering. by Miller A, Lider O, Roberts AB, Sporn MB, Weiner HL.; 1992 Jan 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=48249
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Synthetic copolymer 1 inhibits human T-cell lines specific for myelin basic protein. by Teitelbaum D, Milo R, Arnon R, Sela M.; 1992 Jan 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=48191
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T cells in the lesion of experimental autoimmune encephalomyelitis. Enrichment for reactivities to myelin basic protein and to heat shock proteins. by Mor F, Cohen IR.; 1992 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=443401
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The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis. by Clements CS, Reid HH, Beddoe T, Tynan FE, Perugini MA, Johns TG, Bernard CC, Rossjohn J.; 2003 Sep 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=196926
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The Human Myelin Basic Protein Gene is Included within a 179-Kilobase Transcription Unit: Expression in the Immune and Central Nervous Systems. by Pribyl TM, Campagnoni CW, Kampf K, Kashima T, Handley VW, McMahon J, Campagnoni AT.; 1993 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47844
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The myelin basic protein gene is expressed in differentiated blood cell lineages and in hemopoietic progenitors. by Marty MC, Alliot F, Rutin J, Fritz R, Trisler D, Pessac B.; 2002 Jun 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124388
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The Sp1 Family of Transcription Factors Is Involved in p27Kip1-Mediated Activation of Myelin Basic Protein Gene Expression. by Wei Q, Miskimins WK, Miskimins R.; 2003 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156141
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The structure of bovine brain myelin proteolipid and its organization in myelin. by Laursen RA, Samiullah M, Lees MB.; 1984 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=345183
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Tissue-specific in vitro transcription from the mouse myelin basic protein promoter. by Tamura T, Aoyama A, Inoue T, Miura M, Okano H, Mikoshiba K.; 1989 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=362786
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Tracing Myelin Protein Zero (P0) in vivo by construction of P0-GFP fusion proteins. by Ekici AB, Oezbey S, Fuchs C, Nelis E, Van Broeckhoven C, Schachner M, Rautenstrauss B.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139994
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Transformation of Human T-Cell Clones by Herpesvirus Saimiri: Intact Antigen Recognition by Autonomously Growing Myelin Basic Protein-Specific T Cells. by Weber F, Meinl E, Drexler K, Czlonkowska A, Huber S, Fickenscher H, MullerFleckenstein I, Fleckenstein B, Wekerle H, Hohlfeld R.; 1993 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47919
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Treatment of Experimental Autoimmune Encephalomyelitis by Feeding Myelin Basic Protein Conjugated to Cholera Toxin B Subunit. by Sun J, Rask C, Olsson T, Holmgren J, Czerkinsky C.; 1996 Jul 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38959
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UV Irradiation-Induced Apoptosis Leads to Activation of a 36-kDa Myelin Basic Protein Kinase in HL-60 Cells. by Lu ML, Sato M, Cao B, Richie JP.; 1996 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38580
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Vaccination with a Nogo-A-derived peptide after incomplete spinal-cord injury promotes recovery via a T-cell-mediated neuroprotective response: Comparison with other myelin antigens. by Hauben E, Ibarra A, Mizrahi T, Barouch R, Agranov E, Schwartz M.; 2001 Dec 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=65002
The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with myelin, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “myelin” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for myelin (hyperlinks lead to article summaries): •
A combinatorial network of evolutionarily conserved myelin basic protein regulatory sequences confers distinct glial-specific phenotypes. Author(s): Farhadi HF, Lepage P, Forghani R, Friedman HC, Orfali W, Jasmin L, Miller W, Hudson TJ, Peterson AC. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2003 November 12; 23(32): 10214-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14614079
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12615635
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PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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A human leucocyte antigen-DR1 transgene confers susceptibility to experimental allergic encephalomyelitis elicited by an epitope of myelin basic protein. Author(s): Sireci G, Dieli F, Caccamo N, Barera A, Carta P, Di Sano C, Meraviglia S, Bonanno CT, Salerno A. Source: Scandinavian Journal of Immunology. 2003 August; 58(2): 188-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12869140
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12667664
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A novel mutation of myelin protein zero associated with an axonal form of CharcotMarie-Tooth disease. Author(s): Santoro L, Manganelli F, Di Maria E, Bordo D, Cassandrini D, Ajmar F, Mandich P, Bellone E. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2004 February; 75(2): 2625. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14742601
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A novel mutation, Thr65Ala, in the MPZ gene in a patient with Charcot-Marie-Tooth type 1B disease with focally folded myelin. Author(s): Kochanski A, Drac H, Kabzinska D, Hausmanowa-Petrusewicz I. Source: Neuromuscular Disorders : Nmd. 2004 March; 14(3): 229-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15036333
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A rapid ELISA-based serum assay for myelin basic protein in multiple sclerosis. Author(s): Chamczuk AJ, Ursell M, O'Connor P, Jackowski G, Moscarello MA. Source: Journal of Immunological Methods. 2002 April 1; 262(1-2): 21-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11983216
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Action of treosulfan in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis and human lymphocytes. Author(s): Weissert R, Wiendl H, Pfrommer H, Storch MK, Schreiner B, Barth S, Seifert T, Melms A, Dichgans J, Weller M. Source: Journal of Neuroimmunology. 2003 November; 144(1-2): 28-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14597095
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Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Author(s): Bartzokis G. Source: Neurobiology of Aging. 2004 January; 25(1): 5-18; Author Reply 49-62. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675724
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Aggresome formation in neuropathy models based on peripheral myelin protein 22 mutations. Author(s): Ryan MC, Shooter EM, Notterpek L. Source: Neurobiology of Disease. 2002 July; 10(2): 109-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12127149
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An axonal form of Charcot-Marie-Tooth disease with a novel missense mutation in the myelin protein zero gene. Author(s): Kochanski A, Kabzinska D, Nowakowski A, Drac H, HausmanowaPetrusewicz I. Source: Journal of the Peripheral Nervous System : Jpns. 2004 March; 9(1): 1-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14871447
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Analysis of oxidative processes and of myelin figures formation before and after the loss of mitochondrial transmembrane potential during 7beta-hydroxycholesterol and 7-ketocholesterol-induced apoptosis: comparison with various pro-apoptotic chemicals. Author(s): Miguet-Alfonsi C, Prunet C, Monier S, Bessede G, Lemaire-Ewing S, Berthier A, Menetrier F, Neel D, Gambert P, Lizard G. Source: Biochemical Pharmacology. 2002 August 1; 64(3): 527-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12147305
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12767500
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Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein butyrophilin in multiple sclerosis. Author(s): Guggenmos J, Schubart AS, Ogg S, Andersson M, Olsson T, Mather IH, Linington C. Source: Journal of Immunology (Baltimore, Md. : 1950). 2004 January 1; 172(1): 661-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14688379
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Antibody responses to Acinetobacter spp. and Pseudomonas aeruginosa in multiple sclerosis: prospects for diagnosis using the myelin-acinetobacter-neurofilament antibody index. Author(s): Hughes LE, Bonell S, Natt RS, Wilson C, Tiwana H, Ebringer A, Cunningham P, Chamoun V, Thompson EJ, Croker J, Vowles J. Source: Clinical and Diagnostic Laboratory Immunology. 2001 November; 8(6): 1181-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11687461
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Anti-myelin-associated glycoprotein antibodies alter neurofilament spacing. Author(s): Lunn MP, Crawford TO, Hughes RA, Griffin JW, Sheikh KA. Source: Brain; a Journal of Neurology. 2002 April; 125(Pt 4): 904-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11912122
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Antisense inhibition of surfactant protein A decreases tubular myelin formation in human fetal lung in vitro. Author(s): Klein JM, McCarthy TA, Dagle JM, Snyder JM. Source: American Journal of Physiology. Lung Cellular and Molecular Physiology. 2002 March; 282(3): L386-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11839531
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Association of calnexin with mutant peripheral myelin protein-22 ex vivo: a basis for "gain-of-function" ER diseases. Author(s): Dickson KM, Bergeron JJ, Shames I, Colby J, Nguyen DT, Chevet E, Thomas DY, Snipes GJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 July 23; 99(15): 9852-7. Epub 2002 Jul 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12119418
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Autonomic and respiratory dysfunction in Charcot-Marie-Tooth disease due to Thr124Met mutation in the myelin protein zero gene. Author(s): Stojkovic T, de Seze J, Dubourg O, Arne-Bes MC, Tardieu S, Hache JC, Vermersch P. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2003 September; 114(9): 1609-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12948789
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Autoreactivity to myelin antigens related to HLA associations with multiple sclerosis. Author(s): Yentur SP, Akman-Demir G, Eraksoy M, Saruhan-Direskeneli G. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 August; 8(4): 27883. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12166496
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Bacterial toxin superantigens activate human T lymphocytes reactive with myelin autoantigens. Author(s): Burns J, Littlefield K, Gill J, Trotter JL. Source: Annals of Neurology. 1992 September; 32(3): 352-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1384422
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Balo's concentric sclerosis: surviving normal myelin in a patient with a relapsingremitting dinical course. Author(s): Moore GR, Berry K, Oger JJ, Prout AJ, Graeb DA, Nugent RA. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2001 December; 7(6): 375-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11795459
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Basic protein dissociating from myelin membranes at physiological ionic strength and pH is cleaved into three major fragments. Author(s): Glynn P, Chantry A, Groome N, Cuzner ML. Source: Journal of Neurochemistry. 1987 March; 48(3): 752-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2433395
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B-cell responses to myelin basic protein and its epitopes in autoimmune encephalomyelitis induced by Semple rabies vaccine. Author(s): Piyasirisilp S, Hemachudha T, Griffin DE. Source: Journal of Neuroimmunology. 1999 August 3; 98(2): 96-104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10430042
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Beneficial effect of orally administered myelin basic protein in EAE-susceptible Lewis rats in a model of acute CNS degeneration. Author(s): Monsonego A, Beserman ZP, Kipnis J, Yoles E, Weiner HL, Schwartz M. Source: Journal of Autoimmunity. 2003 September; 21(2): 131-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12935782
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Binding of complement component Clq to myelin oligodendrocyte glycoprotein: a novel mechanism for regulating CNS inflammation. Author(s): Johns TG, Bernard CC. Source: Molecular Immunology. 1997 January; 34(1): 33-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9182874
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Binding of copolymer 1 and myelin basic protein leads to clustering of class II MHC molecules on antigen-presenting cells. Author(s): Fridkis-Hareli M, Teitelbaum D, Pecht I, Arnon R, Sela M. Source: International Immunology. 1997 July; 9(7): 925-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9237101
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Binding of human normal and multiple sclerosis-derived myelin basic protein to phospholipid vesicles: effects on membrane head group and bilayer regions. Author(s): Deber CM, Hughes DW, Fraser PE, Pawagi AB, Moscarello MA. Source: Archives of Biochemistry and Biophysics. 1986 March; 245(2): 455-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2420275
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Binding of monoclonal anti-myelin-associated glycoprotein antibodies to human foetal peripheral neurons in culture. Author(s): Moretto G, Monaco S, Nardelli E, Arlacchi E, Stoppelli I, Rizzuto N. Source: Acta Neuropathologica. 1987; 73(4): 344-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2441562
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Binding of myelin basic protein peptides to human histocompatibility leukocyte antigen class II molecules and their recognition by T cells from multiple sclerosis patients. Author(s): Valli A, Sette A, Kappos L, Oseroff C, Sidney J, Miescher G, Hochberger M, Albert ED, Adorini L. Source: The Journal of Clinical Investigation. 1993 February; 91(2): 616-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7679413
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Binding of swine IgM immunoglobulins to peripheral nerve myelin sheaths in electron microscopic immunocytochemistry. Author(s): Sommer C, Schroder JM. Source: Acta Neuropathologica. 1988; 77(1): 100-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3149120
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Biochemical and immunohistochemical studies with specific polyclonal antibodies directed against bovine myelin/oligodendrocyte glycoprotein. Author(s): Birling MC, Roussel G, Nussbaum F, Nussbaum JL. Source: Neurochemical Research. 1993 August; 18(8): 937-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8371836
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Biological activity of recombinant human myelin basic protein. Author(s): Oettinger HF, al-Sabbagh A, Jingwu Z, LaSalle JM, Weiner HL, Hafler DA. Source: Journal of Neuroimmunology. 1993 May; 44(2): 157-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7685037
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Biological methylation of myelin basic protein: enzymology and biological significance. Author(s): Kim S, Lim IK, Park GH, Paik WK. Source: The International Journal of Biochemistry & Cell Biology. 1997 May; 29(5): 74351. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9251242
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Biology of oligodendrocyte and myelin in the mammalian central nervous system. Author(s): Baumann N, Pham-Dinh D. Source: Physiological Reviews. 2001 April; 81(2): 871-927. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11274346
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Biosynthesis and regulation of expression of the HNK-1 epitope on myelin-associated glycoprotein in a transfected cell model system. Author(s): Pedraza L, Spagnol G, Latov N, Salzer JL. Source: Journal of Neuroscience Research. 1995 April 15; 40(6): 716-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7543157
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Brain myelin in senile patients with brain infarction. Author(s): Niebroj-Dobosz I, Rafalowska J, Barcikowska-Litwin M. Source: Neuropatol Pol. 1986; 24(3): 351-64. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3561796
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Buoyant density and lipid composition of purified myelin of aging human brain. Author(s): Stommel A, Berlet HH, Debuch H. Source: Mechanisms of Ageing and Development. 1989 April; 48(1): 1-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2725072
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Cathepsin G, and not the asparagine-specific endoprotease, controls the processing of myelin basic protein in lysosomes from human B lymphocytes. Author(s): Burster T, Beck A, Tolosa E, Marin-Esteban V, Rotzschke O, Falk K, Lautwein A, Reich M, Brandenburg J, Schwarz G, Wiendl H, Melms A, Lehmann R, Stevanovic S, Kalbacher H, Driessen C. Source: Journal of Immunology (Baltimore, Md. : 1950). 2004 May 1; 172(9): 5495-503. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15100291
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Cathepsin S and an asparagine-specific endoprotease dominate the proteolytic processing of human myelin basic protein in vitro. Author(s): Beck H, Schwarz G, Schroter CJ, Deeg M, Baier D, Stevanovic S, Weber E, Driessen C, Kalbacher H. Source: European Journal of Immunology. 2001 December; 31(12): 3726-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11745393
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CD4 T cell activation by myelin oligodendrocyte glycoprotein is suppressed by adult but not cord blood CD25+ T cells. Author(s): Wing K, Lindgren S, Kollberg G, Lundgren A, Harris RA, Rudin A, Lundin S, Suri-Payer E. Source: European Journal of Immunology. 2003 March; 33(3): 579-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12616478
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Cell transplantation of peripheral-myelin-forming cells to repair the injured spinal cord. Author(s): Kocsis JD, Akiyama Y, Lankford KL, Radtke C. Source: Journal of Rehabilitation Research and Development. 2002 March-April; 39(2): 287-98. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12051471
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12849543
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Cerebrospinal fluid membrane-bound tissue factor and myelin basic protein in the course of vasospasm after subarachnoid hemorrhage. Author(s): Hirashima Y, Endo S, Nakamura S, Kurimoto M, Takaku A. Source: Neurological Research. 2001 October; 23(7): 715-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11680510
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Characteristics of T-cell receptor repertoire and myelin-reactive T cells reconstituted from autologous haematopoietic stem-cell grafts in multiple sclerosis. Author(s): Sun W, Popat U, Hutton G, Zang YC, Krance R, Carrum G, Land GA, Heslop H, Brenner M, Zhang JZ. Source: Brain; a Journal of Neurology. 2004 May; 127(Pt 5): 996-1008. Epub 2004 February 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14985264
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Charcot-Marie-Tooth disease: a novel Tyr145Ser mutation in the myelin protein zero (MPZ, P0) gene causes different phenotypes in homozygous and heterozygous carriers within one family. Author(s): Leal A, Berghoff C, Berghoff M, Del Valle G, Contreras C, Montoya O, Hernandez E, Barrantes R, Schlotzer-Schrehardt U, Neundorfer B, Reis A, Rautenstrauss B, Heuss D. Source: Neurogenetics. 2003 August; 4(4): 191-7. Epub 2003 July 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12845552
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Charcot-Marie-Tooth disease: histopathological features of the peripheral myelin protein (PMP22) duplication (CMT1A) and connexin32 mutations (CMTX1). Author(s): Sander S, Nicholson GA, Ouvrier RA, McLeod JG, Pollard JD. Source: Muscle & Nerve. 1998 February; 21(2): 217-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9466597
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Chemical compositions of brain and myelin in two patients with multiple sulphatase deficiency (a variant form of metachromatic leukodystrophy). Author(s): Eto Y, Meier C, Herschkowitz NN. Source: Journal of Neurochemistry. 1976 November; 27(5): 1071-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12170590
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CNP overexpression induces aberrant oligodendrocyte membranes and inhibits MBP accumulation and myelin compaction. Author(s): Yin X, Peterson J, Gravel M, Braun PE, Trapp BD. Source: Journal of Neuroscience Research. 1997 October 15; 50(2): 238-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9373033
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Comparative proteomics of the Mycobacterium leprae binding protein myelin P0: its implication in leprosy and other neurodegenerative diseases. Author(s): Vardhini D, Suneetha S, Ahmed N, Joshi DS, Karuna S, Magee X, Vijayalakshmi DS, Sridhar V, Karunakar KV, Archelos JJ, Suneetha LM. Source: Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases. 2004 March; 4(1): 21-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15019586
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Conformation of the transmembrane domains in peripheral myelin protein 22. Part 1. Solution-phase synthesis and circular dichroism study of protected 17-residue partial peptides in the first putative transmembrane domain. Author(s): Yamada K, Sato J, Oku H, Katakai R. Source: The Journal of Peptide Research : Official Journal of the American Peptide Society. 2003 August; 62(2): 78-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12823620
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Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS. Author(s): Odermatt B, Wellershaus K, Wallraff A, Seifert G, Degen J, Euwens C, Fuss B, Bussow H, Schilling K, Steinhauser C, Willecke K. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2003 June 1; 23(11): 4549-59. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12805295
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Contribution of changes in ubiquitin and myelin basic protein to age-related cognitive decline. Author(s): Wang DS, Bennett DA, Mufson EJ, Mattila P, Cochran E, Dickson DW. Source: Neuroscience Research. 2004 January; 48(1): 93-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687885
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Corticosteroid- responsive asymmetric neuropathy with a myelin protein zero gene mutation. Author(s): Watanabe M, Yamamoto N, Ohkoshi N, Nagata H, Kohno Y, Hayashi A, Tamaoka A, Shoji S. Source: Neurology. 2002 September 10; 59(5): 767-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12221176
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Critical role of antigen-specific antibody in experimental autoimmune encephalomyelitis induced by recombinant myelin oligodendrocyte glycoprotein. Author(s): Lyons JA, Ramsbottom MJ, Cross AH. Source: European Journal of Immunology. 2002 July; 32(7): 1905-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12115610
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Cross-reactivity between related sequences found in Acinetobacter sp., Pseudomonas aeruginosa, myelin basic protein and myelin oligodendrocyte glycoprotein in multiple sclerosis. Author(s): Hughes LE, Smith PA, Bonell S, Natt RS, Wilson C, Rashid T, Amor S, Thompson EJ, Croker J, Ebringer A. Source: Journal of Neuroimmunology. 2003 November; 144(1-2): 105-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14597104
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12557285
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12604314
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De novo mutation of the myelin Po gene in Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III): two amino acid insertion after Asp 118. Author(s): Ikegami T, Nicholson G, Ikeda H, Ishida A, Johnston H, Wise G, Ouvrier R, Hayasaka K. Source: Human Mutation. 1998; Suppl 1: S103-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9452055
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Definition of a consensus sequence for peptide substrate recognition by p44mpk, the meiosis-activated myelin basic protein kinase. Author(s): Clark-Lewis I, Sanghera JS, Pelech SL. Source: The Journal of Biological Chemistry. 1991 August 15; 266(23): 15180-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1907971
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Degraded myelin-associated glycoprotein (dMAG) formation from pure human brain myelin-associated glycoprotein (MAG) is not mediated by calpain or cathepsin L-like activities. Author(s): Paivalainen S, Suokas M, Lahti O, Heape AM. Source: Journal of Neurochemistry. 2003 February; 84(3): 533-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12558973
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Deimination of myelin basic protein. 2. Effect of methylation of MBP on its deimination by peptidylarginine deiminase. Author(s): Pritzker LB, Joshi S, Harauz G, Moscarello MA. Source: Biochemistry. 2000 May 9; 39(18): 5382-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10820009
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Dejerine-sottas disease with a novel de novo dominant mutation, Ser 149 Arg, of the peripheral myelin protein 22. Author(s): Ohnishi A, Yamamoto T, Izawa K, Yamamori S, Takahashi K, Mega H, Jinnai K. Source: Acta Neuropathologica. 2000 March; 99(3): 327-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10663978
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Dejerine-Sottas neuropathy associated with de novo S79P mutation of the peripheral myelin protein 22 (PMP22) gene. Author(s): Bort S, Sevilla T, Garcia-Planells J, Blesa D, Paricio N, Vilchez JJ, Prieto F, Palau F. Source: Human Mutation. 1998; Suppl 1: S95-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9452053
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Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Author(s): Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H, Ohnishi A, Hayasaka K, Onodera O, Baba M, Yasuda H, Saito T, Nakashima K, Kira J, Kaji R, Oka N, Sobue G; Study Group for Hereditary Neuropathy in Japan. Source: Brain; a Journal of Neurology. 2003 January; 126(Pt 1): 134-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12477701
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Demyelinating diseases, leukodystrophies, and other myelin disorders. Author(s): Suzuki K, Armao D, Stone JA, Mukherji SK. Source: Neuroimaging Clin N Am. 2001 February; 11(1): Vii, 15-35. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11331226
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Detailed analysis of the oligodendrocyte myelin glycoprotein gene in four patients with neurofibromatosis 1 and primary progressive multiple sclerosis. Author(s): Johnson MR, Ferner RE, Bobrow M, Hughes RA. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2000 May; 68(5): 643-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10766898
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Detection of brain-specific autoantibodies to myelin oligodendrocyte glycoprotein, S100beta and myelin basic protein in patients with Devic's neuromyelitis optica. Author(s): Haase CG, Schmidt S. Source: Neuroscience Letters. 2001 July 13; 307(2): 131-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11427318
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Detection of myelin basic protein in cerebrospinal fluid and serum from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. Author(s): Ohta M, Ohta K, Nishimura M, Saida T. Source: Annals of Clinical Biochemistry. 2002 November; 39(Pt 6): 603-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12564844
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Detection of myelin basic protein in cerebrospinal fluid. Author(s): Ohta M, Ohta K. Source: Expert Review of Molecular Diagnostics. 2002 November; 2(6): 627-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12465458
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Development of myelin oligodendrocyte glycoprotein autoreactive transgenic B lymphocytes: receptor editing in vivo after encounter of a self-antigen distinct from myelin oligodendrocyte glycoprotein. Author(s): Litzenburger T, Bluthmann H, Morales P, Pham-Dinh D, Dautigny A, Wekerle H, Iglesias A. Source: Journal of Immunology (Baltimore, Md. : 1950). 2000 November 1; 165(9): 5360-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11046072
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Diaminobenzidine as a myelin stain in semithin plastic sections. Author(s): Muss W. Source: Biotechnic & Histochemistry : Official Publication of the Biological Stain Commission. 2000 January; 75(1): 46-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10810983
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Differences between T-cell reactivities to major myelin protein-derived peptides in opticospinal and conventional forms of multiple sclerosis and healthy controls. Author(s): Minohara M, Ochi H, Matsushita S, Irie A, Nishimura Y, Kira J. Source: Tissue Antigens. 2001 May; 57(5): 447-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11556969
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Differential appearance of autoantibodies to human brain S100 protein, neuron specific enolase and myelin basic protein in psychiatric patients. Author(s): Jankovic BD, Djordjijevic D. Source: The International Journal of Neuroscience. 1991 September; 60(1-2): 119-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1723060
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Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease. Author(s): Mitsunaga Y, Ciric B, Van Keulen V, Warrington AE, Paz Soldan M, Bieber AJ, Rodriguez M, Pease LR. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2002 August; 16(10): 1325-7. Epub 2002 June 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12154009
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Disturbance of muscle fiber differentiation in congenital hypomyelinating neuropathy caused by a novel myelin protein zero mutation. Author(s): Szigeti K, Saifi GM, Armstrong D, Belmont JW, Miller G, Lupski JR. Source: Annals of Neurology. 2003 September; 54(3): 398-402. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12953275
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12853581
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Dysembryoplastic neuroepithelial tumor: an immunohistochemical study with myelin oligodendrocyte glycoprotein. Author(s): Gyure KA, Sandberg GD, Prayson RA, Morrison AL, Armstrong RC, Wong K. Source: Archives of Pathology & Laboratory Medicine. 2000 January; 124(1): 123-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10629143
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Edg-2 in myelin-forming cells: isoforms, genomic mapping, and exclusion in CharcotMarie-Tooth disease. Author(s): Allard J, Barron S, Trottier S, Cervera P, Daumas-Duport C, Leguern E, Brice A, Schwartz JC, Sokoloff P. Source: Glia. 1999 April; 26(2): 176-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10384882
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Effect of interferon beta on human myelin basic protein-specific T-cell lines: comparison of IFNbeta-1a and IFNbeta-1b. Author(s): Weber F, Janovskaja J, Polak T, Poser S, Rieckmann P. Source: Neurology. 1999 March 23; 52(5): 1069-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10102432
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Effects of brain-derived neurotrophic factor (BDNF) on compression-induced spinal cord injury: BDNF attenuates down-regulation of superoxide dismutase expression and promotes up-regulation of myelin basic protein expression. Author(s): Ikeda O, Murakami M, Ino H, Yamazaki M, Koda M, Nakayama C, Moriya H. Source: Journal of Neuropathology and Experimental Neurology. 2002 February; 61(2): 142-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11853017
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Effects of neuroactive steroids on myelin of peripheral nervous system. Author(s): Melcangi RC, Ballabio M, Cavarretta I, Gonzalez LC, Leonelli E, Veiga S, Martini L, Magnaghi V. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 June; 85(2-5): 323-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12943718
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EGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expression. Author(s): Nagarajan R, Svaren J, Le N, Araki T, Watson M, Milbrandt J. Source: Neuron. 2001 May; 30(2): 355-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11394999
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Electrodiagnostic findings in CMTX: a disorder of the Schwann cell and peripheral nerve myelin. Author(s): Lewis RA, Shy ME. Source: Annals of the New York Academy of Sciences. 1999 September 14; 883: 504-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10586285
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Elevated levels of antibody to myelin oligodendrocyte glycoprotein is not specific for patients with multiple sclerosis. Author(s): Karni A, Bakimer-Kleiner R, Abramsky O, Ben-Nun A. Source: Archives of Neurology. 1999 March; 56(3): 311-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10190821
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Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Author(s): Bielekova B, Goodwin B, Richert N, Cortese I, Kondo T, Afshar G, Gran B, Eaton J, Antel J, Frank JA, McFarland HF, Martin R. Source: Nature Medicine. 2000 October; 6(10): 1167-75. Erratum In: Nat Med 2000 December; 6(12): 1412. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11017150
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Epitope specificity of demyelinating monoclonal autoantibodies directed against the human myelin oligodendrocyte glycoprotein (MOG). Author(s): Brehm U, Piddlesden SJ, Gardinier MV, Linington C. Source: Journal of Neuroimmunology. 1999 June 1; 97(1-2): 9-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10408984
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Evidence that a major site of expression of the RHO-GTPASE activating protein, oligophrenin-1, is peripheral myelin. Author(s): Xiao J, Neylon CB, Nicholson GA, Furness JB. Source: Neuroscience. 2004; 124(4): 781-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15026118
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Ex vivo detection of myelin basic protein-reactive T cells in multiple sclerosis and controls using specific TCR oligonucleotide probes. Author(s): Hong J, Zang YC, Li S, Rivera VM, Zhang JZ. Source: European Journal of Immunology. 2004 March; 34(3): 870-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14991617
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Exonic SNPs at positions 220 (A/G) and 445 (C/T) of the peripheral myelin protein 2 (PMP2). Author(s): Besancon R, Latour P, Lara K, Laetitia B, Mularoni A, Chamba G, Vandenberghe A. Source: Human Mutation. 2001 March; 17(3): 237. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11241848
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Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis. Author(s): Bielekova B, Sung MH, Kadom N, Simon R, McFarland H, Martin R. Source: Journal of Immunology (Baltimore, Md. : 1950). 2004 March 15; 172(6): 3893-904. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15004197
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Expression and crystallization of the complex of HLA-DR2 (DRA, DRB1*1501) and an immunodominant peptide of human myelin basic protein. Author(s): Gauthier L, Smith KJ, Pyrdol J, Kalandadze A, Strominger JL, Wiley DC, Wucherpfennig KW. Source: Proceedings of the National Academy of Sciences of the United States of America. 1998 September 29; 95(20): 11828-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9751750
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Expression and purification of the extracellular domain of human myelin protein zero. Author(s): Bond JP, Saavedra RA, Kirschner DA. Source: Protein Expression and Purification. 2001 December; 23(3): 398-410. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11722176
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Expression of glycosylated recombinant human myelin-associated glycoprotein on a neuroblastoma cell line and its reactivity with HNK-1 but not human anti-MAG antibodies. Author(s): Spagnol G, Doneda P, Cavanna B, Sgarzi M, Manfredini E, Allaria S, Scarlato G, Nobile-Orazio E. Source: Neuroscience Letters. 1998 May 1; 246(3): 157-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9792616
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Expression of myelin basic protein (MBP) epitopes in human non-neural cells revealed by two anti-MBP IgM monoclonal antibodies. Author(s): Chignola R, Cestari T, Guerriero C, Riviera AP, Ferrari S, Brendolan A, Gobbo M, Amato S, Sartoris S, Fracasso G, Liuzzi MG, Riccio P, Tridente G, Andrighetto G. Source: Clinical and Experimental Immunology. 2000 December; 122(3): 429-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11122251
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Expression of peripheral myelin protein zero in sural nerve of patients with CharcotMarie-Tooth disease 1B. Author(s): Tachi N, Kozuka N, Ohya K, Chiba S, Sasaki K, Uyemura K. Source: Pediatric Neurology. 2001 January; 24(1): 33-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11182278
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Expression of the genes encoding myelin basic protein and proteolipid protein in human malignant gliomas. Author(s): Golfinos JG, Norman SA, Coons SW, Norman RA, Ballecer C, Scheck AC. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1997 May; 3(5): 799-804. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9815752
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Fabry-like laminated myelin body associated with IgA nephropathy. Author(s): Yoshida A, Morozumi K, Takeda A, Koyama K, Oikawa T. Source: Nippon Jinzo Gakkai Shi. 1994 November; 36(11): 1303-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7853764
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Failure of copolymer I to inhibit the human T-cell response to myelin basic protein. Author(s): Burns J, Littlefield K. Source: Neurology. 1991 August; 41(8): 1317-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1714060
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Fast inversion recovery for myelin suppression (FIRMS). A new magnetic resonance pulse sequence. Author(s): Wolansky LJ, Chiang PK, Liu WC, Gonzales RN, Holodny A, Baker SR. Source: Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging. 1997 July; 7(3): 176-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9237438
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Fast inversion recovery for myelin suppression (FIRMS). A new MRI pulse sequence for highlighting cerebral gray matter. Author(s): Wolansky LJ, Evans A, Belitsis K, Shaderowfsky PD, Gonzales R, Maldjian JA, Lee HJ, Pak J. Source: Clinical Imaging. 1996 July-September; 20(3): 164-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8877167
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Fatty acid composition of myelin proteolipid protein during vertebrate evolution. Author(s): Bizzozero OA, Lees MB. Source: Neurochemical Research. 1999 February; 24(2): 269-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9972874
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Fine specificity of myelin basic protein reactive T-cells: implications for T-cell receptor antagonism. Author(s): Anderton SM, Manickasingham SP, Wraith DC. Source: Biochemical Society Transactions. 1997 May; 25(2): 659-61. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9191175
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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. Author(s): Warren KG, Catz I, Steinman L. Source: Proceedings of the National Academy of Sciences of the United States of America. 1995 November 21; 92(24): 11061-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7479937
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Fish oil and myelin: cautious optimism for treatment of children with disorders of peroxisome biogenesis. Author(s): Noetzel MJ. Source: Neurology. 1998 July; 51(1): 5-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9674767
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Fluorescent myelin proteins provide new tools to study the myelination process. Author(s): Pedraza L, Colman DR. Source: Journal of Neuroscience Research. 2000 June 15; 60(6): 697-703. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10861781
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Focal myelin swellings and tomacula in anti-MAG IgM paraproteinaemic neuropathy: novel teased nerve fiber studies. Author(s): Cai Z, Cash K, Swift J, Sutton-Smith P, Robinson M, Thompson PD, Blumbergs PC. Source: Journal of the Peripheral Nervous System : Jpns. 2001 June; 6(2): 95-101. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11446389
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Focally folded myelin in Charcot-Marie-Tooth neuropathy type 1B with Ser49Leu in the myelin protein zero. Author(s): Fabrizi GM, Taioli F, Cavallaro T, Rigatelli F, Simonati A, Mariani G, Perrone P, Rizzuto N. Source: Acta Neuropathologica. 2000 September; 100(3): 299-304. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10965800
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Focally folded myelin in Charcot-Marie-Tooth type 1B disease is associated with Asn131Lys mutation in myelin protein zero gene: short report. Author(s): Kochanski A, Drac H, Jedrzejowska H, Hausmanowa-Petrusewicz I. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2003 September; 10(5): 547-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12940837
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Four frequently observed polymorphisms in the 3'-UTR of human peripheral myelin protein 22 (PMP22): identification of different haplotypes. Author(s): Young P, Wiebusch H, Stogbauer F, Ringelstein B, Assmann G, Funke H. Source: Clinical Genetics. 1996 June; 49(6): 321-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8884085
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Fractionation of central nervous system myelin proteins by reversed-phase highperformance liquid chromatography. Author(s): van Noort JM, el Ouagmiri M, Boon J, van Sechel AC. Source: Journal of Chromatography. B, Biomedical Applications. 1994 March 4; 653(2): 155-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7515750
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Fragmentation of phospholipid bilayers by myelin basic protein. Author(s): Roux M, Nezil FA, Monck M, Bloom M. Source: Biochemistry. 1994 January 11; 33(1): 307-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7506931
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Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis. Author(s): Chou YK, Bourdette DN, Offner H, Whitham R, Wang RY, Hashim GA, Vandenbark AA. Source: Journal of Neuroimmunology. 1992 May; 38(1-2): 105-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1374422
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From the syndrome of Charcot, Marie and Tooth to disorders of peripheral myelin proteins. Author(s): Harding AE. Source: Brain; a Journal of Neurology. 1995 June; 118 ( Pt 3): 809-18. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7541290
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Function of tetraspan proteins in the myelin sheath. Author(s): Bronstein JM. Source: Current Opinion in Neurobiology. 2000 October; 10(5): 552-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11084316
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Functional properties of adhesion molecules in myelin formation. Author(s): Colman DR. Source: Current Opinion in Neurobiology. 1991 October; 1(3): 377-81. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1821680
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12667661
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Galanin receptor 1 gene (Galnr1) is tightly linked to the myelin basic protein gene on chromosome 18 in mouse. Author(s): Simoneaux DK, Leach RJ, O'Connell P. Source: Mammalian Genome : Official Journal of the International Mammalian Genome Society. 1997; 8(11): 875. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9337411
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Gamma delta T cells participate in the immune response against activated, myelin basic protein-specific, human T cells. Author(s): Burns J, Bartholomew B, Littlefield K. Source: Journal of Neuroimmunology. 1995 May; 58(2): 177-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7759606
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Gangliosides and related glycoconjugates in myelin: relationship to peripheral neuropathies. Author(s): Steck AJ, Burger D, Picasso S, Kuntzer T, Nardelli E, Schluep M. Source: Prog Brain Res. 1994; 101: 305-12. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8029459
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Gene dosage effects in hereditary peripheral neuropathy. Expression of peripheral myelin protein 22 in Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies nerve biopsies. Author(s): Gabriel JM, Erne B, Pareyson D, Sghirlanzoni A, Taroni F, Steck AJ. Source: Neurology. 1997 December; 49(6): 1635-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9409359
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Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. Author(s): Albertson DN, Pruetz B, Schmidt CJ, Kuhn DM, Kapatos G, Bannon MJ. Source: Journal of Neurochemistry. 2004 March; 88(5): 1211-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15009677
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Gene structure and amino acid sequence of Latimeria chalumnae (coelacanth) myelin DM20: phylogenetic relation of the fish. Author(s): Tohyama Y, Kasama-Yoshida H, Sakuma M, Kobayashi Y, Cao Y, Hasegawa M, Kojima H, Tamai Y, Tanokura M, Kurihara T. Source: Neurochemical Research. 1999 July; 24(7): 867-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10403627
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Generation from multiple sclerosis patients of long-term T-cell clones that are activated by both human coronavirus and myelin antigens. Author(s): Boucher A, Denis F, Duquette P, Talbot PJ. Source: Advances in Experimental Medicine and Biology. 2001; 494: 355-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11774492
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Generation of a monoclonal antibody against the myelin protein CNP (2',3'-cyclic nucleotide 3'-phosphodiesterase) suitable for biochemical and for immunohistochemical investigations of CNP. Author(s): Reiser G, Kunzelmann U, Steinhilber G, Binmoller FJ. Source: Neurochemical Research. 1994 December; 19(12): 1479-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7877717
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Genetic heterogeneity in autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths (CMT4B). Author(s): Gambardella A, Bolino A, Muglia M, Valentino P, Bono F, Oliveri RL, Sabatelli M, Brancolini V, Van Broeckhoven C, Romeo G, Devoto M, Quattrone A. Source: Neurology. 1998 March; 50(3): 799-801. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9521281
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Genetic susceptibility in familial multiple sclerosis not linked to the myelin basic protein gene. Author(s): Rose J, Gerken S, Lynch S, Pisani P, Varvil T, Otterud B, Leppert M. Source: Lancet. 1993 May 8; 341(8854): 1179-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7683738
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Genetic susceptibility to multiple sclerosis may be linked to polymorphism of the myelin basic protein gene. Author(s): Ibsen SN, Clausen J. Source: Journal of the Neurological Sciences. 1995 July; 131(1): 96-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7561955
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Genetic variations and humoral immune responses to myelin oligodendroglia glycoprotein in adult phenotypes of X-linked adrenoleukodystrophy. Author(s): Schmidt S, Marrosu GM, Kolsch H, Haase CG, Ferenczik S, Sokolowski P, Kohler W, Schmidt M, Papassotiropoulos A, Heun R, Grosse-Wilde H, Klockgether T. Source: Journal of Neuroimmunology. 2003 February; 135(1-2): 148-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12576235
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Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS. Author(s): Chen M, Gran B, Costello K, Johnson K, Martin R, Dhib-Jalbut S. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2001 August; 7(4): 20919. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11548979
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Glatiramer acetate-reactive peripheral blood mononuclear cells respond to multiple myelin antigens with a Th2-biased phenotype. Author(s): Dhib-Jalbut S, Chen M, Said A, Zhan M, Johnson KP, Martin R. Source: Journal of Neuroimmunology. 2003 July; 140(1-2): 163-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12864985
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Glial cell transplants: experimental therapies of myelin diseases. Author(s): Duncan ID, Milward EA. Source: Brain Pathology (Zurich, Switzerland). 1995 July; 5(3): 301-10. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8520730
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Glial-neuron interactions and the regulation of myelin formation. Author(s): Doyle JP, Colman DR. Source: Current Opinion in Cell Biology. 1993 October; 5(5): 779-85. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7694602
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Glycolipids and myelin proteins in human oligodendrogliomas. Author(s): Sung CC, Collins R, Li J, Pearl DK, Coons SW, Scheithauer BW, Johnson PC, Yates AJ. Source: Glycoconjugate Journal. 1996 June; 13(3): 433-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8781974
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Glycoproteins of myelin sheaths. Author(s): Quarles RH. Source: Journal of Molecular Neuroscience : Mn. 1997 February; 8(1): 1-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9061610
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Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord. Author(s): Buss A, Brook GA, Kakulas B, Martin D, Franzen R, Schoenen J, Noth J, Schmitt AB. Source: Brain; a Journal of Neurology. 2004 January; 127(Pt 1): 34-44. Epub 2003 October 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14534158
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Growth factors and myelin regeneration in multiple sclerosis. Author(s): Webster HD. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 1997 April; 3(2): 113-20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9291164
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Heat shock protein 70 associations with myelin basic protein and proteolipid protein in multiple sclerosis brains. Author(s): Cwiklinska H, Mycko MP, Luvsannorov O, Walkowiak B, Brosnan CF, Raine CS, Selmaj KW. Source: International Immunology. 2003 February; 15(2): 241-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12578854
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Hemizygous mutation of the peripheral myelin protein 22 gene associated with Charcot-Marie-Tooth disease type 1. Author(s): Numakura C, Lin C, Oka N, Akiguchi I, Hayasaka K. Source: Annals of Neurology. 2000 January; 47(1): 101-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10632107
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Hereditary neuropathy with liability to pressure palsies associated with central nervous system myelin lesions. Author(s): Dackovic J, Rakocevic-Stojanovic V, Pavlovic S, Zamurovic N, Dragasevic N, Romac S, Apostolski S. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2001 November; 8(6): 689-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11784354
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High expression of the HNK-1/L2 carbohydrate epitope in the major glycoproteins of shark myelin. Author(s): Zand D, Hammer J, Gould R, Quarles R. Source: Journal of Neurochemistry. 1991 September; 57(3): 1076-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1713613
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High field MRI correlates of myelin content and axonal density in multiple sclerosis-a post-mortem study of the spinal cord. Author(s): Mottershead JP, Schmierer K, Clemence M, Thornton JS, Scaravilli F, Barker GJ, Tofts PS, Newcombe J, Cuzner ML, Ordidge RJ, McDonald WI, Miller DH. Source: Journal of Neurology. 2003 November; 250(11): 1293-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14648144
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High immunogenicity of intracellular myelin oligodendrocyte glycoprotein epitopes. Author(s): Weissert R, Kuhle J, de Graaf KL, Wienhold W, Herrmann MM, Muller C, Forsthuber TG, Wiesmuller KH, Melms A. Source: Journal of Immunology (Baltimore, Md. : 1950). 2002 July 1; 169(1): 548-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12077287
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High levels of cerebrospinal fluid IgM binding to myelin basic protein are associated with early benign course in multiple sclerosis. Author(s): Annunziata P, Pluchino S, Martino T, Guazzi G. Source: Journal of Neuroimmunology. 1997 July; 77(1): 128-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9209277
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High-grade human brain tumors exhibit increased expression of myelin transcription factor 1 (MYT1), a zinc finger DNA-binding protein. Author(s): Armstrong RC, Migneault A, Shegog ML, Kim JG, Hudson LD, Hessler RB. Source: Journal of Neuropathology and Experimental Neurology. 1997 July; 56(7): 77281. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9210873
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Highly deiminated isoform of myelin basic protein from multiple sclerosis brain causes fragmentation of lipid vesicles. Author(s): Boggs JM, Rangaraj G, Koshy KM, Ackerley C, Wood DD, Moscarello MA. Source: Journal of Neuroscience Research. 1999 August 15; 57(4): 529-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10440902
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HLA class II transgenic mice authenticate restriction of myelin oligodendrocyte glycoprotein-specific immune response implicated in multiple sclerosis pathogenesis. Author(s): Khare M, Rodriguez M, David CS. Source: International Immunology. 2003 April; 15(4): 535-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12663683
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HLA-DM polymorphisms do not associate with multiple sclerosis: an association study with analysis of myelin basic protein T cell specificity. Author(s): Ristori G, Carcassi C, Lai S, Fiori P, Cacciani A, Floris L, Montesperelli C, Di Giovanni S, Buttinelli C, Contu L, Pozzilli C, Salvetti M. Source: Journal of Neuroimmunology. 1997 August; 77(2): 181-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9258248
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HLA-DR-restricted presentation of purified myelin basic protein is independent of intracellular processing. Author(s): Vergelli M, Pinet V, Vogt AB, Kalbus M, Malnati M, Riccio P, Long EO, Martin R. Source: European Journal of Immunology. 1997 April; 27(4): 941-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9130648
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hnRNP A2 selectively binds the cytoplasmic transport sequence of myelin basic protein mRNA. Author(s): Hoek KS, Kidd GJ, Carson JH, Smith R. Source: Biochemistry. 1998 May 12; 37(19): 7021-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9578590
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HPRT mutant T-cell lines from multiple sclerosis patients recognize myelin proteolipid protein peptides. Author(s): Trotter JL, Damico CA, Cross AH, Pelfrey CM, Karr RW, Fu XT, McFarland HF. Source: Journal of Neuroimmunology. 1997 May; 75(1-2): 95-103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9143242
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Human anti-idiotypic T cells induced by TCR peptides corresponding to a common CDR3 sequence motif in myelin basic protein-reactive T cells. Author(s): Zang YC, Hong J, Rivera VM, Killian J, Zhang JZ. Source: International Immunology. 2003 September; 15(9): 1073-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12917259
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12210418
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Human monoclonal IgM antibody promotes CNS myelin repair independent of Fc function. Author(s): Ciric B, Howe CL, Paz Soldan M, Warrington AE, Bieber AJ, Van Keulen V, Rodriguez M, Pease LR. Source: Brain Pathology (Zurich, Switzerland). 2003 October; 13(4): 608-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14655764
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Human myelin basic protein specific T cell lines display differential cytotoxicity against astrocytes, but are consistently cytotoxic against monocytes. Author(s): Weber F, Huber S, Aloisi F, Meinl E. Source: Journal of Neuroimmunology. 1998 August 1; 88(1-2): 99-104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9688330
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Human SP-A and a pharmacy-grade porcine lung surfactant extract can be reconstituted into tubular myelin--a comparative structural study of alveolar surfactants using cryo-transmission electron microscopy. Author(s): Larsson M, van Iwaarden JF, Haitsma JJ, Lachmann B, Wollmer P. Source: Clinical Physiology and Functional Imaging. 2003 July; 23(4): 199-203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12914558
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Human T-cell response to myelin basic protein peptide (83-99): extensive heterogeneity in antigen recognition, function, and phenotype. Author(s): Hemmer B, Vergelli M, Tranquill L, Conlon P, Ling N, McFarland HF, Martin R. Source: Neurology. 1997 October; 49(4): 1116-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9339699
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Identification of a positive regulatory element in the myelin-specific promoter of the PMP22 gene. Author(s): Hai M, Bidichandani SI, Patel PI. Source: Journal of Neuroscience Research. 2001 September 15; 65(6): 508-19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11550219
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Identification of Golli and myelin basic proteins in human brain during early development. Author(s): Tosic M, Rakic S, Matthieu JM, Zecevic N. Source: Glia. 2002 March 1; 37(3): 219-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11857680
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Identification of single nucleotide variations in the coding and regulatory regions of the myelin-associated glycoprotein gene and study of their association with multiple sclerosis. Author(s): D'Alfonso S, Mellai M, Giordano M, Pastore A, Malferrari G, Naldi P, Repice A, Liguori M, Cannoni S, Milanese C, Caputo D, Savettieri G, Momigliano-Richiardi P; Italian Group for the Study of Multiple Sclerosis Genetics. Source: Journal of Neuroimmunology. 2002 May; 126(1-2): 196-204. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12020971
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IgG reactivity against citrullinated myelin basic protein in multiple sclerosis. Author(s): de Seze J, Dubucquoi S, Lefranc D, Virecoulon F, Nuez I, Dutoit V, Vermersch P, Prin L. Source: Journal of Neuroimmunology. 2001 July 2; 117(1-2): 149-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11431015
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IL-7-enhanced T-cell response to myelin proteins in multiple sclerosis. Author(s): Traggiai E, Biagioli T, Rosati E, Ballerini C, Mazzanti B, Ben Nun A, Massacesi L, Vergelli M. Source: Journal of Neuroimmunology. 2001 December 3; 121(1-2): 111-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11730947
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Immune responses against the myelin/oligodendrocyte glycoprotein in experimental autoimmune demyelination. Author(s): von Budingen HC, Tanuma N, Villoslada P, Ouallet JC, Hauser SL, Genain CP. Source: Journal of Clinical Immunology. 2001 May; 21(3): 155-70. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11403222
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Immune tolerance to myelin proteins. Author(s): Seamons A, Perchellet A, Goverman J. Source: Immunologic Research. 2003; 28(3): 201-21. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14713715
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Immunopathogenic and clinical relevance of antibodies against myelin oligodendrocyte glycoprotein (MOG) in Multiple Sclerosis. Author(s): Berger T, Reindl M. Source: Journal of Neural Transmission. Supplementum. 2000; (60): 351-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11205153
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Immunotherapy for IgM anti-Myelin-Associated Glycoprotein paraprotein-associated peripheral neuropathies. Author(s): Lunn MP, Nobile-Orazio E. Source: Cochrane Database Syst Rev. 2003; (1): Cd002827. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12535440
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Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors. Author(s): Fouad K, Dietz V, Schwab ME. Source: Brain Research. Brain Research Reviews. 2001 October; 36(2-3): 204-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11690617
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In vitro synthesis of antibodies to myelin antigens by Epstein-Barr virus-transformed B lymphocytes from patients with neurologic disorders. Author(s): Wirguin I, Brenner T, Steinitz M, Abramsky O. Source: Journal of the Neurological Sciences. 1991 July; 104(1): 92-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1717665
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In vivo activation of myelin oligodendrocyte glycoprotein-specific T cells in healthy control subjects. Author(s): Burns JB, Bartholomew BD, Lobo ST. Source: Clinical Immunology (Orlando, Fla.). 2002 November; 105(2): 185-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12482392
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In what direction, or under what laws, does the myelin wrap around the axon? Author(s): Ikuta F, Takahashi H. Source: Neuropathology : Official Journal of the Japanese Society of Neuropathology. 2004 March; 24(1): 110-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15068181
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Increased A beta peptides and reduced cholesterol and myelin proteins characterize white matter degeneration in Alzheimer's disease. Author(s): Roher AE, Weiss N, Kokjohn TA, Kuo YM, Kalback W, Anthony J, Watson D, Luehrs DC, Sue L, Walker D, Emmerling M, Goux W, Beach T. Source: Biochemistry. 2002 September 17; 41(37): 11080-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12220172
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Increased CD8+ cytotoxic T cell responses to myelin basic protein in multiple sclerosis. Author(s): Zang YC, Li S, Rivera VM, Hong J, Robinson RR, Breitbach WT, Killian J, Zhang JZ. Source: Journal of Immunology (Baltimore, Md. : 1950). 2004 April 15; 172(8): 5120-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15067096
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Inducible heat shock protein 70 promotes myelin autoantigen presentation by the HLA class II. Author(s): Mycko MP, Cwiklinska H, Szymanski J, Szymanska B, Kudla G, Kilianek L, Odyniec A, Brosnan CF, Selmaj KW. Source: Journal of Immunology (Baltimore, Md. : 1950). 2004 January 1; 172(1): 202-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14688327
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Inducible nitric oxide synthase in chronic active multiple sclerosis plaques: distribution, cellular expression and association with myelin damage. Author(s): Hill KE, Zollinger LV, Watt HE, Carlson NG, Rose JW. Source: Journal of Neuroimmunology. 2004 June; 151(1-2): 171-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15145615
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Insertion of mutant proteolipid protein results in missorting of myelin proteins. Author(s): Vaurs-Barriere C, Wong K, Weibel TD, Abu-Asab M, Weiss MD, Kaneski CR, Mixon TH, Bonavita S, Creveaux I, Heiss JD, Tsokos M, Goldin E, Quarles RH, Boespflug-Tanguy O, Schiffmann R. Source: Annals of Neurology. 2003 December; 54(6): 769-80. Erratum In: Ann Neurol. 2004 January; 55(1): 149-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14681886
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Interferon gamma responses to myelin peptides in multiple sclerosis correlate with a new clinical measure of disease progression. Author(s): Moldovan IR, Rudick RA, Cotleur AC, Born SE, Lee JC, Karafa MT, Pelfrey CM. Source: Journal of Neuroimmunology. 2003 August; 141(1-2): 132-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12965264
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Intraoperative values of S-100 protein, myelin basic protein, lactate, and albumin in the CSF and serum of neurosurgical patients. Author(s): de Vries J, Thijssen WA, Snels SE, Menovsky T, Peer NG, Lamers KJ. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2001 November; 71(5): 671-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11606682
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Kinetics of anti-peripheral nerve myelin antibody in patients with Guillain-Barre syndrome treated and not treated with plasmapheresis. Author(s): Vriesendorp FJ, Mayer RF, Koski CL. Source: Archives of Neurology. 1991 August; 48(8): 858-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1898263
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Kinetics of MHC class II and transferrin receptor expression by colostral cells stimulated in vitro with concanavalin A and myelin basic protein. Author(s): Nikolova E, Staykova M, Karadjova M, Raicheva D, Goranov I. Source: Immunobiology. 1991 March; 182(2): 174-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1715844
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Lack of association between myelin basic protein gene microsatellite and multiple sclerosis. Author(s): Graham CA, Kirk CW, Nevin NC, Droogan AG, Hawkins SA, McMillan SA, McNeill TA. Source: Lancet. 1993 June 19; 341(8860): 1596. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7685461
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Lack of association of a Taq 1 polymorphism of the human myelin oligodendrocyte glycoprotein gene with multiple sclerosis in a population of patients from the Southampton area. Author(s): Brown J, Hinks L, Thompson RJ. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 1998 January; 64(1): 135-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9436746
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Lack of cerebrospinal fluid myelin basic protein in HIV-infected asymptomatic individuals with intrathecal synthesis of IgG. Author(s): Marshall DW, Brey RL, Butzin CA. Source: Neurology. 1989 August; 39(8): 1127-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2474773
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Lack of cross-reaction between myelin basic proteins and putative demyelinating virus envelope proteins. Author(s): Rubio N, Cuesta A. Source: Molecular Immunology. 1989 July; 26(7): 663-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2476671
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12420096
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Lack of over-expression of T cell receptor Vbeta5.2 in myelin basic protein-specific T cell lines derived from HLA-DR2 positive multiple sclerosis patients and controls. Author(s): Afshar G, Muraro PA, McFarland HF, Martin R. Source: Journal of Neuroimmunology. 1998 April 1; 84(1): 7-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9600703
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Leukocyte gelatinase B cleavage releases encephalitogens from human myelin basic protein. Author(s): Proost P, Van Damme J, Opdenakker G. Source: Biochemical and Biophysical Research Communications. 1993 May 14; 192(3): 1175-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7685161
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Limited restriction in alpha beta T-cell receptor usage of T-cell clones specific for myelin basic protein (a.a. 84-102) and hsp65 (a.a. 3-13) peptides within major histocompatibility complex-identical individuals. Author(s): Hawes G, Struyk L, Godthelp B, van den Elsen P. Source: Annals of the New York Academy of Sciences. 1995 July 7; 756: 313-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7544079
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Limited restriction in the TCR-alpha beta V region usage of antigen-specific clones. Recognition of myelin basic protein (amino acids 84-102) and Mycobacterium bovis 65-kDa heat shock protein (amino acids 3-13) by T cell clones established from peripheral blood mononuclear cells of monozygotic twins and HLA-identical individuals. Author(s): Hawes GE, Struyk L, Godthelp BC, van den Elsen PJ. Source: Journal of Immunology (Baltimore, Md. : 1950). 1995 January 15; 154(2): 555-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7529279
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Linear epitopes of two different autoantigens-La/SSB and myelin basic protein--with a high degree of molecular similarity, cause different humoral immune responses. Author(s): Terzoglou AG, Routsias JG, Sakarellos C, Sakarellos-Daitsiotis M, Moutsopoulos HM, Tzioufas AG. Source: Journal of Autoimmunity. 2003 August; 21(1): 47-57. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12892735
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Linkage analysis of candidate myelin genes in familial multiple sclerosis. Author(s): Seboun E, Oksenberg JR, Rombos A, Usuku K, Goodkin DE, Lincoln RR, Wong M, Pham-Dinh D, Boesplug-Tanguy O, Carsique R, Fitoussi R, Gartioux C, Reyes C, Ribierre F, Faure S, Fizames C, Gyapay G, Weissenbach J, Dautigny A, Rimmler JB, Garcia ME, Pericak-Vance MA, Haines JL, Hauser SL. Source: Neurogenetics. 1999 September; 2(3): 155-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10541588
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Linkage and association analysis of genes encoding cytokines and myelin proteins in multiple sclerosis. Author(s): He B, Xu C, Yang B, Landtblom AM, Fredrikson S, Hillert J. Source: Journal of Neuroimmunology. 1998 June 1; 86(1): 13-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9655468
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Linkage disequilibrium analysis of polymorphisms in the gene for myelin oligodendrocyte glycoprotein in Tourette's syndrome patients from a Chinese sample. Author(s): Huang Y, Li T, Wang Y, Ansar J, Lanting G, Liu X, Zhao JH, Hu X, Sham PC, Collier D. Source: American Journal of Medical Genetics. 2004 January 1; 124B(1): 76-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14681920
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Linkage study of polymorphisms in the gene for myelin oligodendrocyte glycoprotein located on chromosome 6p and attention deficit hyperactivity disorder. Author(s): Barr CL, Shulman R, Wigg K, Schachar R, Tannock R, Roberts W, Malone M, Kennedy JL. Source: American Journal of Medical Genetics. 2001 April 8; 105(3): 250-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11353444
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Localization and partial characterization of a 60 kDa citrulline-containing transport form of myelin basic protein from MO3-13 cells and human white matter. Author(s): Ursell MR, McLaurin J, Wood DD, Ackerley CA, Moscarello MA. Source: Journal of Neuroscience Research. 1995 September 1; 42(1): 41-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8531225
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Localization of a gene responsible for autosomal recessive demyelinating neuropathy with focally folded myelin sheaths to chromosome 11q23 by homozygosity mapping and haplotype sharing. Author(s): Bolino A, Brancolini V, Bono F, Bruni A, Gambardella A, Romeo G, Quattrone A, Devoto M. Source: Human Molecular Genetics. 1996 July; 5(7): 1051-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8817346
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Localization of basic proteins in human myelin. Author(s): McLaurin J, Ackerley CA, Moscarello MA. Source: Journal of Neuroscience Research. 1993 August 15; 35(6): 618-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7692076
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Longitudinal study of myelin basic protein-specific T-cell receptors during the course of multiple sclerosis. Author(s): Lovett-Racke AE, Martin R, McFarland HF, Racke MK, Utz U. Source: Journal of Neuroimmunology. 1997 September; 78(1-2): 162-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9307241
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Loss of myelin basic protein cationicity in DM20 transgenic mice is dosage dependent. Author(s): Mastronardi FG, Ackerley CA, Roots BI, Moscarello MA. Source: Journal of Neuroscience Research. 1996 May 15; 44(4): 301-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8739149
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Lower number and thinner myelin of large myelinated fibers in human cervical compression radiculopathy. Author(s): Oishi Y, Ohnishi A, Suzuki K, Hojo T. Source: Journal of Neurosurgery. 1995 August; 83(2): 342-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7616282
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Microheterogeneity of anti-myelin-associated glycoprotein antibodies. Author(s): Fluri F, Ferracin F, Erne B, Steck AJ. Source: Journal of the Neurological Sciences. 2003 March 15; 207(1-2): 43-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12614930
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Microscopic measurement of the facial nerve root exit zone from central glial myelin to peripheral Schwann cell myelin. Author(s): Tomii M, Onoue H, Yasue M, Tokudome S, Abe T. Source: Journal of Neurosurgery. 2003 July; 99(1): 121-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12854753
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Mutations in the Myelin Protein Zero result in a spectrum of Charcot-Marie-Tooth phenotypes. Author(s): Kochanski A. Source: Acta Myol. 2004 May; 23(1): 6-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15298082
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Mycobacterium leprae binds to a major human peripheral nerve glycoprotein myelin P zero (P0). Author(s): Suneetha LM, Singh SS, Vani M, Vardhini D, Scollard D, Archelos JJ, Srinivasulu M, Suneetha S. Source: Neurochemical Research. 2003 September; 28(9): 1393-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12945534
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Myelin basic protein gene is associated with MS in DR4- and DR5-positive Italians and Russians. Author(s): Guerini FR, Ferrante P, Losciale L, Caputo D, Lombardi ML, Pirozzi G, Luongo V, Sudomoina MA, Andreewski TV, Alekseenkov AD, Boiko AN, Gusev EI, Favorova OO. Source: Neurology. 2003 August 26; 61(4): 520-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12939427
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883934
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12620653
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Myelin molecules limiting nervous system plasticity. Author(s): Schnaar RL. Source: Prog Mol Subcell Biol. 2003; 32: 125-42. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12827974
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Myelin oligodendrocyte glycoprotein-35-55 peptide induces severe chronic experimental autoimmune encephalomyelitis in HLA-DR2-transgenic mice. Author(s): Rich C, Link JM, Zamora A, Jacobsen H, Meza-Romero R, Offner H, Jones R, Burrows GG, Fugger L, Vandenbark AA. Source: European Journal of Immunology. 2004 May; 34(5): 1251-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15114658
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Myelin protein zero gene mutations in Taiwanese patients with Charcot-Marie-Tooth disease type 1. Author(s): Lee YC, Soong BW, Lin KP, Lee HY, Wu ZA, Kao KP. Source: Journal of the Neurological Sciences. 2004 April 15; 219(1-2): 95-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15050444
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Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptor signaling, and correlation with axon regeneration. Author(s): Sandvig A, Berry M, Barrett LB, Butt A, Logan A. Source: Glia. 2004 May; 46(3): 225-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15048847
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Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Author(s): Filbin MT. Source: Nature Reviews. Neuroscience. 2003 September; 4(9): 703-13. Review. Erratum In: Nat Rev Neurosci. 2003 December; 4(12): 1019. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12951563
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Neural CAMS and their role in the development and organization of myelin sheaths. Author(s): Bartsch U. Source: Frontiers in Bioscience : a Journal and Virtual Library. 2003 January 1; 8: D47790. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12456309
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Neurotrophic factors protect myelin from attack. Author(s): Kerschensteiner M, Hohlfeld R. Source: Int Ms J. 2003 April; 10(1): 2-4. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12906763
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New insights on the biology of myelin basic protein gene: the neural-immune connection. Author(s): Givogri MI, Bongarzone ER, Campagnoni AT. Source: Journal of Neuroscience Research. 2000 January 15; 59(2): 153-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10650873
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No association between anti-myelin oligodendrocyte glycoprotein antibodies and serum/cerebrospinal fluid levels of the soluble interleukin-6 receptor complex in multiple sclerosis. Author(s): Padberg F, Haase CG, Feneberg W, Schwarz MJ, Hampel H. Source: Neuroscience Letters. 2001 June 1; 305(1): 13-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11356296
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No evidence for transmission disequilibrium between a new marker at the myelin basic protein locus and multiple sclerosis in French patients. Author(s): Coppin H, Ribouchon MT, Bausero P, Pessac B, Fontaine B, Semana G, Clanet M, Roth MP; French Multiple Sclerosis Genetics Group. Source: Genes and Immunity. 2000 December; 1(8): 478-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11197688
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Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1. Author(s): Niederost B, Oertle T, Fritsche J, McKinney RA, Bandtlow CE. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2002 December 1; 22(23): 10368-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12451136
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Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Author(s): Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME. Source: Nature. 2000 January 27; 403(6768): 434-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10667796
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Novel monoclonal antibodies against proteolipid protein peptide 139-151 demonstrate demyelination and myelin uptake by macrophages in MS and marmoset EAE lesions. Author(s): Laman JD, Visser L, Maassen CB, de Groot CJ, de Jong LA, 't Hart BA, van Meurs M, Schellekens MM. Source: Journal of Neuroimmunology. 2001 September 3; 119(1): 124-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11525809
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Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy. Author(s): Mastaglia FL, Nowak KJ, Stell R, Phillips BA, Edmondston JE, Dorosz SM, Wilton SD, Hallmayer J, Kakulas BA, Laing NG. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 1999 August; 67(2): 174-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10406984
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Nuclear transport of myelin basic protein. Author(s): Pedraza L. Source: Journal of Neuroscience Research. 1997 October 15; 50(2): 258-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9373035
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Oligodendrocyte myelin glycoprotein (OMgp): evolution, structure and function. Author(s): Vourc'h P, Andres C. Source: Brain Research. Brain Research Reviews. 2004 May; 45(2): 115-24. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15145622
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Oligodendrocyte myelin glycoprotein growth inhibition function requires its conserved leucine-rich repeat domain, not its glycosylphosphatidyl-inositol anchor. Author(s): Vourc'h P, Moreau T, Arbion F, Marouillat-Vedrine S, Muh JP, Andres C. Source: Journal of Neurochemistry. 2003 May; 85(4): 889-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716421
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Oligodendrocyte-myelin glycoprotein (OMgp) is an inhibitor of neurite outgrowth. Author(s): Kottis V, Thibault P, Mikol D, Xiao ZC, Zhang R, Dergham P, Braun PE. Source: Journal of Neurochemistry. 2002 September; 82(6): 1566-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12354307
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Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Author(s): Wang KC, Koprivica V, Kim JA, Sivasankaran R, Guo Y, Neve RL, He Z. Source: Nature. 2002 June 27; 417(6892): 941-4. Epub 2002 Jun 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12068310
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On the biogenesis of the myelin sheath: cognate polarized trafficking pathways in oligodendrocytes. Author(s): de Vries H, Hoekstra D. Source: Glycoconjugate Journal. 2000 March-April; 17(3 -4): 181-90. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11201789
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Optimization of gray/white matter contrast with fast inversion recovery for myelin suppression: a comparison of fast spin-echo and echo-planar MR imaging sequences. Author(s): Wolansky LJ, Finden SG, Chen J, Hanna R, Holodny AI, Ahmad I, Liu WC, Contractor S. Source: Ajnr. American Journal of Neuroradiology. 1999 October; 20(9): 1653-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10543636
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Oral administration of myelin induces antigen-specific TGF-beta 1 secreting T cells in patients with multiple sclerosis. Author(s): Hafler DA, Kent SC, Pietrusewicz MJ, Khoury SJ, Weiner HL, Fukaura H. Source: Annals of the New York Academy of Sciences. 1997 December 19; 835: 120-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9616767
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Oral administration of myelin induces antigen-specific TGF-beta 1-secreting T cells in multiple sclerosis patients. Author(s): Kent SC, Fukaura H, Pietrusewicz MJ, Khoury SJ, Weiner HL, Hafler DA. Source: Annals of the New York Academy of Sciences. 1997 April 5; 815: 412-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9186687
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Overloaded endoplasmic reticulum-Golgi compartments, a possible pathomechanism of peripheral neuropathies caused by mutations of the peripheral myelin protein PMP22. Author(s): D'Urso D, Prior R, Greiner-Petter R, Gabreels-Festen AA, Muller HW. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 1998 January 15; 18(2): 731-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9425015
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109
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Overproduction and immuno-affinity purification of myelin proteolipid protein (PLP), an inositol hexakisphosphate-binding protein, in a baculovirus expression system. Author(s): Fukuzono S, Takeshita T, Sakamoto T, Hisada A, Shimizu N, Mikoshiba K. Source: Biochemical and Biophysical Research Communications. 1998 August 10; 249(1): 66-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9705833
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Patients lacking the major CNS myelin protein, proteolipid protein 1, develop lengthdependent axonal degeneration in the absence of demyelination and inflammation. Author(s): Garbern JY, Yool DA, Moore GJ, Wilds IB, Faulk MW, Klugmann M, Nave KA, Sistermans EA, van der Knaap MS, Bird TD, Shy ME, Kamholz JA, Griffiths IR. Source: Brain; a Journal of Neurology. 2002 March; 125(Pt 3): 551-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11872612
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Persistence of immune responses to altered and native myelin antigens in patients with multiple sclerosis treated with altered peptide ligand. Author(s): Kim HJ, Antel JP, Duquette P, Alleva DG, Conlon PJ, Bar-Or A. Source: Clinical Immunology (Orlando, Fla.). 2002 August; 104(2): 105-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12165271
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Phenotypic differences between peripheral myelin protein-22 (PMP22) and myelin protein zero (P0) mutations associated with Charcot-Marie-Tooth-related diseases. Author(s): Shames I, Fraser A, Colby J, Orfali W, Snipes GJ. Source: Journal of Neuropathology and Experimental Neurology. 2003 July; 62(7): 75164. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12901701
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Possible contributions of myelin and oligodendrocyte dysfunction to schizophrenia. Author(s): Stewart DG, Davis KL. Source: Int Rev Neurobiol. 2004; 59: 381-424. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15006496
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Preliminary magnetic resonance study of the macromolecular proton fraction in white matter: a potential marker of myelin? Author(s): Davies GR, Ramani A, Dalton CM, Tozer DJ, Wheeler-Kingshott CA, Barker GJ, Thompson AJ, Miller DH, Tofts PS. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 June; 9(3): 246-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12814170
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Primary structure of equine myelin basic protein by mass spectrometry. Author(s): Wood DD, She YM, Freer AD, Harauz G, Moscarello MA. Source: Archives of Biochemistry and Biophysics. 2002 September 1; 405(1): 137-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176067
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Probable epitopes: Relationships between myelin basic protein antigenic determinants and viral and bacterial proteins. Author(s): Klee L, Zand R. Source: Neuroinformatics. 2004; 2(1): 59-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15067168
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Progesterone synthesis and myelin formation in peripheral nerves. Author(s): Schumacher M, Guennoun R, Mercier G, Desarnaud F, Lacor P, Benavides J, Ferzaz B, Robert F, Baulieu EE. Source: Brain Research. Brain Research Reviews. 2001 November; 37(1-3): 343-59. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11744099
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Protein S-100B, neuron-specific enolase (NSE), myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) and blood of neurological patients. Author(s): Lamers KJ, Vos P, Verbeek MM, Rosmalen F, van Geel WJ, van Engelen BG. Source: Brain Research Bulletin. 2003 August 15; 61(3): 261-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12909296
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Proteins of peripheral myelin are associated with glycosphingolipid/cholesterolenriched membranes. Author(s): Hasse B, Bosse F, Muller HW. Source: Journal of Neuroscience Research. 2002 July 15; 69(2): 227-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12111804
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Quantification of myelin basic protein in the human fetal spinal cord during the midtrimester of gestation. Author(s): Grever WE, Chiu FC, Tricoche M, Rashbaum WK, Weidenheim KM, Lyman WD. Source: The Journal of Comparative Neurology. 1996 December 9; 376(2): 306-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8951645
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Quantitation of the myelin-associated glycoprotein in human nervous tissue from controls and multiple sclerosis patients. Author(s): Johnson D, Sato S, Quarles RH, Inuzuka T, Brady RO, Tourtellotte WW. Source: Journal of Neurochemistry. 1986 April; 46(4): 1086-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2419505
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Rafts in adult peripheral nerve myelin contain major structural myelin proteins and myelin and lymphocyte protein (MAL) and CD59 as specific markers. Author(s): Erne B, Sansano S, Frank M, Schaeren-Wiemers N. Source: Journal of Neurochemistry. 2002 August; 82(3): 550-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12153479
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Rat and human myelin oligodendrocyte glycoproteins induce experimental autoimmune encephalomyelitis by different mechanisms in C57BL/6 mice. Author(s): Oliver AR, Lyon GM, Ruddle NH. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 July 1; 171(1): 462-8. Erratum In: J Immunol. 2003 November 1; 171(9): 4934. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12817031
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Recombinant TCR ligand induces tolerance to myelin oligodendrocyte glycoprotein 35-55 peptide and reverses clinical and histological signs of chronic experimental autoimmune encephalomyelitis in HLA-DR2 transgenic mice. Author(s): Vandenbark AA, Rich C, Mooney J, Zamora A, Wang C, Huan J, Fugger L, Offner H, Jones R, Burrows GG. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 July 1; 171(1): 127-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12816990
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Regenerating myelin. Author(s): Scolding N. Source: Brain; a Journal of Neurology. 2001 November; 124(Pt 11): 2129-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11673315
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Relationships between arteriosclerosis, cerebral amyloid angiopathy and myelin loss from cerebral cortical white matter in Alzheimer's disease. Author(s): Tian J, Shi J, Bailey K, Mann DM. Source: Neuropathology and Applied Neurobiology. 2004 February; 30(1): 46-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14720176
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Remyelination-promoting antibodies activate distinct Ca2+ influx pathways in astrocytes and oligodendrocytes: relationship to the mechanism of myelin repair. Author(s): Paz Soldan MM, Warrington AE, Bieber AJ, Ciric B, Van Keulen V, Pease LR, Rodriguez M. Source: Molecular and Cellular Neurosciences. 2003 January; 22(1): 14-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12595235
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Repair of myelin disease: strategies and progress in animal models. Author(s): Duncan ID, Grever WE, Zhang SC. Source: Molecular Medicine Today. 1997 December; 3(12): 554-61. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9449127
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Retinoic acid promotes the development of Th2-like human myelin basic proteinreactive T cells. Author(s): Lovett-Racke AE, Racke MK. Source: Cellular Immunology. 2002 January; 215(1): 54-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12142036
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Robust myelin water quantification: averaging vs. spatial filtering. Author(s): Jones CK, Whittall KP, MacKay AL. Source: Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2003 July; 50(1): 206-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12815697
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Role of myelin basic protein and proteolipid protein genes in multiple sclerosis: single strand conformation polymorphism analysis of the human sequences. Author(s): Price SE, Sharpe G, Boots A, Poutsma A, Mason C, James J, Hinks L, Thompson RJ. Source: Neuropathology and Applied Neurobiology. 1997 December; 23(6): 457-67. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9460711
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Secreted glycoprotein myocilin is a component of the myelin sheath in peripheral nerves. Author(s): Ohlmann A, Goldwich A, Flugel-Koch C, Fuchs AV, Schwager K, Tamm ER. Source: Glia. 2003 August; 43(2): 128-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12838505
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Sex differences in cytokine responses to myelin peptides in multiple sclerosis. Author(s): Pelfrey CM, Cotleur AC, Lee JC, Rudick RA. Source: Journal of Neuroimmunology. 2002 September; 130(1-2): 211-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12225904
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Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein. Author(s): Blixt O, Collins BE, van den Nieuwenhof IM, Crocker PR, Paulson JC. Source: The Journal of Biological Chemistry. 2003 August 15; 278(33): 31007-19. Epub 2003 May 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12773526
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Signaling mechanisms of the myelin inhibitors of axon regeneration. Author(s): Yiu G, He Z. Source: Current Opinion in Neurobiology. 2003 October; 13(5): 545-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14630216
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Significance of uncompacted myelin lamellae in POEMS syndrome. Author(s): Vital C, Bouillot S, Vital A. Source: Muscle & Nerve. 2003 February; 27(2): 253-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12548537
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12460184
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Specific proliferation towards myelin antigens in patients with multiple sclerosis during a relapse. Author(s): Saez-Torres I, Brieva L, Espejo C, Barrau MA, Montalban X, Martinez-Caceres EM. Source: Autoimmunity. 2002 February; 35(1): 45-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11908706
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12480078
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Structural similarity between the bee venom peptides and the immunodominant human myelin basic proteins: role for pathogenesis of acute disseminated encephalomyelitis. Author(s): Dharmasaroja P. Source: The Journal of Allergy and Clinical Immunology. 2003 February; 111(2): 426-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12589368
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Structure of the Nogo receptor ectodomain: a recognition module implicated in myelin inhibition. Author(s): He XL, Bazan JF, McDermott G, Park JB, Wang K, Tessier-Lavigne M, He Z, Garcia KC. Source: Neuron. 2003 April 24; 38(2): 177-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12718853
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T cell epitope spreading to myelin oligodendrocyte glycoprotein in HLA-DR4 transgenic mice during experimental autoimmune encephalomyelitis. Author(s): Klehmet J, Shive C, Guardia-Wolff R, Petersen I, Spack EG, Boehm BO, Weissert R, Forsthuber TG. Source: Clinical Immunology (Orlando, Fla.). 2004 April; 111(1): 53-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15093552
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T cell epitopes of human myelin oligodendrocyte glycoprotein identified in HLADR4 (DRB1*0401) transgenic mice are encephalitogenic and are presented by human B cells. Author(s): Forsthuber TG, Shive CL, Wienhold W, de Graaf K, Spack EG, Sublett R, Melms A, Kort J, Racke MK, Weissert R. Source: Journal of Immunology (Baltimore, Md. : 1950). 2001 December 15; 167(12): 711925. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11739534
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The current status of structural studies on proteins of the myelin sheath (Review). Author(s): Kursula P. Source: International Journal of Molecular Medicine. 2001 November; 8(5): 475-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11605013
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The human T cell response to myelin oligodendrocyte glycoprotein: a multiple sclerosis family-based study. Author(s): Koehler NK, Genain CP, Giesser B, Hauser SL. Source: Journal of Immunology (Baltimore, Md. : 1950). 2002 June 1; 168(11): 5920-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12023398
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The myelin-associated oligodendrocytic basic protein region MOBP15-36 encompasses the immunodominant major encephalitogenic epitope(s) for SJL/J mice and predicted epitope(s) for multiple sclerosis-associated HLA-DRB1*1501. Author(s): de Rosbo NK, Kaye JF, Eisenstein M, Mendel I, Hoeftberger R, Lassmann H, Milo R, Ben-Nun A. Source: Journal of Immunology (Baltimore, Md. : 1950). 2004 July 15; 173(2): 1426-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15240739
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The Nogo-66 receptor: focusing myelin inhibition of axon regeneration. Author(s): McGee AW, Strittmatter SM. Source: Trends in Neurosciences. 2003 April; 26(4): 193-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12689770
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The oligodendrocyte-myelin glycoprotein gene is highly expressed during the late stages of myelination in the rat central nervous system. Author(s): Vourc'h P, Dessay S, Mbarek O, Marouillat Vedrine S, Muh JP, Andres C. Source: Brain Research. Developmental Brain Research. 2003 September 10; 144(2): 15968. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12935913
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Truncated soluble Nogo receptor binds Nogo-66 and blocks inhibition of axon growth by myelin. Author(s): Fournier AE, Gould GC, Liu BP, Strittmatter SM. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2002 October 15; 22(20): 8876-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12388594
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Tumor necrosis factor modulates transcription of myelin basic protein gene through nuclear factor kappa B in a human oligodendroglioma cell line. Author(s): Huang CJ, Nazarian R, Lee J, Zhao PM, Espinosa-Jeffrey A, de Vellis J. Source: International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience. 2002 June-August; 20(3-5): 28996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12175864
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Two amino-acid substitutions in the myelin protein zero gene of a case of CharcotMarie-Tooth disease associated with light-near dissociation. Author(s): Bienfait HM, Baas F, Gabreels-Festen AA, Koelman JH, Langerhorst CT, de Visser M. Source: Neuromuscular Disorders : Nmd. 2002 March; 12(3): 281-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11801400
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Ultrastructural identification of peripheral myelin proteins by a pre-embedding immunogold labeling method. Author(s): Canron MH, Bouillot S, Favereaux A, Petry KG, Vital A. Source: Journal of the Peripheral Nervous System : Jpns. 2003 March; 8(1): 1-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12678547
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Ultrastructural immunocytochemical abnormalities of peripheral myelin proteins in hereditary sensory-motor neuropathies: 12 cases. Author(s): Anani T, Sindou P, Richard L, Diot M, Vallat JM. Source: Annals of the New York Academy of Sciences. 1999 September 14; 883: 186-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10586244
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Uncompacted inner myelin lamellae in inherited tendency to pressure palsy. Author(s): Yoshikawa H, Dyck PJ. Source: Journal of Neuropathology and Experimental Neurology. 1991 September; 50(5): 649-57. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1895146
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Uncompacted myelin in hereditary neuropathy with liability to pressure palsies with the 17 p11.2 deletion. Author(s): Jedrzejowska H, Fidzianska A, Kochanski A. Source: Folia Neuropathol. 1999; 37(4): 220-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10705641
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Uncompacted myelin lamellae in peripheral nerve biopsy. Author(s): Vital C, Vital A, Bouillot S, Favereaux A, Lagueny A, Ferrer X, Brechenmacher C, Petry KG. Source: Ultrastructural Pathology. 2003 January-February; 27(1): 1-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12554530
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Underexpression of messenger RNA for peripheral myelin protein 22 in hereditary neuropathy with liability to pressure palsies. Author(s): Schenone A, Nobbio L, Mandich P, Bellone E, Abbruzzese M, Aymar F, Mancardi GL, Windebank AJ. Source: Neurology. 1997 February; 48(2): 445-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9040736
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Unmasking of an unusual myelin basic protein epitope during the process of myelin degeneration in humans: a potential mechanism for the generation of autoantigens. Author(s): Matsuo A, Lee GC, Terai K, Takami K, Hickey WF, McGeer EG, McGeer PL. Source: American Journal of Pathology. 1997 April; 150(4): 1253-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9094982
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Urinary myelin basic protein-like material in patients with multiple sclerosis during interferon beta-1b treatment. Author(s): Whitaker JN, Layton BA, Bartolucci AA, Mitchell GW, Bashir K, Goodwin J, Kachelhofer RD. Source: Archives of Neurology. 1999 June; 56(6): 687-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10369307
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Usefulness of a mouse myelin basic protein promoter for gene therapy of malignant glioma: myelin basic protein promoter is strongly active in human malignant glioma cells. Author(s): Miyao Y, Shimizu K, Tamura M, Akita H, Ikeda K, Mabuchi E, Kishima H, Hayakawa T, Ikenaka K. Source: Japanese Journal of Cancer Research : Gann. 1997 July; 88(7): 678-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9310141
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UV irradiation-induced apoptosis leads to activation of a 36-kDa myelin basic protein kinase in HL-60 cells. Author(s): Lu ML, Sato M, Cao B, Richie JP. Source: Proceedings of the National Academy of Sciences of the United States of America. 1996 August 20; 93(17): 8977-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8799139
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Vacuolar myelopathy in transgenic mice expressing human immunodeficiency virus type 1 proteins under the regulation of the myelin basic protein gene promoter. Author(s): Goudreau G, Carpenter S, Beaulieu N, Jolicoeur P. Source: Nature Medicine. 1996 June; 2(6): 655-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8640556
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Variability in the structural requirements for binding of human monoclonal antimyelin-associated glycoprotein immunoglobulin M antibodies and HNK-1 to sphingoglycolipid antigens. Author(s): Ilyas AA, Chou DK, Jungalwala FB, Costello C, Quarles RH. Source: Journal of Neurochemistry. 1990 August; 55(2): 594-601. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1695241
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Variation in STR loci of the human myelin basic protein gene: north Portugal and Sao Tome e Principe. Author(s): Pereira L, Gusmao L, Prata MJ, Mota P, Trovoada MJ, Amorim A. Source: Human Biology; an International Record of Research. 2000 June; 72(3): 481-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10885193
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Variation of myelin basic protein and its antibody in serum in senile dementia patients. Author(s): Ge W, Cheng Y, Zhang S, Ye S, Chen J, Wang R, Li C. Source: Chinese Medical Sciences Journal = Chung-Kuo I Hsueh K'o Hsueh Tsa Chih / Chinese Academy of Medical Sciences. 2000 March; 15(1): 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899395
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Viral homologies with myelin basic protein. Author(s): Souberbielle BE, Kemp G, Russell WC. Source: Immunology Today. 1991 December; 12(12): 464-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1723879
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Visna and myelin basic protein. Author(s): Carnegie PR, Weise MJ. Source: Nature. 1987 September 24-30; 329(6137): 294. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2442623
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Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85-99 complex. Author(s): Krogsgaard M, Wucherpfennig KW, Cannella B, Hansen BE, Svejgaard A, Pyrdol J, Ditzel H, Raine C, Engberg J, Fugger L, Canella B. Source: The Journal of Experimental Medicine. 2000 April 17; 191(8): 1395-412. Erratum In: J Exp Med. 2003 Apr 7; 197(7): 947. Canella B [corrected to Cannella B]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10770805
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Was the ASN a myelin society? American Society for Neurochemistry. Author(s): Smith ME. Source: Neurochemical Research. 2000 October; 25(9-10): 1453-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11059816
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Water content and myelin water fraction in multiple sclerosis. A T2 relaxation study. Author(s): Laule C, Vavasour IM, Moore GR, Oger J, Li DK, Paty DW, MacKay AL. Source: Journal of Neurology. 2004 March; 251(3): 284-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15015007
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Where, when and how much: regulation of myelin proteolipid protein gene expression. Author(s): Wight PA, Dobretsova A. Source: Cellular and Molecular Life Sciences : Cmls. 2004 April; 61(7-8): 810-21. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15095005
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White matter changes in schizophrenia: evidence for myelin-related dysfunction. Author(s): Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR, Buxbaum J, Haroutunian V. Source: Archives of General Psychiatry. 2003 May; 60(5): 443-56. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742865
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Widenings of the myelin lamellae in a typical Guillain-Barre syndrome. Author(s): Vallat JM, Leboutet MJ, Jauberteau MO, Tabaraud F, Couratier P, Akani F. Source: Muscle & Nerve. 1994 April; 17(4): 378-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8170482
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X-ray diffraction evidence for myelin disorder in brain from humans with Alzheimer's disease. Author(s): Chia LS, Thompson JE, Moscarello MA. Source: Biochimica Et Biophysica Acta. 1984 September 5; 775(3): 308-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6466674
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Zinc ions stabilise the association of basic protein with brain myelin membranes. Author(s): Earl C, Chantry A, Mohammad N, Glynn P. Source: Journal of Neurochemistry. 1988 September; 51(3): 718-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2457650
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CHAPTER 2. NUTRITION AND MYELIN Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and myelin.
Finding Nutrition Studies on Myelin 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 “myelin” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
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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 information is typical of that found when using the “Full IBIDS Database” to search for “myelin” (or a synonym): •
Behavioral effects of chronic melatonin and pregnenolone injections in a myelin mutant rat (taiep). Author(s): Department of Psychology, Saint Louis University, St Louis, MO 63103, USA. Source: Bloom, C M Anch, A M Dyche, J S J-Gen-Psychol. 2002 July; 129(3): 226-37 00221309
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Cryoelectron microscopy of protein-lipid complexes of human myelin basic protein charge isomers differing in degree of citrullination. Author(s): Department of Molecular Biology and Genetics, University of Guelph, Guelph, Ontario, N1G 2W1, Canada. Source: Beniac, D R Wood, D D Palaniyar, N Ottensmeyer, F P Moscarello, M A Harauz, G J-Struct-Biol. 2000 February; 129(1): 80-95 1047-8477
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Dietary prenatal lipids affect myelin gene expression in postnatal undernourished rats. Author(s): Neurochemistry Section, Istituto Superiore di Sanita, Rome, Italy.
[email protected] Source: Salvati, S Attorri, L Avellino, C Di Biase, A Sanchez, M Nutr-Neurosci. 2002 September; 5(4): 243-50 1028-415X
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Effects of the osmolyte trimethylamine-N-oxide on conformation, self-association, and two-dimensional crystallization of myelin basic protein. Author(s): Department of Molecular Biology and Genetics, University of Guelph, 50 Stone Road East, Guelph, Ont., Canada N1G 2W1. Source: Hill, C M Bates, I R White, G F Hallett, F R Harauz, G J-Struct-Biol. 2002 July; 139(1): 13-26 1047-8477
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Protein kinase C inhibitors counteract the ethanol effects on myelin basic protein expression in differentiating CG-4 oligodendrocytes. Author(s): Department of Pathology, Anatomy, and Cell Biology, 264 Jefferson Alumni Hall, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA. Source: Bichenkov, E Ellingson, J S Brain-Res-Dev-Brain-Res. 2002 November 15; 139(1): 29-38 0165-3806
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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WebMDHealth: 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 myelin; 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 Vitamin B Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10067,00.html
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Food and Diet Omega-3 Fatty Acids Source: Integrative Medicine Communications; www.drkoop.com
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CHAPTER 3. ALTERNATIVE MEDICINE AND MYELIN Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to myelin. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to myelin 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 “myelin” (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 myelin: •
5'-nucleotidase in rat brain myelin. Author(s): Cammer W, Sirota SR, Zimmerman TR Jr, Norton WT. Source: Journal of Neurochemistry. 1980 August; 35(2): 367-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6256485
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A new approach for the treatment of demyelinating diseases? Author(s): Bohuslavizki KH, Koppenhofer E, Hansel W, Moller WD. Source: Journal of Neuroimmunology. 1988 December; 20(2-3): 251-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3198750
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Activity of myelin membrane Na+/K+-ATPase and 5'-nucleotidase in relation to phospholipid acyl profiles, ganglioside composition and phosphoinositides in developing brains of undernourished rats. Author(s): Shantharam P, SrinivasaRao P.
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Source: Biochimica Et Biophysica Acta. 1989 June 26; 982(1): 115-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2545271 •
Adsorption of natural lung surfactant and phospholipid extracts related to tubular myelin formation. Author(s): Notter RH, Penney DP, Finkelstein JN, Shapiro DL. Source: Pediatric Research. 1986 January; 20(1): 97-101. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3753757
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Alterations in the fatty acid composition of rat brain cells (neurons, astrocytes, and oligodendrocytes) and of subcellular fractions (myelin and synaptosomes) induced by a diet devoid of n-3 fatty acids. Author(s): Bourre JM, Pascal G, Durand G, Masson M, Dumont O, Piciotti M. Source: Journal of Neurochemistry. 1984 August; 43(2): 342-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6736955
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Anatomical and physiological measures of auditory system in mice with peripheral myelin deficiency. Author(s): Zhou R, Assouline JG, Abbas PJ, Messing A, Gantz BJ. Source: Hearing Research. 1995 August; 88(1-2): 87-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8576008
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Ascending myelopathy after chemotherapy for central nervous system acute lymphoblastic leukemia: correlation with cerebrospinal fluid myelin basic protein. Author(s): Bates SE, Raphaelson MI, Price RA, McKeever P, Cohen S, Poplack DG. Source: Medical and Pediatric Oncology. 1985; 13(1): 4-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2578602
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Associated polyneuropathy and demyelinating disease. Case report. Author(s): Rebaudengo N, Bianco C, Ferrero P, Troni W, Bergamasco B. Source: Italian Journal of Neurological Sciences. 1992 December; 13(9): 793-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1483863
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Binding of soluble myelin basic protein to various conformational forms of alpha2macroglobulin. Author(s): Gunnarsson M, Jensen PE. Source: Archives of Biochemistry and Biophysics. 1998 November 15; 359(2): 192-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9808760
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Binding partners for the myelin-associated glycoprotein of N2A neuroblastoma cells. Author(s): Strenge K, Schauer R, Kelm S.
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Source: Febs Letters. 1999 February 5; 444(1): 59-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10037148 •
Calcitonin gene-related peptide produces skeletal muscle vasodilation following antidromic stimulation of unmyelinated afferents in the dorsal root in rats. Author(s): Sato A, Sato Y, Shimura M, Uchida S. Source: Neuroscience Letters. 2000 April 7; 283(2): 137-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10739894
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Cell-based remyelinating therapies in multiple sclerosis: evidence from experimental studies. Author(s): Pluchino S, Furlan R, Martino G. Source: Current Opinion in Neurology. 2004 June; 17(3): 247-55. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15167057
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Changes in fatty acid composition of peripheral nerve myelin in essential fatty acid deficiency. Author(s): Yao JK, Holman RT, Lubozynski MF, Dyck PJ. Source: Archives of Biochemistry and Biophysics. 1980 October 1; 204(1): 175-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7425636
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Characterization of proteolipid protein fatty acylesterase from rat brain myelin. Author(s): Bizzozero OA, Leyba J, Nunez DJ. Source: The Journal of Biological Chemistry. 1992 April 15; 267(11): 7886-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1560018
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Complement regulatory molecules on human myelin and glial cells: differential expression affects the deposition of activated complement proteins. Author(s): Koski CL, Estep AE, Sawant-Mane S, Shin ML, Highbarger L, Hansch GM. Source: Journal of Neurochemistry. 1996 January; 66(1): 303-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8522968
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Degradation of myelin proteins by brain endogenous neutral protease. Author(s): Singh I, Singh AK. Source: Neuroscience Letters. 1983 August 19; 39(1): 77-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6195561
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Demyelination induced by protein kinase C-activating tumor promoters in aggregating brain cell cultures. Author(s): Pouly S, Storch MK, Matthieu JM, Lassmann H, Monnet-Tschudi F, Honegger P.
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Source: Journal of Neuroscience Research. 1997 July 15; 49(2): 121-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9272635 •
Dietary supplementation of undernourished rats with soy or safflower oil: effects on myelin polyunsaturated fatty acids. Author(s): Divakaran P, Pavlina T, Johnson RC, Cotter R, Madsen D, Wiggins R. Source: Metabolic Brain Disease. 1986 June; 1(2): 157-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3508240
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Dissociation of axonally transported proteins from myelin by ethylenediamine tetraacetate (EDTA). Author(s): Elam JS. Source: Journal of Neurochemistry. 1978 July; 31(1): 351-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=97370
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Dose and duration related methylmercury deposition, glycosidases inhibition, myelin degeneration and chelation therapy. Author(s): Vinay SD, Raghu KG, Sood PP. Source: Cell Mol Biol. 1990; 36(5): 609-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2073685
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Effect of a vitamin B-12-deficient diet on lipid and fatty acid composition of spinal cord myelin in the fruit bat. Author(s): van der Westhuyzen J, Cantrill RC, Fernandes-Costa F, Metz J. Source: The Journal of Nutrition. 1983 March; 113(3): 531-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6131113
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Effect of ATP depletion on the palmitoylation of myelin proteolipid protein in young and adult rats. Author(s): Bizzozero OA, Sanchez P, Tetzloff SU. Source: Journal of Neurochemistry. 1999 June; 72(6): 2610-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10349873
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Effect of mercury on rabbit myelin CNP-ase in vitro. Author(s): Domanska-Janik K, Bourre JM. Source: Neurotoxicology. 1987 Spring; 8(1): 23-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3031563
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Effect of pre- and postnatal essential fatty acid deficiency on brain development and myelination. Author(s): McKenna MC, Campagnoni AT.
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Source: The Journal of Nutrition. 1979 July; 109(7): 1195-204. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=448463 •
Effects of a fatty acid deficiency on lipids of whole brain, microsomes, and myelin in the rat. Author(s): Sun GY. Source: Journal of Lipid Research. 1972 January; 13(1): 56-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5059199
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Effects of dietary folate deficiency on developmental increase of myelin lipids in rat brain. Author(s): Hirono H, Wada Y. Source: The Journal of Nutrition. 1978 May; 108(5): 766-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=641593
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Effects of inhibitors of oligosaccharide processing on P0 protein synthesis and incorporation into PNS myelin. Author(s): Smith ME. Source: Journal of Neurochemistry. 1991 August; 57(2): 655-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1712832
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Elucidation of cathepsin B-like activity associated with extracts of human myelin basic protein. Author(s): Berlet HH, Ilzenhofer H. Source: Febs Letters. 1985 January 7; 179(2): 299-302. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2578412
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Enhanced resolution of glycosylphosphatidylinositol-anchored and transmembrane proteins from the lipid-rich myelin membrane by two-dimensional gel electrophoresis. Author(s): Taylor CM, Pfeiffer SE. Source: Proteomics. 2003 July; 3(7): 1303-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12872231
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Essential fatty acid deficiency and CNS myelin. Biochemical and morphological observations. Author(s): Trapp BD, Bernsohn J. Source: Journal of the Neurological Sciences. 1978 July; 37(3): 249-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=681979
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Essential fatty acid deficiency: effects of cross-fostering mice at birth on brain growth and myelination. Author(s): Berkow SE, Campagnoni AT.
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Source: The Journal of Nutrition. 1981 May; 111(5): 886-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7229737 •
Evolution of the myelin integral membrane proteins of the central nervous system. Author(s): Schliess F, Stoffel W. Source: Biol Chem Hoppe Seyler. 1991 September; 372(9): 865-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1722981
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Exogenous lipids in myelination and myelination. Author(s): Di Biase A, Salvati S. Source: Kaohsiung J Med Sci. 1997 January; 13(1): 19-29. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9130819
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Flavonoids inhibit myelin phagocytosis by macrophages; a structure-activity relationship study. Author(s): Hendriks JJ, de Vries HE, van der Pol SM, van den Berg TK, van Tol EA, Dijkstra CD. Source: Biochemical Pharmacology. 2003 March 1; 65(5): 877-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12628496
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Further evidence for an intrinsic neuraminidase in CNS myelin. Author(s): Yohe HC, Saito M, Ledeen RW, Kunishita T, Sclafani JR, Yu RK. Source: Journal of Neurochemistry. 1986 February; 46(2): 623-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3941322
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Gelatinase B is present in the cerebrospinal fluid during experimental autoimmune encephalomyelitis and cleaves myelin basic protein. Author(s): Gijbels K, Proost P, Masure S, Carton H, Billiau A, Opdenakker G. Source: Journal of Neuroscience Research. 1993 November 1; 36(4): 432-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7505841
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Golgi sulfation of the oligosaccharide chain of P0 occurs in the presence of myelin assembly but not in its absence. Author(s): Poduslo JF. Source: The Journal of Biological Chemistry. 1990 March 5; 265(7): 3719-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1689308
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Hexachlorophene myelinopathy in premature infants. Author(s): Powell H, Swarner O, Gluck L, Lampert P. Source: The Journal of Pediatrics. 1973 June; 82(6): 976-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4702917
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In vitro changes in the fine structure and protein composition of light myelin fractions isolated from guinea pig brain. Author(s): Nunzi MG, Chan KF, Webster HD. Source: Journal of Neuroscience Research. 1991 May; 29(1): 51-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1886168
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In vitro insertion of the myelin proteolipid apoprotein into oligodendrocyte plasma membranes. Author(s): Chraibi Z, Alfsen A, Lavialle F. Source: Neurochemical Research. 1989 November; 14(11): 1153-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2594144
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In vivo labeling of myelin lipids and proteolipid protein with [3H]myristate, [14C]linoleate, and [14C]linolenate. Author(s): Burgisser P, Matthieu JM. Source: Neurochemical Research. 1989 January; 14(1): 91-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2469026
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Increased susceptibility to degradation by trypsin and subtilisin of in vitro peroxidized myelin proteins. Author(s): Bongarzone ER, Soto EF, Pasquini JM. Source: Neurochemical Research. 1995 April; 20(4): 421-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7651579
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Induction of allergic encephalomyelitis using hydrosoluble adjuvant and the tryptophan region of myelin basic protein. Author(s): Westall FC, Thompson M, Migliore-Samour D, Jolles P. Source: Immunol Commun. 1975; 4(4): 353-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=52609
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Latency changes in brain stem auditory evoked potentials associated with impaired brain myelination. Author(s): Shah SN, Bhargava VK, Johnson RC, McKean CM. Source: Experimental Neurology. 1978 January 1; 58(1): 111-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=145371
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Lymphocytes binding basic protein of myelin; cytophilic serum antibody and effect of adjuvant. Author(s): Coates AS, Lennon VA. Source: Immunology. 1973 March; 24(3): 425-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4705614
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Macrophage phagocytosis of myelin in vitro determined by flow cytometry: phagocytosis is mediated by CR3 and induces production of tumor necrosis factoralpha and nitric oxide. Author(s): van der Laan LJ, Ruuls SR, Weber KS, Lodder IJ, Dopp EA, Dijkstra CD. Source: Journal of Neuroimmunology. 1996 November; 70(2): 145-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8898723
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Measuring in vivo myelination of human white matter fiber tracts with magnetization transfer MR. Author(s): Rademacher J, Engelbrecht V, Burgel U, Freund H, Zilles K. Source: Neuroimage. 1999 April; 9(4): 393-406. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10191168
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Modelling large areas of demyelination in the rat reveals the potential and possible limitations of transplanted glial cells for remyelination in the CNS. Author(s): Blakemore WF, Chari DM, Gilson JM, Crang AJ. Source: Glia. 2002 April 15; 38(2): 155-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11948809
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MRI evidence that docosahexaenoic acid ethyl ester improves myelination in generalized peroxisomal disorders. Author(s): Martinez M, Vazquez E. Source: Neurology. 1998 July; 51(1): 26-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9674774
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Myelin basic protein in the cerebrospinal fluid of patients with brain tumors. Author(s): Nakagawa H, Yamada M, Kanayama T, Tsuruzono K, Miyawaki Y, Tokiyoshi K, Hagiwara Y, Hayakawa T. Source: Neurosurgery. 1994 May; 34(5): 825-33; Discussion 833. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7519757
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Myelination by transplanted human and mouse central nervous system tissue after long-term cryopreservation. Author(s): Seilhean D, Gansmuller A, Baron-Van Evercooren A, Gumpel M, Lachapelle F. Source: Acta Neuropathologica. 1996; 91(1): 82-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8773151
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Neural precursors as a cell source to repair the demyelinated spinal cord. Author(s): Kocsis JD, Akiyama Y, Radtke C. Source: Journal of Neurotrauma. 2004 April; 21(4): 441-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15115593
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Neutral proteinases secreted by macrophages degrade basic protein: a possible mechanism of inflammatory demyelination. Author(s): Norton WT, Cammer W, Bloom BR, Gordon S. Source: Advances in Experimental Medicine and Biology. 1978; 100: 365-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=80946
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Paclitaxel (Taxol) attenuates clinical disease in a spontaneously demyelinating transgenic mouse and induces remyelination. Author(s): Moscarello MA, Mak B, Nguyen TA, Wood DD, Mastronardi F, Ludwin SK. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 April; 8(2): 130-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11990870
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Peripheral nerve demyelination in rabbits after inoculation with Freund's complete adjuvant alone or in combination with lipid haptens. Author(s): Mizisin AP, Wiley CA, Hughes RA, Powell HC. Source: Journal of Neuroimmunology. 1987 November; 16(3): 381-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2444628
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Polyphosphoinositide mono- and diphosphoesterases of three subfractions of rat brain myelin. Author(s): Deshmukh DS, Kuizon S, Bear WD, Brockerhoff H. Source: Neurochemical Research. 1982 May; 7(5): 617-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6289149
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Postnatal dietary fat influences mRNAS involved in myelination. Author(s): DeWille JW, Farmer SJ. Source: Developmental Neuroscience. 1992; 14(1): 61-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1350977
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Purification of calcium-activated neutral proteinase (CANP) from purified myelin of bovine brain white matter. Author(s): Chakrabarti AK, Banik NL. Source: Neurochemical Research. 1988 February; 13(2): 127-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2834658
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Quantitative electroimmunoblotting study of the calcium-activated neutral protease in human myelin. Author(s): Kerlero de Rosbo N, Carnegie PR, Bernard CC. Source: Journal of Neurochemistry. 1986 October; 47(4): 1007-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2427652
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Rapidly transported proteins released from nerve and isolated with myelin. Author(s): Edwards JA, Hines JF.
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Source: Brain Research. 1982 May 13; 239(2): 507-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6178470 •
Reconstitution of tubular myelin from synthetic lipids and proteins associated with pig pulmonary surfactant. Author(s): Suzuki Y, Fujita Y, Kogishi K. Source: Am Rev Respir Dis. 1989 July; 140(1): 75-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2751175
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Recovery of altered fatty acid composition induced by a diet devoid of n-3 fatty acids in myelin, synaptosomes, mitochondria, and microsomes of developing rat brain. Author(s): Youyou A, Durand G, Pascal G, Piciotti M, Dumont O, Bourre JM. Source: Journal of Neurochemistry. 1986 January; 46(1): 224-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3940283
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Regulation of myelin oligodendrocyte glycoprotein in different species throughout development. Author(s): Slavin AJ, Johns TG, Orian JM, Bernard CC. Source: Developmental Neuroscience. 1997; 19(1): 69-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9078435
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Remyelination in vitro following protein kinase C activator-induced demyelination. Author(s): Pouly S, Matthieu JM, Honegger P. Source: Neurochemical Research. 2001 June; 26(6): 619-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11519722
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Remyelination: cellular and gene therapy. Author(s): Billinghurst LL, Taylor RM, Snyder EY. Source: Semin Pediatr Neurol. 1998 September; 5(3): 211-28. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9777679
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Restoration of function by glial cell transplantation into demyelinated spinal cord. Author(s): Kocsis JD. Source: Journal of Neurotrauma. 1999 August; 16(8): 695-703. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10511242
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Results of occlusion therapy in anisomyopic amblyopia with myelinated nerve fibers. Author(s): Kasmann B, Hoh H, Ruprecht KW. Source: Ger J Ophthalmol. 1996 July; 5(4): 241-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8854109
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Retardation of myelination due to dietary vitamin B12 deficiency: cranial MRI findings. Author(s): Lovblad K, Ramelli G, Remonda L, Nirkko AC, Ozdoba C, Schroth G. Source: Pediatric Radiology. 1997 February; 27(2): 155-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9028851
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Sequential limited proteolysis of myelin basic protein by neutral protease activities of bovine brain. Author(s): Berlet HH, Ilzenhofer H. Source: Journal of Neurochemistry. 1985 July; 45(1): 116-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2582087
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Silver staining of myelin by means of physical development. Author(s): Gallyas F. Source: Neurological Research. 1979; 1(2): 203-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=95356
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Size and surface charge properties of myelin vesicles from normal and diseased (multiple sclerosis) brain. Author(s): Moscarello MA, Chia LS, Leighton D, Absolom D. Source: Journal of Neurochemistry. 1985 August; 45(2): 415-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3925082
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Stimulation of myelin proteolipid protein gene expression by eicosapentaenoic acid in C6 glioma cells. Author(s): Salvati S, Natali F, Attorri L, Raggi C, Di Biase A, Sanchez M. Source: Neurochemistry International. 2004 April; 44(5): 331-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14643750
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The constitutive heat shock protein-70 is required for optimal expression of myelin basic protein during differentiation of oligodendrocytes. Author(s): Aquino DA, Peng D, Lopez C, Farooq M. Source: Neurochemical Research. 1998 March; 23(3): 413-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9482255
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The effects of low temperature on myelin formation in optic nerves of Xenopus tadpoles. Author(s): Cullen MJ, de Webster H. Source: Tissue & Cell. 1977; 9(1): 1-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=898168
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Translocation of myelin basic protein mRNA in oligodendrocytes requires microtubules and kinesin. Author(s): Carson JH, Worboys K, Ainger K, Barbarese E. Source: Cell Motility and the Cytoskeleton. 1997; 38(4): 318-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9415374
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Ultrastructure of myelinated fibers of sciatic nerve in acute vincristine intoxication. Author(s): Maeslinska D, Muzylak M. Source: Folia Neuropathol. 1997; 35(1): 18-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9161096
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Virus-induced autoimmunity: epitope spreading to myelin autoepitopes in Theiler's virus infection of the central nervous system. Author(s): Miller SD, Katz-Levy Y, Neville KL, Vanderlugt CL. Source: Adv Virus Res. 2001; 56: 199-217. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11450300
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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WebMDHealth: 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/
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The following is a specific Web list relating to myelin; 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 Multiple Sclerosis Source: Healthnotes, Inc.; www.healthnotes.com Multiple Sclerosis Source: Integrative Medicine Communications; www.drkoop.com
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Herbs and Supplements Docosahexaenoic Acid Source: Healthnotes, Inc.; www.healthnotes.com
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON MYELIN Overview In this chapter, we will give you a bibliography on recent dissertations relating to myelin. 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 “myelin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on myelin, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Myelin 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 myelin. 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: •
Biophysical approaches for the determination of the effects of multiple sclerosis-like mutations on myelin basic protein by Bates, Ian Randolph, PhD from UNIVERSITY OF GUELPH (CANADA), 2004, 192 pages http://wwwlib.umi.com/dissertations/fullcit/NQ89244
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Chaining myelin to learning by James, Janice, EdD from NORTHERN ILLINOIS UNIVERSITY, 1989, 126 pages http://wwwlib.umi.com/dissertations/fullcit/9000526
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Implications of myelin basic protein processing and presentation on T cell activation and tolerance by Seamons, Audrey, PhD from UNIVERSITY OF WASHINGTON, 2004, 80 pages http://wwwlib.umi.com/dissertations/fullcit/3118869
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Novel synthesis and degradation pathways for the myelin proteolipid proteins by Cypher, Maria Aleksandrovna, PhD from WAYNE STATE UNIVERSITY, 2003, 345 pages http://wwwlib.umi.com/dissertations/fullcit/3086423
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Physical-chemical characterization of myelin basic protein by Fraser, Paul E, PhD from UNIVERSITY OF TORONTO (CANADA), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL43513
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Proteomic analysis of the myelin membrane and its lipid microdomains by Taylor, Christopher Michael, PhD from THE UNIVERSITY OF CONNECTICUT, 2003, 120 pages http://wwwlib.umi.com/dissertations/fullcit/3118973
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Studies on the integration of lipophilin in the human myelin membrane by Kahan, Ileana, PhD from UNIVERSITY OF TORONTO (CANADA), 1987 http://wwwlib.umi.com/dissertations/fullcit/NL36134
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Studies on the mechanism of assembly of myelin in the central nervous system by Pereyra, Pedro M, PhD from MCGILL UNIVERSITY (CANADA), 1983 http://wwwlib.umi.com/dissertations/fullcit/NK66638
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Studies on the myelin proteolipid protein by Ross, Neil Watson, PhD from MCGILL UNIVERSITY (CANADA), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL34263
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T-cell signaling in response to altered myelin basic protein peptides by Beaudoin, Danelle Rae, PhD from UNIVERSITY OF WASHINGTON, 2003, 149 pages http://wwwlib.umi.com/dissertations/fullcit/3090962
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The roles of lipids in normal myelin structure and diseases of myelin by Ohler, Benjamin Gregory, PhD from UNIVERSITY OF CALIFORNIA, SANTA BARBARA, 2003, 135 pages http://wwwlib.umi.com/dissertations/fullcit/3079958
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. PATENTS ON MYELIN Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “myelin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on myelin, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Myelin By performing a patent search focusing on myelin, 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
8Adapted
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 myelin: •
Autoantibody inhibitors Inventor(s): Genain; Claude P. (Mill Valley, CA), Hauser; Stephen L. (Ross, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,333,033 Date filed: August 26, 1999 Abstract: The invention provides methods and compositions for inhibiting pathogenic binding of an pathogenic autoantibody to a myelin oligodendrocyte glycoprotein (MOG) autoantigen and screening for inhibitors of pathogenic binding of an autoantibody to a MOG autoantigen. Excerpt(s): The field of this invention is polypeptide autoantibody inhibitors and methods of use thereof. Multiple sclerosis (MS) is a chronic relapsing remitting disorder disease of the central nervous system that affects 350,000 Americans and, second to trauma, is the leading cause of disability among young adults. MS is an immunemediated disorder characterized pathologically by perivenular white matter infiltrates comprised of macrophages and mononuclear cells (inflammation), and destruction of the myelin sheaths that insulate nerve fibers (demyelination). Experimental allergic encephalomyelitis (EAE) in rodents has been the most widely employed model for testing of therapies for human MS. These traditional disease models for MS generally have promoted the concept that MS is a T-cell-mediated disorder. However, the autoantigens that serve as targets for the immune attack have not been identified and the molecular mechanisms implicated in myelin damage remain uncertain. While it is clear that CNS inflammation in EAE is initiated by autoagressive T-cells that recognize myelin antigens in the context of class II-MHC molecules, many of the models lack the early demyelinating component of the MS lesion. B-cell activation and antibody responses appear necessary for the full development of EAE and earlier studies on immune mediated demyelination using myelinated cultures of CNS tissue have implicated humoral factors as effector mechanisms. Thus, it is not surprising that rodent EAE has not been a robust predictor of efficacy in humans as fundamental differences in the clinical course, pathology, and immunologic response to myelin proteins distinguish rodent EAE from human MS. Web site: http://www.delphion.com/details?pn=US06333033__
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Compounds for stimulating nerve growth Inventor(s): Hasegawa; Akira (Gifu, JP), Schnaar; Ronald L. (Columbia, MD), Yang; Lynda J. S. (Baltimore, MD) Assignee(s): The Johns Hopkins University School of Medicine (Baltimore, MD) Patent Number: 5,962,434 Date filed: August 23, 1996 Abstract: Compounds which can stimulate neuronal growth by inhibiting the neuronal inhibitory activity of myelin-associated glycoprotein (MAG), and a method of using the compounds for stimulating neuronal growth are provided. The invention further provides a method of identifying compounds which inhibit myelin-associated
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glycoprotein inhibition of axonal outgrowth of injured nerve cells. The method involves contacting the compound with myelin-associated glycoprotein under conditions which allow myelin-associated glycoprotein and the compound to bind and detecting the binding. Excerpt(s): This invention relates to methods of identifying and using compounds for stimulating nerve growth. In particular, this invention relates to complex carbohydrate compounds for stimulating nerve regrowth after injury. Nerve cell function depends upon appropriate contacts between the neuron and other cells in its immediate environment (U. Rutishauser, T. M. Jessell, Physiol. Rev. 68:819, 1988). These cells include specialized glial cells, oligodendrocytes in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS), which ensheathe the neuronal axon with myelin, which is an insulating structure of multi-layered membranes (G. Lemke, in An Introduction to Molecular Neurobiology, Z. Hall, Ed. ›Sinauer, Sunderland, Mass., 1992!, p. 281.). Myelin is required for efficient nerve impulse conduction, but has other profound biological effects. The inability of nerves to regenerate after CNS injury in adults may be due largely to the axon'inability to grow when in contact with CNS myelin (P. Caroni, T. Savio, M. E. Schwab, Prog. Brain Res. 78:363, 1988; M. E. Schwab, J. P. Kapfhammer, C. E. Bandtlow, Annu. Rev. Neurosci. 16:565, 1993). Central nervous system injuries are particularly devastating because, unlike peripheral nerves, central nerves do not regenerate, so that central nervous system damage is usually permanent. Web site: http://www.delphion.com/details?pn=US05962434__ •
Heat shock protein peptides that share sequences with cyclic nucleotide phosphodiesterase and methods for modulating autoimmune central nervous system disease Inventor(s): Birnbaum; Gary (2695 Kelly Ave., Excelsior, MN 55331), Braun; Peter Erich (4098 Highland Avenue, Montreal, Quebec, CA), Kotilinek; Linda K. (3740 20th Ave. South, Minneapolis, MN 55407) Assignee(s): none reported Patent Number: 5,874,405 Date filed: December 16, 1994 Abstract: The invention provides for peptides and methods of using peptides to block or inhibit a pathogenic autoimmune response to central nervous system components. The peptides are antigens derived from mycobacterial heat shock proteins and that immunologically crossreact with or are homologous to myelin components. The peptides can also be derived from myelin components such as 2',3' cyclic nucleotide phosphodiesterase and that immunologically crossreact and/or are homologous to mycobacterial heat shock proteins. A method of the invention involves administering a pharmaceutical composition including at least one peptide to an animal in an amount effective to block or inhibit a pathogenic autoimmune response to central nervous system components. The peptides are useful for the prevention, and treatment of autoimmune inflammatory central nervous system disease. Excerpt(s): Heat shock proteins (HSP), or stress proteins, are families of essential proteins present in almost all prokaryotic and eukaryotic cells (Morimoto et al., Stress Proteins in Biology & Medicine, Cold Spring Harbor, N.Y. (1990)). Heat shock proteins are essential for normal cell functions and are expressed both constitutively and in
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increased amounts when cells are stressed in a variety of ways. Some examples of stresses that increase expression of hsp are heat, viral infection of cells, anoxia, and exposure to certain cytokines, such as tumor necrosis factor and interferon-gamma. They are the immunodominant antigens of many bacteria and parasites, both pathogenic and non-pathogenic, and immune responses to these proteins are ubiquitous in normal individuals (Monk et al., J. Immunol., 143:2844 (1989)). Despite their ubiquity, immune responses to hsp may be important in several human and experimental diseases. (Elias et al., PNAS, 88:3088(1991); Van Eden et al., Curr Top Microbial Immuno., 147:27 (1989)). There are several examples of human and experimental autoimmune diseases associated with immune responses to hsp, especially HSP65 (Van Eden, W., Apmis, 98:383-394 (1990); Gaston, Semn. Immunol., 3:35-42 (1991)). These diseases include rheumatoid arthritis, type 1 diabetes mellitus, rheumatic diseases and systemic lupus erythmatosis. (Gaston, J. Semn. Immunol., 3:35-42 (1991)). Several facts about hsp support their potential importance in the development of autoimmune diseases. (Jones et al., Immunol. Today, 14:115 (1993)). First, hsp are phylogenetically conserved. Thus, there is greater than 50% sequence homology between certain prokaryotic hsp and those of mammalian cells. Second, hsp are the immunodominant antigens for many infectious agents, including bacteria, mycobacteria, and parasites. The resulting strong immune response to these agents' hsp have the potential either to crossreact with the host's hsp, or with normal tissue components of the host. Web site: http://www.delphion.com/details?pn=US05874405__ •
Histochemical labeling stain for myelin in brain tissue Inventor(s): Schmued; Laurence C. (200 Elizabeth Ann Dr., Pine Bluff, AR 71602) Assignee(s): none reported Patent Number: 6,372,451 Date filed: April 23, 2001 Abstract: A novel aurophosphate stain for staining a slide-mounted brain tissue slice or section to label myelin therein, the method of staining, and the method of making the stain. The stain is potassium aurophosphate or sodium aurophosphate produced as the reaction product of an aurochloride and a dibasic potassium or sodium phosphate. Slide-mounted brain tissue slices are stained by immersing the slice in a warn solution of the aurophosphate. The stained slice may be intensified by immersing the slidemounted stained tissue slice in a potassium tetrachloroaureate solution. The stained or intensified slice can be fixed by immersion in a sodium thiosulfate solution. Large bundles of stained myelin appear deep red-brown, while smaller bundles and individual fibers appear black. Excerpt(s): The present invention relates to a histochemical stain, a method for producing the stain, and a method for the post-mortem detection and localization of myelin in brain tissue slices. On the most fundamental level, the brain can be divided into two distinctly different appearing types of matter, the white matter and the gray matter. In recent years, numerous histochemical techniques have been developed for the localization of neuronal and astrocytic markers within the gray matter. Fewer markers, however, are available to the researcher studying the myelin which comprises the white matter. Existing methods for staining myelin include those based on lipid solubility such as Sudan black or Oil red O, the affinity for non-solvent extractable phospholipids by Luxol Fast Blue, the chelation of complex lipid polymers with potassium dichromate followed by hematoxylin, the suppression of non-myelin argyrophilia with pyridine
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followed by diamine silver, the immunohistochemical localization of myelin basic protein, and the use of aqueous gold chloride solutions. The use of gold salts as a myelin stain has a long and controversial history. The use of gold chloride as a sensitive myelin stain is known in the art. The use of gold chloride in hypotonic phosphate buffered saline to study the myelinopathy resulting from exposure to isoniazid or fumonisin indicates that although the gold chloride based method has the potential to detect myelin pathologies, it, like the previous gold chloride based methods, also suffered from a certain degree of capriciousness. Web site: http://www.delphion.com/details?pn=US06372451__ •
Immunological composition and its method of use to transiently disrupt mammalian central nervous system myelin to promote neuronal regeneration Inventor(s): Dyer; Jason K. (N. Van, CA), Keirstead; Hans S. (Vancouver, CA), Steeves; John D. (N. Vancouver, CA) Assignee(s): University of British Columbia (CA) Patent Number: 6,548,061 Date filed: October 28, 1998 Abstract: Novel compositions are described comprising the combined administration of serum complement proteins with complement-fixing antibodies. The antibodies specifically bind to one or more epitopes of myelin, and complement proteins. These compositions are useful for promoting regrowth, repair, and regeneration of neurons in the CNS of a mammalian subject. The compositions and method can be used following immediate or chronic injury. Excerpt(s): This invention relates to compositions and their methods of use in promoting the growth and/or regeneration of neurological tissue within the central nervous system (CNS). Approximately 1,100 new spinal cord injuries occur each year in Canada; over 10,000 per year occur in the United States. These numbers are five times higher if one also includes patients suffering brain damage involving inhibition to neural growth following traumatic brain injury. The number of patients with chronic spinal cord injuries in North America is in the order of 300,000. Again, this number is five times higher if one includes patients suffering from brain damage involving inhibition to neural growth following traumatic brain injury. Spinal cord injuries often result in a permanent loss of voluntary movement below the site of damage. Mostly young and otherwise healthy persons become paraplegic or quadriplegic because of spinal cord injuries. There are an estimated 200,000 quadriplegics in the United States. Given the amount of care required, it is not difficult to envision how health care costs associated with caring for patients with central nervous system (CNS) damage is well over $10 billion a year for North America. Web site: http://www.delphion.com/details?pn=US06548061__
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Increased resistance to stroke by developing immunologic tolerance to myelin or components thereof Inventor(s): Becker; Kyra J. (Seattle, WA), Hallenbeck; John M. (Kensington, MD), McCarron; Richard M. (Kensington, MD) Assignee(s): The United States of America as represented by the Department of Health (Washington, DC) Patent Number: 6,068,844 Date filed: December 19, 1997 Abstract: The present invention relates to a method of inducing oral tolerance to ischemic injury which has the objective of minimizing the severity and size of injured regions in the brain that arise as a result of ischemia. The method responds rapidly to the onset of infarction, with treatment that is short in duration. The procedure is specifically focused on the injured area of the infarct by virtue of being targeted immunologically to the ischemic site. The method therefore avoids the possibility of inducing systemic side effects affecting other organs of the patient. The present invention involves administering myelin or a component thereof such as myelin basic protein or proteolipid protein to a subject either orally or by inhalation. The amount administered and the duration of the treatment are effective to minimize the size and severity of the infarct in the brain of the subject. The method is intended for acute conditions related either to an actual recent cerebral ischemic event or to a potential ischemic event that might arise as a result of medical or surgical treatment planned for the subject. Excerpt(s): The present invention relates to a method of minimizing the size and severity of stroke in a mammalian subject. The method involves the development of immunologic tolerance to myelin or a component thereof, such as myelin basic protein, by means of oral administration or inhalation. The mammalian gut is provided with specialized tissues of the immune system that serve several related functions. A principal tissue carrying out these functions is the Peyer's patches, specialized sites facing the lumen of the gut. Peyer's patches sample the contents of the lumen, process antigen, and develop an immune response. This response can lead to either cell mediated or humoral immunity, or it can lead to immunologic tolerance. The type of immune response that develops depends upon how the antigen is processed and the current physiological milieu within the Peyer's patches. Analogous immune processes are believed to occur in the airways involved in breathing. The immunological mechanisms associated with oral tolerization may be classified as active suppression, clonal anergy, and clonal deletion. In general, depending on conditions, these mechanisms may operate independently or in combination. The distinction between these mechanisms depends primarily on the dose of antigen detected by the mucosal tissues, and by the incidence of dosing. Active suppression occurs with repetitive low doses of antigen, in which the result is induction of regulatory T.sub.h2 and T.sub.h3 cells. These cells, when restimulated by the autoantigen, secrete cytokines such as transforming growth factor (TGF)-beta, interleukin (IL)-4, and IL-10, which act to suppress inflammatory responses. Clonal anergy may result with high doses of antigen. A state of unresponsiveness is induced in T.sub.h1 cells, whereby their T cell receptors become incapable of responding to the specific antigen, when processed and presented by the major histocompatibility complex on an antigen presenting cell, that would normally trigger their activation. Clonal deletion, in contrast, occurs upon a single administration of a very high dose of the autoantigen, and results in actual destruction of the T cell clones bearing the specific T cell receptor responsive to the processed
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antigen. In the presence of high concentrations of antigen in the gut, it is believed that T cells specific for that antigen are eliminated, both within the Peyer's patch itself as well as in the thymus gland. Web site: http://www.delphion.com/details?pn=US06068844__ •
Induced regeneration and repair of damaged neurons and nerve axon myelin Inventor(s): Schwartz; George R. (P.O. Box 1968, Santa Fe, NM 87504) Assignee(s): none reported Patent Number: 6,776,984 Date filed: August 17, 2000 Abstract: A method of treatment of and composition for human degenerative neurologic diseases discloses the administration of therapeutically amounts of an enhancement agent, such as thrombopoietin, to enhance the repair of neurons, including remyelinization. A regulatory agent, such as thyroid hormone or thyrotropin, may also be included as part of the method and composition as a regulator of cell division and oligodendroglia production. Excerpt(s): This invention relates to treatment of human neurologic damage, and in particular to a method for increased regeneration and repair of damaged neurons and nerve axon myelin coatings, and nerve cell repair. Demyelination occurs when the myelin coating around nerve axons degenerates resulting in a defect in the ability to transmit nerve impulses. For example, multiple sclerosis is a disease of unknown cause in which degeneration occurs in the myelin sheath surrounding the nerves. This demyelination is also found in many other diseases such as transverse myelitis. Demyelination also occurs after trauma to the brain or spinal cord, after a stroke, in neurodegenerative diseases such as amyotropic lateral sclerosis and Alzheimer's disease, as well as in viral diseases including AIDS. A cell type in the nervous system called the oligodendroglia is intimately involved in myelin regeneration, repair and maintenance of the nerve cells. Repair occurs by the repetitive wrapping of the plasma membranes of the oligodendroglia cells around damaged nerve cells and offers continuing metabolic nerve cell support. In the art, it has been established that for 0-2A progenitor cells that produce oligodendroglia cells proliferation is induced in culture by type-1 astrocytes. A recognized mitogen for 0-2A progenitor cells is platelet-derived growth factor (PDGF), and PDGF is a potent mitogen for 0-2A progenitor cells in vitro. Thus, laboratory experimentation has suggested that PDGF is crucial for the control of nerve cell repair and myelination in the nervous system. Web site: http://www.delphion.com/details?pn=US06776984__
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Laser inactivation of inhibitory molecules in central nervous system myelin Inventor(s): Jay; Daniel G. (Brighton, MA) Assignee(s): President and Fellows of Harvard College () Patent Number: 6,479,053 Date filed: June 12, 2000 Abstract: Methods for specifically inactivating myelin proteins which inhibit nerve regeneration are described. These methods are useful to promote axon regeneration.
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Excerpt(s): The invention relates to methods for specifically inactivating myelin proteins which inhibit nerve regeneration. These methods are useful to promote axon regeneration. Axon regeneration occurs from a severed end by forming a new neuronal growth cone, the sensory motile organelle at the ends of axons that is responsible for neurite extension and axon guidance of developing neurons. While central nervous system ("CNS") neurons do not regenerate after injury, peripheral nerves do. For example, severed nerves within the adult optic nerve generally do not regenerate (reviewed in Aguayo et al., 1991). It is thought that if the severed nerves reform circuitry, then significant function can be reestablished (Cheng et al., 1996). David et al. (1981) showed that CNS nerves extended axons into bridges of peripheral tissue demonstrating that the difference between the CNS and peripheral nervous system environments is critical for regeneration. It has recently been shown that the major difference in regenerative capacity is due to inhibitory molecules present in the myelin sheaths that surround spinal cord axons of the adult CNS (Schwab et al., 1993). Spinal cord neurons show increased collateral sprouting when myelin is absent (Schwegler et al., 1995). Application of a myelin-derived fraction to neurons cultured in the absence of myelin caused growth cone collapse and neurite retraction (Caroni and Schwab, 1988a). Web site: http://www.delphion.com/details?pn=US06479053__ •
Method and compositions for treating arthritis Inventor(s): Root-Bernstein; Robert S. (East Lansing, MI) Assignee(s): Board of Trustees Operating Michigan State University (E. Lansing, MI) Patent Number: 5,942,491 Date filed: October 22, 1996 Abstract: The present invention provides a process for the treatment of arthritis including the step of administering to an animal or human patient in need of such treatment a plurality of peptides each of which peptides contains a sequence of amino acid residues that is identical to or homologous to residues 110-121 or 152-161 of myelin basic protein. Novel peptides for use in that process are also provided. Excerpt(s): The field of this invention is the treatment of arthritis. More particularly, the present invention provides a process of treating arthritis using peptides that are identical to or homologous to anti-arthritic portions of myelin basic protein. Arthritis is a very common human bane. Although many animals models of arthritis exist and have been extensively studied, no adequate treatment exists for most forms of arthritis or for related autoimmune diseases with rheumatoid sequelae such as lupus erythematosis. Rheumatoid arthritis presents a particular problem, since it often results in the crippling of affected individuals. While working with one animal model of arthritis (Lewis rats inoculated in the footpad with Mycobacteria, which normally develop adjuvant arthritis), the unexpected observation was made that rats inoculated with a combination of mycobacteria and measles or mycobacteria and measles-mumps-rubella vaccines did not develop arthritis. It was also observed that rats pretreated with porcine myelin basic protein prior to footpad inoculation with mycobacteria were also protected against arthritis. Further experiments showed that the vaccines or MBP were capable of suppressing arthritis once induced. A literature search has revealed two additional striking observations. First, measles proteins and MBP share extensive regions of homology, suggesting that their common action may share a common mechanism mediated by peptides. This prediction was verified by synthesis of homologous peptides, which also protected and suppressed arthritis. A second observation suggests
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how important these results may be. Several clinicians have noted that measles infections occasionally mitigate or cure Still's disease, the juvenile form of rheumatoid arthritis. Thus, the treatment regimens described here may represent a significant step towards a treatment or cure for rheumatoid and other forms of arthritis, both in human beings and animals. Web site: http://www.delphion.com/details?pn=US05942491__ •
Method for diagnosing and distinguishing stroke and diagnostic devices for use therein Inventor(s): Jackowski; George (Kettleby, CA) Assignee(s): Syn X Pharma (Mississauga, CA) Patent Number: 6,235,489 Date filed: February 22, 2000 Abstract: A method for determining whether a subject has had a stroke and, if so, the type of stroke which includes analyzing the subject's body fluid for at least four selected markers of stroke, namely, myelin basic protein, S100 protein, neuronal specific enolase and a brain endothelial membrane protein such as thrombomodulin or a similar molecule. The data obtained from the analyses provide information as to the type of stroke, the onset of occurrence and the extent of brain damage and allow a physician to determine quickly the type of treatment required by the subject. Excerpt(s): This application hereby claims foreign priority benefits under 35 USC 119(a)(d) of Canadian Patent Application 2,263,063, filed Feb. 26, 1999. This application is directed to a method for diagnosing whether a subject has had a stroke and, if so, differentiating between the different types of stroke. More specifically, the method includes analyzing the subject's body fluid for at least four selected markers of stroke. There are also described diagnostic devices and kits for use in the method. The impact of stroke on the health of human beings is very great when considered in terms of mortality and even more devastating when disability is considered. For example, stroke is the third leading cause of death in adults in the United States, after ischemic heart disease and all forms of cancer. For people who survive, stroke is the leading cause of disability. The direct medical costs due to stroke and the cost of lost employment amount to billions of dollars annually. Approximately 85% of all strokes are ischemic (thrombotic and embolic) with the remainder being hemorrhagic. Web site: http://www.delphion.com/details?pn=US06235489__
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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
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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 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 of extracting axon fibers and clusters Inventor(s): Vogt; Robert C. (Ann Arbor, MI) Assignee(s): ERIM International, Inc. (Ann Arbor, MI) Patent Number: 5,850,464 Date filed: September 9, 1996 Abstract: The extraction and pre-cueing of axon fibers and clusters is performed on transmission electron micrograph (TEM) image mosaics to reduce neuroanatomist workload. Given a multiplicity of myelin-sheathed axon fibers in a cross-sectional image containing many such fibers, the inventive method uses these grey-level operators to effectively identify co-occurrences of the axon fibers and their myelin sheaths and output a result representative of these co-occurrences. The co-occurrences may then be sorted in terms of their geometry to identify groups of fibers indicative of axon clusters. Specifically, a grey-level opening and conditional dilation is performed on the image to obtain a first residue representative of potential axons A grey-level closing and conditional erosion of the first opening image is then performed to obtain a second residue representative of potential axon fibers, including their respective myelin sheaths. The first residue may then be used as a marker to conditionally dilate over the second residue to identify the co-occurrences. The method of the invention significantly reduces the workload of the reviewers by identifying roughly 95 percent of the axons, with only a one to two percent false alarm rate, based on a reasonable computation time of about one hour per sample on a fast workstation. Excerpt(s): This application claims priority of U.S. provisional application Ser. No. 60/010,048, filed Jan. 16, 1996. The present invention relates generally to the identification of axons and axon clusters, as might be useful, for example, in a nerve
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regeneration study, and, more particularly, to a method of automatically queuing axons and axon groups through morphological operations. Diabetes is a progressive disease with many negative side effects that appear in its later stages. One of these effects is the degeneration of peripheral nerve tissue, leading to numbness in the extremities, and sometimes contributing to cell death, gangrene, and the loss of toes or feet. Certain drugs are now under development to reduce or reverse this loss, by triggering regeneration of nerve cells that have previously atrophied. Web site: http://www.delphion.com/details?pn=US05850464__ •
Method of reducing perivascular lesions using insulin-like growth factor I Inventor(s): Hudson; Lynn D. (Bethesda, MD), Komoly; Samuel (Budapest, HU), Liu; Xia (Ossning, NY), Webster; Henry de Forest (Chevy Chase, MD), Yao; Da-Lin (Germantown, MD) Assignee(s): National Institutes of Health (Rockville, MD) Patent Number: 5,965,531 Date filed: August 30, 1996 Abstract: A disease or disorder associated with myelin injury, such as multiple sclerosis, is treated by administering to a patient in need thereof an effective amount of insulinlike growth factor I (IGF-I). The method reduces blood brain and blood nerve barrier permeability defects. It also decreases the size and number of perivascular lesions (often associated with myelin breakdown) and reduces the formation of sclerotic plaques in the central nervous system. IGF-I administration also reverses the clinical deficits associated with myelin injury, including visual defects, unsteadiness, poor coordination, muscular weakness and paralysis. Excerpt(s): The present invention relates to a method for preventing and/or reducing and/or eliminating perivascular lesions by the administration of insulin-like growth factors. Neurons communicate with one another by sending electrical impulses along cellular processes called axons; these processes are insulated with a protein-lipid composite substance called myelin. Myelin is produced by specialized cells (generically referred to as glial cells, or glia). In the central nervous system (CNS, i.e. the brain and spinal cord), the myelin producing glia are called oligodendrocytes, while in the peripheral nervous system the myelin-producing glia are called Schwann cells. In both cases, the myelin sheath is not continuous, but consists of segments of myelin approximately 1 millimeter in length separated by 0.5-1.5 micrometer gaps called nodes of Ranvier. These periodic gaps in the myelin sheath are important in the propagation of electrical signals down the axon. When myelin sheaths or oligodendrocytes sustain injury, entire segments of myelin degenerate, and their remnants are phagocytosed by macrophages and to a much lesser degree by astrocytes. This process is called "primary demyelination" if most axons remain uninjured and is characteristic of the myelin breakdown seen in multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), and progressive multifocal leukoencephalopathy. "Secondary demyelination" is defined as degeneration of myelin secondary to axonal disease; two well characterized examples include Wallerian degeneration and axonal degeneration ("dying back phenomenon"). In addition, degeneration of myelinated fibers may be secondary to destruction of dorsal root ganglion neurons. Web site: http://www.delphion.com/details?pn=US05965531__
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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), Gaur; Amitabh (San Diego, CA), Ling; Nicholas (San Diego, CA), Steinman; Lawrence (Palo Alto, CA) Assignee(s): Neurocrine Biosciences, Inc. (San Diego, CA), Stanford University Medical Center (Palo Alto) Patent Number: 6,369,033 Date filed: October 20, 1997 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=US06369033__
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Methods of measuring urinary myelin basic protein-like material Inventor(s): Bradley, Jr.; Edwin Luther (Birmingham, AL), Burgard; Sheila Loughran (Lake Bluff, IL), Kachelhofer; Robert David (Birmingham, AL), Layton; Beverly Ann (Birmingham, AL), Morrison; Wendy Jean (Vancouver, CA), Paty; Donald Winston (Vancouver, CA), Reder; Anthony Thomas (Oak Park, IL), Whitaker; John Nicholas (Birmingham, AL), Zhao; Guojun (Vancouver, CA) Assignee(s): UAB Research Foundation (Birmingham, AL) Patent Number: 5,998,150 Date filed: October 1, 1996 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 levels of urinary myelin basic protein-like material 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 levels of urinary myelin basic protein-like material in the patient. Further provided is a method of monitoring myelination in a developing child, comprising the step of: measuring the levels of myelin basic protein-like material in the urine of said child. Excerpt(s): The present invention relates generally to the field of neurology. More specifically, the present invention relates to an assay measuring urinary myelin basic
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protein like material 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 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, primary chronic progressive (CP) and secondary chronic progressive according to the clinical appearance and persistence of neurological deficit. The development of disease progression, whether from onset as in primary chronic progressive-multiple sclerosis or as secondary chronic progressive-multiple sclerosis subsequent to an earlier period of relapses, can be viewed as the failure of remission. The failure of remission, or progression, is the principal cause of disability and decline in the quality of life. The natural history of multiple sclerosis 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: (1) male gender; (2) later age of onset of the disease; (3) corticospinal and cerebellar involvement; (4) increased number of relapses in the first five years; and (5) 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 multiple sclerosis 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=US05998150__ •
Methods using CNS neurite outgrowth modulators Inventor(s): Schachner; Melitta (Zurich, CH) Assignee(s): Acorda Therapeutics (Hawthorne, NY) Patent Number: 6,576,607 Date filed: August 6, 1998 Abstract: The invention features a method for promoting neural growth in vivo in the mammalian central nervous system by administering a neural cell adhesion molecule which can overcome inhibitory molecular cues found on glial cells and myelin to promote neural growth. Also featured active fragments, cognates, congeners, mimics, analogs, secreting cells and soluble molecules thereof, as well as antibodies thereto, and DNA molecules, vectors and transformed cells capable of expressing them. The neuroprotective of the agents as well as their ability to promote and effect myelination and remyelination are alse disclosed, as are the concomitant benefits that these capabilities confer, in the former instance, with regard to reduction of apoptosis and necrosis, and in the latter instance, the treatment of Parkinsonism, Alzheimer's disease and multiple sclerosis. The invention also includes transgenic mouse lines expressing a neural adhesion molecule in differentiated astrocytes, and cells and tissues derived therefrom. The expression of the neural adhesion molecule enhances neurite outgrowth on central nervous system tissue derived from these transgenic mice. The invention also features methods for enhancing neuronal outgrowth of CNS neurons, for enhancing memory and for increasing synaptic efficacy. Also featured are methods of testing drugs
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which modulate the effects of the neural adhesion molecule, and assay systems suitable for such methods. Excerpt(s): This invention relates generally to the modulation of neural growth in the central nervous system, and more particularly to methods and associated agents, constructs and compositions for improving CNS neural growth. Specifically, the invention relates to the use of cellular adhesion molecules, and preferably neural cell adhesion molecules such as L1, to foster and improve such neural growth. The ability of neurons to extend neurites is of prime importance in establishing neuronal connections during development. It is also required during regeneration to re-establish connections destroyed as a result of a lesion. Neurites elongate profusely during development both in the central and peripheral nervous systems of all animal species (Cajal (1928) Degeneration and regeneration in nervous system, Oxford University Press, London). This phenomenon pertains to axons and dendrites. However, in adults, axonal and dendritic regrowth in the central nervous system is increasingly lost with evolutionary progression. Web site: http://www.delphion.com/details?pn=US06576607__ •
Myelin basic protein MRNA transport and translation enhancer sequences Inventor(s): Ainger; Kevin (Zurich, CH), Avossa; Daniela (Zurich, CH), Carson; John (West Hartford, CT), Kwon; Sunjong (Newington, CT) Assignee(s): Research Corporation Technologies, Inc. (Tucson, AZ) Patent Number: 6,225,082 Date filed: May 9, 1997 Abstract: The present invention provides isolated nucleic acid molecules which comprise sequences from the 3' UTR of myelin basic protein (MBP) mRNA. The subject isolated nucleic acid molecules confer properties such as localization, transport and increased translational efficiency of a heterologous mRNA transcript when transcribed into such mRNA. The present invention also provides vectors comprising the subject isolated nucleic acids. The vectors are useful for increasing translational efficiency of mRNA transcripts produced by a heterologous gene incorporated therein. Also provided by the present invention are methods for increasing translation of a heterologous gene. The methods comprise transforming a eukaryotic cell with at least one of the subject vectors having coding sequence for a heterologous gene. Methods for enhancing gene therapy are also provided. Excerpt(s): Newly synthesized mRNA which is exported from the nucleus is subject to a variety of competing macromolecular interactions. The 5' cap and poly(A) tail are substrates for binding by cap binding protein and poly(A)-binding protein, respectively. The mRNA is also competent for interaction with the translational machinery by formation of the initiation complex, which includes ribosome subunit binding (Hershey, J. W. B., 1991, Ann. Rev. Biochem. 60:717-55). Interactions which are inhibitory to translation can also occur masking the mRNA and creating a nontranslated pool of messages (Curtis, D., et al., 1995, Cell, 81:171-178; Vasalli, J. D., et al., 1989, Genes & Devel., 3:2163-2171; Richter, J. D., 1991, Bioessays, 13(4):179-183). Some mRNAs are transported and localized to specific subcellular sites, which must involve association with a transport machinery while the mRNA is in transit. Localization of mRNA may also involve interaction with immobile components of the cell in order to anchor the mRNA at the correct destination. mRNAs are also subject to degradation which must
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involve recognition by degradation enzymes (Pelz, S. W., et al., 1992, Curr. Opin. Cell Biol., 14:979-983; Sachs, A., 1993, Cell, 74(3):413-421). An mRNA, therefore, represents a substrate for many interactions which determine its subcellular location, concentration, and level of expression. Presumably, there are discrete elements within the mRNA that mediate each of these various interactions. The first suggestion of spatial localization of specific mRNAs within cells came from studies of myelin and myelin basic protein (MBP) mRNA (Colman, D. R., et al., 1982, J. Cell Biol., 95:598-608). Detection of MBP mRNA in a highly purified myelin fraction was the basis for later research that showed the localization of MBP mRNA to the peripheral myelin membranes of oligodendrocytes in vivo (Kristensson, K., et al., 1986, Nature (Lond.), 322:544-547; Verity, N. A., et al., 1988, J. Neurosci. Res., 21:238-248) and in vitro (Holmes, E., et al., 1988, J. Neurosci. Res., 19:389-396; Shiota, C., et al., 1989, Dev. Brain Res., 45:83-94; Barbarese, E., 1991, J. Neurosci. Res., 29:271-281). In retrospect, previous work on targeting of mRNA for secretory and membrane proteins to the rough endoplasmic reticulum (ER) by the nascent polypeptide chain also implicitly describes a localization of mRNA to a subcellular site (Blobel, G., et al., 1975, J. Cell Biol., 67:835-851). Recently, evidence for the localization of mRNAs to subdomains within the rough ER has been reviewed (Okita, T. W., et al., 1994, Trends Cell Biol., 4:91-96). Functional consequences of RNA localization have been demonstrated in Drosophila. Proper localization of Drosophila bicoid and nanos mRNA is required for establishment of the anterior/posterior axis of the embryo (St. Johnston, D., et al., 1992, Cell, 68(2):201-219). Many RNAs are also localized during creation of the dorsal/ventral axis in Xenopus oocytes (Melton, D. A., et al., 1989, In Ciba Foundation Symposium, Cellular Basis of Morphogenesis, 144:16-30). In addition, motile fibroblasts (Singer, R. H., et al., 1989, J. Cell Biol., 108(6):2343-2353), and terminally differentiated neurons localize specific messages (Garner, C. C., et al., 1988, Nature (Lond.), 336:674-677; Bruckenstein, D. A., et al., 1990, Neuron, 5:809-819; Kleiman, R., et al., 1990, Neuron, 5:821-830). The localization of mRNAs has been extensively reviewed (Steward, O., et al., 1992, Trends Neurosci, 15(5):180-186; Wilhelm, J. E., et al., 1993, J. Cell Biol., 123(2):269-274; St. Johnston, D., 1995, Cell, 81:161-170). Web site: http://www.delphion.com/details?pn=US06225082__ •
Neurite growth regulatory factors Inventor(s): Caroni; Pierenrico W. (Zurich, CH), Paganetti; Paolo A. (Zurich, CH), Schwab; Martin E. (Zurich, CH) Assignee(s): Erziehungsdirektion of the Canton Zurich (Zurich, CH) Patent Number: 6,103,232 Date filed: June 5, 1995 Abstract: The present invention relates to methods of inducing neurite outgrowth in the central nervous system by antagonizing neural growth inhibitory factors. More particularly, the present invention is directed to use of antibodies to the central nervous system (CNS) myelin associated proteins; such antibodies can be used in the diagnosis and therapies of nerve damage resulting from trauma, infarction, and degenerative disorders of the CNS. In a specific embodiment of the invention, the monoclonal antibody IN-1 may be used to promote neurite outgrowth of nerve fibers over long distances in spinal cord lesions. Excerpt(s): The present invention is directed to genes and their encoded proteins which regulate neurite growth, antibodies thereto, and the therapeutic and diagnostic uses of
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such proteins and antibodies. The proteins of the present invention include central nervous system myelin associated inhibitory proteins, and metalloproteases associated with malignant tumors, in particular, primary brain tumors such as glioblastoma and other tumors capable of metastasizing to and spreading in the brain. The central nervous system myelin associated inhibitory proteins inhibit neurite outgrowth and fibroblast spreading and can have important uses in the treatment of malignant tumors. Antibodies to such inhibitory proteins can have uses in the diagnosis of malignant tumors and in the treatment of central nervous system damage and degenerative nerve diseases. In a specific embodiment of the invention, antibody to neurite growth inhibitor may be used to promote the regeneration of neurons over long distances following spinal cord damage. The metalloproteases of the invention allow invasive growth of glioblastomas and allow neurite outgrowth in central nervous system tissue. They may have important uses in the treatment of central nervous system damage and degenerative nerve diseases. Inhibition of the metalloprotease can be therapeutically useful in the treatment of malignant tumors. Cell attachment, cell spreading, cell motility, and, in particular, neurite outgrowth are strongly dependent on cell-substrate interactions (Sanes, 1983, Ann. Rev. Physiol. 45:581-600; Carbonetto et al., 1987, J. Neurosci. 7:610-620). An increasing number of substrate molecules favoring neuroblast migration or neurite outgrowth have been found in central and peripheral nervous tissue (Cornbrooks et al., 1983, Proc. Natl. Acad. Sci. USA 80:3850-3854; Edelman, 1984, Exp. Cell Res. 161:1-16; Liesi, 1985, EMBO J. 4:1163-1170; Chiu, A. Y. et al., 1986, J. Cell Biol. 103:1383-1398; Fischer et al., 1986, J. Neurosci. 6:605-612; Lindner et al., 1986, Brain Res. 377:298-304; Mirsky et al., 1986, J. Neurocytol. 15:799-815; Stallcup et al., 1986, J. Neurosci. 5:1090-1101; Carbonetto et al., 1987, J. Neurosci. 7:610-620). The appearance of some of these factors can be correlated with specific developmental stages, and, in the peripheral nervous system (PNS), also with denervation (Edelman, 1984, Exp. Cell Res. 161:1-16; Liesi, 1985, EMBO J. 4:1163-1170; Stallcup et al., 1985, J. Neurosci. 5:1090-1101; Daniloff et al., 1986, J. Cell Biol. 103:929-945; Carbonetto et al., 1987, J. Neurosci. 7:610620). The extracellular matrix protein tenascin has been shown to possess nonpermissive substrate properties (Chiquet-Ehrismann et al., 1986, Cell 47:131-139). One of the most characterized of the soluble factors favoring neurite outgrowth is nerve growth factor (NGF). NGF promotes nerve fiber outgrowth from embryonic sensory and sympathetic ganglia in vivo and in vitro as well as neurite outgrowth (reviewed in Thoenen et al., 1982, In: Repair and Regeneration of the Nervous System, J. G. Nicholls, ed., SpringerVerlag, NY, pp. 173-185). NGF may also guide the direction of such neurite outgrowth. Three different molecular forms of NGF have been recognized. One type is a dimer (molecular weight.about.26,000) composed of two noncovalently linked, identical polypeptide chains. The second form is stable at neutral pH and contains three different polypeptide chains,.alpha.,.beta. and.gamma. (molecular weight.about.140,000). The.beta. chain is the biologically active chain and is identical to the first form of NGF. The third form, which is isolated primarily from mouse L cells, (see U.S. Pat. No. 4,230,691, by Young, issued Oct. 28, 1980, and references therein) has a molecular weight of about 160,000 but is unstable at neutral pH. NGF has thus far been isolated from the submandibullar glands of mice, mouse L cells, and the prostate gland of the guinea pig and bull (reviewed in Thoenen et al., 1982, supra). No differences between the biological action of mouse, guinea pig and bull NGF have been detected. In addition, NGF isolated from mice have been found to bind to the human NGF receptor (Johnson et al., 1986, Cell 47:545-554). Web site: http://www.delphion.com/details?pn=US06103232__
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Peptides derived from immunodominant epitopes of myelin basic protein Inventor(s): Hafler; David A. (West Newton, MA), Weiner; Howard L. (Brookline, MA) Assignee(s): Autoimmune, Inc. (Lexington, MA) Patent Number: 6,039,947 Date filed: August 11, 1994 Abstract: Peptides containing immunodominant epitopes of myelin basic protein that are recognized by groups of T-cells from remitting-relapsing multiple sclerosis patients. Excerpt(s): This invention pertains to agents and methods for treating Multiple Sclerosis. More specifically, the invention is directed to therapeutic agents comprising a T-cell receptor and fragments or analogs thereof which are believed to be involved in the pathogenic mechanism of the disease, and to methods of using such agents to suppress disease symptoms. Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system white matter of humans and is believed to be of autoimmune etiology. The disease is characterized by prominent T-cell and macrophage infiltrates, demyelination and neurological dysfunction. Myelin basic protein (MBP) has been extensively studied as a potential autoantigen in the disease because of its role as an inducing agent in the major animal model of MS, experimental allergic encephalomyelitis (EAE), as well as its role in the human disease post viral encephalomyelitis. A major hypothesis regarding the pathogenesis of MS is that T-cells reactive with myelin basic protein in the white matter of the CNS initiate the inflammatory process. The demonstration that activated T-cells specific for myelin basic protein (MBP) can be isolated from MS patients (Allegretta, M., et al., Science: 247: 778, 1990) implicates MBP-reactive T-cells in the pathogenesis of the disease. Web site: http://www.delphion.com/details?pn=US06039947__
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Pseudomonas exotoxin-myelin basic protein chimeric proteins Inventor(s): Beraud; Eveline (Marseille, FR), Lorberboum-Galski; Haya (Jerusalem, IL), Marianovsky; Irina (Jerusalem, IL), Steinberger; Ida (Jerusalem, IL), Yarkoni; Shai (KfarSaba, IL) Assignee(s): Yissum Research Development Company of the Hebrew University of Jerusalem (IL) Patent Number: 6,531,133 Date filed: January 27, 1999 Abstract: A chimeric protein comprising a Pseudomonas aeruginosa exotoxin (PE) moiety linked to a myelin basic protein (MBP) moiety is disclosed. The MBP moiety is selected from the group comprising: (a) MBP; (b) amino acids 69-88 of guinea-pig myelin basic protein or an antigenic portion thereof; (c) amino acids 84-102 of human myelin basic protein or an antigenic portion thereof; (d) amino acids 143-168 of human myelin basic protein or an antigenic portion thereof; and (e) an amino acid sequence in which one or more amino acids have been deleted, added, substituted or mutated in the amino acid sequences of (a), (b), (c) or (d), the modified sequence of (e) retaining at least 75% homology with the amino acid sequences of (a), (b), (c) or (d), respectively. Each of the MBP moieties of (b), (c) and (d) are linked to the PE moiety by a pentapeptide linker repeated 1-3 times. The chimeric protein is useful in treating autoimmune diseases, and especially multiple sclerosis.
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Excerpt(s): The present invention relates to antigen-toxin chimeric proteins useful in the targeted immunotherapy of autoimmune diseases, and particularly of multiple sclerosis. The development of selective immunosuppressive agents is one of the major goals in the treatment of autoimmune diseases. In the ignorance of the identity of the specific antigen involved, treatment has until now been oriented toward nonspecific killing of rapidly dividing cells by means of cytotoxic agents, as well as inhibiting the action of mediators of inflammation with anti inflammatory agents. More recently, specific and selective agents for the therapy of disorders of the immune response have been developed, based on our increased understanding of the immune response, advances in genetic engineering and improved models of autoimmune diseases. Web site: http://www.delphion.com/details?pn=US06531133__ •
Transgenic mouse expressing APP.sub.770 Inventor(s): Leibowitz; Paul J. (185 Freeman St., Apt. 446, Brookline, MA 02146), Snyder; Benjamin (52 Hancock Hill Dr., Worcester, MA 01609), Wadsworth; Samuel (12 Ferncroft Rd., Shrewsbury, MA 01545), Wei; Cha-Mer (1101 Old Connecticut Path, Framingham, MA 01701) Assignee(s): none reported Patent Number: 5,811,633 Date filed: June 7, 1995 Abstract: The construction of transgenic mouse models for testing potential treatments for Alzheimer's disease are described. The models are characterized by a greater similarity to the conditions existing in naturally occurring Alzheimer's disease, based on expression of all three forms of the.beta.-amyloid precursor protein (APP), APP.sub.695, APP.sub.751, and APP.sub.770), as well as various point mutations based on naturally occurring mutations, such as the London and Indiana familial Alzheimer's disease (FAD) mutations at amino acid 717, and predicted mutations in the APP gene. The APP gene constructs are prepared using the naturally occurring promoter, as well as inducible promoters such as the mouse metallothionine promoter, which can be regulated by addition of heavy metals such as zinc to the mouse's water or diet, and promoters such as the rat neuron specific enolase promoter, human.beta. actin gene promoter, human platelet derived growth factor B (PDGF-B) chain gene promoter, rat sodium channel gene promoter, mouse myelin basic protein gene promoter, human copper-zinc superoxide dismutase gene promoter, and mammalian POU-domain regulatory gene promoter. The constructs are introduced into mouse embryos using standard techniques such as microinjection. Mouse cells can be isolated from the transgenic mice or prepared using the same constructs with standard techniques such as lipofection or electroporation. The transgenic mice, or mouse cells, are used to screen for compounds altering the pathological course of Alzheimer's Disease as measured by their effect on the amount and histopathology of APP and.beta.-amyloid peptide in the mice, as well as by behavioral alterations. Excerpt(s): Transgenic technology is described for the production of animals that exhibit symptoms of human Alzheimer's disease through the expression of the Alzheimer's precursor protein or a modified version thereof. Alzheimer's Disease (AD) is a degenerative disorder of the brain first described by Alios Alzheimer in 1907 after examining one of his patients who suffered drastic reduction in cognitive abilities and had generalized dementia ("The early story of Alzheimer's Disease", edited by Bick K, Amaducci L, and Pepeu G. (Raven Press, New York 1987). It is the leading cause of
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dementia in elderly persons. AD patients have increased problems with memory loss and intellectual functions which progress to the point where they cannot function as normal individuals. With the loss of intellectual skills the patients exhibit personality changes, socially inappropriate actions and schizophrenia ("A guide to the understanding of Alzheimer's Disease and related disorders", edited by Jorm AF.; (New York University Press, New York 1987). AD is devastating for both victims and their families, for there is no effective palliative or preventive treatment for the inevitable neurodegeneration. The most common problems in the Alzheimer's patient are inability to dress unaided, restlessness by day, urinary incontinence and sleep disturbances. The family members report embarrassment, anxiety, depression, and a decreased social life. The impact of AD on society and on the national economy is enormous. It is expected that the demented elderly population in the United States will increase by 41% by the year 2000. It is expensive for the health care systems that must provide institutional and ancillary care for the patients at an estimated annual cost of $40 billion (Jorm, 1987; Fisher, L M: New York Times, Aug. 23, 1989 D1 "Alzheimer's Disease", edited by Reisberg, B.; (The Free Press, New York & London 1983). These factors imply preventive action must be taken to decrease AD incidence by allocating resources into AD research. Web site: http://www.delphion.com/details?pn=US05811633__ •
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). 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
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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__ •
Use of recombinant myelin protein for treating T-cell-mediated autoimmune diseases of the peripheral nervous system Inventor(s): Gold; Ralf (Neurologisch Klinik und Polyklinik im Kopfklinikum, JosefSchneider-Strasse, Wurzburg, DE), Weishaupt; Andreas (Neurologisch Klinik und Polyklinik im Kopfklinikum, Josef-Schneider-Strasse, Wurzburg, DE) Assignee(s): none reported Patent Number: 6,319,892 Date filed: March 15, 1999 Abstract: The present invention relates to the use of recombinant myelin protein for treating T cell-mediated autoimmune diseases of the peripheral nervous system. Excerpt(s): This invention relates to the use of recombinant myelin protein for treating T cell-mediated autoimmune diseases of the peripheral nervous system. Neuropathies of autoimmune genesis have been treated by immunosuppressive or immunomodulating therapy so far. Common treatment methods are the administration of steroids (e.g. cortisone), immunoglobulins and long-term immunosuppressive agents (e.g. azathiopine) or the conduction of plasmapheresis. However, many undesired sideeffects accompany these measures as drawbacks, and success is often insufficient. Therefore, it is the object of the present invention to provide a successful and careful method for treating T cell-mediated autoimmune diseases of the peripheral nervous system. Web site: http://www.delphion.com/details?pn=US06319892__
Patent Applications on Myelin As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to myelin:
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This has been a common practice outside the United States prior to December 2000.
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Antigen-specific induction of peripheral immune tolerance Inventor(s): August, Thomas J.; (Baltimore, MD), Georgantas, Robert; (Lockport, IL), Leong, Kam W.; (Baltimore, MD) Correspondence: Banner & Witcoff; 1001 G Street N W; Suite 1100; Washington; DC; 20001; US Patent Application Number: 20030118659 Date filed: June 6, 2002 Abstract: Fas ligand (CD95L) induces apoptosis in activated T cells through the process of Activation Induced Cell Death (AICD). Gelatin nanoparticles are virus sized gelatinprotein-DNA complexes which can encapsulate multiple DNA vectors and proteins, and which are thought to act by increasing in vivo transfection of antigen presenting cells. By injecting mice with gelatin nanoparticles containing a murine Fas ligand (CD95L) DNA vector and a.beta.-galactosidase (LacZ) model antigen vector, the T cell response specific for.beta.-gal was ablated without effecting the response to a secondary antigen. In effect, this "tolerization" injection induced antigen specific peripheral tolerance in study mice, and is applicable to the treatment of autoimmune diseases when selfantigens such as Myelin Basic Protein are co-delivered with the fas ligand. Excerpt(s): This invention is related to the area of immune diseases. More particularly it relates to autoimmune diseases, allergic diseases, and transplantation rejection. Immunologic tolerance to self antigens is a necessary mechanism for protecting an organism from destruction by its own immune system. When this mechanism malfunctions, allowing self-reactive immune cells to proliferate, an autoimmune disease develops within the host. A number of diseases such as Multiple Sclerosis, Lupis, Myathenia Gravis, and Rheumatoid Arthritis have been shown to result from loss of self-tolerance in T and B lymphocytes. There is a continuing need in the art for additional methods and tools for treating autoimmune diseases, as well as allergic diseases and transplantation rejection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Autoimmune inner ear disease diagnostic assay Inventor(s): Yoo, Tai-June; (Memphis, TN) Correspondence: Jamie L. Greene; Kilpatrick Stockton Llp; 2400 Monarch Tower; 3424 Peachtree Road, N.E.; Atlanta; GA; 30326; US Patent Application Number: 20010036644 Date filed: February 22, 2001 Abstract: Methods for diagnosing and monitoring autoimmune inner ear diseases such as Meniere's disease by combining a sample with one or more antigens and detecting the binding of antibodies in the sample to the antigen. The antigen is an inner ear collagen protein or peptide including type II collagen, type IX collagen, or type XI collagen. Binding is detected using an assay method such as an ELISA immunoassay. The assay may further include one or more additional inner ear antigens such as the signal transduction protein Raf-1, the myelin protein P0 and.beta.-tubulin. Excerpt(s): This application claims priority to Provisional Patent Application No. 60/184,085 filed Feb. 22, 2000 and Provisional Patent Application No. 60/184,141 filed Feb. 22, 2000. This relates to the field of immunology and more specifically relates to
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immunoassay methods for detecting an autoimmune disease of the inner ear. Hearing problems can result from a variety of disorders, diseases or traumas of the inner ear. Symptoms of inner ear problems include, but are not limited to, hearing loss, dizziness, vertigo and tinnitus. Several inner ear diseases have recently been classified as autoimmune diseases. These include, but are not limited to, Meniere's disease, progressive bilateral sensorineural hearing loss (PSHL), otosclerosis and sudden hearing loss. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
AXON REGENERATION WITH PKC INHIBITIORS Inventor(s): He, Zhigang; (Boston, MA), Koprivica, Vuk; (Boston, MA), Sivasankaran, Rajeev; (Boston, MA) Correspondence: Richard Aron Osman; Science And Technology Law Group; 75 Denise Drive; Hillsborough; CA; 94010 Patent Application Number: 20030176423 Date filed: March 14, 2002 Abstract: Regenerative growth of an adult mammalian central nervous system neuron axon subject to growth inhibition by endogenous, myelin growth repulsion factors is promoted by delivering to the axon a therapeutically effective amount of a specific inhibitor of protein kinase C, whereby regenerative growth of the axon is promoted and a resultant promotion of the regenerative growth of the axon id detected. Excerpt(s): The invention is in the field of promoting axon regeneration with PKC inhibitors. Protein kinase C (PKC) is ubiquitously expressed in CNS tissues. Behavioral, genetic and pharmacological evidence have associated PKC activity with a wide range of neural functions, from controlling neurotransmitter release and synaptic efficacy to learning and memory processes (Tanaka et al., Annu Rev Neurosci 1994, 17, 551-67; Le Merrer et al., Pharmacol Res 2000, 41, 503-14; Battaini, 2001, Pharmacol Res 44, 1043-61). In addition, PKC activation has been implicated in neural cell proliferation, contraction and survival (Maher 2001, J Neurosci 21, 2929-38). For examples, PKC inhibitors have been reported to block neurite outgrowth in a retinal axons (Heacock et al. 1997 Neurochem Res 22, 1179-850), dorsal root ganglion neurons (Theodore et al. 1995, J Neurosci 15, 7185-97), sympathetic neurons (Campenot et al. 1994, J. Neurochem 63, 86878), PC12 cells (Kolkova et al. 2000 J Neurosci 20, 2238-46) and hippocampal organotypic cultures (Toni et al. Synapse 27, 199-207) PKC inhibitors have also been shown to promote dendritic growth in Purkinje cells in cerebellar slice cultures (Metzger et al. 2000, Eu J Neurosci 12, 1993-2005) and to promote extension of dorsal root ganglion cells filopodia (Bonsall et al. 1999, Brain Res 839, 120-32); see also, Prang et al. 2001, Exp Neuro 169, 135-147; Powell et al. 2001, Glia 33, 268-97. Prior studies have identified a vast number of compositions that when added to isolated neurons in culture, appear to enhance, retard or repel cell growth. Growth promoters include complex reagents like serum, growth factors like NGF, specific guidance molecules like netrins and semaphorins, and many small molecule activators, like 7.beta.-Acetoxy-8,13-epoxy1.alpha.,6.beta.,9.alpha.-trihydroxylabd-14-en- e-11-one (U.S. Pat No. 6,268,352; Song et al. 1998, Science 281, 1515-18). However, those skilled in the art recognize that in vitro growth regulation of isolated neurons is not predictive of the behavior of CNS neurons in an environment where they are subject to growth repulsion mediated by endogenous neural growth repulsion factors (see review by Tessier-Lavigne and Goodman (1996, Science 274, 1123-1133); compounds found to promote nerve growth in vitro and/or in
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embryonic systems are generally unable to overcome in situ repulsion present in the adult CNS. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
BMOG, a novel protein member of the myelin-oligodendrocyte glycoprotein family and its use for immunomodulatory purposes Inventor(s): Browning, Jeffrey; (Brookline, MA) Correspondence: Fish & Neave; 1251 Avenue OF The Americas; 50th Floor; New York; NY; 10020-1105; US Patent Application Number: 20040110218 Date filed: October 28, 2003 Abstract: BMOG, A Novel Protein Member of the Myelin-Oligodendrocyte Glycoprotein Family which is expressed by germinal center B cells and Its Use For Immunomodulatory Purposes Excerpt(s): This is a continuation of PCT/US98/23826, filed on 5 Nov. 1998 as a continuation of prior U.S. provisional Serial No. 60/064,761, filed 7 Nov. 1997. The entire disclosure of each of the aforesaid patent applications are incorporated herein by reference. The present invention relates to the use of a novel protein, BMOG (B cell myelin-oligodendrocyte glycoprotein) which is expressed by germinal center B cells. This protein may have immunoregulatory functions and soluble or chimeric fusion proteins of BMOG may be used to regulate the immune system in autoimmune or inflammatory disease. MOG or myelin-oligodendrocyte glycoprotein is a member of a family of proteins that includes butyrophilin, a glycoprotein expressed in lactating tissue. MOG and butyrophilin are considered to be part of a larger group called the B7 family (1, 2). These proteins have one or two immunoglobulin superfamily domains followed by one or two transmembrane domains. The intracellular domain is either very short such as in MOG, or longer as in the case of butyrophilin, and resembles a B30 ring finger domain. MOG is the best characterized member of the family of single Ig domain members and is a component of myelin. In experimental allergic encephalitis (EAE), immunization of mice with MOG itself or a peptide from the extracellular region of the molecule induces myelin degeneration resulting in a motor neuron deficit (3-5). The disease in this case resembles that in human multiple sclerosis (MS) and therefore murine EAE is considered a model of MS (6). In MS, some initiating event for which viral infections have been postulated, leads to recognition of several proteins in the myelin including, MOG, myelin basic protein (MBP) and proteolipid protein (PLP). MOG is a glycoprotein and has an unusual oligosaccharide epitope on its extracellular domain, i.e. the NHK domain (7) and its role in the nervous system is unclear. The two Ig domain members of this family are the B7-1 and B7-2 ligands for the CTLA-4 and CD28 receptors. The B7 ligands are critical components of T cell activation, and binding to their receptors initiates a co-stimulatory signal (8). Since the B7 proteins play a critical costimulatory role, it is likely that other members of this family will signal through specific receptors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Chlamydial peptides and their mimics in demyelinating disease Inventor(s): Hudson, Alan P.; (Novi, MI), Lenz, Derel C.; (Farmington Hills, MI), Swanborg, Robert H.; (Clinton Township, MI), Whittum-Hudson, Judith A.; (Novi, MI) Correspondence: Venable, Baetjer, Howard And Civiletti, Llp; P.O. Box 34385; Washington; DC; 20043-9998; US Patent Application Number: 20040038920 Date filed: August 4, 2003 Abstract: Subsequent to reports that Chlamydia pneumoniae (Cpn) was present in the CSF of a subset of multiple sclerosis (MS) patients, a 20-mer peptide from a protein specific to C. pneumoniae (Cpn) which shares a seven amino acid motif with a critical epitope of myelin basic protein (MBP), a major central nervous system antigen targeted by the autoimmune response in MS was identified. This bacterial peptide induces a Th1 response accompanied by severe clinical and histological experimental autoimmune encephalomyelitis in Lewis rats, a condition closely reflective of many aspects of MS. Various non-encephalitogenic peptide analogues and derivatives are disclosed and are useful for inhibiting such Th1 responses, inducing protective Th2 responses, and for treating a subject having MS or delaying onset of preventing MS in a subject at risk. Excerpt(s): The present invention in the field of immunology and medicine is directed to a novel 20-mer peptide from Chlamydia pneumoniae that elicits autoimmune disease in an animal model of multiple sclerosis and has applicability in the diagnosis, prognosis and therapy of related demyelinating and neurodegenerative diseases. Multiple sclerosis (MS) is characterized by the presence of autoreactive T cells which target antigens associated with central nervous system (CNS) myelin, including myelin basic protein (MBP), proteolipid protein, and myelin oligodendrocyte glycoprotein (K. Ota et al., Nature 346:183 (1990); R. Martin et al., J. Exp. Med. 173:19 (1991); J. L. Trotter et al., J. Neuroimmunol. 33, 55 (1991); C. C. A. Bernard et al., J. Mol. Med. 75:77 (1997)). Detailed study of tissue samples from MS patients reveals demyelination and mononuclear cell infiltration of CNS white matter, oligoclonal immunoglobulin in the cerebrospinal fluid (CSF), and in many cases axonal degeneration (U. Traugott et al., Science 219, 308 (1983); Raine, C. S. et al., Ann. Neurol. 46:144 (1999); B. D. Trapp et al., N. Engl. J. Med. 338:278 (1998)). Patients with MS usually display one of two courses of disease progression, i.e., chronic disease of increasing severity or, more commonly, a remitting/relapsing disease form that progresses to incapacity at a slower rate. Because of its many clinical and immunopathologic similarities to MS, experimental autoimmune encephalomyelitis (EAE) in rodents has become a widely accepted model for study of the human disease. In the genetically susceptible Lewis (LEW) rat, immunization with a specific peptide from MBP (see below) induces an acute episode of paralysis that is mediated by infiltration of activated CD4+ inflammatory T cells into the CNS, thereby duplicating this and other important characteristics of MS pathology (S. S. Zamvil et al., Annu. Rev. Immunol. 8:579 (1992); R. H. Swanborg, Clin. Immunol. Immunopathol. 77:4 (1995)). The etiology of MS remains elusive, but one explanation put forth for disease development postulates that specific antigenic epitopes from an unspecified infectious agent or agents induce(s) a host immune response in which cross-reactivity with myelin triggers disease, a concept referred to as molecular mimicry (R. S. Fujinami et al., Science 230, 1043 (1985)). In this scenario, certain T cells and/or antibodies produced in response to antigens from the infectious agent also recognize relevant self-antigens in the CNS, thereby initiating the destructive autoimmune process. To date little direct evidence exists to support the molecular mimicry hypothesis, although some data appear to support an infectious cause for MS (S. S. Soldan et al., Nature Med. 3, 1394-1397 (1997)
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and see below). Further, studies in mice have shown that infection with Theiler's virus elicits an inflammatory response in the CNS which does progress to relapsing/remitting EAE (Y. Katz-Levy et al., J. Clin. Invest. 104, 599 (1999)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
CNS neurite outgrowth modulators, and compositions, cells and methods embodying and using same Inventor(s): Schachner, Melitta; (Zurich, CH) Correspondence: Klauber & Jackson; 411 Hackensack Avenue; Hackensack; NJ; 07601 Patent Application Number: 20040022790 Date filed: June 9, 2003 Abstract: The invention features a method for promoting neural growth in vivo in the mammalian central nervous system by administering a neural cell adhesion molecule which can overcome inhibitory molecular cues found on glial cells and myelin to promote neural growth. Also featured active fragments, cognates, congeners, mimics, analogs, secreting cells and soluble molecules thereof, as well as antibodies thereto, and DNA molecules, vectors and transformed cells capable of expressing them. The neuroprotective of the agents as well as their ability to promote and effect myelination and remyelination are alse disclosed, as are the concomitant benefits that these capabilities confer, in the former instance, with regard to reduction of apoptosis and necrosis, and in the latter instance, the treatment of Parkinsonism, Alzheimer's disease and multiple sclerosis. The invention also includes transgenic mouse lines expressing a neural adhesion molecule in differentiated astrocytes, and cells and tissues derived therefrom. The expression of the neural adhesion molecule enhances neurite outgrowth on central nervous system tissue derived from these transgenic mice. The invention also features methods for enhancing neuronal outgrowth of CNS neurons, for enhancing memory and for increasing synaptic efficacy. Also featured are methods of testing drugs which modulate the effects of the neural adhesion molecule, and assay systems suitable for such methods. Excerpt(s): This application is a continuation-in-part of co-pending application Ser. No. ______, filed Aug. 3, 1998, which is, in turn, a continuation-in-part of co-pending application Ser. No. 08/636,514, filed Apr. 19, 1996, which is in turn, a continuation-inpart of co-pending application Ser. No. 08/483,959, filed Jun. 7, 1995, which is in turn, a continuation-in-part of co-pending application Ser. No. 08/424,995, filed Apr. 19, 1995, the disclosures of which are hereby incorporated by reference in their entireties. Applicants claim the benefits of these Applications under 35 U.S.C.sctn. 120. This invention relates generally to the modulation of neural growth in the central nervous system, and more particularly to methods and associated agents, constructs and compositions for improving CNS neural growth. Specifically, the invention relates to the use of cellular adhesion molecules, and preferably neural cell adhesion molecules such as L1, to foster and improve such neural growth. The ability of neurons to extend neurites is of prime importance in establishing neuronal connections during development. It is also required during regeneration to re-establish connections destroyed as a result of a lesion. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compositions for treatment of diseases arising from secretion of mast cell biochemicals Inventor(s): Theoharides, Theoharis C.; (Brookline, MA) Correspondence: DR. Melvin Blecher; Law Offices OF DR. Melvin Blecher; 4329 Van Ness ST., NW; Washington; DC; 20016; US Patent Application Number: 20030232100 Date filed: May 16, 2003 Abstract: Compositions for treatment of diseases arising from products secreted by activated tissue mast cells, composed of, as active ingredients, unprocessed olive kernel (pit) extract that increases absorption of these compositions in various routes of administration, and one or more of a heavily sulfated, non-bovine proteoglycan such as shark cartilage chondroitin sulfate C, a hexosamine sulfate such as D-glucosamine sulfate, a flavonoid such as quercetin, S-adenosylmethionine, a histamine-1 receptor antagonist, a histamine-3 receptor agonist, a CRH antagonist, caffeine, fragments of myelin basic protein, rutin, polyunsaturated fatty acids, Bitter Willow Extract and a polyamine. Excerpt(s): This application is a continuation-in-part of co-pending U.S. Ser. No. 09/773,576, filed Feb. 2, 2001, which is a divisional of co-pending U.S. Ser. No. 09/056,707, filed Apr. 8, 1998. The invention generally relates to the treatment of diseases arising from mast cell secretory products. More specifically, the invention relates to compositions containing inhibitors of mast cell activation and secretion that are designed to be used as dietary supplements alone or as or adjuvants to conventional approved medications for the relief of said diseases. The expression "arising from" is intended herein to mean any process that leads to pathophysiology that involves any product secreted from mast cells. The term "secretory product" is intended to mean any biochemical(s) secreted from mast cells, whether preformed or newly synthesized. By "disease" is mean any condition, syndrome or other pathophysiological entity leading to dysfunction in the patient. A recent meta-analysis showed potential therapeutic benefit of chondroitin sulfate and/or glucosamine in osteoarthritis [McAlindon et al. J Am Med Assn. 283:1469 (2000)], while a double-blind clinical trial with glucosamine showed definite benefits in osteoarthritis with respect to pain, radiographic joint appearance and progression [Reginster et al., Lancet 337:252 (2001); Pavelka et al., Arch Intern Med. 162:2113(2002)]. However, less than 5% of the chondroitin sulfate in commercially available preparations is absorbed orally, because the size of the molecule and the degree of sulfation impede its absorption from the gastrointestinal tract, which greatly reduces the effectiveness of such preparations. Furthermore, such commercial preparations use chondroitin sulfate obtained from cow trachea, with the possible danger of contracting spongiform encephalopathy or "mad cow disease". In fact, the European Union has banned even cosmetics that contain bovine-derived products. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Diagnostic test kits Inventor(s): Gersdorff, Michel; (Brussels, BE), Rousseau, Guy; (Brussels, BE), Tomasi, Jean-Paul; (Brussels, BE) Correspondence: Trask Britt; P.O. Box 2550; Salt Lake City; UT; 84110; US Patent Application Number: 20030082171 Date filed: October 16, 2002 Abstract: The invention provides a method for the treatment of prophylaxis of autoimmune inner ear disease, in particular, deafness caused by autoimmune inner ear disease, which comprises administering to a host in need thereof a vaccine comprising peripheral myelin protein zero. The invention further provides diagnostic methods and kits derived from the protein. Excerpt(s): This application is a divisional of Ser. No. 09/611,908, filed Jul. 7, 2000, which is a continuation of U.S. application Ser. No. 09/125,754, filed Sep. 29, 1998, abandoned, which is a 371 of International Application Serial No. PCT/EP97/01003, filed Feb. 28, 1997, published as PCT International Publication Number WO 97/32598 on Sep. 12, 1997, the contents of which are incorporated by this reference. This invention relates to novel vaccine and pharmaceutical formulations and to their manufacture and use in the treatment of deafness. In particular, the invention relates to the use of the protein known as major peripheral myelin protein zero (abbreviated to MPP, Pzero or Po) in a vaccine. The invention further relates to the use of the protein in diagnostic methods and to a kit for use in carrying out such methods. There is a high incidence of inner ear diseases such as progressive sensorineural hearing loss, sudden deafness, otosclerosis and Meniere's disease. The etiology of these inner ear diseases remains unclear or unknown. However, evidence now suggests that certain inner ear diseases, including those above, appear to be of autoimmune origin. In patients with inner ear disease, several attempts have been made to identify specific antigens with which circulating antibodies and active lymphocytes react. Antibodies against type II collagen and heat shock protein p70 have been described in patients suffering from idiopathic inner ear disease (e.g. Yoo et al., Science 1982, 217, 1153-1155). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Formulation for the prevention and treatment of multiple sclerosis and other demyelinating conditions Inventor(s): Bennett, Duane; (Wilbraham, MA) Correspondence: Melvin K. Silverman; Suite 500; 500 West Cypress Creek Road; FT. Lauderdale; FL; 33309; US Patent Application Number: 20040001899 Date filed: March 12, 2003 Abstract: A method for prevention and treatment of multiple sclerosis and other demyelinating conditions is disclosed. The method includes two subsequent phases. In each phase, a patient orally administers daily a regimen which includes a specific combination of amino acids, fatty acids, vitamins and minerals. The particular regimens provide vital nutrients necessary to re-build fatty acids that may have been lost or reduced in the myelin sheathing and other locations of brain, therefore decrease one's susceptibility to multiple sclerosis and prevent reoccurrence of the disease.
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Excerpt(s): This application is a non-provisional patent application of provisional patent application Serial No. 60/363,894 filed Mar. 14, 2002. Applicant claims the benefit of 35 U.S.C. 119(e). This invention relates to the treatment of multiple sclerosis ("MS") and other demyelinating conditions. MS is a chronic, often disabling disease of the central nervous system. Various and converging lines of evidence point to the possibility that the disease is caused by a disturbance in the immune function, although the cause of this disturbance has not been established. This disturbance permits cells of the immune system to "attack" myelin, the fat containing insulating sheath that surrounds the nerve axons located in the central nervous system ("CNS"). When myelin is damaged, electrical pulses cannot travel quickly or normally along nerve fiber pathways in the brain and spinal cord. This results in disruption of normal electrical conductivity within the axons, fatigue and disturbances of vision, strength, coordination, balance, sensation, and bladder and bowel function. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Inhibitors of myelin-associated glycoprotein (MAG) activity for regulating neural growth and regeneration Inventor(s): Cao, Zixuan; (Elmhurst, NY), Domeniconi, Marco; (New York, NY), Filbin, Marie T.; (New York, NY) Correspondence: Fish & Neave; 1251 Avenue OF The Americas; 50th Floor; New York; NY; 10020-1105; US Patent Application Number: 20040121341 Date filed: December 20, 2002 Abstract: The present invention relates generally to products, compositions and methods useful for promoting neural repair and regeneration. The products and compositions of this invention include myelin-associated glycoprotein (MAG) derivatives that are inhibitors of endogenous MAG (e.g., mutant MAG proteins) and Nogo Receptor (NgR) binding inhibitors that are peptides derived from MAG, Nogo and OMgp that can bind to NgR and block NgR signaling. Peptides that can bind and activate NgR signaling are also provided. Inhibitory MAG derivatives and NgR binding inhibitors are useful for blocking the inhibition of neural regeneration mediated by proteins such as MAG, Nogo and/or OMgp in the nervous system. These inhibitors are also useful for treating neural degeneration associated with injuries, disorders or diseases. Excerpt(s): This invention relates to inhibitors of myelin-associated glycoprotein (MAG) activity, such as MAG derivatives and Nogo receptor (NgR) ligand blocking peptides, and compositions and methods comprising such derivatives and peptides, useful for regulating neural growth and regeneration. The mammalian nervous system does not regenerate after injury despite the fact that there are many molecules present which encourage/promote axonal (nerve) growth. There are at least three factors that are responsible for this lack of regeneration: the formation of a glial scar, the presence of inhibitors of regeneration in myelin, and the intrinsic growth capacity of adult axons. In situations involving injury, the glial scar takes some time after injury to form. It would be advantageous to encourage axonal growth during this "window-of-opportunity", before the scar forms. It would also be desirable to be able to encourage axonal growth irrespective of scarring, e.g., for treating or preventing neural degeneration or damage associated with a disorder, disease or condition. Blocking the function of the inhibitors of regeneration present in myelin can be achieved by, e.g., neutralizing the inhibitors or
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altering the growth capacity of the axon so that it no longer responds to the inhibitors. To date, three inhibitors have been identified in myelin: myelin-associated glycoprotein (MAG) (McKerracher, L. et al., Neuron, 13, pp. 805-811 (1994); Mukhopadhyay, G. et al., Neuron, 13, pp. 757-767 (1994); U.S. Pat. No. 5,932,542; U.S. Pat. No. 6,203,792; and U.S. Pat. No. 6,399,577; and WO 97/01352), Nogo (Chen, M. S. et al., Nature, 403, pp. 434-439 (2000); Grandpre, T. et al., Nature, 403, pp. 439-444 (2000)); and oligodendrocyte myclin glycoprotein (OMgp) (Wang, K. C. et al., Nature, 417, pp. 941-944 (2002). Interestingly, all three of these inhibitors bind to the same receptor to exert their inhibitory effects (Wang et al., supra; Domeniconi, M. et al., Neuron, 35, pp. 283-290 (2002); Fournier, A. E. et al., Nature, 409, pp. 341-346 (2001); Liu, B. P. et al., Science, 297, pp. 1190-1193 (2002)). Because this receptor was first identified as being a receptor for Nogo-66 ligand (a 66 amino acid extracellular domain shared by different isoforms of Nogo), it is referred to as the Nogo-66 receptor ("NgR")(Fournier, A. E. et al., supra). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method for diagnosing multiple sclerosis and an assay therefore Inventor(s): Chamczuk, Andrea; (Toronto, CA), Moscarello, Mario Anthony; (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
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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 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 treatment of neurodegenerative diseases and effects of aging Inventor(s): Delack, Elaine A.; (Stanwood, WA) Correspondence: Todd N. Hathaway; Attorney AT Law; 119 N. Commercial ST., # 620; Bellingham; WA; 98225-4437; US Patent Application Number: 20030113309 Date filed: June 21, 2001 Abstract: A method for treatment of neurodegenerative disease conditions stemming from multiple sclerosis, aging, autoimmune diseases and fibromyalgia. A compound effective to increase neuronal metabolism of histamine to a histamine H.sub.2 agonist is administered in an amount sufficient to stimulate production of cyclic AMP at a level which is sufficient to maintain myelin against undergoing self-degeneration. The compound is selected from the group consisting of histamine M-methyltransferase, monoamineoxidase-A, monoamineoxidase-A agonists and histamine H.sub.3 antagonists. The histamine M-methyltransferase may be administered to increase neuronal metabolism of histamine to tele-methylhistamine, whereas the monoamineoxidase-A or monoamineoxidase-A agonist may be administered so as to increase neuronal metabolism of telemethylhistamine to an H.sub.2 agonist. Separately or in conjunction with the others, the histamine H.sub.3 antagonist may be administered so as to inhibit metabolism of the telemethylhistamine to an H.sub.3 agonist, thereby increasing metabolism of the telemethylhistamine to an H.sub.2 agonist. The increased histamine H.sub.2 agonist levels reduce demyelination and the symptoms that are associated with these conditions.
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Excerpt(s): The present invention relates generally to methods for the treatment of neurological conditions, and, more particularly, to a method for alleviating/controlling symptoms associated with neurodegeneration and similar conditions stemming from multiple sclerosis, aging, autoimmune diseases and other causes, by administration of compositions which induce an increased presence of histamine H2 and cyclic AMP in the body. Neurodegenerative conditions, which include diseases of autoimmunity, strike an increasing number of individuals each year, and for many of these conditions conventional treatments offer little in the way of true relief. In some instances, the neurodegenerative conditions are more or less specifically associated with a particular disease, such as multiple sclerosis, while in other instances the conditions are associated more generally with aging or some other condition or process of the body, such as a genetic disorder or an autoimmune disease, fibromyalgia, for example. As a group, however, these conditions are characterized by weakness and impaired physical functions, and, sometimes, impaired mental functions as well. Debilitation is often progressive, and, as stated, conventional treatments and therapies have been limited in their success. For purposes of illustration the invention will be described below largely in the context of multiple sclerosis, which is a condition to which the invention has particular applicability; however, it will be understood that the present invention is applicable to neurodegenerative conditions, including autoimmune diseases, fibromyalgia, having any of a variety of sources, therefore it is not limited in scope to the treatment of multiple sclerosis alone. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
METHODS FOR MODULATING THE IMMUNE SYSTEM Inventor(s): STEINMAN, LAWRENCE; (PALO ALTO, CA), ZAMVIL, SCOTT; (BOSTON, MA) Correspondence: Seed Intellectual Property Law Group Pllc; 701 Fifth Ave; Suite 6300; Seattle; WA; 98104-7092; US Patent Application Number: 20020076412 Date filed: June 7, 1995 Abstract: Methods for modulating the immune system of an animal, as well as tolerizing such an immune system through the administration of one or more polypeptides derived from human myelin basic protein (hMBP), are provided. Such polypeptides include residues 87-99 of hMBP, as well as residues His-Phe-Phe-Lys and/or Lys-IlePhe-Lys of hMBP. Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 08/125,407, filed Sep. 22, 1993, which is a continuation-in-part of U.S. Ser. No. 08/066,325, filed May 21, 1993, which is a file wrapper continuation of U.S. Ser. No. 07/877,444, filed Apr. 30, 1992, which is continuation-in-part of U.S. Ser. No. 07/517,245, filed May 1, 1990, and International Application Ser. No. PCT/US91/02991, filed May 1, 1991. This application is also a continuation-in-part of application Ser. No. 07/379,500, filed Jul. 12, 1989, which is a continuation-in-part of application Ser. No. 07/086,694, filed Aug. 17, 1987, the disclosures of all of which are specifically incorporated herein by reference. The subject invention relates generally to the treatment of diseases, particularly autoimmune diseases. Autoimmune diseases are a result of a failure of the immune system to avoid recognition of self. The attack by the immune system of host cells can result in a large number of disorders, including such neural diseases as multiple sclerosis and myasthenia gravis diseases of the joints, such as rheumatoid arthritis, attacks on nucleic
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acids, as observed with systemic lupus erythematosus and such other diseases associated with various organs, as psoriasis, juvenile onset diabetes, Sjogren's disease, and thyroid disease. These diseases can have a variety of symptoms, which can vary from minor and irritating to life-threatening. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods for promoting production of myelin by schwann cells Inventor(s): Moore, Emma E.; (Seattle, WA), Novak, Julia E.; (Bainbridge Island, WA) Correspondence: Paul G. Lunn, ESQ.; Zymogenetics, INC.; 1201 Eastlake Avenue East; Seattle; WA; 98102; US Patent Application Number: 20020039568 Date filed: February 27, 2001 Abstract: A method for promoting the expression of myelin or Protein Zero in Schwann cells using Zcyto7 or IL-17. Zcyto7 or IL-17 are further used to promote myelination of the peripheral nervous system. This is particularly useful in treating diseases dymyelinating diseases such as diabetic neuropathy, Guillain - Barr Syndrome, chronic demyelinating disease, acute demyelinating polyneuropathy and human immunodeficiency viral demyelinating neuropathy or demyelination caused by trauma. Excerpt(s): This claims the benefit of U.S. Provisional Patent Application No. 60/185,666 filed on Feb. 29, 2000. The peripheral nervous system (PNS) serves as a bridge between the environment and the central nervous system (CNS). The PNS is comprised of primary afferent neurons, which sends information from sensory receptors to the CNS, somatic motor neurons, which transmit electrical stimuli from the CNS to voluntary muscles, and autonomic motor neurons, which transmit electrical stimuli to cardiac muscle, smooth muscle or glands. A neuron generally has a cell body, and an axon, which is a long nerve cell process extending from the cell body that is capable of rapidly conducting nerve impulses over long distances so as to deliver signals to cells. The axons of many vertebrate neurons are insulated by a myelin sheath, which greatly increases the rate at which an axon can conduct an action potential. Schwann cells are responsible for myelinating nerve cells in the peripheral nervous system. The Schwann cells wrap layer upon layer of their own plasma membrane in a tight spiral around the axon thereby insulating the axonal membrane so that almost no current leaks across it. Unmyelinated axons in the PNS are nonetheless embedded in Schwann cells although they are not ensheathed by myelin. A number of neuropathies of the PNS are associated with demyelination or failure of the Schwann cells to properly ensheath the axons of the PNS. They are diabetic neuropathy, Guillain-Barr disease (acute demyelinating polyneuropathy), chronic inflammatory demyelinating polyradiculoneuropathy (CIPD), and HIV inflammatory demyelinating disease. Also axon damage due to physical trauma may result in demyelination of the PNS. Thus, there is a need to discover agents that can be used to promote the production of myelin by Schwann cells. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Methods for stimulating nervous system regeneration and repair by regulating arginase I and polyamine synthesis Inventor(s): Filbin, Marie T.; (New York, NY), Ratan, Rajiv R.; (Cambridge, MA) Correspondence: Fish & Neave; 1251 Avenue OF The Americas; 50th Floor; New York; NY; 10020-1105; US Patent Application Number: 20030215428 Date filed: April 7, 2003 Abstract: This invention relates to the novel identification of arginase as an enzymatic activity which can reverse inhibition of neuronal regeneration in the central and peripheral nervous system. Assays to monitor the effects of various agents on arginase expression and thus on neuronal regeneration and repair and to identify agents which will block or promote the inhibitory effects on neuronal outgrowth are provided. This invention also relates to compositions and methods using agents that can reverse the inhibitory effects of myelin on neural regeneration by affecting arginase activity or putrescine and derivative polyamine levels in a neuron. Methods for regulating and for promoting (or repressing) neuronal growth or regeneration in the nervous system, methods for treating injuries or damage to nervous tissue or neurons, and methods for treating neural degeneration associated with conditions, disorders or diseases, comprising the step of administering at least one of the compositions according to this invention, are provided. Excerpt(s): The adult, mammalian central nervous system (CNS) does not regenerate after injury despite the fact that there are many molecules present which promote nerve and axonal growth. The adult, mammalian peripheral nervous system (PNS), in contrast, does regenerate to some extent. It is believed that the lack of regeneration in the CNS is caused by the presence of molecules which actively prevent or inhibit regeneration. In the PNS, to the extent that neurons can regenerate, these inhibitors are thought to be removed or inactive and are thus not encountered by the re-growing axon. Hence, the well documented inability of the adult mammalian CNS to regenerate after injury is believed to result from a predominance of inhibitory molecules. There are at least three factors that are responsible for the lack of regeneration: the formation of a glial scar, inhibitors of regeneration in myelin and the intrinsic growth capacity of adult axons. The glial scar takes some time after injury to form. Therefore, it would be advantageous to encourage growth in this "window-of-opportunity", before the scar forms. The main obstacles immediately after injury, therefore, are inhibitors of neuronal regeneration present in myelin. To overcome these inhibitors, they could either be neutralized or the growth capacity of the axon could be changed such that the axons no longer respond to myelin by being inhibited. In this way, they would resemble young axons which regenerate in vivo and which are not inhibited by myelin in vitro. Previously, we showed that if the endogenous levels of cAMP are elevated in older neurons, either artificially with dibutyryl cAMP or by pre-treating the neurons with neurotrophins ("priming"), they are not inhibited by either myelin in general or by a specific myelin inhibitor, myelin-associated glycoprotein (MAG). See Cai, D. et al., Neuron 22:89-101 (1999); see also U.S. Pat. Nos. 5,932,542 and 6,203,792, the entire disclosures of which are incorporated herein by reference. We have also shown that the endogenous level of cAMP in young neurons is very high and that their ability to regenerate in vivo and to grow on myelin is cAMP-dependent (Cai et al., supra; 2001). The drop in neuronal cAMP concentration seems to parallel the developmentally regulated switch that decreases the ability of axons to regenerate. Thus, cAMP levels may play an important role in regulating the capacity of a neuron to undergo axonal
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regeneration. Downstream effectors which are directly responsible for improved neuronal growth on myelin remain unknown. One candidate may be polyamines, such as spermidine and spermine, and their diamine precursor putrescine, which are ubiquitously distributed in prokaryotic and eukaryotic cells and eukaryotic tissues. 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), Gaur, Amitabh; (San Diego, CA), Ling, Nicholas; (San Diego, CA), Steinman, Lawrence; (Palo Alto, 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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Myelin oligodendrocyte glycoprotein-like protein (MOGp) Inventor(s): Chopra, Arvind; (Gaithersburg, MD), Gentz, Reiner L.; (Rockville, MD), Olsen, Henrik S.; (Gaithersburg, MD), Ruben, Steven M.; (Olney, MD) Correspondence: Human Genome Sciences Inc; 9410 Key West Avenue; Rockville; MD; 20850 Patent Application Number: 20030166898 Date filed: July 19, 2002 Abstract: The present invention relates to a novel MOGp protein which is a member of the Ig superfamily. In particular, isolated nucleic acid molecules are provided encoding the human MOGp protein. MOGp polypeptides are also provided as are vectors, host cells and recombinant methods for producing the same. Also provided are diagnostic
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and therapeutic methods for detecting and treating cancer, inflammation, and multiple sclerosis (MS). Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/035,445, which is incorporated herein by reference. The present invention relates to a novel member of the immunoglobin gene superfamily. More specifically, isolated nucleic acid molecules are provided encoding a human myelin oligodendrocyte glycoprotein-like protein (MOGp). MOGp polypeptides are also provided, as are vectors, host cells and recombinant methods for producing the same. Also provided are diagnostic and therapeutic methods for detecting and treating cancer, inflammation, and multiple sclerosis (MS). The immunoglobin (Ig) gene superfamily is comprised of a diverse group of genes that share evolutionary homology. Members of this superfamily are often associated with immune recognition, cell adhesion, or cell surface interaction. These proteins are generally integral membrane proteins comprising one or more extracellular domains, a transmembrane region, and an intracellular domain. See Hunkapillar et al., Adv. Immunol. 44:1-63 (1989). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Myelination of congenitally dysmyelinated forebrains using oligodendrocyte progenitor cells Inventor(s): Goldman, Steven A.; (South Salem, NY), Roy, Neeta Singh; (New York, NY), Windrem, Martha; (New York, NY) Correspondence: Michael L. Goldman; Nixon Peabody Llp; Clinton Square; P.O. Box 31051; Rochester; NY; 14603-1051; US Patent Application Number: 20030223972 Date filed: February 14, 2003 Abstract: One form of the present invention is directed to a method of remyelinating demyelinated axons by treating the demyelinated axons with oligodendrocyte progenitor cells under conditions which permit remyelination of the axons. Another aspect of the present invention relates to a method of treating a subject having a condition mediated by a loss of myelin or a loss of oligodendrocytes by administering to the subject oligodendrocyte progenitor cells under conditions effective to treat the condition mediated by a loss of myelin or a loss of oligodendrocytes. A further aspect of the present invention relates to an in vitro method of identifying and separating oligodendrocyte progenitor cells from a mixed population containing other mammalian brain or spinal cord cell types. This further aspect of the present invention involves removing neurons and neuronal progenitor cells from the mixed population to produce a treated mixed population. Oligodendrocyte progenitor cells are then separated from the treated mixed population to form an enriched population of oligodendrocyte progenitor cells. Excerpt(s): This application claims benefit of U.S. Provisional Patent Application Serial No. 60/358,006, filed Feb. 15, 2002. The present invention is directed to the myelination of congenitally dysmyelinated forebrains using oligodendrocyte progenitor cells and to a method of treating a subject having a condition mediated by a loss of myelin or a loss of oligodendrocytes. Also disclosed is a method for the identification and separation of oligodendrocyte progenitor cells from a mixed population containing other mammalian brain or spinal cord cell types. A broad range of diseases, from the inherited leukodystrophies to vascular leukoencephalopathies to multiple sclerosis, result from
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myelin injury or loss. In the pediatric leukodystrophies, in particular, compact myelin either fails to properly develop, or is injured in the setting of toxic storage abnormalities. Recent studies have focused on the use of transplanted oligodendrocytes or their progenitors for the treatment of these congenital myelin diseases. Both rodent and human-derived cell implants have been assessed in a variety of experimental models of congenital dysmyelination. The myelinogenic potential of implanted brain cells was first noted in the shiverer mouse (Lachapelle et al., "Transplantation of CNS Fragments Into the Brain of Shiverer Mutant Mice: Extensive Myelination by Implanted Oligodendrocytes," Dev. Neurosci 6:325-334 (1983)). The shiverer is a mutant deficient in myelin basic protein (MBP), by virtue of a premature stop codon in the MBP gene that results in the omission of its last 5 exons (Roach et al., "Chromosomal Mapping of Mouse Myelin Basic Protein Gene and Structure and Transcription of the Partially Deleted Gene in Shiverer Mutant Mice," Cell 42:149-155 (1985)). Shiverer is an autosomal recessive mutation, and shi/shi homozygotes fail to develop central compact myelin. They die young, typically by 20-22 weeks of age, with ataxia, dyscoordination, spasticity, and seizures. When fetal human brain tissue was implanted into shiverers, evidence of both oligodendrocytic differentiation and local myelination was noted (Lachapelle et al., "Transplantation of Fragments of CNS Into the Brains of Shiverer Mutant Mice: Extensive Myelination by Implanted Oligodendrocytes," Dev. Neurosci 6:326-334 (1983); Gumpel et al., "Transplantation of Human Embryonic Oligodendrocytes Into Shiverer Brain," Ann NY Acad Sci 495:71-85 (1987); and Seilhean et al., "Myclination by Transplanted Human and Mouse Central Nervous System Tissue After Long-Term Cryopreservation," Acta Neuropathol 91:82-88 (1996)). However, these unfractionated implants yielded only patchy remyelination and would have permitted the co-generation of other, potentially undesired phenotypes. Enriched glial progenitor cells were thus assessed for their myelinogenic capacity, and were found able to myelinate shiverer axons (Warrington et al., "Differential Myelinogenic Capacity of Specific Development Stages of the Oligodendrocyte Lineage Upon Transplantation Into Hypomyelinating Hosts," J. Neurosci Res 34:1-13 (1993)), though with low efficiency, likely due to predominantly astrocytic differentiation by the grafted cells. Snyder and colleagues (Yandava et al., "Global Cell Replacement is Feasible via Neural Stem Cell Transplantation: Evidence from the Dysmyelinated Shiverer Mouse Brain," Proc. Natl. Acad. Sci. 96:7029-7034 (1999)) subsequently noted that immortalized multipotential progenitors could also contribute to myelination in shiverers. Duncan and colleagues similarly noted that oligosphere-derived cells raised from the neonatal rodent subventricular zone could engraft another dysmyelinated mutant, the myelin-deficient rat, upon perinatal intraventricular administration (Learish et al., "Intraventricular Transplantation of Oligodendrocyte Progenitors into a Fetal Myelin Mutant Results in Widespread Formation of Myelin," Ann Neurol 46:716-722 (1999)). These studies notwithstanding, the ability of human oligodendrocyte progenitor cell isolates to myelinate dysmyelinated brain has not hitherto been examined. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Oligodendrocytes derived from human embryonic stem cells for remyelination and treatment of spinal cord injury Inventor(s): Keirstead, Hans S.; (Irvine, CA), Nistor, Gabriel I.; (Placentia, CA) Correspondence: Bozicevic, Field & Francis Llp; 200 Middlefield RD; Suite 200; Menlo Park; CA; 94025; US Patent Application Number: 20040009593 Date filed: April 4, 2003 Abstract: This invention provides populations of neural cells bearing markers of glial cells, such as oligodendrocytes and their precursors. The populations are generated by differentiating pluripotent stem cells such as human embryonic stem cells under conditions that promote enrichment of cells with the desired phenotype or functional capability. Various combinations of differentiation factors and mitogens can be used to produce cell populations that are over 95% homogeneous in morphological appearance, and the expression of oligodendrocyte markers such as GalC. The cells are capable of forming myelin sheaths, and can be used therapeutically improve function of the central nervous system. Excerpt(s): This application claims the benefit of U.S. Provisional Application Serial No. 60/395,382, filed Jul. 11, 2002, which application is incorporated herein by reference. This invention relates generally to the field of cell biology of embryonic cells and neural progenitor cells. More specifically, this invention provides enriched populations of oligodendrocytes and their precursors, suitable for use in biological research, drug screening, and human therapy. Oligodendrocytes play a vital physiological role in support of the central nervous system. Availability of oligodendrocytes for human therapy may facilitate healing of disabling conditions that result from defects in the myelin sheath that insulates nerve cells. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Peptide specificity of anti-myelin basic protein and the administration of myelin basic protein peptides to multiple sclerosis patients Inventor(s): Catz, Ingrid; (Edmonton, CA), Warren, Kenneth G.; (Edmonton, CA) Correspondence: Intellectual Property Group; Pillsbury Winthrop Llp; 50 Fremont Street; San Francisco; CA; 94105-2228; US Patent Application Number: 20020111312 Date filed: March 20, 2001 Abstract: Human myelin basic protein (h-MBP) has a molecular weight of 18.5 KD and contains 170 amino acid residues. Synthetic peptides ranging in length from about 8 to 25 residues and covering the entire length of the protein have been produced. Antibodies to h-MBP (anti-MBP) were found to be neutralized by the synthetic peptides, in vitro, which span the h-MBP from about amino acid residue 61 to about amino acid residue 106. The peptides, which cover both the amino (about residues 1 to 63) and carboxy (about residues 117 to 162) terminals of h-MBP did not neutralize purified antiMBP. Intrathecal administration of peptide MBP75-95, either as a single dose, or as repeated injections for periods up to 10 weeks, produced complete bindingneutralization of free (F) anti-MBP with no change in bound (B) levels. A control peptide MBP35-58 had no effect on F or B anti-MBP levels. Intravenous administration of
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MBP75-95 resulted in significant decline of F and B CSF anti-MBP levels over a period of one month. Administration of MBP synthetic peptides to MS patients either intrathecally or intravenously did not have any adverse neurological effects and systemic complications did not occur. The MBP epitope for MS anti-MBP has been localized to an area between Pro85 and Pro96. Excerpt(s): This invention is concerned with selected polypeptides and their use in the immunoregulation of antibodies to human myelin basic protein. This invention also relates to novel pharmaceutical compositions containing these selected polypeptides and to a method of using these peptides for the treatment of Multiple Sclerosis. Multiple sclerosis (MS) is a multifocal demyelinating disease of the human central nervous system (CNS) associated with inflammation. Increased intra-blood-brain barrier (intraBBB) IgG synthesis is a hallmark of MS (Tourtelotte, W. W., J Neurol Sci 10: 279-304, 1970; Link, H. and Tibbling, G., Scand J Clin Lab Invest 37: 397-401, 1977; Tourtelotte, W. W. and Ma, B., Neurology 28: 76-83, 1978; Walsh, J. M. and Tourtelotte, W. W., In: Hallpike, J. F., Adams, C. W. M. and Tourtelotte, W. W., eds. Multiple sclerosis. Baltimore. Williams & Wilkins, 1982: 275-358; and Warren, K. G., and Catz, I. Ann Neurol 17: 475-480, 1985). IgG synthesis within the BBB is generally elevated in clinically definite MS patients (Schumacher, G. A., Beebe, G., Kibler R. E., et al., Ann NY Acad Sci 15:266-272, 1965) with active or inactive disease. The specificity of the majority of the CNS IgG is unknown. While a small proportion has antiviral activity or reacts against brain antigens, nucleic acids, erythrocytes or smooth muscle antigens, the nonspecific portion may represent polyclonal activation of B-cells (Tourtelotte, W. W., and Ma, B., Neurology 28:76-83, 1978). During the last decade there has been considerable interest in the study of antibodies to specific myelin proteins. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Reducing myelin-mediated inhibition of axon regeneration Inventor(s): He, Zhigang; (Boston, MA), Kim, Jieun A.; (Boston, MA), Koprivica, Vuk; (Boston, MA), Wang, Kevin C.; (Boston, MA) Correspondence: Richard Aron Osman; Science And Technology Law Group; 75 Denise Drive; Hillsborough; CA; 94010 Patent Application Number: 20030113325 Date filed: December 3, 2001 Abstract: Oligodendrocyte-myelin glycoprotein (OMgp)-specific binding agents are used to reduce OMgp-mediated axon growth inhibition. Mixtures of axons and OMgp and mixtures of Nogo receptor (NgR) and OMgp are used in pharmaceutical screens to characterize agents as inhibiting binding of NgR to OMgp and promoting axon regeneration. Excerpt(s): The invention is in the field of reducing meylin-mediated inhibition of axon regeneration. Most axons in the adult mammalian central nervous system (CNS) have little innate ability for repair after injury (Horner and Gage, 2000). Examination of postlesioned axons in the adult nervous system reveals that their proximal ends are able to form growth cones, the primary navigating entity of growing axons, that appear both morphologically and functionally identical to those of developing nerve fibers (reviewed by Tessier-Lavgine and Goodman, 2000). Studies over the past two decades have identified a number of guidance cues that can influence the motility and directionality of projecting axons during embryonic development (Tessier-Lavigne and
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Goodman, 1996; Song and Poo, 2001). It is believed that the combined influences of attractants and repellents orchestrate the precise motile behavior of individual axons. Conversely, either a lack of permissive cues and/or the presence of dominant inhibitors in the adult CNS seem to contribute significantly to the inability of lesioned axons to regenerate (Schwab & Bartholdi, 1996; Fournier and Strittmatter, 2001). In addition to the actual physical barrier presented by glial scarring at the lesion sites (KcKeon et al., 1991; Davies et al., 1997; Moon et al., 2001), inhibitory factors in oligodendrocytederived myelin clearly play a role in limiting axon regeneration. Immobilized CNS myelin proteins have been shown to potently inhibit axon outgrowth from a variety of neurons in vitro (Schwab and Caroni, 1988; Savio and Schwab, 1989). In addition, antimyelin antibodies have been used to neutralize the inhibitory effects of myelin and, more importantly, stimulate regeneration of the corticospinal tract in vivo (Schnell and Schwab, 1990; Bregmann et al., 1995; Huang et al., 1999). Most of the efforts towards identifying these myelin-associated inhibitors thus far have centered on assaying biochemical fractions of CNS myelin for growth-inhibitory activity in vitro and then isolating the corresponding molecules (Caroni and Schwab, 1988; McKerracher et al., 1994; Spillmann et al., 1998; Niederost et al., 1999). Several myelin components have been identified as putative inhibitors of regeneration through such approaches. One such component is myelin associated glycoprotein (MAG), a transmembrane protein with a five immunoglobulin domain-harboring extracellular region (Arquint et al., 1987; Salzer et al., 1987). Even though MAG is capable of inhibiting axon outgrowth from different types of cultured neurons (McKerracher et al., 1994; Mukhopadhyay et al., 1994; Li et al., 1996; Tang et al., 1997), knockout animals provide conflicting data on the effects of removing the MAG protein product on axon regeneration in vivo (Bartsch et al., 1995; Li et al., 1996; Schafer et al., 1996). In addition to MAG, neurite outgrowthinhibitory activity has also been found to associate with chondroitin sulfate proteoglycans (CSPGs) in CNS myelin (Niederost et al., 1999). However, it is unclear whether this inhibitory activity results from CSPGs themselves or from a combination with additional factors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Specific autoimmune reactions against isomerised/optically inverted epitopes: application for diagnosis of autoimmune diseases Inventor(s): Christgau, Stephan; (Gentofte, DK), Cloos, Paul; (Kobenhavn, DK) Correspondence: Jones Day; 51 Louisiana Aveue, N.W; Washington; DC; 20001-2113; US Patent Application Number: 20040058851 Date filed: February 15, 2002 Abstract: Antibodies and T-lymphocytes having immune reactivity with proteins isomerised at an aspartic acid, asparagine, glutamine or glutamic acid residue are found to be associated with auto-immune conditions involving auto-reactivity to IgG (rheumatoid arthritis) and myelin basic protein (multiple sclerosis). Diagnosis assays for auto-immune reactivity to isomerised protein sequences are described. Excerpt(s): The present invention relates to methods of assay for immune system components such as auto-antibodies and auto-reactive T-cells and techniques for developing diagnostic immunoassays for initial diagnosis and monitoring of autoimmune diseases. Autoimmune diseases comprise a complex group of conditions with the common denominator, that autologous components of the organism are recognised by the immune-system resulting in initiation of an aberrant immune-
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response. In order for an autoimmune reaction to occur, the normally well maintained immunological tolerance, which is maintained throughout life in healthy individuals, has to `break down` (Cooke 1988) (see "References" below). The reason for this is generally difficult to assess, because the initiation of the autoimmune reactions may occur several years prior to the clinical diagnosis of the disease, and the initiating events may vary considerably in different diseases. Given the large number of potential autoantigens in the human body it is remarkable that autoimmune diseases seem to be limited to only a few tissues and antigens. Given the localisation of the target antigen and distribution of autoimmune reactions in the organism, autoimmune diseases may be classified as either organ specific or non-organic specific (systemic). In either case the immuno-reactions may involve both the humoral (i.e. antibody synthesising) and the cellular part of the immune system (Cooke 1988). The present invention relates to techniques for characterising immune system components such as autoantibodies and auto-reactive T-cells or B-cells and molecules which are interactive therewith such as auto-antigens, for detection and quantification of such immune system components and auto-antigens. In an example of the application of the techniques and uses of the invention, autoimmune phenomena associated with the systemic autoimmune disorder rheumatoid arthritis (RA) or multiple sclerosis (MS) are described. However this is merely meant as an illustration of the invention, and by no means intended to limit the scope of the invention to only RA or MS. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
T-CELL VACCINATION FOR THE TREATMENT OF MULTIPLE SCLEROSIS Inventor(s): CORREALE, JORGE D.; (BUENOS AIRES, AR), WEINER, LESLIE P.; (LOS ANGELES, CA) 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 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
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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 •
Transgenically produced non-secreted proteins Inventor(s): Chen, Li-How; (Acton, MA), DiTullio, Paul; (Northboro, MA), Meade, Harry; (Newton, MA) Correspondence: Gtc Biotherapeutics, INC.; 175 Crossing Boulevard, Suite 410; Framingham; MA; 01702; US Patent Application Number: 20030213003 Date filed: February 4, 2003 Abstract: The invention provides a method of making and secreting a non-secreted protein. The method includes expressing the protein from a nucleic acid construct which includes: (a) a mammary epithelial specific promoter; (b) a milk protein specific signal sequence which can direct the secretion of a protein; (c) optionally, a sequence which encodes a sufficient portion of the amino terminal coding region of a secreted protein to allow secretion in the milk of a transgenic mammal, of the non-secreted protein; and (d) a sequence which encodes a non-secreted protein, wherein elements (a), (b), optionally (c), and (d) are preferably operatively linked in the order recited. Both glutamic acid decarboxylase (GAD) and myelin basic protein (MBP), which are cytoplasmic proteins, have been produced by the methods of the present invention. The invention also provides methods for treating diabetes and multiple sclerosis using proteins produced by the methods of the present invention. Excerpt(s): This application claims the benefit of a previously filed Provisional Application No. 60/038,998, filed Feb. 25, 1997, which is hereby incorporated by reference. This invention relates to the production and secretion of proteins which are not ordinarily secreted. A growing number of recombinant proteins are being developed for therapeutic and diagnostic applications. However, many of these proteins may be difficult or expensive to produce in a functional form and/or in the required quantities using conventional methods. Conventional methods involve inserting the gene responsible for the production of a particular protein into host cells such as bacteria, yeast, or mammalian cells, e.g., COS cells, and then growing the cells in culture media. The cultured cells then synthesize the desired protein. Traditional bacteria or yeast systems may be unable to produce many complex proteins in a functional form. While mammalian cells can reproduce complex proteins, they are generally difficult and
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expensive to grow, and often produce only mg/L quantities of protein. In addition, nonsecreted proteins are relatively difficult to purify from procaryotic or mammalian cells as they are not secreted into the culture medium. 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 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
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Use of Ulip-and/or Ulip2 in the treatment of myelin disorders Inventor(s): Aguera, Michelle; (Caluire, FR), Belin, Marie-Francoise; (Lyon, FR), Charrier, Emmanuelle; (Les Herbiers, FR), Honorat, Jerome; (Brion, FR), Ricard, Damien; (Lyon, FR), Rogemond, Veronique; (Lyon, FR) Correspondence: Larson & Taylor, Plc; 1199 North Fairfax Street; Suite 900; Alexandria; VA; 22314; US Patent Application Number: 20020119944 Date filed: November 9, 2001 Abstract: This invention relates to methods and compositions for the prevention or treatment of myelin disorders which involve modulating of Ulip/CRMP activity. In particular, a method for the prevention or treatment of myelin disorders is provided which comprises administering to a patient in need of such treatment a therapeutically effective amount of an agent which modulates Ulip/CRMP activity, and which can be a
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Ulip/CRMP protein, a nucleic acid coding for a Ulip/CRMP protein, an anti-sense sequence capable of specifically hybridizing with said nucleic acid, an antibody directed against the Ulip/CRMP protein, or an aptamer capable of binding said protein, and a pharmacologically acceptable carrier. Excerpt(s): This application claims the benefit of U.S. provisional application No. 60/246,751, filed Nov. 9, 2000. The present invention relates to the modulation of Ulip/CRMP activity in the prevention or treatment of myelin disorders. A new protein family with four members, homologous to the UNC-33 protein required in nematodes for appropriate axonal and synaptic organization (Li et al., 1992), has recently been identified in human, rat, mouse, and chicken brain. These proteins, known variously as TOAD-64 (Turned On After Division) (Minturn et al., 1995a), CRMP (Collapsin Response Mediator Protein) (Wang and Strittmatter, 1996), DRP (Dihydropyrimidinase Related Protein) (Hamajima et al., 1996), C-22 (Quach et al., 1997), or Ulip (Unc-33-Like Protein) (Byk et al., 1998, WO 98137 192), are highly expressed by neural cells in the developing brain, the highest expression being seen, in the rodent, at the end of embryonic life during the period of maximal axonal growth (Minturn et al., 1995a; Wang and Strittmatter, 1996). Members of this protein family are presumed to be involved in axonal outgrowth in response to Sema3A (Goshima et al., 1995; Semaphorin Nomenclature Committee, 1999), a member of the semaphorin protein family (Kolodkin et al., 1997). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Keeping Current In order to stay informed about patents and patent applications dealing with myelin, 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 “myelin” (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 myelin. You can also use this procedure to view pending patent applications concerning myelin. 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 6. BOOKS ON MYELIN Overview This chapter provides bibliographic book references relating to myelin. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on myelin 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: 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 “myelin” at online booksellers’ Web sites, you may discover nonmedical books that use the generic term “myelin” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “myelin” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
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
•
A Multidisciplinary Approach to Myelin Diseases (Nato Asi Series a, Life Sciences, Vol 142) by G. Serlupi Crescenzi; ISBN: 0306427761; http://www.amazon.com/exec/obidos/ASIN/0306427761/icongroupinterna
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A Multidisciplinary Approach to Myelin Diseases II (Nato Asi Series, Series a : Life Sciences, Vol 258) by S. Salvati; ISBN: 0306446340; http://www.amazon.com/exec/obidos/ASIN/0306446340/icongroupinterna
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Atlas of the central nervous system in sectional planes: Selected myelin stained sections of the human brain and spinal cord by Susanna Zuleger; ISBN: 0806722010; http://www.amazon.com/exec/obidos/ASIN/0806722010/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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Disorders of Myelin in the Central and Peripheral Nervous Systems by Fernando Dangond, Fernando, MD Dangond; ISBN: 0750672536; http://www.amazon.com/exec/obidos/ASIN/0750672536/icongroupinterna
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Dynamic Interactions of Myelin Proteins (Progress in Clinical and Biological Research, Vol 336) by George A. Hashim, Mario Moscarello; ISBN: 0471567299; http://www.amazon.com/exec/obidos/ASIN/0471567299/icongroupinterna
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Enzyme and protein changes in myelin breakdown and multiple sclerosis: A review of some recent histochemical and biochemical studies (Progress in histochemistry and cytochemistry) by J. F Hallpike; ISBN: 3437102737; http://www.amazon.com/exec/obidos/ASIN/3437102737/icongroupinterna
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Hashim Myelin - Chemistry and Biology by G HASHIM; ISBN: 0471564249; http://www.amazon.com/exec/obidos/ASIN/0471564249/icongroupinterna
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Magnetic Resonance of Myelin, Myelination, and Myelin Disorders by Marjo S. Van Der Knaap, J. Valk; ISBN: 0387592776; http://www.amazon.com/exec/obidos/ASIN/0387592776/icongroupinterna
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Visual System in Myelin Disorders (Developments in Hydrobiology) by A. Neetens, et al; ISBN: 9061938074; http://www.amazon.com/exec/obidos/ASIN/9061938074/icongroupinterna
Chapters on Myelin In order to find chapters that specifically relate to myelin, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and myelin 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 “myelin” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on myelin: •
Peripheral Neuropathy Pain Source: in Senneff, J.A. Numb Toes and Aching Soles: Coping with Peripheral Neuropathy. San Antonio, TX: MedPress. 1999. p. 15-19. Contact: Available from MedPress. P.O. Box 691546, San Antonio, TX 78269. (888) 6339898. Website: www.medpress.com. PRICE: $19.95 for soft back book; $29.95 for case bound book; plus shipping and handling. ISBN 0967110726. Summary: This chapter focuses on the physical and psychological aspects of peripheral neuropathy (PN) pain. Although people who have PN experience many problems, the worst have to do with pain, particularly pain resulting from sensory neuropathies. There appear to be both physical and psychological components to PN pain. The physical basis is an alteration of the electrical signals that are formed by sensors in various parts of the body and transmitted through the peripheral nervous system to the brain. Alteration of the electrical signals may be the result of degeneration of the axon of
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the nerve cell or of the nerve cell itself or the destruction of the myelin sheath around the nerve. A recent theory about the physical basis of neuropathic pain hypothesizes that an excessive level of proteins called cytokines is a causative factor. Theories about the psychological basis of PN pain include the gate theory. The basis of this theory is that a theoretical gate in the spinal cord transmits or blocks pain signals at the brain's discretion, with positive emotions closing the gate and negative emotions opening the gate. Other researchers believe that nerve impulses giving rise to chronic pain actually travel a different pathway than does acute pain. In addition, there is speculation that there may be a relationship between a person's psychological state and the intensity of the pain experience, with stress, depression, or anxiety increasing the intensity of pain.
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CHAPTER 7. PERIODICALS AND NEWS ON MYELIN Overview In this chapter, we suggest a number of news sources and present various periodicals that cover myelin.
News Services and Press Releases One of the simplest ways of tracking press releases on myelin 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 “myelin” (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 myelin. 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 “myelin” (or synonyms). The following was recently listed in this archive for myelin: •
High-dose myelin basic protein protects mice against experimental MS Source: Reuters Industry Breifing Date: October 20, 2000
•
IV immunoglobulins ineffective for myelin repair in multiple sclerosis Source: Reuters Medical News Date: January 26, 2000
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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 “myelin” (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 “myelin” (or synonyms). If you know the name of a company that is relevant to myelin, 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 “myelin” (or synonyms).
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Academic Periodicals covering Myelin Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to myelin. In addition to these sources, you can search for articles covering myelin 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 8. 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 myelin. 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 myelin. 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 myelin: Immune Globulin Intravenous (Human) •
Human - U.S. Brands: Gamimune N 10%; Gamimune N 10% S/D; Gamimune N 5%; Gamimune N 5% S/D; Gammagard S/D; Gammagard S/D 0.5 g; Gammar-P IV; Iveegam; Panglobulin; Polygam S/D; Sandoglobulin; Venoglobulin–I; Venoglobulin-S http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202641.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. 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
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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 Institute10: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
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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
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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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.11 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:12 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
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Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
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Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
11
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). 12 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
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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
The NLM Gateway13 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “myelin” (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 28864 93 753 38 261 30009
HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 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.17 Simply search by “myelin” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
13
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
14
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). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17
The HSTAT URL is http://hstat.nlm.nih.gov/.
Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.
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Coffee Break: Tutorials for Biologists18 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.19 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.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
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/.
18 Adapted 19
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
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. 20 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.
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APPENDIX 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 myelin 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 myelin. 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 myelin. 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 “myelin”:
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Brain Diseases http://www.nlm.nih.gov/medlineplus/braindiseases.html Charcot-Marie-Tooth Disease http://www.nlm.nih.gov/medlineplus/charcotmarietoothdisease.html Leukodystrophies http://www.nlm.nih.gov/medlineplus/leukodystrophies.html Multiple Sclerosis http://www.nlm.nih.gov/medlineplus/multiplesclerosis.html Neurologic Diseases http://www.nlm.nih.gov/medlineplus/neurologicdiseases.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. 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 myelin. 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: •
Trigeminal Neuralgia: A Primer for Physicians and Patients Source: Barnegat Light, NJ: Trigeminal Neuralgia Association. 200x. 9 p. Contact: Available from Trigeminal Neuralgia Association. P.O. Box 340, Barnegat Light, NJ 08006. (609) 361-6250. Fax (609) 361-0982. E-mail:
[email protected]. Website: www.tna-support.org. PRICE: Single copy free. Summary: Trigeminal neuralgia (TN) is a chronic disorder that usually affects people in middle or late life and is characterized by excruciating pain around the eyes, nose, lips, jaw, forehead, or scalp. This brochure provides an overview of the causes, diagnosis, medical treatments, and surgical options for trigeminal neuralgia. TN is believed to be caused when a blood vessel presses on the trigeminal nerve (vascular compression) and causes the covering (myelin sheath) to deteriorate. This deterioration causes the nerve to send abnormal signals to the brain which can cause a soft touch or simple facial movement to feel painful. TN can be easily diagnosed by a dentist or physician familiar with its pain and symptoms. There is no specific test to confirm TN. Many patients find that TN can be effectively managed with medication, usually on an ongoing basis (at least four to six weeks on medications, then a gradual tapering off if the pain stays in remission). The most commonly prescribed medications for TN are anticonvulsants, which work by suppressing the abnormal signaling activity of the trigeminal nerve. Surgical options can include radiofrequency rhizotomy (or electrocoagulation), glycerol
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rhizotomy, balloon compression, microvascular decompression, and stereotactic (or gamma knife or LINAC) radiosurgery. The brochure concludes with information about the non profit Trigeminal Neuralgia Association (TNA), a group that sponsors support groups, a national patient network, and educational outreach (www.tna-support.org). 1 figure. 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 myelin. 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. 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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WebMDHealth: http://my.webmd.com/health_topics
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to myelin. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with myelin. 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 myelin. 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 “myelin” (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 “myelin”. 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 “myelin” (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 “myelin” (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.21
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
21
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)22: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
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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
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California: Gateway Health Library (Sutter Gould Medical Foundation)
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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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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/
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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
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Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
22
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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•
Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
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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
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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
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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
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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
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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
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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
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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/
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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
•
Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
•
Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
•
Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/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). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on myelin: •
Basic Guidelines for Myelin Myelin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002261.htm
•
Nutrition for Myelin Fat Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002468.htm Lipids Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002468.htm Protein Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm
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Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
•
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
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MYELIN DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] 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] Aberrant: Wandering or deviating from the usual or normal course. [EU] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcholinesterase: An enzyme that catalyzes the hydrolysis of acetylcholine to choline and acetate. In the CNS, this enzyme plays a role in the function of peripheral neuromuscular junctions. EC 3.1.1.7. [NIH] Acidemia: Increased acidity of blood. [NIH] Acidity: The quality of being acid or sour; containing acid (hydrogen ions). [EU] Acinetobacter: A genus of gram-negative bacteria of the family Neisseriaceae, found in soil and water and of uncertain pathogenicity. [NIH] Acoustic: Having to do with sound or hearing. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acute Disease: Disease having a short and relatively severe course. [NIH] Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH]
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Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] 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] 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] 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] 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 Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenoleukodystrophy: A chromosome X-linked disease. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] 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]
Dictionary 217
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 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] Airways: Tubes that carry air into and out of the lungs. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] 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] 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] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allogeneic: Taken from different individuals of the same species. [NIH] Allografts: A graft of tissue obtained from the body of another animal of the same species but with genotype differing from that of the recipient; tissue graft from a donor of one genotype to a host of another genotype with host and donor being members of the same species. [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] Amblyopia: A nonspecific term referring to impaired vision. Major subcategories include
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stimulus deprivation-induced amblyopia and toxic amblyopia. Stimulus deprivationinduced amblopia is a developmental disorder of the visual cortex. A discrepancy between visual information received by the visual cortex from each eye results in abnormal cortical development. Strabismus and refractive errors may cause this condition. Toxic amblyopia is a disorder of the optic nerve which is associated with alcoholism, tobacco smoking, and other toxins and as an adverse effect of the use of some medications. [NIH] Ambulatory Care: Health care services provided to patients on an ambulatory basis, rather than by admission to a hospital or other health care facility. The services may be a part of a hospital, augmenting its inpatient services, or may be provided at a free-standing facility. [NIH]
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: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a conserved sequence which can be represented by a consensus sequence. [NIH]
Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] 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] Amphetamines: Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopression, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amygdala: Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the brain, within the temporal lobe. The amygdala is part of the limbic system. [NIH]
Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet
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conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anergic: 1. Characterized by abnormal inactivity; inactive. 2. Marked by asthenia or lack of energy. 3. Pertaining to anergy. [EU] Anergy: Absence of immune response to particular substances. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] 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] Angiopathy: Disease of the blood vessels (arteries, veins, and capillaries) that occurs when someone has diabetes for a long time. There are two types of angiopathy: macroangiopathy and microangiopathy. In macroangiopathy, fat and blood clots build up in the large blood vessels, stick to the vessel walls, and block the flow of blood. In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. Then the cells, for example, the ones in the center of the eye, do not get enough blood and may be damaged. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] 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] Anoxia: Clinical manifestation of respiratory distress consisting of a relatively complete absence of oxygen. [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]
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Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsants: Drugs used to prevent seizures or reduce their severity. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with 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] Anti-inflammatory: Having to do with reducing 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] Antiseptic: A substance that inhibits the growth and development of microorganisms without necessarily killing them. [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] Antiviral: Destroying viruses or suppressing their replication. [EU] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA
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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] 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] 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] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] 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] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articular: Of or pertaining to a joint. [EU] 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] 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] Astringent: Causing contraction, usually locally after topical application. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, star-shaped cells
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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] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] Auditory Cortex: Area of the temporal lobe concerned with hearing. [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] 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] 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] Avidity: The strength of the interaction of an antiserum with a multivalent antigen. [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] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or
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bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacterial Proteins: Proteins found in any species of bacterium. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing 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] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [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] 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] Benign: Not cancerous; 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] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [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] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding agent: A substance that makes a loose mixture stick together. For example, binding agents can be used to make solid pills from loose powders. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biogenesis: The origin of life. It includes studies of the potential basis for life in organic compounds but excludes studies of the development of altered forms of life through mutation and natural selection, which is evolution. [NIH]
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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] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [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-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 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]
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Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small 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] 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 Infarction: The formation of an area of necrosis in the brain, including the cerebral hemispheres (cerebral infarction), thalami, basal ganglia, brain stem (brain stem infarctions), or cerebellum secondary to an insufficiency of arterial or venous blood flow. [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] Brain Stem Infarctions: Infarctions that occur in the brain stem which is comprised of the midbrain, pons, and medulla. There are several named syndromes characterized by their distinctive clinical manifestations and specific sites of ischemic injury. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [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] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] 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] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [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
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weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] 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] 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] Capillary Fragility: The lack of resistance, or susceptibility, of capillaries to damage or disruption under conditions of increased stress. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [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] Carboxy: Cannabinoid. [NIH] Carcinogenic: Producing carcinoma. [EU] Cardiac: Having to do with the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [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] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [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] 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] Caudate Nucleus: Elongated gray mass of the neostriatum located adjacent to the lateral ventricle of the brain. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be
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analyzed from an epidemiologic viewpoint. [NIH] Caustic: An escharotic or corrosive agent. Called also cauterant. [EU] 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] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell Lineage: The developmental history of cells as traced from the first division of the original cell or cells in the embryo. [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 adhesion: The close adherence (bonding) to adjoining cell surfaces. [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] 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]
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Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chelation: Combination with a metal in complexes in which the metal is part of a ring. [EU] Chelation Therapy: Therapy of heavy metal poisoning using agents which sequester the metal from organs or tissues and bind it firmly within the ring structure of a new compound which can be eliminated from the body. [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] Chemotherapy: Treatment with anticancer drugs. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Chimeric Proteins: Proteins in individuals that are derived from genetically different zygotes. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is
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important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Chondrodysplasia Punctata: A heterogeneous group of bone dysplasias, the common character of which is stippling of the epiphyses in infancy. The group includes a severe autosomal recessive form (Chondrodysplasia punctata, rhizomelic), an autosomal dominant form (Conradi-Hunermann syndrome), and a milder X-linked form. Metabolic defects associated with impaired peroxisomes are present only in the rhizomelic form. [NIH] 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] 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] Clathrin: The main structural coat protein of coated vesicles which play a key role in the intracellular transport between membranous organelles. Clathrin also interacts with cytoskeletal proteins. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clonal Anergy: Functional inactivation of T- or B-lymphocytes rendering them incapable of eliciting an immune response to antigen. This occurs through different mechanisms in the two kinds of lymphocytes and can contribute to self tolerance. [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] Coated Vesicles: Vesicles formed when cell-membrane coated pits invaginate and pinch off. The outer surface of these vesicles are covered with a lattice-like network of coat proteins, such as clathrin, coat protein complex proteins, or caveolins. [NIH]
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Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] 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]
Cochlear: Of or pertaining to the cochlea. [EU] Cochlear Diseases: Diseases of the cochlea, the part of the inner ear that is concerned with hearing. [NIH] Cochlear Implantation: Surgical insertion of an electronic device implanted beneath the skin with electrodes to the cochlear nerve to create sound sensation in persons with sensorineural deafness. [NIH] Cochlear Implants: Electronic devices implanted beneath the skin with electrodes to the cochlear nerve to create sound sensation in persons with sensorineural deafness. [NIH] Cochlear Nerve: The cochlear part of the 8th cranial nerve (vestibulocochlear nerve). The cochlear nerve fibers originate from neurons of the spiral ganglion and project peripherally to cochlear hair cells and centrally to the cochlear nuclei (cochlear nucleus) of the brain stem. They mediate the sense of hearing. [NIH] Coculture: The culturing of normal cells or tissues with infected or latently infected cells or tissues of the same kind (From Dorland, 28th ed, entry for cocultivation). It also includes culturing of normal cells or tissues with other normal cells or tissues. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Coliphages: Viruses whose host is Escherichia coli. [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] 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] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable
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compounds at once. [NIH] Communication Disorders: Disorders of verbal and nonverbal communication caused by receptive or expressive language disorders, cognitive dysfunction (e.g., mental retardation), psychiatric conditions, and hearing disorders. [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] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH]
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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] Cone: One of the special retinal receptor elements which are presumed to be primarily concerned with perception of light and color stimuli when the eye is adapted to light. [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] Connexins: A group of homologous proteins which form the intermembrane channels of gap junctions. The connexins are the products of an identified gene family which has both highly conserved and highly divergent regions. The variety contributes to the wide range of functional properties of gap junctions. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved sequences. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] 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] Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [NIH]
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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] 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 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] Coronavirus Infections: Virus diseases caused by the Coronavirus genus. Some specifics include transmissible enteritis of turkeys, feline infectious peritonitis, and transmissible gastroenteritis of swine. [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] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] 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] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cryofixation: Fixation of a tissue by localized cooling at very low temperature. [NIH] Cryopreservation: Preservation of cells, tissues, organs, or embryos by freezing. In histological preparations, cryopreservation or cryofixation is used to maintain the existing form, structure, and chemical composition of all the constituent elements of the specimens. [NIH]
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Crystallization: The formation of crystals; conversion to a crystalline form. [EU] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] 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] 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] Cysteine: A thiol-containing non-essential amino acid that is oxidized 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] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] 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] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [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
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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] 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] DeDendrites: 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] 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] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [NIH] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, 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] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH]
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Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilate: Relax; expand. [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] 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] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diuresis: Increased excretion of urine. [EU] 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] 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;
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superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Drive: A state of internal activity of an organism that is a necessary condition before a given 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 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] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dyscrasia: A term formerly used to indicate an abnormal mixture of the four humours; in surviving usages it now is roughly synonymous with 'disease' or 'pathologic condition'. [EU] Dystrophic: Pertaining to toxic habitats low in nutrients. [NIH] Ear Diseases: Diseases of the ear, general or unspecified. [NIH] Ectoderm: The outer of the three germ layers of the embryo. [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] Efferent: Nerve fibers which conduct impulses from the central nervous system to muscles and glands. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Electric Conductivity: The ability of a substrate to allow the passage of electrons. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the
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chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]
Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Emollient: Softening or soothing; called also malactic. [EU] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] 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] 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] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles
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or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endosomes: Cytoplasmic vesicles formed when coated vesicles shed their clathrin coat. Endosomes internalize macromolecules bound by receptors on the cell surface. [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-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] Energetic: Exhibiting energy : strenuous; operating with force, vigour, or effect. [EU] Enhancer: Transcriptional element in the virus genome. [NIH] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH] Enteritis: Inflammation of the intestine, applied chiefly to inflammation of the small intestine; see also enterocolitis. [EU] 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] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [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
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lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]
Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] 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] Ethanolamine: A viscous, hygroscopic amino alcohol with an ammoniacal odor. It is widely distributed in biological tissue and is a component of lecithin. It is used as a surfactant, fluorimetric reagent, and to remove CO2 and H2S from natural gas and other gases. [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] 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] 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] Exhaustion: The feeling of weariness of mind and body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH]
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Exotoxin: Toxic substance excreted by living bacterial cells. [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 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] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Facial: Of or pertaining to the face. [EU] Facial Expression: Observable changes of expression in the face in response to emotional stimuli. [NIH] 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] Fallopian tube: The oviduct, a muscular tube about 10 cm long, lying in the upper border of the broad ligament. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatal Outcome: Death resulting from the presence of a disease in an individual, as shown by a single case report or a limited number of patients. This should be differentiated from death, the physiological cessation of life and from mortality, an epidemiological or statistical concept. [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]
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
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observed in the newborn. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] 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] Foetal: Of or pertaining to a fetus; pertaining to in utero development after the embryonic period. [EU] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [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
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megaloblastic anemia. [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] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [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] Gamma knife: Radiation therapy in which high-energy rays are aimed at a tumor from many angles in a single treatment session. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gangliosides: Protein kinase C's inhibitor which reduces ischemia-related brain damage. [NIH]
Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [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] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastroenteritis: An acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhoea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Called also enterogastritis. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH]
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Gastrointestinal tract: The stomach and intestines. [NIH] 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] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. [NIH] Gene Duplication: It encodes the major envelope protein and includes all the specifications for HBsAg. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Generator: Any system incorporating a fixed parent radionuclide from which is produced a daughter radionuclide which is to be removed by elution or by any other method and used in a radiopharmaceutical. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] 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] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germinal Center: The activated center of a lymphoid follicle in secondary lymphoid tissue where B-lymphocytes are stimulated by antigens and helper T cells (T-lymphocytes, helperinducer) are stimulated to generate memory cells. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU]
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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] Glial Fibrillary Acidic Protein: An intermediate filament protein found only in glial cells or cells of glial origin. MW 51,000. [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] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH] Glucocorticoids: A group of corticosteroids that affect carbohydrate metabolism (gluconeogenesis, liver glycogen deposition, elevation of blood sugar), inhibit corticotropin secretion, and possess pronounced anti-inflammatory activity. They also play a role in fat and protein metabolism, maintenance of arterial blood pressure, alteration of the connective tissue response to injury, reduction in the number of circulating lymphocytes, and functioning of the central nervous system. [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 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]
Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] 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] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycan:
A
type
of
long,
unbranched
polysaccharide
molecule.
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Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [NIH] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] 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] 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 recipient. [NIH] Grafting: The operation of transfer of tissue from one site to another. [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] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Gravis: Eruption of watery blisters on the skin among those handling animals and animal products. [NIH] Growth Cones: Bulbous enlargement of the growing tip of nerve axons and dendrites. They are crucial to neuronal development because of their pathfinding ability and their role in synaptogenesis. [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] Growth Inhibitors: Endogenous or exogenous substances which inhibit the normal growth of human and animal cells or micro-organisms, as distinguished from those affecting plant growth (plant growth regulators). [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] 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] 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
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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 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] Hearing Disorders: Conditions that impair the transmission or perception of auditory impulses and information from the level of the ear to the temporal cortices, including the sensorineural pathways. [NIH] Heavy Chain Disease: A disorder of immunoglobulin synthesis in which large quantities of abnormal heavy chains are excreted in the urine. The amino acid sequences of the N(amino-) terminal regions of these chains are normal, but they have a deletion extending from part of the variable domain through the first domain of the constant region, so that they cannot form cross-links to the light chains. The defect arises through faulty coupling of the variable (V) and constant (C) region genes. [NIH] Hematoxylin: A dye obtained from the heartwood of logwood (Haematoxylon campechianum Linn., Leguminosae) used as a stain in microscopy and in the manufacture of ink. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH]
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Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] 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] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterodimer: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
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] 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]
Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH]
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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] 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 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] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Illusion: A false interpretation of a genuine percept. [NIH] Immersion: The placing of a body or a part thereof into a liquid. [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] Immune-response: The production of antibodies or particular types of cytotoxic lymphoid cells on challenge with an antigen. [NIH] Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer
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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] 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] 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] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] 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] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within
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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] 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] 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] 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]
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] 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] 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] 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] Inpatients: Persons admitted to health facilities which provide board and room, for the purpose of observation, care, diagnosis or treatment. [NIH]
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Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Intercellular Junctions: Strictly, and so far as it can be distinguished, the amorphous isotropic layer between adjacent primary walls of cells. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Internal 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] Intervertebral: Situated between two contiguous vertebrae. [EU]
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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] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intracranial Hypertension: Increased pressure within the cranial vault. This may result from several conditions, including hydrocephalus; brain edema; intracranial masses; severe systemic hypertension; pseudotumor cerebri; and other disorders. [NIH] Intrathecal: Describes the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. Drugs can be injected into the fluid or a sample of the fluid can be removed for testing. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
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] 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 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] 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] 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] Isoniazid: Antibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis. [NIH] Isozymes: The multiple forms of a single enzyme. [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] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel.
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Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Kinesin: A microtubule-associated mechanical adenosine triphosphatase, that uses the energy of ATP hydrolysis to move organelles along microtubules toward the plus end of the microtubule. The protein is found in squid axoplasm, optic lobes, and in bovine brain. Bovine kinesin is a heterotetramer composed of two heavy (120 kDa) and two light (62 kDa) chains. EC 3.6.1.-. [NIH] Kinetic: Pertaining to or producing motion. [EU] 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 osseous and a membranous portion. [NIH] Lacrimal: Pertaining to the tears. [EU] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Language Disorders: Conditions characterized by deficiencies of comprehension or expression of written and spoken forms of language. These include acquired and developmental disorders. [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] 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] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Leprosy: A chronic granulomatous infection caused by Mycobacterium leprae. The granulomatous lesions are manifested in the skin, the mucous membranes, and the peripheral nerves. Two polar or principal types are lepromatous and tuberculoid. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]
Leukemia: Cancer of blood-forming tissue. [NIH]
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Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukoencephalopathy: A condition with spongy holes in the brain's white matter. [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] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Limbic System: A set of forebrain structures common to all mammals that is defined functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival behaviors (feeding, mating, emotion). For most authors, it includes the amygdala, epithalamus, gyrus cinguli, hippocampal formation (see hippocampus), hypothalamus, parahippocampal gyrus, septal nuclei, anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Bilayers: Layers of lipid molecules which are two molecules thick. Bilayer systems are frequently studied as models of biological membranes. [NIH] Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [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] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Locomotor: Of or pertaining to locomotion; pertaining to or affecting the locomotive apparatus of the body. [EU] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH]
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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] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [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] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macroglia: A type of neuroglia composed of astrocytes. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [NIH] 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] 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]
Mammary: Pertaining to the mamma, or breast. [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,
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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] Maxillary: Pertaining to the maxilla : the irregularly shaped bone that with its fellow forms the upper jaw. [EU] Maxillary Nerve: The intermediate sensory division of the trigeminal (5th cranial) nerve. The maxillary nerve carries general afferents from the intermediate region of the face including the lower eyelid, nose and upper lip, the maxillary teeth, and parts of the dura. [NIH]
Measles-Mumps-Rubella Vaccine: A combined vaccine used to prevent measles, mumps, and rubella. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediastinum: The area between the lungs. The organs in this area include the heart and its large blood vessels, the trachea, the esophagus, the bronchi, and lymph nodes. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Lipids: Lipids, predominantly phospholipids, cholesterol and small amounts of glycolipids found in membranes including cellular and intracellular membranes. These lipids may be arranged in bilayers in the membranes with integral proteins between the layers and peripheral proteins attached to the outside. Membrane lipids are required for active transport, several enzymatic activities and membrane formation. [NIH] 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] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental deficiency: A condition of arrested or incomplete development of mind from inherent causes or induced by disease or injury. [NIH]
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Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]
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] 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] 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] Methyltransferase: A drug-metabolizing enzyme. [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] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Microvilli: Minute projections of cell membranes which greatly increase the surface area of the cell. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH]
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Millimeter: A measure of length. A millimeter is approximately 26-times smaller than an inch. [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] 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] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mononuclear: A cell with one nucleus. [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] Morula: The early embryo at the developmental stage in which the blastomeres, resulting from repeated mitotic divisions of the fertilized ovum, form a compact mass. [NIH] Motility: The ability to move spontaneously. [EU] Motor Neurons: Neurons which activate muscle cells. [NIH]
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Motor Skills: Performance of complex motor acts. [NIH] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] 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] Muscular Diseases: Acquired, familial, and congenital disorders of skeletal muscle and smooth muscle. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myasthenia: Muscular debility; any constitutional anomaly of muscle. [EU] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [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 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] 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] Myristate: Pharmacological activator of protein kinase C. [NIH] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [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,
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prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neocortex: The largest portion of the cerebral cortex. It is composed of neurons arranged in six layers. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] 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] Nephropathy: Disease of the kidneys. [EU] 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 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] Nerve Regeneration: Renewal or physiological repair of damaged nerve tissue. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [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 Crest: A strip of specialized ectoderm flanking each side of the embryonal neural plate, which after the closure of the neural tube, forms a column of isolated cells along the dorsal aspect of the neural tube. Most of the cranial and all of the spinal sensory ganglion cells arise by differentiation of neural crest cells. [NIH] Neuralgia: Intense or aching pain that occurs along the course or distribution of a peripheral or cranial nerve. [NIH] Neuraminidase: An enzyme that catalyzes the hydrolysis of alpha-2,3, alpha-2,6-, and alpha-2,8-glycosidic linkages (at a decreasing rate, respectively) of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid, and synthetic substrate. (From Enzyme Nomenclature, 1992) EC 3.2.1.18. [NIH] Neurites: In tissue culture, hairlike projections of neurons stimulated by growth factors and other molecules. These projections may go on to form a branched tree of dendrites or a single axon or they may be reabsorbed at a later stage of development. "Neurite" may refer to any filamentous or pointed outgrowth of an embryonal or tissue-culture neural cell. [NIH] Neuritis: A general term indicating inflammation of a peripheral or cranial nerve. Clinical manifestation may include pain; paresthesias; paresis; or hypesthesia. [NIH]
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Neuroanatomy: Study of the anatomy of the nervous system as a specialty or discipline. [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] Neurologic: Having to do with nerves or 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 Junction: The synapse between a neuron and a muscle. [NIH] Neuromyelitis Optica: A self-limiting, demyelinating disease of the optic nerves, the optic chiasm, and the spinal cord characterized by bilateral retrobulbar neuritis, usually accompanied by papillitis and transverse myelitis. [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] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] Neuropsychology: A branch of psychology which investigates the correlation between experience or behavior and the basic neurophysiological processes. The term neuropsychology stresses the dominant role of the nervous system. It is a more narrowly defined field than physiological psychology or psychophysiology. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neurotrophins: A nerve growth factor. [NIH] Neutralization: An act or process of neutralizing. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Neutrophil Infiltration: The diffusion or accumulation of neutrophils in tissues or cells in response to a wide variety of substances released at the sites of inflammatory reactions. [NIH]
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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] 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] Nonverbal Communication: Transmission of emotions, ideas, and attitudes between individuals in ways other than the spoken language. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] 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] Nucleolus: A small dense body (sub organelle) within the nucleus of eukaryotic cells, visible by phase contrast and interference microscopy in live cells throughout interphase. Contains RNA and protein and is the site of synthesis of ribosomal RNA. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleus Accumbens: Collection of pleomorphic cells in the caudal part of the anterior horn of the lateral ventricle, in the region of the olfactory tubercle, lying between the head of the caudate nucleus and the anterior perforated substance. It is part of the so-called ventral striatum, a composite structure considered part of the basal ganglia. [NIH] Occipital Lobe: Posterior part of the cerebral hemisphere. [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
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the oculomotor nuclei of the midbrain. [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] Oligodendroglioma: A rare, slow-growing tumor that begins in brain cells called oligodendrocytes, which provide support and nourishment for cells that transmit nerve impulses. Also called oligodendroglial tumor. [NIH] Oligodeoxyribonucleotides: A group of deoxyribonucleotides (up to 12) in which the phosphate residues of each deoxyribonucleotide act as bridges in forming diester linkages between the deoxyribose moieties. [NIH] Oligonucleotide Probes: Synthetic or natural oligonucleotides used in hybridization studies in order to identify and study specific nucleic acid fragments, e.g., DNA segments near or within a specific gene locus or gene. The probe hybridizes with a specific mRNA, if present. Conventional techniques used for testing for the hybridization product include dot blot assays, Southern blot assays, and DNA:RNA hybrid-specific antibody tests. Conventional labels for the probe include the radioisotope labels 32P and 125I and the chemical label biotin. [NIH] Oligosaccharides: Carbohydrates consisting of between two and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Ophthalmic: Pertaining to the eye. [EU] 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] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Opioid Peptides: The endogenous peptides with opiate-like activity. The three major classes currently recognized are the enkephalins, the dynorphins, and the endorphins. Each of these families derives from different precursors, proenkephalin, prodynorphin, and proopiomelanocortin, respectively. There are also at least three classes of opioid receptors, but the peptide families do not map to the receptors in a simple way. [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
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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 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] 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] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Ossicles: The hammer, anvil and stirrup, the small bones of the middle ear, which transmit the vibrations from the tympanic membrane to the oval window. [NIH] 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] Otosclerosis: The formation of spongy bone in the labyrinth capsule. The ossicles can become fixed and unable to transmit sound vibrations, thereby causing deafness. [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] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH]
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Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]
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] Palsies: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH] 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] Paralysis: Loss of ability to move all or part of the body. [NIH] Paraparesis: Mild to moderate loss of bilateral lower extremity motor function, which may be a manifestation of spinal cord diseases; peripheral nervous system diseases; muscular diseases; intracranial hypertension; parasagittal brain lesions; and other conditions. [NIH] Paraproteins: Abnormal immunoglobulins synthesized by atypical cells of the reticuloendothelial system. Paraproteins containing only light chains lead to Bence Jones paraproteinemia, while the presence of only atypical heavy chains leads to heavy chain disease. Most of the paraproteins show themselves as an M-component (monoclonal gammopathy) in electrophoresis. Diclonal and polyclonal paraproteins are much less frequently encountered. [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] 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] 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] Paresthesias: Abnormal touch sensations, such as burning or prickling, that occur without an outside stimulus. [NIH] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parietal Lobe: Upper central part of the cerebral hemisphere. [NIH] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to
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therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]
Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
Pelvic: Pertaining to the pelvis. [EU] 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] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make 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 multiple sets of these or other symbols such as geometric figures. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral 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
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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] Peritonitis: Inflammation of the peritoneum; a condition marked by exudations in the peritoneum of serum, fibrin, cells, and pus. It is attended by abdominal pain and tenderness, constipation, vomiting, and moderate fever. [EU] Perivascular: Situated around a vessel. [EU] Periventricular Leukomalacia: Rare form of epilepsy. [NIH] Peroneal Nerve: The lateral of the two terminal branches of the sciatic nerve. The peroneal (or fibular) nerve provides motor and sensory innervation to parts of the leg and foot. [NIH] Peroxisomal Disorders: A heterogeneous group of inherited metabolic disorders marked by absent or dysfunctional peroxisomes. Peroxisomal enzymatic abnormalities may be single or multiple. Biosynthetic peroxisomal pathways are compromised, including the ability to synthesize ether lipids and to oxidize long-chain fatty acid precursors. Diseases in this category include Zellweger syndrome; infantile Refsum disease; rhizomelic chondrodysplasia (chondrodysplasia punctata, rhizomelic); hyperpipecolic acidemia; neonatal adrenoleukodystrophy; and adrenoleukodystrophy (X-linked). Neurologic dysfunction is a prominent feature of most peroxisomal disorders. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Phallic: Pertaining to the phallus, or penis. [EU] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [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] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [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]
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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 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] 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] 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] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]
Plant Growth Regulators: Any of the hormones produced naturally in plants and active in controlling growth and other functions. There are three primary classes: auxins, cytokinins, and gibberellins. [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] 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 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] 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] 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 Aggregation: The attachment of platelets to one another. This clumping together
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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 alphagranules 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] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]
Pleomorphic: Occurring in various distinct forms. In terms of cells, having variation in the size and shape of cells or their nuclei. [NIH] Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Pollen: The male fertilizing element of flowering plants analogous to sperm in animals. It is released from the anthers as yellow dust, to be carried by insect or other vectors, including wind, to the ovary (stigma) of other flowers to produce the embryo enclosed by the seed. The pollens of many plants are allergenic. [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] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] 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] Polyradiculoneuropathy: Diseases characterized by injury or dysfunction involving multiple peripheral nerves and nerve roots. The process may primarily affect myelin or nerve axons. Two of the more common demyelinating forms are acute inflammatory polyradiculopathy (Guillain-Barre syndrome) and polyradiculoneuropathy, chronic inflammatory demyelinating. Polyradiculoneuritis refers to inflammation of multiple peripheral nerves and spinal nerve roots. [NIH] Polyradiculopathy: Disease or injury involving multiple spinal nerve roots. Polyradiculitis refers to inflammation of multiple spinal nerve roots. [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] 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] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postnatal: Occurring after birth, with reference to the newborn. [EU] Post-synaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Potassium Dichromate: Chromic acid (H2Cr2O7), dipotassium salt. A compound having bright orange-red crystals and used in dyeing, staining, tanning leather, as bleach, oxidizer, depolarizer for dry cells, etc. Medically it has been used externally as an astringent, antiseptic, and caustic. When taken internally, it is a corrosive poison. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prefrontal Cortex: The rostral part of the frontal lobe, bounded by the inferior precentral fissure in humans, which receives projection fibers from the mediodorsal nucleus of the thalamus. The prefrontal cortex receives afferent fibers from numerous structures of the diencephalon, mesencephalon, and limbic system as well as cortical afferents of visual, auditory, and somatic origin. [NIH] Pregnenolone: Steroid hormone. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [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] 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]
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Progressive disease: Cancer that is increasing in scope or severity. [NIH] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [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] 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] Prostate gland: A gland in the male reproductive system just below the bladder. It surrounds part of the urethra, the canal that empties the bladder, and produces a fluid that forms part of semen. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein 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 Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] 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] Proteoglycan: A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues. [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
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formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] 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] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoacoustic: That branch of psychophysics dealing with acoustic stimuli. [NIH] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychophysics: The science dealing with the correlation of the physical characteristics of a stimulus, e.g., frequency or intensity, with the response to the stimulus, in order to assess the psychologic factors involved in the relationship. [NIH] Psychophysiology: The study of the physiological basis of human and animal behavior. [NIH]
Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [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] 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]
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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] 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] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quercetin: Aglucon of quercetrin, rutin, and other glycosides. It is widely distributed in the plant kingdom, especially in rinds and barks, clover blossoms, and ragweed pollen. [NIH] Quiescent: Marked by a state of inactivity or repose. [EU] Rabies: A highly fatal viral infection of the nervous system which affects all warm-blooded animal species. It is one of the most important of the zoonoses because of the inevitably fatal outcome for the infected human. [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] Radicular: Having the character of or relating to a radicle or root. [NIH] Radiculopathy: Disease involving a spinal nerve root (see spinal nerve roots) which may result from compression related to intervertebral disk displacement; spinal cord injuries; spinal diseases; and other conditions. Clinical manifestations include radicular pain, weakness, and sensory loss referable to structures innervated by the involved nerve root. [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] 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]
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Radiolabeled: Any compound that has been joined with a radioactive substance. [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] 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] 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] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] 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] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflective: Capable of throwing back light, images, sound waves : reflecting. [EU] 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] Relapse: The return of signs and symptoms of cancer after a period of improvement. [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] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH]
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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] 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] Response Elements: Nucleotide sequences, usually upstream, which are recognized by specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promotor and enhancer regions. [NIH]
Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [NIH] 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] Retraction: 1. The act of drawing back; the condition of being drawn back. 2. Distal movement of teeth, usually accomplished with an orthodontic appliance. [EU] Retrobulbar: Behind the pons. [EU] 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] 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] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve
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impulses to the brain. [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] Rickettsiae: One of a group of obligate intracellular parasitic microorganisms, once regarded as intermediate in their properties between bacteria and viruses but now classified as bacteria in the order Rickettsiales, which includes 17 genera and 3 families: Rickettsiace. [NIH]
Rituximab: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. [NIH] 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] Rubella: An acute, usually benign, infectious disease caused by a togavirus and most often affecting children and nonimmune young adults, in which the virus enters the respiratory tract via droplet nuclei and spreads to the lymphatic system. It is characterized by a slight cold, sore throat, and fever, followed by enlargement of the postauricular, suboccipital, and cervical lymph nodes, and the appearances of a fine pink rash that begins on the head and spreads to become generalized. Called also German measles, roetln, röteln, and three-day measles, and rubeola in French and Spanish. [EU] Rutin: 3-((6-O-(6-Deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranosyl)oxy)-2-(3,4dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one. Found in many plants, including buckwheat, tobacco, forsythia, hydrangea, pansies, etc. It has been used therapeutically to decrease capillary fragility. [NIH] Saline: A solution of salt and water. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [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] Schwann: A neurilemmal cell from the sheath of a peripheral nerve fiber. [NIH]
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Schwann Cells: Neuroglial cells of the peripheral nervous system which form the insulating myelin sheaths of peripheral axons. [NIH] Sciatic Nerve: A nerve which originates in the lumbar and sacral spinal cord (L4 to S3) and supplies motor and sensory innervation to the lower extremity. The sciatic nerve, which is the main continuation of the sacral plexus, is the largest nerve in the body. It has two major branches, the tibial nerve and the peroneal nerve. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Sclerotic: Pertaining to the outer coat of the eye; the sclera; hard, indurated or sclerosed. [NIH]
Screening: Checking for disease when there are no symptoms. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Self Tolerance: The normal lack of the ability to produce an immunological response to autologous (self) antigens. A breakdown of self tolerance leads to autoimmune diseases. The ability to recognize the difference between self and non-self is the prime function of the immune system. [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] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] 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] Septate: An organ or structure that is divided into compartments. [NIH] Sequela: Any lesion or affection following or caused by an attack of disease. [EU]
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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] Sequester: A portion of dead bone which has become detached from the healthy bone tissue, as occurs in necrosis. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Channels: Cell membrane glycoproteins selective for sodium ions. Fast sodium
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current is associated with the action potential in neural membranes. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Somatosensory Cortex: Area of the parietal lobe concerned with receiving general sensations. It lies posterior to the central sulcus. [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] 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] 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 distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Speech Perception: The process whereby an utterance is decoded into a representation in terms of linguistic units (sequences of phonetic segments which combine to form lexical and grammatical morphemes). [NIH] Sperm: The fecundating fluid of the male. [NIH] Spermidine: A polyamine formed from putrescine. It is found in almost all tissues in association with nucleic acids. It is found as a cation at all pH values, and is thought to help stabilize some membranes and nucleic acid structures. It is a precursor of spermine. [NIH] Spermine: A biogenic polyamine formed from spermidine. It is found in a wide variety of organisms and tissues and is an essential growth factor in some bacteria. It is found as a polycation at all pH values. Spermine is associated with nucleic acids, particularly in viruses, and is thought to stabilize the helical structure. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in
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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 Vascular Diseases: Hypoxic-ischemic and hemorrhagic disorders of the spinal cord. Arteriosclerosis, emboli, and vascular malformations are potential causes of these conditions. [NIH] Spinal Nerve Roots: The paired bundles of nerve fibers entering and leaving the spinal cord at each segment. The dorsal and ventral nerve roots join to form the mixed segmental spinal nerves. The dorsal roots are generally afferent, formed by the central projections of the spinal (dorsal root) ganglia sensory cells, and the ventral roots efferent, comprising the axons of spinal motor and autonomic preganglionic neurons. There are, however, some exceptions to this afferent/efferent rule. [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] Spinous: Like a spine or thorn in shape; having spines. [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] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [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] Steady state: Dynamic equilibrium. [EU] 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] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [NIH] 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] 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]
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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] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure-activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Substrate: A substance upon which an enzyme acts. [EU] Subtilisin: A serine endopeptidase isolated from Bacillus subtilis. It hydrolyzes proteins with broad specificity for peptide bonds, and a preference for a large uncharged residue in P1. It also hydrolyzes peptide amides. (From Enzyme Nomenclature, 1992) EC 3.4.21.62. [NIH]
Superantigens: Microbial antigens that have in common an extremely potent activating effect on T-cells that bear a specific variable region. Superantigens cross-link the variable region with class II MHC proteins regardless of the peptide binding in the T-cell receptor's
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pocket. The result is a transient expansion and subsequent death and anergy of the T-cells with the appropriate variable regions. [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] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Suppositories: A small cone-shaped medicament having cocoa butter or gelatin at its basis and usually intended for the treatment of local conditions in the rectum. [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] Sural Nerve: A branch of the tibial nerve which supplies sensory innervation to parts of the lower leg and foot. [NIH] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]
Symphysis: A secondary cartilaginous joint. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] 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] 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] Synchrotron: An accelerator in which the particles are guided by an increasing magnetic field while they are accelerated several times in an approximately circular path by electric fields produced by a high-frequency generator. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] 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] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [NIH]
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Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Temporal Lobe: Lower lateral part of the cerebral hemisphere. [NIH] Tendon: A discrete band of connective tissue mainly composed of parallel bundles of collagenous fibers by which muscles are attached, or two muscles bellies joined. [NIH] Teratogen: A substance which, through immediate, prolonged or repeated contact with the skin may involve a risk of subsequent non-hereditable birth defects in offspring. [NIH] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [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] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] 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] 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] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH]
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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] Thyrotropin: A peptide hormone secreted by the anterior pituitary. It promotes the growth of the thyroid gland and stimulates the synthesis of thyroid hormones and the release of thyroxine by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tibial Nerve: The medial terminal branch of the sciatic nerve. The tibial nerve fibers originate in lumbar and sacral spinal segments (L4 to S2). They supply motor and sensory innervation to parts of the calf and foot. [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] 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] 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] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] 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] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH]
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Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] 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] 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] Treosulfan: A substance that is being studied as a treatment for cancer. It belongs to the
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family of drugs called alkylating agents. [NIH] 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] Trigeminal Nerve: The 5th and largest cranial nerve. The trigeminal nerve is a mixed motor and sensory nerve. The larger sensory part forms the ophthalmic, mandibular, and maxillary nerves which carry afferents sensitive to external or internal stimuli from the skin, muscles, and joints of the face and mouth and from the teeth. Most of these fibers originate from cells of the trigeminal ganglion and project to the trigeminal nucleus of the brain stem. The smaller motor part arises from the brain stem trigeminal motor nucleus and innervates the muscles of mastication. [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 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] Trophoblast: The outer layer of cells of the blastocyst which works its way into the endometrium during ovum implantation and grows rapidly, later combining with mesoderm. [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] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberculostatic: Inhibiting the growth of Mycobacterium tuberculosis. [EU] 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] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH]
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Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] 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] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [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]
Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] 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] VE: The total volume of gas either inspired or expired in one minute. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] 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 blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Venter: Belly. [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
Dictionary 289
body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] 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] 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] Vestibulocochlear Nerve: The 8th cranial nerve. The vestibulocochlear nerve has a cochlear part (cochlear nerve) which is concerned with hearing and a vestibular part (vestibular nerve) which mediates the sense of balance and head position. The fibers of the cochlear nerve originate from neurons of the spiral ganglion and project to the cochlear nuclei (cochlear nucleus). The fibers of the vestibular nerve arise from neurons of Scarpa's ganglion and project to the vestibular nuclei. [NIH] Vestibulocochlear Nerve Diseases: Diseases of the vestibular and/or cochlear (acoustic) nerves, which join to form the vestibulocochlear nerve. Vestibular neuritis, cochlear neuritis, and acoustic neuromas are relatively common conditions that affect these nerves. Clinical manifestations vary with which nerve is primarily affected, and include hearing loss, vertigo, and tinnitus. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vibrissae: Stiff hairs projecting from the face around the nose of most mammals, acting as touch receptors. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] 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] Visual Cortex: Area of the occipital lobe concerned with vision. [NIH] Visual Pathways: Set of cell bodies and nerve fibers conducting impulses from the eyes to the cerebral cortex. It includes the retina, optic nerve, optic tract, and geniculocalcarine tract.
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[NIH]
Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] 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] Zebrafish: A species of North American fishes of the family Cyprinidae. They are used in embryological studies and to study the effects of certain chemicals on development. [NIH] Zoonoses: Diseases of non-human animals that may be transmitted to man or may be transmitted from man to non-human animals. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
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293
INDEX 3 3-dimensional, 8, 61, 215, 272 A Abdomen, 215, 225, 253, 255, 281, 289 Abducens, 215, 236 Abducens Nerve, 215, 236 Abducens Nerve Diseases, 215, 236 Aberrant, 49, 56, 80, 170, 179, 215 Acceptor, 215, 266 Acetylcholine, 215, 229, 262, 263 Acetylcholinesterase, 45, 215 Acidemia, 215, 268 Acidity, 215, 268 Acinetobacter, 75, 81, 215 Acoustic, 45, 215, 273, 289 Actin, 58, 158, 215, 260 Acute Disease, 18, 215 Acute lymphoblastic leukemia, 126, 215, 216 Acute lymphocytic leukemia, 215, 216 Acyl, 20, 125, 216 Acylation, 20, 216 Adaptability, 216, 227 Adaptation, 58, 216, 269 Adenosine, 216, 222, 225, 254, 269 Adjustment, 216 Adjuvant, 9, 20, 34, 131, 133, 148, 216, 244 Adoptive Transfer, 10, 17, 19, 47, 216 Adrenal Medulla, 216, 239, 240, 263 Adrenoleukodystrophy, 20, 93, 216, 268 Adverse Effect, 216, 218, 279 Aerobic, 216, 259 Aetiology, 170, 216 Afferent, 49, 172, 216, 241, 265, 271, 281 Affinity, 45, 105, 109, 144, 216, 217, 221, 279 Agar, 217, 234, 269 Age of Onset, 153, 217 Agonist, 38, 39, 45, 166, 170, 217, 236 Airways, 146, 217 Albumin, 100, 217, 269 Alertness, 217, 225 Algorithms, 8, 217, 224 Alkaline, 217, 218, 225 Alkaloid, 217, 230 Alkylating Agents, 217, 287 Alleles, 6, 69, 217 Allergen, 217, 278
Allogeneic, 217, 246 Allografts, 217, 248 Alternative medicine, 190, 217 Amblyopia, 134, 217 Ambulatory Care, 218 Amine, 218, 248 Amino Acid Motifs, 218, 232 Amino Acid Sequence, 23, 38, 62, 92, 157, 218, 220, 232, 240, 244, 247 Amino Acid Substitution, 46, 51, 218 Ammonia, 218, 245, 288 Amphetamines, 218, 230 Amplification, 26, 218 Amygdala, 218, 223, 255, 284 Amyloid, 111, 158, 218 Anaesthesia, 219, 251 Anal, 219, 242 Analogous, 28, 146, 219, 270, 286 Anaphylatoxins, 219, 231 Anatomical, 50, 126, 219, 228, 236, 250, 258, 266, 278 Anergic, 9, 219 Anergy, 146, 219, 283 Aneurysm, 219, 288 Angiogenesis, 219, 257 Angiopathy, 111, 219 Anions, 217, 219, 253, 279, 283 Anisotropy, 8, 219 Anoxia, 61, 144, 219 Antagonism, 53, 64, 88, 219, 225 Antibacterial, 220, 253, 280 Antibiotic, 219, 220, 225, 267, 280 Anticoagulant, 220, 272 Anticonvulsants, 204, 220 Antigen-Antibody Complex, 220, 231 Antigen-presenting cell, 64, 76, 220, 235 Anti-inflammatory, 18, 57, 220, 245 Antimicrobial, 220, 235 Antineoplastic, 217, 220, 244, 289 Antiseptic, 220, 271 Antiserum, 220, 222 Antiviral, 178, 220, 252, 267 Anxiety, 159, 187, 220 Aponeurosis, 220, 243 Apoptosis, 13, 29, 39, 47, 57, 62, 72, 74, 117, 153, 161, 165, 220, 226 Applicability, 36, 164, 171, 221 Aqueous, 38, 145, 221, 234, 238, 249
294
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Arginase, 173, 221 Arginine, 219, 221, 263, 265, 274, 287 Arterial, 221, 225, 233, 245, 272 Arteries, 219, 221, 224, 233, 258 Arterioles, 221, 224, 226 Arteriolosclerosis, 221 Arteriosclerosis, 111, 221, 281 Artery, 219, 221, 224, 233, 238, 273, 277, 288 Articular, 221, 265 Aspartic, 20, 179, 221 Aspartic Acid, 20, 179, 221 Assay, 10, 21, 26, 29, 38, 43, 49, 73, 152, 154, 161, 165, 169, 179, 221, 250, 274 Asthenia, 219, 221 Astringent, 221, 271 Astrocytes, 18, 48, 49, 97, 111, 126, 147, 151, 153, 165, 221, 222, 256, 258 Astrocytoma, 221, 245 Asymptomatic, 15, 35, 101, 222 Ataxia, 176, 222, 284 ATP, 128, 222, 236, 244, 254, 269, 272, 286 Atrophy, 222, 262 Attenuated, 180, 222, 288 Atypical, 222, 266 Auditory, 44, 126, 131, 222, 240, 247, 271 Auditory Cortex, 45, 222 Autoantibodies, 19, 29, 83, 84, 86, 105, 113, 169, 180, 222 Autoantigens, 10, 13, 34, 52, 76, 102, 116, 142, 159, 222 Autoimmunity, 9, 13, 33, 52, 53, 58, 65, 76, 81, 102, 113, 136, 171, 181, 222 Autologous, 13, 79, 179, 180, 222, 278 Autonomic, 75, 172, 215, 222, 260, 263, 267, 268, 281 Autonomic Nervous System, 222, 267 Avidity, 10, 87, 222 Axonal, 8, 12, 21, 23, 27, 35, 38, 41, 53, 56, 60, 64, 73, 74, 82, 95, 99, 105, 109, 143, 151, 154, 164, 168, 172, 173, 183, 222 Axotomy, 11, 48, 222 B Bacteria, 144, 181, 216, 220, 222, 223, 238, 246, 258, 277, 280, 286, 288 Bacterial Physiology, 216, 223 Bacterial Proteins, 110, 223 Bactericidal, 223, 240 Bacteriophage, 48, 223, 269, 286 Bacterium, 223 Basal Ganglia, 222, 223, 225, 243, 245, 255, 263
Basal Ganglia Diseases, 222, 223 Basement Membrane, 18, 223, 241, 254 Benign, 95, 221, 223, 243, 247, 261, 275, 277 Benzene, 223, 253 Beta-pleated, 218, 223 Bilateral, 162, 223, 262, 266 Bile, 21, 223, 248, 255, 281 Bile Acids, 223, 281 Bile Acids and Salts, 223 Bilirubin, 217, 223 Binding agent, 178, 223 Biogenesis, 36, 89, 108, 223 Biological therapy, 224, 246 Biological Transport, 224, 235 Biopsy, 28, 116, 224 Biosynthesis, 78, 224, 279 Biotechnology, 61, 72, 190, 199, 224 Bladder, 168, 224, 251, 260, 272, 288 Blastocyst, 49, 224, 232, 287 Blood Coagulation, 224, 226, 284 Blood pressure, 224, 245, 259, 279 Blood-Brain Barrier, 53, 178, 224 Blot, 224, 250, 264 Blotting, Western, 224, 250 Body Fluids, 224, 279 Bolus, 23, 224 Bolus infusion, 224 Bone Marrow, 49, 215, 216, 223, 224, 225, 244, 250, 256, 257, 259, 282 Bone Marrow Transplantation, 49, 225 Bone scan, 225, 277 Bowel, 168, 219, 225, 253, 282 Brachytherapy, 225, 252, 253, 274, 290 Bradykinin, 225, 263, 269 Brain Infarction, 78, 225 Brain Stem, 131, 225, 227, 230, 236, 287 Brain Stem Infarctions, 225 Breeding, 29, 35, 225 Broad-spectrum, 27, 225 Bronchi, 225, 240, 257, 286 Bronchial, 225, 248 Buccal, 225, 255 C Caffeine, 150, 166, 225, 274 Calcification, 221, 225 Calcium, 49, 57, 133, 225, 226, 231, 257 Callus, 226, 238 Calpain, 82, 226 Capillary, 225, 226, 277, 289 Capillary Fragility, 226, 277 Capsules, 226, 244 Carbohydrate, 94, 143, 226, 245, 270
295
Carbon Dioxide, 226, 234, 242, 276, 288 Carboxy, 177, 226 Carcinogenic, 217, 223, 226, 251, 264, 272, 281 Cardiac, 172, 225, 226, 233, 240, 260, 281 Cardiovascular, 45, 226, 279 Carotene, 226, 276 Carrier Proteins, 226, 269, 274 Caspase, 13, 226 Catabolism, 21, 226, 288 Cations, 226, 253 Caudal, 226, 235, 263, 271 Caudate Nucleus, 223, 226, 263 Cause of Death, 149, 226 Caustic, 227, 271 Cell Adhesion, 153, 154, 165, 175, 227, 252 Cell Adhesion Molecules, 154, 165, 227 Cell Cycle, 32, 227 Cell Death, 4, 10, 13, 38, 46, 51, 57, 151, 161, 220, 227, 229, 261 Cell Differentiation, 227 Cell Division, 36, 147, 222, 227, 246, 257, 259, 269, 272, 278 Cell Lineage, 71, 227 Cell membrane, 23, 46, 224, 226, 227, 243, 258, 260, 268, 271, 279 Cell motility, 156, 227 Cell proliferation, 11, 13, 162, 221, 227, 252 Cell Respiration, 227, 259, 276 Cell Size, 227, 242 Cell Survival, 51, 227, 246 Cell Transplantation, 134, 176, 227 Cellular adhesion, 154, 165, 227 Centrifugation, 227, 283 Cerebellar, 47, 153, 162, 222, 227, 275 Cerebellum, 225, 227, 271, 275 Cerebral Cortex, 8, 222, 228, 240, 242, 261, 289 Cerebral hemispheres, 223, 225, 228, 245, 283 Cerebral Palsy, 41, 228, 280 Cerebrospinal, 59, 63, 74, 79, 83, 90, 95, 101, 105, 106, 110, 126, 130, 132, 164, 170, 228 Cerebrospinal fluid, 59, 63, 74, 79, 83, 90, 95, 101, 105, 106, 110, 126, 130, 132, 164, 170, 228 Cerebrum, 228, 283 Cervical, 104, 228, 277 Cervix, 228, 276 Character, 228, 229, 235, 274 Chelation, 39, 128, 144, 228
Chelation Therapy, 128, 228 Chemokines, 15, 57, 228 Chemotactic Factors, 228, 231 Chemotherapy, 126, 228 Chimeras, 34, 228 Chimeric Proteins, 37, 157, 158, 228 Chin, 228, 257 Cholesterol, 99, 110, 223, 228, 257, 281 Choline, 215, 228 Chondrodysplasia Punctata, 229, 268 Chondroitin sulfate, 166, 179, 229 Choroid, 229, 276 Chromatin, 220, 229 Chromosomal, 176, 218, 229, 276, 277 Chromosome, 34, 67, 91, 103, 216, 229, 255, 277, 278 Chronic Disease, 164, 229 CIS, 7, 229, 276 Clathrin, 229, 239 Clinical Medicine, 229, 271 Clinical trial, 4, 5, 86, 153, 166, 199, 229, 237, 273, 275 Clonal Anergy, 146, 229 Clonal Deletion, 146, 229 Clone, 6, 47, 63, 229 Cloning, 13, 66, 224, 229 Coated Vesicles, 229, 239 Coca, 230 Cocaine, 91, 230 Cochlea, 230, 251 Cochlear, 44, 230, 285, 289 Cochlear Diseases, 230, 285 Cochlear Implantation, 45, 230 Cochlear Implants, 44, 230 Cochlear Nerve, 230, 289 Coculture, 11, 230 Codon, 176, 230, 244 Cofactor, 27, 230, 272, 284 Colchicine, 230, 287 Coliphages, 223, 230 Collagen, 161, 167, 218, 223, 230, 241, 242, 244, 257, 270, 272 Collapse, 148, 230 Colloidal, 217, 230, 238, 279 Combinatorial, 54, 72, 230 Communication Disorders, 45, 198, 231 Complement, 10, 59, 63, 76, 127, 145, 219, 231, 244, 252, 256, 269, 278 Complementary and alternative medicine, 125, 137, 231 Complementary medicine, 125, 231 Computational Biology, 199, 231
296
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Computed tomography, 231, 232, 277 Computerized axial tomography, 231, 232, 277 Computerized tomography, 3, 231, 232 Concentric, 76, 221, 232 Conception, 51, 232, 242 Concomitant, 153, 165, 232 Conduction, 7, 26, 35, 36, 40, 43, 53, 143, 160, 169, 232, 260 Cone, 57, 148, 232, 283 Conjugated, 72, 223, 232, 234 Conjunctiva, 232, 287 Connective Tissue, 224, 230, 232, 235, 242, 243, 244, 245, 256, 267, 272, 276, 282, 283, 284 Connexins, 15, 25, 49, 232, 243 Consciousness, 232, 235, 236, 273 Consensus Sequence, 82, 218, 232 Conserved Sequence, 218, 232 Constitutional, 232, 260 Constriction, 232, 253, 263, 277 Contraindications, ii, 232 Contrast Sensitivity, 232, 265 Conventional therapy, 232 Conventional treatment, 171, 232 Coordination, 36, 151, 168, 227, 233, 260 Cor, 233, 245 Coronary, 233, 258 Coronary Thrombosis, 233, 258 Coronavirus, 16, 92, 233 Coronavirus Infections, 16, 233 Cortex, 3, 45, 218, 233, 239, 240, 271, 275 Cortical, 4, 8, 21, 44, 49, 56, 60, 111, 218, 233, 240, 271, 278, 284 Cortisol, 217, 233 Cortisone, 160, 233 Cranial, 28, 135, 215, 227, 230, 233, 241, 247, 253, 257, 261, 263, 265, 267, 268, 287, 289 Craniocerebral Trauma, 215, 223, 233, 247, 284, 285, 287 Crossing-over, 233, 275 Cryofixation, 233 Cryopreservation, 132, 176, 233 Crystallization, 65, 87, 122, 234 Cues, 57, 153, 165, 178, 234 Culture Media, 181, 217, 234 Cultured cells, 181, 234 Curative, 234, 263, 284 Cutaneous, 234, 255 Cyclic, 22, 39, 49, 92, 143, 149, 150, 170, 171, 225, 226, 234, 246, 263, 268
Cysteine, 226, 228, 234 Cytochrome, 45, 234 Cytokine, 10, 13, 14, 16, 19, 26, 29, 30, 33, 45, 53, 55, 112, 234 Cytoplasm, 24, 57, 60, 220, 227, 234, 239, 246, 259, 260, 277, 283 Cytoskeletal Proteins, 31, 226, 229, 234 Cytoskeleton, 31, 32, 38, 58, 136, 234, 252, 258 Cytotoxic, 97, 99, 158, 234, 249, 250, 275 Cytotoxicity, 97, 234 D De novo, 81, 82, 234 Decarboxylation, 234, 248, 274 Decompression, 205, 234, 235 Decompression Sickness, 234, 235 Degenerative, 147, 150, 155, 156, 158, 235, 247, 265 Deletion, 7, 12, 43, 67, 116, 146, 220, 229, 235, 244, 247 Delivery of Health Care, 235, 247 Dementia, 30, 117, 158, 235 Demyelinating Diseases, 28, 30, 32, 60, 125, 182, 260 Dendrites, 56, 154, 235, 246, 261, 262 Dendritic, 8, 13, 48, 55, 154, 162, 235, 276 Dendritic cell, 13, 55, 235 Density, 4, 6, 8, 43, 64, 78, 95, 227, 235, 242, 264, 280 Dentate Gyrus, 235, 248 Deoxyribonucleotides, 235, 264 Deprivation, 218, 235 Dermis, 235, 286 Detergents, 38, 235 Diabetes Mellitus, 144, 235, 245, 247 Diagnostic procedure, 3, 141, 190, 235 Diencephalon, 235, 271, 283, 284 Diffusion, 8, 15, 49, 50, 60, 224, 235, 251, 262 Digestion, 223, 225, 235, 253, 255, 281, 288 Dihydroxy, 236, 277 Dilatation, Pathologic, 236, 288 Dilate, 150, 236 Dilation, 150, 225, 236, 288 Diplopia, 169, 215, 236, 287 Direct, iii, 6, 26, 30, 32, 49, 64, 84, 149, 164, 181, 193, 229, 236, 275, 283 Discrete, 155, 236, 284 Disinfectant, 236, 240 Dissociation, 115, 128, 216, 236 Dissociative Disorders, 236 Distal, 23, 35, 222, 236, 268, 276
297
Diuresis, 225, 236 Dizziness, 162, 236, 289 DNA Topoisomerase, 236, 244 Dopamine, 230, 236, 262, 268 Dorsal, 23, 49, 60, 127, 151, 155, 162, 236, 261, 271, 281 Dorsum, 236, 237, 243 Double-blind, 166, 237 Drive, ii, vi, 28, 29, 54, 55, 121, 237 Drug Interactions, 194, 237 Drug Tolerance, 237, 285 Duodenum, 223, 237, 281 Dura mater, 237, 257, 266 Dyes, 60, 219, 237, 242 Dyscrasia, 68, 237 Dystrophic, 23, 237 E Ear Diseases, 162, 167, 237 Ectoderm, 237, 261 Effector, 9, 17, 18, 19, 30, 55, 142, 215, 231, 237, 268 Effector cell, 17, 30, 237 Efferent, 237, 241, 281 Efficacy, 5, 15, 17, 29, 58, 142, 153, 162, 165, 237 Elastic, 237, 280, 283 Elasticity, 221, 237 Elastin, 230, 237, 241 Electric Conductivity, 219, 237 Electrolyte, 237, 271, 279 Electrons, 237, 253, 256, 266, 274, 275 Electrophoresis, 25, 129, 238, 266 Elementary Particles, 237, 238, 256, 262, 273 Embolus, 238, 251 Embryo, 66, 155, 224, 227, 237, 238, 251, 259, 270 Embryogenesis, 41, 238 Emollient, 238, 245 Emulsion, 238, 242 Encephalitis, 163, 238 Encephalitis, Viral, 238 Encephalopathy, 59, 166, 238 Endemic, 35, 238, 281 Endocrine System, 238, 262 Endocytosis, 38, 238 Endogenous, 6, 42, 44, 60, 127, 162, 168, 173, 222, 226, 236, 239, 246, 264, 272, 286 Endorphins, 239, 262, 264 Endosomes, 36, 239 Endothelial cell, 224, 239, 284 Endothelium, 239, 263
Endothelium-derived, 239, 263 Endotoxic, 239, 255 Endotoxins, 231, 239 Energetic, 23, 239 Enhancer, 154, 239, 276 Enkephalins, 42, 239, 262, 264 Enteritis, 233, 239 Enteropeptidase, 239, 287 Entorhinal Cortex, 56, 239, 248 Environmental Exposure, 6, 239 Environmental Health, 198, 200, 239 Enzymatic, 31, 58, 173, 218, 226, 231, 239, 248, 257, 268, 276 Epidermal, 239, 254 Epidermis, 235, 239, 253, 254, 271 Epinephrine, 236, 240, 262, 263, 287 Epithelial, 8, 66, 181, 224, 240, 248, 254 Epithelium, 223, 239, 240 Erythrocytes, 178, 224, 226, 240, 278 Estrogen, 6, 45, 240 Estrogen receptor, 45, 240 Ethanol, 22, 122, 240 Ethanolamine, 22, 240 Ether, 240, 268 Eukaryotic Cells, 143, 174, 234, 240, 251, 263, 265, 288 Evoke, 240, 281 Evoked Potentials, 131, 240 Excitation, 44, 218, 240, 242, 262 Excitatory, 39, 240, 245 Exhaustion, 219, 240 Exogenous, 130, 239, 240, 246, 272 Exon, 51, 240 Exotoxin, 157, 241 Extensor, 241, 273 External-beam radiation, 241, 253, 274, 290 Extracellular Matrix, 31, 53, 57, 156, 232, 241, 242, 252, 257 Extracellular Matrix Proteins, 241, 257 Extracellular Space, 241 Extraction, 150, 241 Extremity, 241, 266, 278 F Facial, 104, 204, 241 Facial Expression, 241 Facial Nerve, 104, 241 Fallopian tube, 241, 276 Family Planning, 199, 241 Fat, 133, 168, 213, 219, 223, 224, 226, 233, 238, 241, 245, 255, 260, 270, 276, 280, 283, 284
298
Myelin
Fatal Outcome, 241, 274 Fatigue, 150, 168, 169, 241 Fetal Alcohol Syndrome, 22, 241 Fetus, 242, 249, 271, 288 Fibroblasts, 20, 155, 242, 252 Fibrosis, 242, 278 Fissure, 215, 235, 242, 271, 287 Fixation, 63, 233, 242, 278 Flow Cytometry, 26, 132, 242 Fluorescence, 31, 36, 242 Fluorescent Dyes, 242 Foetal, 77, 242 Folate, 129, 242 Folic Acid, 242 Fovea, 242, 243 Fractionation, 22, 90, 243, 283 Free Radicals, 30, 236, 243 Frontal Lobe, 243, 271 Fungi, 243, 258, 288, 290 G Gadolinium, 5, 243 Gamma knife, 205, 243 Ganglia, 156, 215, 223, 243, 261, 268, 281 Ganglion, 56, 151, 162, 230, 243, 261, 263, 276, 287, 289 Gangliosides, 29, 91, 243 Gangrene, 151, 243 Gap Junctions, 25, 232, 243 Gas, 218, 226, 235, 240, 243, 249, 263, 288 Gastric, 243, 248 Gastrin, 243, 248 Gastroenteritis, 233, 243 Gastrointestinal, 166, 225, 233, 240, 243, 244, 279, 282 Gastrointestinal tract, 166, 240, 244, 279 Gelatin, 161, 234, 244, 245, 283, 284 Gene Deletion, 41, 46, 244 Gene Duplication, 35, 244 Gene Expression, 7, 29, 30, 37, 38, 39, 58, 61, 69, 71, 85, 118, 122, 135, 244 Gene Therapy, 117, 134, 154, 244 Generator, 244, 283 Genetic Code, 244, 263 Genetic Engineering, 50, 158, 224, 229, 244 Genetics, 5, 16, 40, 53, 60, 80, 90, 98, 103, 106, 122, 244 Genistein, 45, 244 Genotype, 51, 217, 244, 268 Germ Cells, 244, 257, 264, 265, 280, 284 Germinal Center, 163, 244 Gestation, 110, 244, 267
Gland, 20, 216, 233, 245, 256, 266, 272, 278, 281, 284, 285 Glial Fibrillary Acidic Protein, 110, 245 Glioblastoma, 156, 245 Glioma, 117, 135, 245 Glucocorticoids, 64, 65, 245 Gluconeogenesis, 245 Glucose, 235, 245, 247, 251, 252, 269 Glucose Intolerance, 235, 245 Glutamate, 3, 38, 60, 245, 253 Glutamic Acid, 179, 181, 242, 245, 262, 272 Glutamine, 179, 245 Glycerol, 64, 204, 245, 268 Glycerophospholipids, 245, 268 Glycine, 218, 223, 245, 262, 279 Glycogen, 245, 269 Glycosaminoglycan, 229, 245 Glycosidic, 246, 261, 264, 269 Governing Board, 246, 271 Gp120, 246, 267 Grade, 95, 97, 246 Graft, 14, 217, 246, 250 Graft Rejection, 14, 246, 250 Grafting, 246, 250 Gram-negative, 215, 239, 246 Gram-Negative Bacteria, 215, 239, 246 Granule, 235, 246, 277 Granulocytes, 246, 254, 290 Gravis, 161, 171, 246 Growth Cones, 23, 178, 246 Growth factors, 11, 44, 94, 151, 162, 246, 258, 261 Growth Inhibitors, 105, 246 Guanylate Cyclase, 246, 263 H Half-Life, 24, 246 Haplotypes, 90, 246 Haptens, 133, 216, 246, 274 Headache, 225, 247 Health Care Costs, 145, 247 Health Expenditures, 247 Hearing Disorders, 231, 247 Heavy Chain Disease, 247, 266 Hematoxylin, 144, 247 Heme, 223, 234, 247 Hemoglobin, 240, 247, 254 Hemoglobinopathies, 244, 247 Hemorrhage, 79, 233, 247, 282 Hemostasis, 247, 252, 279 Hepatic, 217, 247 Hepatitis, 17, 247 Hepatocytes, 247, 248
299
Hereditary, 15, 81, 82, 91, 92, 94, 107, 115, 116, 248, 262 Heredity, 244, 248 Herpes, 6, 248 Herpes virus, 6, 248 Herpes Zoster, 248 Heterodimer, 56, 248 Heterogeneity, 19, 66, 92, 97, 153, 216, 248 Hippocampus, 42, 235, 248, 255, 282 Histamine, 149, 166, 170, 171, 219, 248 Histidine, 248 Histocompatibility, 63, 77, 118, 170, 248 Homeostasis, 20, 248 Homodimer, 56, 248, 286 Homogeneous, 177, 221, 248 Homologous, 7, 12, 143, 148, 183, 217, 232, 233, 244, 248, 260, 278, 283 Homozygotes, 176, 248 Hormone, 26, 45, 46, 147, 233, 240, 243, 248, 252, 257, 270, 271, 276, 284, 285, 286 Humoral, 53, 93, 102, 142, 146, 170, 180, 246, 248, 284 Humour, 248 Hybrid, 12, 43, 229, 248, 249, 264 Hybridomas, 52, 249, 252 Hydrogen, 215, 218, 226, 241, 249, 259, 262, 266, 268, 273, 283 Hydrogen Peroxide, 249, 283 Hydrolysis, 215, 221, 249, 254, 261, 270, 272, 287 Hydrophobic, 170, 235, 245, 249 Hydroxylysine, 230, 249 Hydroxyproline, 218, 230, 249 Hypersensitivity, 13, 217, 249, 276, 278 Hypoxia, 39, 41, 249, 284 Hypoxic, 39, 41, 56, 59, 249, 281 I Idiopathic, 167, 249 Illusion, 249, 289 Immersion, 144, 249 Immune function, 168, 249, 250, 286 Immune Sera, 249 Immune system, 9, 13, 33, 146, 161, 163, 168, 171, 179, 220, 222, 224, 237, 249, 250, 256, 260, 278, 290 Immune Tolerance, 13, 159, 161, 249 Immune-response, 180, 249 Immunization, 53, 54, 57, 163, 164, 216, 249, 250, 278 Immunoassay, 161, 162, 250 Immunoblotting, 19, 250 Immunodeficiency, 117, 172, 250
Immunodominant Epitopes, 157, 250 Immunogenic, 250, 255, 274 Immunoglobulin, 5, 7, 19, 42, 117, 163, 164, 170, 179, 220, 247, 250, 259 Immunohistochemistry, 16, 250 Immunologic, 19, 26, 30, 66, 98, 142, 146, 159, 161, 180, 216, 228, 249, 250, 275, 284 Immunosuppression, 250 Immunosuppressive, 17, 22, 158, 160, 250 Immunosuppressive Agents, 158, 160, 250 Immunosuppressive therapy, 250 Immunotherapy, 99, 158, 180, 216, 224, 250 Impairment, 41, 170, 222, 250, 258 Implant radiation, 250, 252, 253, 274, 290 Implantation, 23, 49, 69, 232, 250, 287 In situ, 16, 19, 33, 39, 42, 163, 168, 250 In Situ Hybridization, 16, 33, 39, 42, 250 Incision, 251, 253 Incontinence, 159, 251, 260 Incubated, 38, 251 Induction, 9, 13, 16, 18, 20, 25, 30, 47, 52, 57, 68, 131, 146, 159, 161, 251 Infantile, 251, 268 Infarction, 146, 155, 225, 233, 251, 258 Infiltration, 18, 164, 170, 251 Inhalation, 146, 251, 270 Initiation, 9, 26, 31, 54, 55, 65, 154, 179, 251, 272, 286 Inner ear, 161, 162, 167, 230, 251 Innervation, 241, 251, 268, 278, 283, 285, 287 Inositol, 49, 107, 109, 251 Inositol Phosphates, 49, 251 Inpatients, 5, 251 Insight, 14, 16, 31, 49, 252 Insulator, 252, 260 Insulin, 29, 151, 252 Insulin-dependent diabetes mellitus, 252 Insulin-like, 29, 151, 252 Integrins, 31, 252 Intercellular Junctions, 68, 252 Interferon, 5, 58, 85, 100, 116, 144, 252, 256 Interferon-alpha, 252 Interleukin-6, 106, 252 Interleukins, 250, 252 Internal radiation, 252, 253, 274, 290 Interneurons, 49, 252 Interstitial, 225, 241, 252, 253, 290 Intervertebral, 252, 274 Intestine, 223, 225, 239, 253, 275, 279 Intoxication, 136, 253, 290
300
Myelin
Intracellular Membranes, 253, 257 Intracranial Hypertension, 215, 247, 253, 266, 285 Intrathecal, 101, 177, 253 Intravenous, 5, 57, 177, 194, 253 Intrinsic, 48, 130, 168, 173, 216, 223, 253 Invasive, 156, 169, 253, 256 Ion Channels, 40, 221, 253 Ionizing, 239, 253, 275 Ions, 50, 60, 119, 215, 236, 237, 249, 253, 269, 271, 279 Irradiation, 72, 117, 253, 290 Ischemia, 39, 48, 61, 66, 146, 215, 222, 243, 253, 260 Isoflavones, 45, 253 Isoniazid, 145, 253 Isozymes, 22, 253 K Kainate, 38, 236, 253 Kb, 198, 253 Keratin, 253, 254 Keratinocytes, 13, 254 Kinesin, 136, 254 Kinetic, 24, 31, 63, 253, 254 L Labile, 231, 254 Labyrinth, 230, 251, 254, 265, 278, 289 Lacrimal, 241, 254 Laminin, 223, 241, 254 Language Disorders, 231, 254 Larynx, 254, 286 Latent, 65, 170, 254 Latent period, 170, 254 Lectin, 254, 257 Leprosy, 80, 254 Lesion, 5, 19, 71, 142, 152, 154, 165, 174, 179, 254, 255, 278 Lethal, 46, 49, 223, 254 Leucine, 61, 107, 254 Leucocyte, 73, 254, 256 Leukemia, 35, 244, 254 Leukocytes, 224, 228, 246, 252, 255, 259, 287 Leukoencephalopathy, 151, 255 Ligament, 241, 255, 272 Ligands, 44, 53, 54, 57, 163, 227, 252, 255 Ligation, 30, 255 Limbic, 218, 255, 271 Limbic System, 218, 255, 271 Linkage, 5, 102, 103, 255 Lipid A, 12, 36, 128, 255 Lipid Bilayers, 67, 255
Lipopolysaccharides, 255 Liver, 20, 217, 223, 226, 238, 242, 245, 247, 248, 255, 277, 288 Liver scan, 255, 277 Localization, 11, 12, 19, 22, 40, 51, 64, 66, 103, 144, 154, 250, 255 Localized, 33, 34, 51, 154, 178, 233, 242, 251, 254, 255, 260, 269 Locomotion, 31, 255, 269 Locomotor, 48, 255 Loop, 68, 255 Lumbar, 255, 278, 285 Lupus, 144, 148, 255, 283 Lymph, 57, 228, 239, 248, 255, 256, 257, 277 Lymph node, 57, 228, 256, 257, 277 Lymphatic, 239, 251, 255, 256, 270, 277, 281, 284 Lymphatic system, 255, 256, 277, 281, 284 Lymphoblasts, 215, 216, 256 Lymphocyte, 22, 45, 111, 220, 250, 256 Lymphoid, 8, 220, 244, 249, 254, 256, 284 Lymphoma, 4, 256 Lysine, 152, 249, 256, 287 M Macroglia, 256, 258 Macrophage, 53, 58, 132, 157, 181, 256 Magnetic Resonance Imaging, 8, 45, 50, 256, 277 Magnetic Resonance Spectroscopy, 60, 256 Major Histocompatibility Complex, 64, 102, 146, 246, 256 Malignancy, 35, 256 Malignant, 88, 117, 156, 220, 221, 245, 256, 261, 275 Malignant tumor, 156, 256 Malnutrition, 217, 222, 256 Mammary, 181, 256 Manifest, 222, 256, 282 Mastication, 256, 287 Matrix metalloproteinase, 18, 256 Maxillary, 257, 287 Maxillary Nerve, 257, 287 Measles-Mumps-Rubella Vaccine, 148, 257 Medial, 221, 257, 265, 285 Mediastinum, 257, 284 Mediate, 7, 11, 15, 29, 42, 57, 62, 106, 155, 227, 230, 236, 257 Medical Records, 6, 257 MEDLINE, 199, 257
301
Megakaryocytes, 257, 284 Meiosis, 82, 257, 260, 283 Melanin, 257, 268, 287 Membrane Lipids, 257, 268 Membrane Proteins, 24, 50, 66, 67, 130, 155, 175, 257 Memory, 42, 153, 159, 162, 165, 235, 244, 257 Meninges, 227, 233, 237, 257, 281 Meningitis, 59, 257 Mental, iv, 4, 46, 59, 171, 182, 198, 200, 228, 231, 235, 236, 241, 257, 258, 273, 277 Mental deficiency, 241, 257 Mental Health, iv, 4, 198, 200, 258, 273 Mental Processes, 236, 258, 273 Mental Retardation, 46, 231, 258 Mercury, 128, 242, 258 Meta-Analysis, 166, 258 Metabolic disorder, 258, 268 Metastasis, 227, 257, 258 Methyltransferase, 170, 258 MI, 106, 126, 148, 150, 164, 214, 258 Microbe, 258, 286 Microbiology, 19, 51, 216, 222, 258 Microglia, 30, 48, 53, 221, 258 Microorganism, 230, 258, 267, 290 Micro-organism, 246 Micro-organism, 258 Micro-organism, 269 Microtubules, 58, 136, 254, 258 Microvilli, 11, 258 Migration, 19, 27, 44, 57, 156, 258 Millimeter, 151, 259 Mitochondria, 134, 259, 265 Mitochondrial Swelling, 259, 261 Mitosis, 221, 259 Mobilization, 56, 259 Modeling, 50, 259 Modification, 50, 218, 244, 259, 274 Modulator, 34, 259 Monitor, 173, 259, 263 Monoclonal antibodies, 40, 64, 87, 107, 250, 259, 277 Monocytes, 97, 252, 255, 259 Mononuclear, 28, 57, 69, 93, 102, 142, 164, 259, 287 Morphological, 33, 60, 129, 151, 177, 238, 259 Morphology, 8, 12, 41, 259 Morula, 224, 259 Motility, 136, 178, 259, 279 Motor Neurons, 172, 259
Motor Skills, 3, 260 Mucinous, 243, 260 Mucosa, 255, 260, 282 Multivalent, 112, 222, 260 Muscular Diseases, 260, 266 Mutagenesis, 12, 31, 50, 260 Mutagens, 260 Myasthenia, 171, 260 Mydriatic, 236, 260 Myelitis, 147, 260, 262 Myocardium, 258, 260 Myofibrils, 226, 260 Myristate, 131, 260 N Natural selection, 223, 260 NCI, 1, 197, 229, 260 Necrosis, 115, 153, 165, 220, 225, 245, 251, 258, 261, 279 Neocortex, 4, 8, 261 Neonatal, 39, 42, 48, 56, 176, 261, 268 Neoplasia, 261 Neoplasm, 261, 287 Neoplastic, 22, 249, 256, 261 Nephropathy, 88, 261 Nerve Endings, 261, 283 Nerve Fibers, 4, 26, 40, 43, 64, 134, 142, 155, 178, 230, 261, 281, 285, 289 Nerve Growth Factor, 156, 261, 262 Nerve Regeneration, 11, 58, 147, 148, 151, 261 Neural, 9, 13, 40, 49, 55, 70, 87, 98, 106, 132, 145, 153, 154, 155, 162, 165, 168, 171, 173, 176, 177, 183, 216, 219, 248, 258, 261, 280 Neural Crest, 70, 261 Neuralgia, 204, 261 Neuraminidase, 130, 261 Neurites, 154, 165, 261 Neuritis, 62, 261, 262, 265, 289 Neuroanatomy, 60, 255, 262 Neuroblastoma, 87, 126, 262 Neurodegenerative Diseases, 80, 147, 164, 170, 223, 262 Neuroendocrine, 26, 262 Neurologic, 99, 147, 204, 245, 262, 268 Neuromuscular, 23, 35, 73, 115, 215, 262 Neuromuscular Junction, 35, 215, 262 Neuromyelitis Optica, 83, 262 Neuropathy, 7, 27, 48, 63, 74, 81, 82, 84, 89, 91, 92, 94, 103, 107, 116, 172, 262, 268 Neuropeptides, 226, 262 Neuropsychology, 60, 262
302
Myelin
Neurotransmitter, 4, 162, 215, 216, 218, 221, 225, 236, 245, 248, 253, 262, 263, 282 Neurotrophins, 56, 173, 262 Neutralization, 17, 177, 262 Neutrons, 253, 262, 274 Neutrophil, 18, 262 Neutrophil Infiltration, 18, 262 Niacin, 263, 287 Nitric Oxide, 30, 100, 132, 263 Nitrogen, 217, 218, 235, 241, 242, 245, 263, 287 Nonverbal Communication, 231, 263 Norepinephrine, 236, 262, 263 Nuclear, 47, 50, 68, 107, 115, 223, 238, 240, 243, 245, 255, 261, 263, 276, 284 Nuclei, 23, 218, 230, 237, 244, 255, 256, 259, 262, 263, 264, 265, 270, 273, 277, 289 Nucleic acid, 154, 172, 174, 175, 178, 181, 183, 244, 250, 260, 263, 264, 274, 280, 289 Nucleolus, 263, 277 Nucleus Accumbens, 91, 263 O Occipital Lobe, 236, 263, 289 Ocular, 48, 263 Oculomotor, 236, 263 Oculomotor Nerve, 236, 263 Oligodendroglia, 18, 37, 39, 59, 68, 93, 147, 260, 264 Oligodendroglial, 8, 19, 32, 39, 60, 66, 264 Oligodendroglioma, 115, 264 Oligodeoxyribonucleotides, 22, 264 Oligonucleotide Probes, 86, 264 Oligosaccharides, 261, 264 Oncogenic, 252, 264 Oocytes, 155, 264 Opacity, 235, 264 Operon, 264, 272, 275 Ophthalmic, 264, 287 Ophthalmology, 242, 264 Opiate, 42, 264 Opioid Peptides, 239, 264 Opium, 264 Opsin, 264, 276 Optic Chiasm, 262, 264, 265 Optic disc, 265 Optic Nerve, 11, 48, 60, 135, 148, 218, 262, 264, 265, 266, 276, 278, 289 Optic Neuritis, 48, 169, 265 Orbital, 215, 265, 287 Organ Culture, 265, 285 Organelles, 36, 227, 229, 234, 254, 259, 265, 269
Ornithine, 265, 274 Osmotic, 217, 259, 265, 279 Ossicles, 265 Osteoarthritis, 166, 265 Otosclerosis, 162, 167, 265 Outpatient, 265 Ovaries, 265, 276 Ovary, 265, 266, 270, 282 Overexpress, 35, 47, 265 Ovum, 244, 259, 266, 287, 290 Oxidation, 20, 215, 234, 266 P Pachymeningitis, 257, 266 Palliative, 159, 266, 284 Palsies, 91, 94, 116, 266 Palsy, 116, 266 Pancreas, 252, 266, 287 Paralysis, 21, 68, 150, 151, 152, 164, 170, 174, 181, 182, 266, 280 Paraparesis, 35, 83, 266 Paraproteins, 68, 266 Parasite, 266 Parasitic, 55, 266, 277 Parenchyma, 18, 266 Paresis, 261, 266 Paresthesias, 261, 266 Parietal, 266, 280 Parietal Lobe, 266, 280 Partial remission, 266, 275 Particle, 267, 280, 286, 289 Patch, 147, 150, 267, 286 Pathogen, 17, 28, 267 Pathogenesis, 5, 8, 16, 17, 18, 20, 26, 28, 35, 39, 45, 51, 54, 95, 113, 157, 267 Pathologic, 54, 221, 224, 233, 237, 249, 267, 273, 281 Pathologic Processes, 221, 267 Pathologies, 27, 35, 145, 267 Pathophysiology, 41, 50, 60, 166, 267 Patient Education, 204, 208, 210, 214, 267 Pelvic, 267, 272 Penicillin, 219, 267, 288 Penis, 267, 268, 276 Peptide T, 143, 267 Perception, 232, 247, 267, 277 Perfusion, 249, 267, 285 Perinatal, 42, 176, 267 Peripheral blood, 10, 69, 93, 102, 252, 267 Peripheral Nerves, 27, 38, 110, 112, 143, 148, 254, 267, 268, 270, 281 Peripheral Nervous System Diseases, 266, 268
303
Peripheral Neuropathy, 7, 15, 25, 42, 50, 68, 91, 186, 268 Peritonitis, 233, 268 Perivascular, 18, 151, 258, 264, 268 Periventricular Leukomalacia, 41, 268 Peroneal Nerve, 268, 278 Peroxisomal Disorders, 132, 268 PH, 3, 12, 268 Phagocytosis, 30, 130, 132, 258, 268 Phallic, 242, 268 Pharmaceutical Preparations, 240, 244, 268 Pharmacologic, 11, 246, 268, 285, 286 Phenotype, 12, 26, 33, 35, 46, 53, 93, 97, 170, 177, 244, 268 Phenylalanine, 68, 268, 287 Phosphodiesterase, 22, 31, 92, 143, 149, 268 Phospholipids, 144, 241, 251, 257, 268 Phosphorus, 226, 269 Phosphorylase, 226, 269 Phosphorylation, 24, 32, 43, 269, 272 Physiologic, 9, 42, 54, 217, 224, 246, 269, 275 Physiology, 43, 45, 75, 97, 222, 269 Phytic Acid, 251, 269 Pigments, 226, 269, 276 Plant Growth Regulators, 246, 269 Plants, 217, 221, 225, 226, 228, 230, 245, 254, 259, 263, 269, 270, 271, 277, 286 Plaque, 152, 174, 269 Plasma cells, 4, 54, 170, 220, 269 Plasma protein, 217, 269, 279 Plasmapheresis, 29, 100, 160, 269 Plasticity, 49, 105, 269 Plastids, 265, 269 Platelet Aggregation, 219, 263, 269 Platelet-Derived Growth Factor, 147, 270 Platelets, 226, 257, 263, 269, 270, 279, 284 Platinum, 255, 270 Pleomorphic, 263, 270 Plexus, 270, 278 Pneumonia, 232, 270 Point Mutation, 7, 25, 42, 68, 158, 270 Poisoning, 228, 243, 253, 258, 270 Pollen, 270, 274 Polymerase, 270, 272, 275 Polymers, 144, 270, 272 Polymorphism, 51, 92, 101, 112, 270 Polypeptide, 44, 142, 155, 156, 218, 230, 232, 270, 272, 290 Polyradiculoneuropathy, 172, 270
Polyradiculopathy, 270 Polysaccharide, 220, 245, 270, 272 Polyunsaturated fat, 128, 166, 270 Pons, 215, 225, 271, 276 Posterior, 45, 155, 219, 222, 227, 229, 236, 237, 263, 265, 266, 271, 278, 280 Postnatal, 21, 41, 42, 122, 128, 133, 241, 271, 281 Post-synaptic, 271, 283 Potassium, 43, 144, 271 Potassium Channels, 43, 271 Potassium Dichromate, 144, 271 Practice Guidelines, 200, 271 Preclinical, 58, 271 Precursor, 32, 40, 48, 158, 174, 229, 236, 237, 239, 263, 268, 271, 280, 286, 287, 288 Prefrontal Cortex, 37, 60, 271 Pregnenolone, 122, 271 Prenatal, 122, 238, 241, 271 Presynaptic, 261, 262, 271 Prevalence, 6, 35, 40, 271 Prickle, 254, 271 Probe, 21, 31, 60, 264, 271 Progression, 6, 21, 51, 53, 100, 153, 154, 164, 166, 169, 180, 219, 271 Progressive disease, 151, 153, 272 Projection, 252, 263, 265, 271, 272, 275 Proline, 61, 230, 249, 272 Promoter, 30, 47, 71, 97, 117, 158, 181, 272 Promotor, 272, 276 Prophase, 260, 264, 272, 283 Prophylaxis, 167, 272, 288 Prostate, 156, 272, 276 Prostate gland, 156, 272 Protease, 18, 127, 133, 135, 272 Protein Binding, 272, 285 Protein Conformation, 218, 253, 272 Protein Kinases, 30, 272 Protein S, 12, 31, 36, 60, 70, 97, 110, 129, 149, 164, 179, 181, 224, 232, 244, 272, 277 Protein-Tyrosine Kinase, 244, 272 Proteoglycan, 166, 272 Proteolytic, 78, 231, 239, 272 Protocol, 17, 20, 273 Protons, 249, 253, 256, 273, 274 Protozoa, 258, 273, 288 Psoriasis, 172, 273 Psychiatric, 84, 231, 273 Psychiatry, 59, 73, 83, 100, 101, 107, 118, 242, 273 Psychic, 257, 273, 278 Psychoacoustic, 44, 273
304
Myelin
Psychoactive, 273, 290 Psychology, 122, 236, 262, 273 Psychophysics, 45, 273 Psychophysiology, 262, 273 Puberty, 273, 284 Public Health, 42, 46, 200, 273 Public Policy, 199, 273 Publishing, 61, 273 Pulmonary, 134, 224, 233, 273, 283, 288 Pulse, 88, 259, 273 Pupil, 236, 260, 265, 273 Purines, 274, 279 Putrefaction, 243, 274 Putrescine, 173, 174, 274, 280 Pyrimidines, 274, 279 Q Quality of Life, 153, 274 Quercetin, 166, 274 Quiescent, 48, 274 R Rabies, 76, 274 Race, 258, 274 Radiation, 215, 238, 239, 241, 242, 243, 249, 250, 252, 253, 274, 275, 277, 290 Radiation therapy, 215, 241, 243, 252, 253, 274, 290 Radicular, 274 Radiculopathy, 104, 274 Radioactive, 225, 246, 249, 250, 252, 253, 255, 259, 263, 264, 274, 275, 277, 290 Radioimmunoassay, 63, 274 Radioisotope, 264, 274 Radiolabeled, 224, 253, 274, 275, 290 Radiotherapy, 225, 253, 274, 275, 281, 290 Randomized, 237, 275 Reagent, 240, 275 Recombinant, 14, 37, 62, 77, 81, 87, 111, 160, 174, 175, 181, 275, 288 Recombinant Proteins, 181, 275 Recombination, 7, 69, 244, 275 Reconstitution, 18, 134, 275 Rectum, 243, 251, 272, 275, 283 Red Nucleus, 222, 275 Refer, 1, 225, 231, 236, 239, 242, 243, 248, 252, 255, 261, 262, 275, 286 Reflective, 164, 275 Refraction, 219, 275, 280 Refractive Errors, 218, 236, 275 Refractory, 60, 275 Regimen, 5, 167, 237, 275 Relapse, 5, 21, 113, 153, 182, 275 Remission, 21, 153, 170, 204, 275
Repressor, 46, 264, 275 Reproductive system, 45, 272, 276 Respiration, 226, 259, 276 Response Elements, 13, 276 Retina, 12, 229, 265, 276, 277, 289, 290 Retinal, 48, 56, 162, 232, 265, 276 Retinal Ganglion Cells, 48, 265, 276 Retinol, 276 Retraction, 38, 148, 276 Retrobulbar, 262, 265, 276 Retroviral vector, 244, 276 Retrovirus, 35, 276 Rheumatism, 276 Rheumatoid, 58, 144, 148, 161, 171, 179, 180, 276 Rheumatoid arthritis, 58, 144, 148, 171, 179, 180, 276 Rhodopsin, 264, 276 Ribosome, 154, 277, 286 Rickettsiae, 277, 288 Rituximab, 4, 277 Rods, 243, 276, 277 Rubella, 257, 277 Rutin, 71, 166, 274, 277 S Saline, 145, 277 Salivary, 241, 277 Salivary glands, 241, 277 Satellite, 264, 277 Scans, 3, 5, 277 Schizoid, 277, 290 Schizophrenia, 8, 37, 59, 109, 118, 159, 277, 290 Schizotypal Personality Disorder, 277, 290 Schwann, 11, 13, 15, 25, 26, 35, 43, 56, 64, 69, 70, 85, 104, 143, 151, 172, 260, 277, 278 Schwann Cells, 69, 172, 278 Sciatic Nerve, 136, 268, 278, 285 Sclera, 229, 232, 278 Sclerotic, 151, 278 Screening, 7, 59, 142, 177, 229, 278 Secretion, 26, 56, 58, 166, 181, 245, 248, 252, 258, 278, 286, 288 Secretory, 155, 166, 278 Sedimentation, 227, 278, 287 Segregation, 275, 278 Seizures, 59, 176, 220, 245, 278 Self Tolerance, 229, 278 Semen, 272, 278 Semicircular canal, 251, 278 Senile, 78, 117, 278
305
Sensitization, 19, 278 Sensory loss, 260, 274, 278, 284 Septate, 40, 278 Sequela, 41, 278 Sequence Homology, 13, 144, 267, 279 Sequester, 27, 228, 279 Serine, 7, 43, 279, 282, 287 Serologic, 250, 279 Serotonin, 262, 279, 287 Serum Albumin, 274, 279 Shock, 53, 71, 94, 100, 102, 135, 143, 167, 279, 286 Side effect, 146, 151, 193, 216, 224, 279, 285 Signs and Symptoms, 275, 279 Skeletal, 127, 260, 279 Skeleton, 215, 279 Skull, 233, 279, 284 Small intestine, 237, 239, 248, 253, 279, 287 Smooth muscle, 172, 178, 218, 219, 225, 226, 248, 260, 279, 282 Social Environment, 274, 279 Sodium, 43, 64, 144, 158, 279 Sodium Channels, 43, 64, 279 Soft tissue, 224, 279, 280 Solvent, 144, 223, 240, 245, 265, 280 Soma, 280 Somatic, 172, 238, 248, 255, 257, 259, 267, 268, 271, 280 Somatic cells, 257, 259, 280 Somatosensory Cortex, 49, 280 Sound wave, 232, 275, 280 Soybean Oil, 271, 280 Spastic, 35, 83, 280 Spatial disorientation, 236, 280 Specialist, 205, 236, 280 Species, 19, 44, 134, 154, 160, 217, 223, 227, 230, 232, 240, 243, 248, 257, 258, 259, 266, 274, 279, 280, 282, 286, 287, 289, 290 Spectrum, 104, 258, 280 Speech Perception, 44, 280 Sperm, 229, 270, 280, 287 Spermidine, 174, 280 Spermine, 174, 280 Spinal Cord Diseases, 266, 281 Spinal Cord Vascular Diseases, 260, 281 Spinal Nerve Roots, 270, 274, 281 Spinal Nerves, 267, 268, 281 Spinous, 239, 254, 281 Spleen, 57, 256, 281 Sporadic, 262, 281 Staging, 277, 281 Standard therapy, 5, 281
Steady state, 9, 31, 281 Stem Cells, 49, 177, 281 Stereotactic, 205, 281 Steroid, 85, 223, 233, 271, 281 Stimulant, 225, 248, 281, 288 Stimulus, 44, 218, 237, 240, 251, 253, 266, 273, 281 Stomach, 243, 244, 248, 279, 281 Stool, 251, 282 Strabismus, 218, 236, 282 Strand, 112, 270, 282 Stress, 143, 187, 222, 226, 233, 243, 276, 282 Striatum, 263, 282 Stroke, 30, 38, 39, 60, 66, 146, 147, 149, 198, 282 Stroma, 266, 282 Stromal, 49, 282 Stromal Cells, 49, 282 Structure-Activity Relationship, 130, 282 Subacute, 251, 282 Subarachnoid, 18, 79, 247, 282 Subclinical, 28, 251, 278, 282 Subiculum, 248, 282 Subspecies, 280, 282 Substance P, 275, 278, 282 Substrate, 31, 57, 82, 155, 156, 237, 261, 282 Subtilisin, 131, 282 Superantigens, 76, 282 Superoxide, 85, 158, 283 Superoxide Dismutase, 85, 158, 283 Supplementation, 128, 283 Support group, 205, 283 Suppositories, 244, 283 Suppression, 39, 41, 45, 62, 68, 88, 108, 144, 146, 283 Suppressive, 30, 283 Sural Nerve, 87, 283 Surfactant, 75, 97, 126, 134, 240, 283 Symphysis, 228, 272, 283 Synapse, 162, 262, 271, 283, 286 Synaptic, 60, 153, 162, 165, 183, 262, 283 Synaptosomes, 126, 134, 283 Synchrotron, 38, 283 Synergistic, 41, 283 Systemic, 144, 146, 172, 178, 180, 224, 240, 251, 253, 274, 283, 286, 290 Systemic lupus erythematosus, 172, 283 T Telencephalon, 223, 228, 283 Temporal, 12, 22, 32, 44, 218, 222, 247, 248, 284 Temporal Lobe, 218, 222, 284
306
Myelin
Tendon, 243, 284 Teratogen, 22, 284 Testis, 20, 284 Thalamic, 60, 222, 284 Thalamic Diseases, 222, 284 Thalamus, 8, 235, 255, 271, 284 Therapeutics, 153, 194, 284 Thermal, 219, 236, 262, 284 Threonine, 7, 267, 279, 284 Thrombin, 270, 272, 284 Thrombomodulin, 149, 272, 284 Thrombopoietin, 147, 284 Thrombosis, 252, 272, 282, 284 Thrombus, 233, 251, 270, 284 Thymus, 147, 229, 250, 256, 284 Thymus Gland, 147, 284 Thyroid, 46, 147, 172, 284, 285, 287 Thyroid Gland, 284, 285 Thyroid Hormones, 285, 287 Thyrotropin, 147, 285 Thyroxine, 217, 268, 285 Tibial Nerve, 278, 283, 285 Tinnitus, 162, 285, 289 Tissue Culture, 8, 15, 46, 261, 285 Tissue Distribution, 45, 285 Tolerance, 9, 13, 20, 53, 57, 66, 68, 98, 111, 139, 146, 159, 161, 180, 216, 245, 278, 285 Tomography, 3, 256, 285 Tone, 44, 285 Tonus, 285 Tooth Preparation, 216, 285 Topical, 221, 240, 249, 285 Torsion, 251, 285 Toxic, iv, 42, 51, 176, 217, 218, 223, 234, 237, 238, 239, 241, 262, 274, 285, 286 Toxicity, 5, 58, 237, 258, 286 Toxicology, 200, 286 Toxin, 72, 76, 158, 239, 285, 286 Trachea, 166, 225, 254, 257, 284, 285, 286 Transcriptase, 276, 286 Transcription Factors, 9, 27, 38, 71, 276, 286 Transdermal, 150, 286 Transduction, 24, 30, 32, 44, 57, 161, 251, 286 Transfection, 25, 30, 42, 47, 161, 224, 244, 286 Transfer Factor, 250, 286 Transforming Growth Factor beta, 70, 286 Transgenes, 44, 286 Translation, 58, 154, 218, 286 Translational, 154, 286
Transmitter, 215, 221, 236, 253, 263, 286 Transplantation, 8, 33, 44, 49, 79, 161, 176, 250, 256, 286 Trauma, 22, 23, 38, 59, 142, 147, 155, 172, 261, 286 Treosulfan, 73, 286 Trigeminal, 204, 257, 287 Trigeminal Nerve, 204, 287 Trochlear Nerve, 236, 287 Trochlear Nerve Diseases, 236, 287 Trophic, 35, 287 Trophoblast, 224, 287 Trypsin, 131, 239, 287, 290 Tryptophan, 131, 230, 279, 287 Tubercle, 263, 287 Tuberculosis, 253, 255, 287 Tuberculostatic, 253, 287 Tubulin, 161, 258, 287 Tumor Necrosis Factor, 29, 69, 132, 144, 287 Tumour, 243, 287 Tyrosine, 11, 21, 24, 32, 44, 236, 272, 287 U Ubiquitin, 46, 80, 288 Urea, 221, 265, 288 Urethra, 267, 272, 288 Urinary, 116, 152, 159, 251, 288 Urine, 152, 224, 236, 247, 251, 288 Uterus, 228, 265, 276, 288 V Vaccination, 68, 72, 288 Vaccines, 148, 180, 288, 289 Vacuoles, 238, 265, 288 Vagina, 228, 276, 288 Valine, 68, 288 Vascular, 175, 204, 229, 235, 239, 251, 263, 281, 284, 285, 288 Vasodilation, 127, 288 Vasodilator, 225, 236, 248, 288 VE, 34, 288 Vector, 161, 286, 288 Vein, 219, 253, 263, 277, 288 Venom, 113, 288 Venous, 225, 272, 288 Venous blood, 225, 288 Venter, 288 Ventral, 155, 263, 271, 281, 288 Ventricle, 218, 226, 233, 248, 263, 273, 284, 288, 289 Ventricular, 39, 233, 289 Venules, 224, 226, 289 Vertebrae, 252, 281, 289
307
Vertigo, 162, 289 Vestibule, 230, 251, 278, 289 Vestibulocochlear Nerve, 230, 285, 289 Vestibulocochlear Nerve Diseases, 285, 289 Veterinary Medicine, 199, 289 Vibrissae, 49, 289 Vinblastine, 287, 289 Vinca Alkaloids, 289 Vincristine, 136, 287, 289 Virulence, 222, 286, 289 Virus Replication, 16, 18, 289 Viscera, 280, 289 Visual Cortex, 218, 236, 289 Visual Pathways, 48, 289 Vitamin A, 251, 276, 290 Vitreous, 276, 290 Vitreous Body, 276, 290 Vitro, 7, 8, 11, 13, 21, 30, 32, 35, 42, 43, 44, 46, 47, 57, 60, 62, 70, 71, 75, 78, 99, 101, 128, 131, 132, 134, 147, 155, 156, 162, 173, 175, 177, 179, 244, 251, 285, 290
Vivo, 8, 10, 11, 13, 14, 16, 22, 25, 29, 32, 36, 40, 42, 43, 44, 46, 47, 48, 50, 56, 58, 63, 70, 71, 75, 83, 86, 99, 131, 132, 153, 155, 156, 161, 165, 173, 179, 244, 251, 290 W White blood cell, 21, 215, 216, 220, 251, 255, 256, 262, 269, 290 Windpipe, 284, 290 Withdrawal, 35, 290 Womb, 276, 288, 290 Wound Healing, 227, 252, 257, 290 X Xenograft, 219, 290 X-ray, 24, 37, 60, 62, 119, 231, 232, 242, 253, 263, 274, 275, 277, 281, 290 X-ray therapy, 253, 290 Y Yeasts, 243, 268, 290 Z Zebrafish, 12, 290 Zoonoses, 274, 290 Zygote, 232, 290 Zymogen, 272, 290
308
Myelin
