NEUROFIBROMATOSIS TYPE 1
A
3-in-1
Medical
Reference
A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers TO INTERNET REFERENCES
NEUROFIBROMATOSIS TYPE 1 A BIBLIOGRAPHY AND DICTIONARY FOR PHYSICIANS, PATIENTS, AND GENOME RESEARCHERS
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 7404 Trade Street San Diego, CA 92121 USA Copyright ©2007 by ICON Group International, Inc. Copyright ©2007 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher’s note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Neurofibromatosis Type 1: A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers/ James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-11261-2 1. Neurofibromatosis Type 1-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 neurofibromatosis type 1. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Chaired Professor of Management Science at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 7404 Trade Street San Diego, CA 92121 USA Fax: 858-635-9414 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON NEUROFIBROMATOSIS TYPE 1................................................................... 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Neurofibromatosis Type 1? .............................................................................................. 3 How Common Is Neurofibromatosis Type 1?................................................................................ 4 What Genes Are Related to Neurofibromatosis Type 1?................................................................ 4 How Do People Inherit Neurofibromatosis Type 1? ...................................................................... 4 Where Can I Find More Information about Neurofibromatosis Type 1?....................................... 5 References....................................................................................................................................... 7 What Is the Official Name of the NF1 Gene? ................................................................................ 8 What Is the Normal Function of the NF1 Gene? ........................................................................... 8 What Conditions Are Related to the NF1 Gene?........................................................................... 8 Where Is the NF1 Gene Located?................................................................................................... 9 References....................................................................................................................................... 9 Federally Funded Research on Neurofibromatosis Type 1 ........................................................... 11 The National Library of Medicine: PubMed ................................................................................ 34 CHAPTER 2. ALTERNATIVE MEDICINE AND NEUROFIBROMATOSIS TYPE 1 .................................. 81 Overview...................................................................................................................................... 81 National Center for Complementary and Alternative Medicine.................................................. 81 Additional Web Resources ........................................................................................................... 86 General References ....................................................................................................................... 87 CHAPTER 3. BOOKS ON NEUROFIBROMATOSIS TYPE 1................................................................... 88 Overview...................................................................................................................................... 88 Book Summaries: Online Booksellers........................................................................................... 88 The National Library of Medicine Book Index ............................................................................. 89 APPENDIX A. HELP ME UNDERSTAND GENETICS ......................................................................... 91 Overview...................................................................................................................................... 91 The Basics: Genes and How They Work....................................................................................... 91 Genetic Mutations and Health................................................................................................... 102 Inheriting Genetic Conditions ................................................................................................... 108 Genetic Consultation ................................................................................................................. 116 Genetic Testing .......................................................................................................................... 118 Gene Therapy ............................................................................................................................. 124 The Human Genome Project and Genomic Research................................................................. 127 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 130 Overview.................................................................................................................................... 130 NIH Guidelines.......................................................................................................................... 130 NIH Databases........................................................................................................................... 131 Other Commercial Databases..................................................................................................... 134 APPENDIX C. PATIENT RESOURCES .............................................................................................. 135 Overview.................................................................................................................................... 135 Patient Guideline Sources.......................................................................................................... 135 Finding Associations.................................................................................................................. 138 Resources for Patients and Families........................................................................................... 139 ONLINE GLOSSARIES................................................................................................................ 140 Online Dictionary Directories ................................................................................................... 140 NEUROFIBROMATOSIS TYPE 1 DICTIONARY .................................................................. 141
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INDEX .............................................................................................................................................. 194
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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 neurofibromatosis type 1 is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about neurofibromatosis type 1, 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 neurofibromatosis type 1, from the essentials to the most advanced areas of research. Special attention has been paid to present the genetic basis and pattern of inheritance of neurofibromatosis type 1. 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 neurofibromatosis type 1. 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 neurofibromatosis type 1, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. We hope these resources will prove useful to the widest possible audience seeking information on neurofibromatosis type 1. The Editors
1
From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/.
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CHAPTER 1. STUDIES ON NEUROFIBROMATOSIS TYPE 1 Overview In this chapter, we will show you how to locate peer-reviewed references and studies on neurofibromatosis type 1. For those interested in basic information about neurofibromatosis type 1, we begin with a condition summary published by the National Library of Medicine.
Genetics Home Reference Genetics Home Reference (GHR) is the National Library of Medicine’s Web site for consumer information about genetic conditions and the genes or chromosomes responsible for those conditions. Here you can find a condition summary on neurofibromatosis type 1 that describes the major features of the condition, provides information about the condition’s genetic basis, and explains its pattern of inheritance. In addition, a summary of the gene or chromosome related to neurofibromatosis type 1 is provided.2 The Genetics Home Reference has recently published the following summary for neurofibromatosis type 1:
What Is Neurofibromatosis Type 1?3 Neurofibromatosis type 1 is a condition characterized by changes in skin coloring (pigmentation) and the growth of tumors along nerves in the skin, brain, and other parts of the body. The signs and symptoms of this condition vary widely among affected people. Beginning in early childhood, almost all people with neurofibromatosis type 1 have multiple café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. These spots increase in size and number as the individual grows older. Freckles in the underarms and groin typically develop later in childhood. 2 3
This section has been adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/.
Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/condition=neurofibromatosistype1.
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Neurofibromatosis Type 1
Most adults with neurofibromatosis type 1 develop neurofibromas, which are noncancerous (benign) tumors that are usually located on or just under the skin. These tumors may also occur in nerves near the spinal cord or along nerves elsewhere in the body. Some people with neurofibromatosis type 1 develop cancerous tumors that grow along nerves. These tumors, which usually develop in adolescence or adulthood, are called malignant peripheral nerve sheath tumors. People with neurofibromatosis type 1 also have an increased risk of developing other cancers, including brain tumors and cancer of blood-forming tissue (leukemia). During childhood, benign growths called Lisch nodules often appear in the colored part of the eye (the iris). Lisch nodules do not interfere with vision. Some affected individuals also develop tumors that grow along the nerve leading from the eye to the brain (the optic nerve). These tumors, which are called optic gliomas, may lead to reduced vision or total vision loss. In some cases, optic gliomas have no effect on vision. Additional signs and symptoms of neurofibromatosis type 1 include high blood pressure (hypertension), short stature, an unusually large head (macrocephaly), and skeletal abnormalities such as an abnormal curvature of the spine (scoliosis). Although most people with neurofibromatosis type 1 have normal intelligence, learning disabilities and attention deficit hyperactivity disorder (ADHD) occur frequently in affected individuals.
How Common Is Neurofibromatosis Type 1? Neurofibromatosis type 1 occurs in 1 in 3,000 to 4,000 people worldwide.
What Genes Are Related to Neurofibromatosis Type 1? Mutations in the NF1 (http://ghr.nlm.nih.gov/gene=nf1) gene cause neurofibromatosis type 1. The NF1 gene provides instructions for making a protein called neurofibromin. This protein is produced in many cells, including nerve cells and specialized cells surrounding nerves (oligodendrocytes and Schwann cells). Neurofibromin acts as a tumor suppressor, which means that it keeps cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the NF1 gene lead to the production of a nonfunctional version of neurofibromin that cannot regulate cell growth and division. As a result, tumors such as neurofibromas can form along nerves throughout the body. It is unclear how mutations in the NF1 gene lead to the other features of neurofibromatosis type 1, such as café-au-lait spots and learning disabilities.
How Do People Inherit Neurofibromatosis Type 1? Neurofibromatosis type 1 is considered to have an autosomal dominant pattern of inheritance. People with this condition are born with one mutated copy of the NF1 gene in each cell. In about half of cases, the altered gene is inherited from an affected parent. The remaining cases result from new mutations in the NF1 gene and occur in people with no history of the disorder in their family.
Studies
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Unlike most other autosomal dominant conditions, in which one altered copy of a gene in each cell is sufficient to cause the disorder, two copies of the NF1 gene must be altered to trigger tumor formation in neurofibromatosis type 1. A mutation in the second copy of the NF1 gene occurs during a person's lifetime in specialized cells surrounding nerves. Almost everyone who is born with one NF1 mutation acquires a second mutation in many cells and develops the tumors characteristic of neurofibromatosis type 1.
Where Can I Find More Information about Neurofibromatosis Type 1? You may find the following resources about neurofibromatosis type 1 helpful. These materials are written for the general public. NIH Publications - National Institutes of Health •
National Human Genome Research Institute: http://www.genome.gov/14514225
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National Institute of Neurologic Disorders and Stroke: http://www.ninds.nih.gov/disorders/neurofibromatosis/neurofibromatosis.htm MedlinePlus - Health Information
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Encyclopedia: Neurofibromatosis-1: http://www.nlm.nih.gov/medlineplus/ency/article/000847.htm
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Health Topic: Neurofibromatosis: http://www.nlm.nih.gov/medlineplus/neurofibromatosis.html Educational Resources - Information Pages
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Ask the Geneticist: About neurofibromatosis 1: http://www.askthegen.org/question.php?question_id=33
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California Department of Developmental Services: http://www.ddhealthinfo.org/ggrc/doc2.asp?ParentID=3170
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Centre for Genetics Education: http://www.genetics.com.au/factsheet/40.htm
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Children's Hospital Boston: http://www.childrenshospital.org/az/Site1346/mainpageS1346P0.html
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Cleveland Clinic Health Information Center: http://www.clevelandclinic.org/health/health-info/docs/3600/3699.asp?index=12103
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Genetic Science Learning Center, University of Utah: http://learn.genetics.utah.edu/units/disorders/nf1/
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Harvard Medical School Center for Neurofibromatosis and Allied Disorders: http://www.understandingnf1.org/
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Neurofibromatosis Type 1
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KidsHealth from the Nemours Foundation: http://kidshealth.org/parent/medical/brain/nf.html
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Madisons Foundation: http://www.madisonsfoundation.org/content/3/1/display.asp?did=275
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Mayo Clinic: http://www.mayoclinic.org/neurofibromatosis/
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New York Online Access to Health: http://www.noah-health.org/en/bns/disorders/neuro/
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Orphanet: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=636
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Penn State Children's Hospital: http://www.hmc.psu.edu/childrens/healthinfo/n/neurofibro.htm
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The Merck Manual of Medical Information, Second Home Edition: http://www.merck.com/mmhe/sec06/ch088/ch088d.html
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University of Alabama at Birmingham Neurofibromatosis Center: http://138.26.140.9/aboutnf.htm Patient Support - for Patients and Families
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Children's Tumor Foundation (formerly the National Neurofibromatosis Foundation): http://www.ctf.org/
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Family Village: http://www.familyvillage.wisc.edu/lib_neuf.htm
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March of Dimes: http://www.marchofdimes.com/pnhec/4439_1217.asp
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National Organization for Rare Disorders: http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Neurofibromat osis+Type+1+(NF-1)
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Resource list from the University of Kansas Medical Center: http://www.kumc.edu/gec/support/neurofib.html Professional Resources
You may also be interested in these resources, which are designed for healthcare professionals and researchers. •
Gene Reviews - Clinical summary: http://www.genetests.org/query?dz=nf1
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Gene Tests - DNA tests ordered by healthcare professionals: http://www.genetests.org/query?testid=2125
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Genetic Tools - Teaching cases: http://www.genetests.org/servlet/access?fcn=y&filename=/tools/cases/nf-40/
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ClinicalTrials.gov - Linking patients to medical research: http://clinicaltrials.gov/search/condition=%22neurofibromatosis+type+1%22?recruitin g=false
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Online Books - Medical and science texts: http://books.mcgrawhill.com/getommbid.php?isbn=0071459960&template=ommbid&c=39
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OMIM - Genetic disorder catalog: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=162200
References These sources were used to develop the Genetics Home Reference condition summary on neurofibromatosis type 1. •
Arun D, Gutmann DH. Recent advances in neurofibromatosis type 1. Curr Opin Neurol. 2004 Apr;17(2):101-5. Review. PubMed citation
•
Baralle D, Mattocks C, Kalidas K, Elmslie F, Whittaker J, Lees M, Ragge N, Patton MA, Winter RM, ffrench-Constant C. Different mutations in the NF1 gene are associated with Neurofibromatosis-Noonan syndrome (NFNS). Am J Med Genet A. 2003 May 15;119(1):1-8. PubMed citation
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Cohen, M Michael((Meyer Michael),); Neri, Giovanni; Weksberg, Rosanna; Overgrowth syndromes; New York : Oxford University Press, 2002. p130-151. NLM Catalog
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De Luca A, Bottillo I, Sarkozy A, Carta C, Neri C, Bellacchio E, Schirinzi A, Conti E, Zampino G, Battaglia A, Majore S, Rinaldi MM, Carella M, Marino B, Pizzuti A, Digilio MC, Tartaglia M, Dallapiccola B. NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. Am J Hum Genet. 2005 Dec;77(6):1092-101. Epub 2005 Oct 26. PubMed citation
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GeneReviews
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Hart L. Primary care for patients with neurofibromatosis 1. Nurse Pract. 2005 Jun;30(6):38-43. Review. No abstract available. Erratum in: Nurse Pract. 2005 Jul;30(7):4. PubMed citation
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Huffmeier U, Zenker M, Hoyer J, Fahsold R, Rauch A. A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene. Am J Med Genet A. 2006 Dec 15;140(24):2749-56. PubMed citation
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Kandt RS. Tuberous sclerosis complex and neurofibromatosis type 1: the two most common neurocutaneous diseases. Neurol Clin. 2003 Nov;21(4):983-1004. Review. PubMed citation
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Levine TM, Materek A, Abel J, O'Donnell M, Cutting LE. Cognitive profile of neurofibromatosis type 1. Semin Pediatr Neurol. 2006 Mar;13(1):8-20. Review. PubMed citation
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Reynolds RM, Browning GG, Nawroz I, Campbell IW. Von Recklinghausen's neurofibromatosis: neurofibromatosis type 1. Lancet. 2003 May 3;361(9368):1552-4. Review. No abstract available. PubMed citation
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Rose VM. Neurocutaneous syndromes. Mo Med. 2004 Mar-Apr;101(2):112-6. Review. PubMed citation
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Neurofibromatosis Type 1
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Theos A, Korf BR; American College of Physicians; American Physiological Society. Pathophysiology of neurofibromatosis type 1. Ann Intern Med. 2006 Jun 6;144(11):842-9. Review. No abstract available. PubMed citation
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Tonsgard JH. Clinical manifestations and management of neurofibromatosis type 1. Semin Pediatr Neurol. 2006 Mar;13(1):2-7. Review. PubMed citation
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Ward BA, Gutmann DH. Neurofibromatosis 1: from lab bench to clinic. Pediatr Neurol. 2005 Apr;32(4):221-8. Review. PubMed citation
A summary of the gene related to neurofibromatosis type 1 is provided below:
What Is the Official Name of the NF1 Gene?4 The official name of this gene is “neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease).” NF1 is the gene's official symbol. The NF1 gene is also known by other names, listed below.
What Is the Normal Function of the NF1 Gene? The NF1 gene provides instructions for making a protein called neurofibromin. This protein is produced in many types of cells, including nerve cells and specialized cells called oligodendrocytes and Schwann cells that surround nerves. These specialized cells form myelin sheaths, which are the fatty coverings that insulate and protect certain nerve cells. Neurofibromin acts as a tumor suppressor protein. Tumor suppressors normally prevent cells from growing and dividing too rapidly or in an uncontrolled way. This protein appears to prevent cell overgrowth by turning off another protein (called ras) that stimulates cell growth and division. Other potential functions for neurofibromin are under investigation.
What Conditions Are Related to the NF1 Gene? Neurofibromatosis Type 1 - Caused by Mutations in the NF1 Gene More than 1,000 NF1 mutations that cause neurofibromatosis type 1 have been identified. Most of these mutations are unique to a particular family. Many NF1 mutations result in the production of an extremely short version of neurofibromin. This shortened protein cannot perform its normal job of inhibiting cell division. When mutations occur in both copies of the NF1 gene in Schwann cells, the resulting loss of neurofibromin allows noncancerous tumors called neurofibromas to form. Research indicates that the formation of neurofibromas requires the interaction of Schwann cells with other cells, including mast cells. Mast cells are normally involved in wound healing and tissue repair.
4
Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=nf1;jsessionid=E6E45A9C43E9D04742BAB4B116336832.
Studies
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Cancers - Associated with the NF1 Gene More than 1,000 NF1 mutations that cause neurofibromatosis type 1 have been identified. Most of these mutations are unique to a particular family. Many NF1 mutations result in the production of an extremely short version of neurofibromin. This shortened protein cannot perform its normal job of inhibiting cell division. When mutations occur in both copies of the NF1 gene in Schwann cells, the resulting loss of neurofibromin allows noncancerous tumors called neurofibromas to form. Research indicates that the formation of neurofibromas requires the interaction of Schwann cells with other cells, including mast cells. Mast cells are normally involved in wound healing and tissue repair.
Where Is the NF1 Gene Located? Cytogenetic Location: 17q11.2 Molecular Location on chromosome 17: base pairs 26,446,242 to 26,725,589
The NF1 gene is located on the long (q) arm of chromosome 17 at position 11.2. More precisely, the NF1 gene is located from base pair 26,446,242 to base pair 26,725,589 on chromosome 17.
References These sources were used to develop the Genetics Home Reference gene summary on the NF1 gene. •
Arun D, Gutmann DH. Recent advances in neurofibromatosis type 1. Curr Opin Neurol. 2004 Apr;17(2):101-5. Review. PubMed citation
•
Carroll SL, Stonecypher MS. Tumor suppressor mutations and growth factor signaling in the pathogenesis of NF1-associated peripheral nerve sheath tumors: II. The role of dysregulated growth factor signaling. J Neuropathol Exp Neurol. 2005 Jan;64(1):1-9. Review. PubMed citation
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Carroll SL, Stonecypher MS. Tumor suppressor mutations and growth factor signaling in the pathogenesis of NF1-associated peripheral nerve sheath tumors. I. The role of
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Neurofibromatosis Type 1
tumor suppressor mutations. J Neuropathol Exp Neurol. 2004 Nov;63(11):1115-23. Review. PubMed citation •
Cooper LJ, Shannon KM, Loken MR, Weaver M, Stephens K, Sievers EL. Evidence that juvenile myelomonocytic leukemia can arise from a pluripotential stem cell. Blood. 2000 Sep 15;96(6):2310-3. PubMed citation
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Dasgupta B, Gutmann DH. Neurofibromatosis 1: closing the GAP between mice and men. Curr Opin Genet Dev. 2003 Feb;13(1):20-7. Review. PubMed citation
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Gutmann DH. Neurofibromin in the brain. J Child Neurol. 2002 Aug;17(8):592-601; discussion 602-4, 646-51. Review. PubMed citation
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Gutzmer R, Herbst RA, Mommert S, Kiehl P, Matiaske F, Rutten A, Kapp A, Weiss J. Allelic loss at the neurofibromatosis type 1 (NF1) gene locus is frequent in desmoplastic neurotropic melanoma. Hum Genet. 2000 Oct;107(4):357-61. PubMed citation
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Kluwe L, Friedrich RE, Korf B, Fahsold R, Mautner VF. NF1 mutations in neurofibromatosis 1 patients with plexiform neurofibromas. Hum Mutat. 2002 Mar;19(3):309. PubMed citation
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Korf BR. Clinical features and pathobiology of neurofibromatosis 1. J Child Neurol. 2002 Aug;17(8):573-7; discussion 602-4, 646-51. Review. PubMed citation
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Korf BR. Malignancy in neurofibromatosis type 1. Oncologist. 2000;5(6):477-85. Review. PubMed citation
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Lauchle JO, Braun BS, Loh ML, Shannon K. Inherited predispositions and hyperactive Ras in myeloid leukemogenesis. Pediatr Blood Cancer. 2006 May 1;46(5):579-85. Review. PubMed citation
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Packer RJ, Gutmann DH, Rubenstein A, Viskochil D, Zimmerman RA, Vezina G, Small J, Korf B. Plexiform neurofibromas in NF1: toward biologic-based therapy. Neurology. 2002 May 28;58(10):1461-70. Review. PubMed citation
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Reed N, Gutmann DH. Tumorigenesis in neurofibromatosis: new insights and potential therapies. Trends Mol Med. 2001 Apr;7(4):157-62. Review. PubMed citation
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Trovo-Marqui AB, Tajara EH. Neurofibromin: a general outlook. Clin Genet. 2006 Jul;70(1):1-13. Review. PubMed citation
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Trovo-Marqui AB, Tajara EH. Neurofibromin: a general outlook. Clin Genet. 2006 Jul;70(1):1-13. Review. PubMed citation
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Viskochil DH. It takes two to tango: mast cell and Schwann cell interactions in neurofibromas. J Clin Invest. 2003 Dec;112(12):1791-3. Review. PubMed citation
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Ward BA, Gutmann DH. Neurofibromatosis 1: from lab bench to clinic. Pediatr Neurol. 2005 Apr;32(4):221-8. Review. PubMed citation
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Yang FC, Ingram DA, Chen S, Hingtgen CM, Ratner N, Monk KR, Clegg T, White H, Mead L, Wenning MJ, Williams DA, Kapur R, Atkinson SJ, Clapp DW. Neurofibromindeficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells. J Clin Invest. 2003 Dec;112(12):1851-61. PubMed citation
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Yohay KH. The genetic and molecular pathogenesis of NF1 and NF2. Semin Pediatr Neurol. 2006 Mar;13(1):21-6. Review. PubMed citation
Studies
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Federally Funded Research on Neurofibromatosis Type 1 The U.S. Government supports a variety of research studies relating to neurofibromatosis type 1. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.5 CRISP (Computerized Retrieval of Information on Scientific Projects) CRISP is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to neurofibromatosis type 1. 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 neurofibromatosis type 1. The following is typical of the type of information found when searching the CRISP database for neurofibromatosis type 1: •
Project Title: ADVANCED NEUROFIBROMATOSIS
MOLECULAR
DIAGNOSTIC
TEST
FOR
Principal Investigator & Institution: Gite, Sadanand; Director; Ambergen, Inc. 100 Beaver Street Waltham, Ma 02453 Timing: Fiscal Year 2005; Project Start 15-SEP-2005; Project End 30-SEP-2007 Summary: (provided by applicant): Neurofibromatosis (NF) is an autosomal dominant disorder caused by mutations in the NF1 and NF2 genes. Currently, more than 100,000 Americans suffer from NF type 1 (NF1) which has one of the highest prevalence rates for a genetic disease (1/3,500 births). NF1 is caused by mutations in the NF1 gene which codes for the tumor suppressor protein neurofibromin. Most mutations (>80%) are chain truncating and generally result in inactive proteins. The preferred method to detect such mutations is the Protein Truncation Test (PTT). However, conventional PTT has many disadvantages for routine clinical use. For this reason, current diagnosis is based on established clinical symptoms. The objective of this proposal is to develop a costeffective technology to screen for mutations in the NF1 gene. This will provide significant benefit to public health by identifying earlier and more reliably persons suffering from NF1 and aligns with the mission of the NINDS. Two different methods will be developed and evaluated which are both based on in vitro expression of peptides from overlapping segments of PCR amplified NF1 genomic DMA and mRNA. One approach utilizes a newly developed ELISA-based protein truncation test (ELISA-PTT) to detect chain-truncations arising mainly from frame-shift mutations, which constitute greater than 80% of all mutations in NF1. In contrast to conventional protein truncation tests, ELISA-PTT eliminates the need for electrophoresis and radioactivity. A second approach, based on mass spectrometric analysis of in vitro expressed proteins (MASSIVE-PRO) is able to scan for all possible mutations, including amino acid substitutions. A key to this approach is the development of an in vitro expression 5
Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
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system which has very low levels of proteolytic activity. Preliminary studies by us demonstrate that both approaches are feasible and can offer a very low cost and high throughput alternative to full DMA sequencing. The technology will be extensively evaluated in collaboration with Dr. Ludwine Messiaen, Director of Genomics at the University of Alabama using a repository of validated genomic DNA and mRNA samples from NF1 patients. During Phase II, an optimized system for screening NF1 mutations will be developed and clinically evaluated. •
Project Title: ANIMAL MODEL OF TRANSMISSABLE NEUROFIBROMAS Principal Investigator & Institution: Schmale, Michael C.; Associate Professor; University of Miami-Rosenteil School 4600 Rickenbacker Causeway Miami, Fl 33149 Timing: Fiscal Year 2006; Project Start 08-JUL-1998; Project End 28-FEB-2007 Summary: A unique animal system , damselfish, neurofibromatosis (DNF), will be used to address basic questions in the pathogenesis of neurofibromas, malignant peripheral nerve sheath tumors and chromatophoromas. Investigation of the mechanisms controlling alterations of Schwann cells, perineurial cells and axons during the development of peripheral nerve sheath tumors in humans could be greatly facilitated by the use of an animal model in which these tumors and the neoplastic process could be manipulated experimentally, both in vivo and in vitro. DNF is caused by an unusual, transmissible, virus-like agent, the damselfish-virus like agent (DVLA), and appears to be the only naturally occurring example of a transmissible tumor involving any neuroectodermally the only naturally occurring example of a transmissible tumor involving any neuroectodermally derived cell type. Thus, this model system provides a unique opportunity for experimental manipulation of this carcinogenic process at many levels. Ongoing research on DNF will address hypotheses relevant to a complete characterization of this agent and its relationship to neoplastic transformation of these neuroectodermal cell types through four interrelated aims: (1) The complete sequence and transcriptional pattern of DVLA will be documented and infectious clones of the DVLA genome will be created. (2) The status of DVLA replication in tumors and infected non-tumor cell types from diseased fish will be determined in vivo and in vitro. (3) Factors controlling replication, transcription, translation and production of infectious material in vitro will be identified by manipulating cell lines chronically infected with DVLA and developing infection assay systems. These systems will also be used to assess the tumorigenicity of isolates of this agent in vivo. (4) The full range of proteins expressed by DVLA will be identified and antibodies developed to selected viral proteins. The proposed studies should yield information on mechanisms of tumor development in the peripheral nervous system applicable to understanding these processes in human disorders such as neurofibromatosis type 1.
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Project Title: CELL SIGNALING AND DENDRITIC SPINE PLASTICITY Principal Investigator & Institution: Wu, Gang-Yi; Assistant Professor; Molecular Physiology & Biophysics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2006; Project Start 01-FEB-2006; Project End 31-DEC-2009 Summary: (provided by applicant): Neurofibromatosis type 1 (NF1) is a common dominant genetic disorder characterized by multiple benign and malignant tumors of neural origin and, often, cognitive deficits in children. The protein encoded by NF1, neurofibromin, contains a GAP domain, known to inhibit Ras-mediated signal transduction, a pathway known to be required for both memory consolidation and longterm neuronal plasticity. The long-term goal of our research is to delineate the cellular
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mechanisms and signal transduction pathways underlying dendritic spine formation and plasticity. This proposal will test the hypothesis that NF1 plays an essential role in dendritic spine formation and plasticity by serving as a negative regulator for Ras (and MARK) signaling. Our specific aims are to: 1) determine if NF1 deficiency leads to deficits in the formation and maturation of dendritic spines; 2) determine if NF1 deficiency leads to deficits in synapse formation and synaptic function; 3) determine if NF1 deficiency leads to hyperactive Ras-MAPK signaling; and 4) determine if NF1deficient cells have an altered capacity to undergo morphological plasticity after spaced depolarizing stimuli, and whether the deficits in morphology can be rescued by manipulating Ras-MAPK signaling. Multidisciplinary approaches, including time-lapse imaging confocal microscopy, molecular imaging with FRET, quantitative immunocytochemistry, whole-cell patch-clamp recording, genetic mouse models, and pharmacological and molecular manipulations such as dominant negative constructs and small interfering RNAs (siRNAs), will be used to define the NF1 function in synapse formation and morphogenesis of dendritic spines. The combination of structural and functional analyses with the assessment of the underlying signal transduction mechanisms at the single cell level should provide better new insights into NF1 function in neurons and will shed light on the mechanism by which dysregulation of this function leads to cognitive deficits in NF1 patients. •
Project Title: CELLULAR ASTROCYTOMA
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Principal Investigator & Institution: Zhu, Yuan; Internal Medicine; University of Michigan at Ann Arbor 3003 South State Street, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2006; Project Start 01-JUL-2006; Project End 31-MAY-2011 Summary: (provided by applicant): Astrocytomas are the most common primary brain tumors and account for more than 60% of all primary central nervous system (CMS) neoplasms. The most malignant form of astrocytoma (grade IV astrocytoma), also known as glioblastoma multiforme (GBM), is 1 of the most aggressive human cancers with a median survival of less than 1 year. Unfortunately, this prognosis has not changed significantly over the past 2 decades, despite advances in neurosurgery, radiation and chemotherapy. 2 characteristic features of malignant astrocytomas play a major role in defining the deadly nature of the disease. First, unlike most human solid tumors, astrocytoma cells extensively invade normal brain tissue even at the low-grade stage, which essentially prevents surgical cure. Second, low-grade astrocytomas have a high propensity to transform into GBMs, which are resistant to all of the current therapeutic modalities. Thus, 1 of the major challenges for treating malignant astrocytomas is to understand the cellular and molecular basis that underlies the highly invasive nature of astrocytoma cells. Particularly, (1) it remains elusive what cell type(s) in the brain gives rise to malignant astrocytoma, (2) insights have been slower to emerge regarding how the specific genetic defects contribute to the abnormal phenotypic traits of astrocytoma cells, despite recent advances in the identification of genetic lesions associated with the development of malignant astrocytomas. Thus, the goals of the specific aims described in this proposal is to use genetic, molecular and cellular approaches to determine whether neural stem cells (NSCs) in the adult brain are the cell-of-origin for malignant astrocytoma. Specifically, we will determine (1) whether tumor suppressors p53 and Neurofibromatosis type 1 (NF1) play physiological roles in regulating NSC proliferation, apoptosis and differentiation in the adult brain and (2) whether malignant astrocytoma can be induced when p53 and NF1 mutations are specifically targeted into NSCs in the adult brain.
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Project Title: COMPREHENSIVE NF1 MUTATIONAL ANALYSIS IN LEUKEMIA CELLS Principal Investigator & Institution: Messiaen, Ludwine Maria.; Genetics; University of Alabama at Birmingham 1530 3Rd Avenue South Birmingham, Al 35294 Timing: Fiscal Year 2005; Project Start 30-SEP-2005; Project End 31-AUG-2007 Summary: (provided by applicant): Juvenile myelomonocytic leukemia (JMML) is a clonal, mixed myeloproliferative/myelodysplastic disorder afflicting young children. Children with neurofibromatosis type 1 have a 500 fold increased incidence of developing JMML. Since 1986 a team of investigators at the University of Alabama at Birmingham (UAB) have been conducting translational research studies in JMML. The UAB team consists of a blend of investigators in basic science and clinical investigations and this mix has allowed this team to play significant leading roles spanning the breadth of JMML research, from basic science pathogenesis investigations, to translational investigations, to clinical protocols and registries. The pathogenesis of JMML has been linked to dysregulated GM-CSF growth factor signal transduction through the Ras signaling pathway, resulting in GM-CSF hypersensitivity, a hallmark of the disease. Potential causative mutations or other genetic abnormalities in three genes, RAS, NF1, and PTPN11, all of which are positioned in the GM-CSF signal transduction pathway appear to account for up to 75% of cases of JMML. These gene abnormalities, approximately 20% for RAS, approximately 25% for NF1, and approximately 30% for PTPN11, appear to be mutually exclusive suggesting that any one abnormality is sufficient for causation. The approximately 25% estimation of NF1 gene abnormalities is based on the utilization of loss of heterozygosity assays and in vitro transcription/translation assays from primary patient samples and EBV-transformed cell lines derived from these samples. Dr. Messiaen is a new recruit to UAB from Belgium where she developed more comprehensive methodologies for NF1 mutation analysis beyond the above-described assays. Further, she has developed new techniques, which obviate the need for EBVcell line generation. The major hypothesis of this proposal is that the estimated 25% incidence of NF1 mutations in JMML may be inaccurately low, and that additional NF1 mutations can be found in the group of JMML patients previously categorized as no known genetic mutation. Patient material to test this hypothesis, and to develop more efficient methodologies which obviate the need for EBV lines, will be obtained from the currently active Children's Oncology Group protocol for JMML. This is a multi-institutional Cooperative Group trial sponsored by the NCI, which is seeking to determine if genetic differences in JMML predict for different prognoses, and/or varying responses to the targeted therapeutics being tested.
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Project Title: CONNECTING PTEN AND NF2 CANCER PREDISPOSITION SYNDROMES Principal Investigator & Institution: Georgescu, Maria-Magdalena; Neuro-Oncology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009 Timing: Fiscal Year 2005; Project Start 12-SEP-2005; Project End 30-JUN-2010 Summary: (provided by applicant): Cancer predisposition syndromes are autosomal dominantly inherited conditions in which the affected individuals have a high relative risk for developing cancer. PTEN and neurofibromatosis-2 (NF2) are tumor suppressors that are inactivated in both somatic cancers and in cancer predisposition syndromes that belong to a clinically defined group (phakomatoses). The mechanism for tumor suppression is known only for PTEN and relies on its ability to dephosphorylate phosphoinositides and antagonize the growth promoting effects of the phosphatidylinositol-3 OH (PI-3) kinase. The regulation of both PTEN and NF2 (merlin)
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is not yet understood, but it appears to depend on the recruitment of both proteins to the plasma membrane and on their phosphorylation. In spite of the similarities between these tumor suppressors, no previous study attempted to link them in a common pathway. The broad objective of this project is to characterize a molecular connection between PTEN and NF2 tumor suppressors. The new finding that PTEN associates with an adaptor molecule that was previously shown to bind to NF2 will constitute the major focus of this study. The detailed project attempts to cover the following topics: (1) the role of the adaptor molecule in cell growth and migration of cultured gene-deficient cells, and in tumor formation and metastasis in the gene-deficient animals already generated in the laboratory; (2) the analysis of the complex between the three molecules in terms of specific binding affinities, size of the complex by gel filtration and membrane co-localization by density gradient fractionation and immunofluorescence; and (3) interrelations in regulation and signaling between PTEN and NF2 in terms of phosphorylation, stability, Akt/PKB kinase and Rac GTP-ase activation. Finding a common molecular link between PTEN and NF2 tumor suppressors that determine similar cancer predisposition syndromes and are frequently inactivated in brain cancer is fundamental to the understanding of the pathogenesis of cancer and constitutes the basis of a targeted cancer therapy. •
Project Title: DYNAMIC REGULATION OF RAS VIA THE NF1 TUMOR SUPPRESSOR Principal Investigator & Institution: Cichowski, Karen M.; Brigham and Women's Hospital Research Administration Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 01-JUL-2005; Project End 30-JUN-2010 Summary: (provided by applicant): Neurofibromatis type I is a prevalent familial cancer syndrome affecting 1 in 3500 individuals worldwide. Loss-of-function mutations in NF1 tumor suppressor gene underlie the disease. The NF1-encoded protein, neurofibromin, has been shown to function as a Ras-GTPase activating protein (GAP); however, little is known about how its activity is normally regulated or its precise role in controlling Ras signaling pathways. We have recently identified the first mechanism known to regulate neurofibromin. We found that it is rapidly degraded by the proteasome following growth factor treatment and is subsequently re-elevated to turn off Ras. In our unpublished studies we have further observed that the re-synthesized protein is phosphorylated. Because neurofibromin phosphorylation occurs precisely as Ras becomes inactivated, we hypothesize that phosphorylation may enhance neurofibromin function to acutely terminate the Ras signal. This hypothesis is supported by a variety of genetic and biochemical evidence. Our data also suggest that ERK is the regulatory kinase. Therefore, this event may represent a normal negative feedback loop that is required for proper termination of Ras signaling pathways. In the first aim we will determine the functional consequences of neurofibromin phosphorylation and firmly establish whether ERK is the regulatory kinase in vivo. In the second aim we will determine the biological significance of neurofibromin phosphorylation in a mouse model system and in cell lines expressing the phospho-mutant protein. Finally, we have also identified a novel neurofibromin interacting protein. Because it was isolated under conditions in which neurofibromin is phosphorylated, we will determine the role of phosphorylation in mediating this interaction in Aim 3. Regardless, we will molecularly dissect this interaction and test its involvement in neurofibromin function. Importantly, this avenue of investigation may enable us to identify the first new function for NF 1 in over a decade. Collectively, these aims will serve to dramatically increase our knowledge about the regulation and function of the NF1 tumor suppressor. They will also greatly contribute to our understanding of the mechanisms governing appropriate
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Ras attenuation and the biological importance of this fine-tuned regulation. As a result these findings may ultimately impact future therapeutic strategies for NF1 and non-NF1 related tumors. •
Project Title: GENETIC DISSECTION OF TUMOR PROGRESSION IN NF-1 AML Principal Investigator & Institution: Wallace, Margaret R.; Professor; Molecular Genetics & Microbiol; University of Florida 219 Grinter Hall Gainesville, Fl 32611 Timing: Fiscal Year 2005; Project Start 01-MAY-2002; Project End 30-APR-2007 Summary: (provided by applicant) Juvenile myelomonocytic leukemia (JMML) is a disease that occurs in young children and is associated with a high mortality rate. In most patients, JMML has a progressive course leading to death by virtue of infection, bleeding or progression to acute myeloid leukemia (AML). As it is known that children with Neurofibromatosis type 1 (NF1) have a markedly increased risk of developing JMML, we were able to develop a mouse model of JMML by reconstituting lethally irradiated mice with hematopoetic stem cells homozygous for a loss of function mutation in the Nfl gene. In the course of these experiments, we found that all these genetically identical reconstituted mice developed a JMML-like disorder, but only a subset went on to develop more acute disease. This result strongly suggests that additional genetic lesions are responsible for disease progression. The focus of this proposal is to identify these additional genetic lesions as a means to better understand leukemic progression. Toward this goal, we have placed the Nf1 mutation on the BXH-2 mouse genetic background, a strain known to contain a somatically infectious ecotropic retrovirus. Using this powerful somatic mutagenesis system, we have identified three common ecotropic proviral integration (Epi) sites. We hypothesize that these Epi sites will allow identification of genes that are involved in myeloid tumor progression. We have four specific aims: Specific Aim 1:Determine if viral integration at the Epil site leads to deregulation of the c-myb gene. Specific Aim 2:Characterize the gene interrupted by viral integrations at the Epi2 locus. Specific Aim 3: Characterize the gene interrupted by viral integrations at the Epi3 locus. Specific Aim 4: Identify additional Epi sites involved in tumor progression of JMML.
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Project Title: GENOMICS OF PEDIATRIC HEADACHE DISORDERS Principal Investigator & Institution: Hershey, Andrew D.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2005; Project Start 15-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): This project will examine gene expression in the blood of patients with migraine. We have used microarrays to show that there are unique blood genomic profiles in rats following ischemia, hemorrhage, status epilepticus, and insulin-induced hypoglycemia. Recent results in humans demonstrate that gender and age have profound effects on blood genomic expression, with genes on the Y-chromosome distinguishing male from female blood samples, and lymphocytespecific genes decreasing with older age. We have also shown a specific blood genomic profile for Neurofibromatosis type 1, an autosomal dominant disease. We postulated that migraine, a non-Mendelian, hereditary disease, will have a specific blood genomic profile. Indeed, our preliminary data demonstrate that children with both acute, episodic, migraine headaches and children with chronic daily headaches have specific blood genomic profiles that are similar to each other but different from control children with other neurological diseases or to healthy controls. This proposal is designed to confirm these initial findings, and to determine whether acute migraine and chronic daily headache patients have similar or different blood genomic profiles, and whether
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there is a different blood genomic profile in patients that respond to NSAIDs (nonsteroidal anti-inflammatory drugs) compared to those patients that require triptans as rescue medication. The study involves taking blood samples from patients with migraine and chronic daily headaches during the headaches and during headache free intervals (internal control), and comparing these to control patients without migraine or a family history of migraine. RNA from whole blood is isolated, labeled and applied to human oligonucleotide microarrays that survey most of the human genome. Recently developed statistical programs are used to identify potential transcripts regulated in headache compared to control patients. Quantitative, real time RT-PCR will be used to confirm these regulated genes in each of the comparisons. The results of this study should help in beginning to develop a molecular genomic approach for the diagnosis and treatment of different headache disorders. •
Project Title: GROWTH FACTOR-INDUCED PERIPHERAL GLIOGENESIS Principal Investigator & Institution: Pizzo, Donald P.; Veterans Medical Research Fdn/San Diego Foundation of San Diego San Diego, Ca 92161 Timing: Fiscal Year 2005; Project Start 01-JUN-2004; Project End 30-APR-2008 Summary: (provided by applicant): Neurofibromatosis Type 1 and Type 2 (NF1 and NF2) are phenotypically related yet genotypically distinct cancers of the nervous system which share the proliferation of Schwann cells adjacent to the spinal cord. Thus, the dorsal root ganglion (DRG) and associated nerve root are an active locus of Schwann cell proliferation in both NF1 and NF2 and provides an ideal location to study mechanisms shared by the Neurofibromatoses. Administration of nerve growth factor (NGF) results in abnormal proliferation of Schwann and satellite cells within and adjacent to the DRG. Long-term infusion in rats leads to Schwann cell hyperplasia that invades the central nervous system similar to hamartomas in NF. Infusion of NGF for 2 weeks results in a massive increase in Schwann cells detected by using bromodeoxyuridine (BrdU) to label dividing cells. Quantitative assessment of proliferation with BrdU immunohistochemistry using unbiased stereology indicates a greater than 2-fold increase in Schwann cells in the trigeminal ganglia and DRG. This proliferation models one aspect of both NF1 and NF2 and thus may serve as a novel method to quantitatively assess the role of different growth factors receptor signaling cascades in tumor progression. The underlying theme of this proposal is that growth factor induced proliferation of peripheral glia cells offers a model of Schwann cell tumors found in NF1 and NF2. Using quantitative immunohistochemical methods, the signaling cascades, which regulate glia proliferation, can be investigated in an in vivo model. To study growth factor-induced Schwann cell proliferation as a quantitative model of the neurofibromatoses, three aims are proposed: 1) identify which receptor system of the growth factors is critical for Schwann cell proliferation by comparing infusions of different neurotrophins (NT) and secondly by infusing the optimal NT in NT receptor knockout mice, 2) determine the molecules involved in tumor development and the CNS invasion of these cells by combining infusions of NT and meningeal cell mitogens, and in parallel profiling molecules involved in breach of the CNS, and 3) investigate second messenger systems wherein neurotrophin receptors signals impinge upon either merlin or neurofibromin by infusing NT into NF1 or NF2 transgenic mice, and secondly by administering inhibitors of the growth factor cascades. These studies will elucidate the mechanisms and signaling pathways through which growth factors play a role in Schwann cell proliferation and impinge upon the proteins mutated in NF1 and NF2. Furthermore, the development of a quantitative tumor model allows for the assessment of small molecule therapeutics in a pre-clinical setting.
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Project Title: IDENTIFYING THERAPEUTIC TARGETS FOR MPNST Principal Investigator & Institution: Miller, Shyra J.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2005; Project Start 18-MAY-2005; Project End 28-FEB-2008 Summary: (provided by applicant): This application requests support for a promising young investigator in Neurofibromatosis Type 1 (NF1). The candidate's long-term career goal is to oversee an academic research lab aimed at delineating a molecular model of tumor progression in NF1, guiding therapeutic strategies. The training objectives of this proposal are to provide: 1) contemporary training in bioinformatics, statistics, and research ethics, 2) experience handling large amounts of gene expression microarray data, 3) sufficient preliminary data to develop an independent research program, 4) contacts and collaborations with other investigators in the fields of Neurofibromatosis, Pharmacogenomics, and Translational Neuroscience. The mentors, Dr. Nancy Ratner and Dr. Bruce Aronow, have carefully designed a career development plan including courses, research, and participation in scientific meetings. Dr. Ratner's expertise in Neurofibromatosis, Dr. Aronow's expertise in Bioinformatics, and the interdisciplinary environment of the Cincinnati Children's Hospital Research Foundation will provide the candidate with an exceptional environment to achieve these goals. The research objective of this proposal is to test the hypothesis that global gene expression analysis of tumor cells by microarray technology identifies therapeutic targets for malignant peripheral nerve sheath tumors (MPNST). MPNST is an aggressive cancer with poor prognosis that occurs at a high frequency and mortality in patients with NF1. Preliminary comparison of gene expression profiles of 2 sporadic and 6 NF1associated MPNST cell lines to 7 normal Schwann cell samples and a panel of 45 primary MPNST samples resulted in the identification of a molecular signature for malignant transformation of Schwann cells. One gene consistently overexpressed in MPNST samples, TWIST, is a transcription factor that can cause tumor cell chemoresistance. Another gene, matrix metalloproteinase 1 (MMP1), can cause tumor cell invasion and was dramatically overexpressed in a subset of MPNST. Specific research aims of this proposal are to: 1) confirm the 67 gene MPNST expression signature, and identify additional gene signatures, characteristic of subsets of MPNST; 2) test the hypothesis that TWIST contributes to MPNST chemo-resistance; 3) test the hypothesis that MMP1 contributes to MPNST invasion and 4) test the hypothesis that an effective therapeutic agent would normalize gene expression in MPNST cell lines, a pilot pharmacogenomics study.
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Project Title: MECHANISM OF INV(16) MEDIATED LEUKEMOGENESIS Principal Investigator & Institution: Hiebert, Scott W.; Professor, Department of Biochemistry; Biochemistry; Vanderbilt University Medical Center Nashville, Tn 372036869 Timing: Fiscal Year 2006; Project Start 01-JUN-2000; Project End 30-APR-2010 Summary: (provided by applicant): The inv(16) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML). This translocation fuses the promoter and most of the gene encoding the enhancer core binding factor-6 (CBFB) to MYH11, which encodes a smooth muscle myosin heavy chain to create the inv(16) fusion grotein (the "IFF"). CBFB acts as a co-factor for the RUNX1 transcription factor and the IFF stimulates RUNX1-dependent transcriptional repression. We found that the IFF contains a C-terminal repression domain that associates with the mSinSA corepressor and histone deacetylase 8 (HDAC8) and that it cooperates with RUNX1 to repress the transcription of genes such as the pi4ARF tumor suppressor. Given that we
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also demonstrated that RUNX1 recruits mSin3A and HDACs, we hypothesize that the IFF traps RUNX1 in a complex with co-repressors and HDACs to create a dominant repressor of RUNX1-regulated genes. To test this hypothesis, we have developed a mouse model of inv(16)-induced AML that uses recombinant retroviruses to express the IFF in hematopoietic stem cells. While murine hematopoiesis is somewhat different that human hematopoiesis, the leukemia that the IFF induces in mice contains many of the hallmarks of the human inv(16)-related myelomonocytic AML. Importantly, the IFF repression domain, which contains the mSinSA and HDACS binding sites, is required for the in vivo action of the inv(16) in leukemogenesis. Because this mouse model is ideal for structure/function analyses, a major goal of this proposal is to identify the functional domains of the IFF that are required for leukemogenesis in vivo. Also, because the repression domain is a key functional domain, we will further dissect this domain to define the sequences that contribute to transcriptional repression and myeloid cell transformation. This includes determining the 3 dimensional structure of the minimal transcriptional repression domain of the IFF. Finally, we will use this mouse model to address fundamental questions as to how this chromosomal translocation causes acute leukemia, including whether continued expression of the IFF is required to maintain the leukemic phenotype. This information is critical for the future development of therapeutic approaches that target the IFF. By combining structural biology, biochemistry, and mouse a model, we anticipate collaborative synergy and expect rapid progress that may be quickly translated into novel therapeutic approaches. •
Project Title: MECHANISMS FOR NEUROLOGICAL DYSFUNCTION IN NF1 Principal Investigator & Institution: Mody, Istvan; Neurobiology; University of California Los Angeles Office of Research Administration Los Angeles, Ca 90024 Timing: Fiscal Year 2006; Project Start 04-SEP-1998; Project End 31-DEC-2007 Summary: (provided by applicant): Specific learning disabilities are the most common neurological complication in children with neurofibromatosis type I (NF1), a disorder affecting 1/4000 people world-wide. This genetic disease is caused by mutations in the NF1 gene which encodes neurofibromin, a Ras GTPase activating protein that is highly expressed in the brain. Our studies of mice mutant for the neurofibromin gene (Nf1+/- ) indicated that these mutants showed enhanced GABAA-mediated inhibition, deficits in long-term potentiation (LTP) and in spatial learning. In this application we propose to test the hypotheses that the spatial learning deficits of mice with an heterozygous-null germ-line Nf1 mutation (Nf1+/- mice), that model closely the human condition, are due to enhanced inhibition (either because of pre- or post-synaptic changes) that leads to deficits in LTP and subsequently to abnormalities in learning. We propose to pin-point both the cellular mechanism by which the Nf1+/- mutation affects inhibition, plasticity and learning and the brain region(s) affected by this mutation. To accomplish this we will use transgenic mice with cell-type (inhibitory or excitatory neurons) restricted deletions of Nf1, Adeno-Associated Virus type 2 Cre-recombinase (AAV-Cre) driven and region-specific (hippocampus, prefrontal cortex) deletions of Nf1, as well as a number of pharmacological, electrophysiological and behavioral tools. The specific aims of this proposal are: SPECIFIC AIM #1 - To determine whether deletions of Nf1 in either hippocampus or prefrontal cortex can account for the learning deficits of the Nf1 mutant mice. SPECIFIC AIM #2- To determine the critical cellular locus for neurofibromin's role in learning and memory. SPECIFIC AIM #3 - To determine how neurofibromin affects GABA-mediated inhibition and LTP. Although there is a great deal of data that implicate Ras/MAPK signaling in plasticity and learning, it is still unclear how this signaling pathway modulates these complex processes. The studies proposed here will
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further our understanding of the role of neurofibromin/Ras/MAPK signaling in the modulation of GABA-mediated inhibition, LTP and learning. Importantly, they will also be crucial for developing targeted treatments for the debilitating learning disabilities associated with Neurofibromatosis Type I. •
Project Title: MITOGENIC ACTIVITIES IN NEUROFIBROMATOSIS Principal Investigator & Institution: Ratner, Nancy; Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2006; Project Start 01-AUG-1990; Project End 31-JAN-2011 Summary: (provided by applicant): Individuals with neurofibromatosis type 1 (NF1) carry mutations in the NF1 tumor suppressor and develop benign peripheral nerve sheath tumors called neurofibromas. Neurofibromas contain normal nerve constituents: axons, Schwann cells, fibroblasts, and mast cells, as well as increased numbers of mast cells, excessive collagen, and Schwann cells free of axons. Tumorigenesis results from complete loss of function at NF1, as neurofibromas are characterized by biallelic mutations in tumor Schwann cells. Other cell types may be recruited secondarily. We developed a mouse model system for Schwann cell tumorigenesis in NF1, and identified aberrant expression of epidermal growth factor receptor in this model. EGFR also shows increased expression in human tumor samples. We expressed EGFR in transgenic mouse Schwann cells reproducing early phases of neurofibroma formation in mice including Schwann cell migration from axons, attraction of mast cells to peripheral nerve, and fibrosis. These models provide unique opportunities to study early events in peripheral nerve tumorigenesis. In this application we propose to use cell culture systems to test when in development EGFR expression generates a tumorigenic cell, and to characterize a human EGFR-expressing Schwann cell within neurofibromas. Finally, we will define cellular changes secondary to EGFR expression in the new transgenic model, focusing on the effects of mast cell recruitment. Together, these studies will identify cellular and molecular underpinnings of tumor formation in the nervous system, and identify therapeutic targets for the treatment of NF1.
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Project Title: MLK3 FUNCTION IN NEUROFIBROMATOSIS TUMOR CELLS Principal Investigator & Institution: Kyriakis, John M.; Professor; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2005; Project Start 01-JUL-2005; Project End 30-APR-2010 Summary: (provided by applicant): The predisposition of type 1 and 2 neurofibromatosis (NF1 and NF2, respectively) patients to both benign and malignant nerve sheath, myeloid cell and other cancers represents for these diseases the principal cause of morbidity and mortality. The effective treatment of these tumors represents a major unmet medical need. NF1 and NF2 are genetic loss of function diseases in which the cognate genes, NF1 and NF2 are subject to a broad suite of inactivating mutations or truncations. Given this genetic heterogeneity, coupled with the loss of function phenotype, targeting or exploiting neurofibromin (the product of NF1) or merlin (the product of NF2) as a therapeutic approach is impractical. By contrast, neurofibromin is a Ras inactivator, and ongoing work indicates that blunting Ras signaling could be beneficial to the treatment of NF1 tumors insofar as inhibition of Ras itself, or inhibition of Ras effectors such as the extracellular signal-regulated kinase (ERK) group of mitogen-activated protein kinases (MAPKs) can significantly blunt NF1 cell proliferation. In a somewhat similar vein, merlin, by an unknown mechanism, suppresses signaling by the Jun-N-terminal kinase (JNK), and possibly the ERK MAPKs. However, the biological consequences of merlin-mediated inhibition of JNK is unclear;
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and overall, our knowledge of MAPK pathway regulation and function in NF1 and NF2 tumor cell biology is incomplete. Clearly, further studies are needed to identify suitable targets for new treatment approaches. Our preliminary work identifies the Ser/Thr kinase mixed lineage kinase-3 (MLK3) as a required component for the proliferation of malignant schwannoma cell lines from NF1 and NF2 patients, and for murine NF2-/cells. We find that MLK3 is also required for mitogen activation of NF1/2 cell MAPKs. Surprisingly, MLK3, by an as yet unknown, indirect mechanism, recruits B-Raf to activate ERK. This project will explore the biochemical function(s) that MLK3 performs in mitogen-treated NF tumor cells and the molecular basis by which merlin and neurofibromin regulate MLK.3. Accordingly, in Aim 1 we will use biochemical, pharmacologic, RNAi, morpholino antisense RNA and inducible cell lines to explore (i) if NF2 cell proliferation is ERK and/or JNK-dependent, (ii) if induction of merlin or the NF1 GTPase activating protein-related domain (GRD) inhibits MLK3 and its effectors and if this inhibition is lost in NF2 or NF1 mutants associated with disease, and (iii) how MLK3 regulates ERK-specific MAP3Ks of the Raf family. In Aim 2, we will use RNAi, morpholino antisense RNA and inducible cell lines to assess the degree to which ablation or induction of NF1 or NF2 affects the activity of endogenous MLK3, its effectors and downstream functions. Finally, we find that endogenous and recombinant merlin and MLK3 associate in vivo in a mitogen-reversible manner. Merlin is a negative regulator of JNK activity, and possesses a proline-rich segment which could bind to the SH3 domain of MLK3. Alternatively, merlin could repress the recruitment of MLK3 by Rho family GTPases. In Aim 3, we will use biochemical and molecular biological methods to explore these possibilities. •
Project Title: MOLECULAR CHARACTERIZATION OF MEDULLOBLASTOMA Principal Investigator & Institution: Lee, Eunice Y.; Developmental Biology; Stanford University 1215 Welch Road, Mod B Stanford, Ca 943055402 Timing: Fiscal Year 2005; Project Start 01-SEP-2005; Project End 31-AUG-2008 Summary: (provided by applicant): Medulloblastoma, the most common pediatric malignant tumor, arises from the granule cell precursors (GCPs) in the cerebellum. Sonic hedgehog (Shh)/Patched signaling tightly regulates the proliferation of the GCPs during development. Deregulation of this pathway results in uncontrolled growth and subsequent medulloblastoma formation in both humans and mice. Using a mouse model of medulloblastoma with reduced Patchedl function, we have identified molecular events contributing to early and late tumor lesions in the cerebellum through expression analyses. This proposal is focused on determining the roles of these factors in the developing cerebellum, the mechanisms by which they regulate cell division of the GCPs, and how they cooperate with the Shh/Patched signaling pathway to promote cellular proliferation during normal development and tumorigenesis of the cerebellum. A deeper understanding of the complex signaling networks underlying the proliferation and oncogenic transformation of the cerebellar precursor cells will reveal new targets for developing effective treatments.
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Project Title: NEURAL STEM CELLS IN DRG AND NEUROFIBROMATOSIS TYPE 1 Principal Investigator & Institution: Joseph, Nancy M.; Internal Medicine; University of Michigan at Ann Arbor 3003 South State Street, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2005; Project Start 01-JUL-2004; Project End 30-JUN-2007 Summary: The neural crest is a heterogeneous population of progenitors that migrates from the dorsal neural tube and gives rise to the sensory and autonomic neurons and
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gila of the peripheral nervous system. Among the migrating progenitors are neural crest stem cells (NCSCs), which are defined based on their ability to self-renew and their ability to undergo multilineage differentiation, forming neurons, gila, and myofibroblasts. However, little is known about when, where, and how NCSCs undergo restrictions to a sensory or autonomic lineage. Some studies have suggest that neural crest progenitors become restricted at the onset of migration from the neural tube such that they can only give rise to either sensory and autonomic neuronal subtype, and that migrating and post migratory NCSCs specifically are unable to give rise to sensory neurons. However, other studies have suggested that at least some single cells in the emigrating population of neural crest cells retain the ability to generate both sensory and autonomic neurons in vivo. Moreover, I have recently discovered that the fetal dorsal root (sensory) ganglion (DRG) contains a population of multipotent progenitors that can form sensory neurons in culture and that these cells may persist in postnatal DRG. These observations raise the question of whether a population of NCSCs with both sensory and autonomic potential persists in developing and postnatal DRG. The persistence of multipotent progenitors in the postnatal DRG also raises the question of whether these progenitors are transformed by neurofibromin 1 (NF1) deficiency to form plexiform neurofibromas containing neurons, gila, and myofibroblasts. To address these questions, I propose to first purify and characterize the multipotent progenitors within embryonic and postnatal DRG and then study the effect of NF1 deficiency on these cells. I hope to gain important new insights into the regulation of NCSC fate determination, the role of stem cells in PNS development, and the etiology of neurofibromatosis. •
Project Title: NEUROBIOLOGY AND TREATMENT OF READING DISABILITY IN NF1 Principal Investigator & Institution: Cutting, Laurie E.; Assistant Professor of Neurology; Kennedy Krieger Research Institute, Inc. 707 North Broadway, Rm 614 Baltimore, Md 21205 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-JAN-2011 Summary: (provided by applicant): Neurofibromatosis Type 1 (NF1) is a common autosomal dominant neurocutaneous syndrome. NF1 has range of phenotypic expression, with neurological abnormalities often present, including high signal intensity foci on T2 weighted images and megalencephaly (increased brain volume). However, the most common concern of parents with children with NF1 is learning disabilities (LDs). Approximately half of children with NF1 have LDs, the most debilitating and common of which are reading disabilities. The overall purpose of this research is to gain a deeper understanding of the characteristics and treatment of reading disabilities in NF1. The first goal is to determine whether children with NF1 who have specific deficits in reading respond the same way, both neurobiologically and neuropsychologically, to specialized treatment known to ameliorate decoding deficits in reading in the general population; an additional goal is to determine which type of intervention is the best for particular type of learner profiles. To accomplish these goals, we will compare children with NF1 who show weaknesses in reading to children with reading disabilities from the general population pre and post two different types of intervention, using both behavioral and neurobiological (fMRI) measures. Both interventions focus on teaching sound-symbol relationships, but vary in terms of relative emphasis on verbal versus visual methods of teaching. Determining if children with NF1 with deficits in reading respond to interventions known to be effective for children with reading disabilities in the general population, and, in particular, which type of intervention approach they respond to best, will advance knowledge about the best therapies for LDs in NF1. Another goal of this research is to determine further the
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similarities/differences between the cognitive profiles of children with NF1 who have reading disabilities, versus children with reading disabilities in the general population; in particular, this is to determine if interventions developed for other deficits in reading disabilities, besides decoding, will also be useful for children with NF1 who show weaknesses in reading. Finally, we will characterize the neuropsychological and neurobiological differences between children with NF1 who have reading disabilities, versus children with NF1 without a reading disability; the goal of this last aim is to gain an understanding of which factors may serve as "protective" factors in NF1, in terms of developing reading problems. This research utilizes what is known about treatment of LDs in the general population, as well as fMRI methodology, which will further our understanding of how the NF1 gene affects cognition and the brain. Additionally, this research is also highly valuable because it will further our knowledge about effective treatments for reading disabilities in general. •
Project Title: NEUROFIBROMATOSIS TYPE 1 GENE REGULATES MYELOPOIESIS Principal Investigator & Institution: Clapp, David W.; Professor; Pediatrics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2005; Project Start 01-APR-1997; Project End 30-JUN-2007 Summary: (provided by applicant): Mutatons in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF-1). NF1 encodes a GTPase activating protein (GAP) for p21 ras (Ras) called neurofibromin. Neurofibromin converts p21 ras from its active GTP to its inactive GDP bound conformation. Individuals with NFl have a propensity to acquire benign and malignant tumors. Additionally, children with NFl are predisposed to juvenile myelomonocytic leukemia (JMML). A hallmark of myeloid progenitors (CFU-GM) from JMML bone marrow cells is their propensity to hyperproliferate in response to low doses of the growth factor granulocyte macrophage colony stimulating factor (GM-CSF). Homozygous disruption of Nfl is lethal in utero; however we found that murine Nf1 -deficient fetal hematopoletic cells show an abnormal pattern of CFUGM growth and hyperactivation of Ras effectors in response to multiple growth factors, including GM-CSF and stem cell factor (SCF), the ligand for the c-kit receptor tyrosine kinase. C-kit is encoded by the murine dominant white spotting locus, W). Since the W and Nfl loci appeared to function along a common developmental pathway, mice with mutations at both loci were generated. We found that haploinsufficiency of Nfl partially rescued the mast cell and coat color defects in W41 mice. These data offered genetic evidence that haploinsufficiency at Nfl modulates cell fates in vitro and in vivo in two lineages that are affected in individuals with NFl. The results support the emerging concept that heterozygous inactivation of tumor suppressor genes may have important biological effects.While loss of neurofibromin increases p21 ras activity in specific cell lineages, identification of alterations in distinct p21 ras effector pathways that control proliferation and survival in NF1-deficient cells is incomplete and critical for understanding disease pathogenesis. Most previous studies argue that loss of neurofibromin results in increased activation of the classical p21 ras-Raf-Mek-ERK pathway. However, we have preliminary data to support an alternative biochemical model where the growth advantage of Nfl1-deficient cells is mediated through increased signals from p21 ras to the small Rho GTPase, Rac2, a Rac isoform expressed only in hematopoietic cells. We propose studies to examine how activation of p21 ras and Rac isoforms cooperate to alter the biology of Nfl +/- mast cells and Nf 1 -/- stem and myeloid progenitor cells utilizing mice with genetic mutations in these loci.
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Project Title: NEUROFIBROMIN (NF1) SIGNALING AND TARGET GENES IN OSTEOBLASTS Principal Investigator & Institution: Elefteriou, Florent; Medicine; Vanderbilt University Medical Center Nashville, Tn 372036869 Timing: Fiscal Year 2006; Project Start 01-SEP-2006; Project End 31-AUG-2008 Summary: (provided by applicant): Our laboratory is interested in identifying and elucidating the molecular mechanism of action of regulators of bone remodeling. This interest led us to study the role of neurofibronin, a GTPase activating protein encoded by the NF1 gene in bone remodeling. Mutation in NF1 causes Neurofibromatosis Type 1 (NF1), a syndrome characterized, among other manifestations, by disabling skeletal abnormalities, whose origin is unknown. To characterize the role of Nf1 in bone biology and to overcome the embryonic lethality of Nf1-/- mice, we generated mice deficient for Nf1 specifically in osteoblasts (Nf1ob-/- mice). In preliminary data, we show that Nf1 deficiency in osteoblasts leads to a high bone mass caused by an increase in bone formation. We also present evidence that the kinases ERK and RSK2 as well as ATF4, a transcription factor required for osteoblast differentiation, may be a target of Nf1 signaling involved in the high bone mass of Nf1ob-/- mice. Surprisingly, Nf1 deficiency in osteoblasts also increases osteoclast differentiation and bone resorption through yet unknown mechanisms. These data, along with our recent findings related to the role of ATF4 in bone resorption therefore suggest that, in osteoblasts, an increase in ATF4 activity may be responsible for most of the NF1 skeletal manifestations, including the increase in bone resorption observed in Nf1ob-/- mice and humans. In this application, we propose to use WT and Nf1-/- osteoblast/osteoclast co-cultures and cell signaling studies to characterize the signaling pathways whereby Nf1 in osteoblasts regulate osteoclastogenesis, bone resorption, collagen synthesis and bone formation. To confirm that ATF4 is a target of Nf1 signaling in osteoblasts and to demonstrate the in vivo relevance of these findings, we will attempt to rescue the bone phenotypes of Nf1ob-/mice, genetically by removing one copy of Atf4 in Nf1ob-/- mice and pharmacologically by blocking Ras and MARK in Nf1ob-/- mice and osteoblasts. Relevance: Neurofibromatosis (NF1) is characterized by debilitating skeletal abnormalities that are often progressive and difficult to treat. This project aims at understanding the origin of these bony abnormalities and to test pharmacological candidates that could ameliorate the skeletal manifestations of the syndrome using a mouse model of NF1. It also aims at characterizing novel signaling pathways and target genes regulating bone remodeling, with the long-term goal to better understand diseases affecting the skeleton and to propose rationale therapies.
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Project Title: NEUROFIBROMIN, DEVELOPMENT
NEURAL
CREST
AND
CARDIAC
Principal Investigator & Institution: Epstein, Jonathan A.; Professor; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2005; Project Start 08-JUL-1999; Project End 30-NOV-2008 Summary: (provided by applicant): This application represents a revised version of a competing renewal of a project focusing on the role of the Nf1 gene product neurofibromin during cardiac development. In humans, NF1 is mutated in patient with von Recklinghausen Neurofibromatosis, a disease characterized by benign and malignant tumors of neural crest origin. Nf1 knockout mice display enlarged endocardial cushions and succumb during mid-gestation with evidence of cardiovascular impairment. The cardiac defects include pulmonic stenosis, double outlet right ventricle and thinned myocardium, defects that are seen in other mouse and chick
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models of cardiac neural crest-related congenital heart disease. However, our recent studies demonstrate that neural crest migration and patterning in the heart is normal in Nf1-deficient embryos. Furthermore, inactivation of Nf1 in neural crest (using three distinct Cre mice) does not reproduce embryonic lethality or the cardiac phenotype of null embryos. Rather, these mice are born and display hyperplasia of numerous neural crest-derived structures including peripheral ganglia and the adrenal gland. Surprisingly, inactivation of Nf1 in endothelial cells using Tie2-Cre recapitulates the embryonic cardiac defects seen in Nf1 null embryos. These results establish a novel and unexpected role for neurofibromin in endothelium. Moreover, we have observed elevated levels of activated MAPK in endothelium of mutant embryos consistent with a role for Nf1 in down-regulating Ras activity. We also demonstrate enhanced nuclear localization of NFATc1 (a factor known to be required for endocardial cushion formation) in Nf1-null endocardium. Here, we propose to test the hypothesis that Nf1 deficiency in endothelial cells results in activation of Ras. We will examine downstream effectors of Ras signaling in endothelium. We will also examine the mechanism by which Ras activation modulates subsequent nuclear localization of NFATc1 and potentially Smads, and we will test the hypothesis that nuclear localization of NFATc1 is required for enhanced epithelial-mesenchymal transformation in the endocardial cushions of Nf1-deficient mice using both genetic and biochemical approaches. We will examine the function of Nf1 in adult endothelial cells and in adult and embryonic smooth muscle with the use if inducible tissue-specific Cre mice. •
Project Title: NEUROFIBROMIN, DEVELOPMENT
RAS
&
NFAT
IN
CARDIOVASCULAR
Principal Investigator & Institution: Ismat, Fraz Ahmed.; Children's Hospital of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318 Timing: Fiscal Year 2005; Project Start 15-JAN-2005; Project End 31-DEC-2009 Summary: (provided by applicant): I am proposing a training program with didactic coursework and experiments that are logical extensions of our previous work in understanding how Nf1 functions in cardiovascular development. Neuro-fibromatosis type 1 (Von Recklinghausen's Disease) is an autosomal dominant condition affecting 1 in 3000-4000 individuals. It is characterized by pathology of neural crest-derived tissues, but also causes cardiovascular abnormalities. The gene NF1 encodes neurofibromin, a large molecule that in part acts as a ras GTPase activating protein (GAP). Mice homozygous for a null allele of the murine homologue (Nf1) have a set of embryonic lethal cardiovascular defects reminiscent of common forms of congenital heart disease. Endothelial specific disruption of Nf1 reproduces much of this cardiovascular phenotype. Further, we believe that it occurs through the ras-GAP function of neurofibromin and its effect on nuclear localization of the transcription factor NFATc1 (nuclear factor of activated T-cells). Specific Aim 1 will test the hypothesis that ras-GAP function is the critical aspect of neurofibromin responsible for proper cardiovascular development. The ras GAP related domain of neurofibromin has been knocked into the Rosa26 locus by me and will be expressed in a tissue-specific manner in mice through the activity of cre recombinase. Specific Aim 2 will test the hypothesis that the loss of Nf1 in vascular smooth muscle will recapitulate the vascular disease of neurofibromatosis. I will test this by crossing floxed Nf1 mice with a tamoxifeninducible, smooth muscle specific cre line. Specific Aim 3 will test the hypothesis that NF1 and NFATc1 are in the same genetic pathway in cardiovascular development. Through genetic analysis of mice and mouse embryos deficient in both NF1 and NFATc1, I will determine the role of NFATc1 in the development of the cardiovascular phenotype of Nf1 null embryos. Finally, Specific Aim 4 will extend our previous work
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on the observation that NFATc1 undergoes nuclear localization in endothelial cells in the setting of elevated ras activity. I will continue testing specific signaling pathways downstream of ras to determine those that are critical for this phenotype. This experimental work will be supported by a foundation of didactic training in molecular and developmental biology. Together this training program will prepare me for independent investigation, lead to a better understanding of cardiovascular abnormalities in neurofibromatosis, and address fundamental issues of cardiovascular development. •
Project Title: NEUROFIBROMIN, RAS AND BDNF/TRKB SIGNALING Principal Investigator & Institution: Krueger, Bruce K.; Professor; Physiology; University of Maryland Balt Prof School Professional School Baltimore, Md 21201 Timing: Fiscal Year 2005; Project Start 01-SEP-2004; Project End 30-APR-2007 Summary: (provided by applicant): Neurofibromatosis 1 (NF1) is an autosomal dominant disorder resulting from a spontaneous or inherited loss-of-function mutation in the gene encoding the regulatory protein, neurofibromin (NF). NF1 is characterized by tumors (neurofibromas) associated with the peripheral nervous system and by cognitive impairments including attention deficit hyperactivity disorder and learning and memory deficits. Although the genetic basis for NF1 has been established, the biological mechanisms by which loss of one copy of NF leads to the characteristic symptoms of the disease are not well understood. Studies with transgenic mice indicate that cognitive deficits are associated with the loss of GTPase activating protein (GAP) activity of NF. This research program will focus on the cellular and molecular mechanisms by which loss of NF GAP activity can lead to cognitive dysfunction and will test the hypothesis that the normal function of NF is to maintain low basal activity in the brain-derived neurotrophic factor (BDNF) signaling pathway by deactivating the G-protein, Ras. A prediction of this hypothesis is that partial loss of NF GAP activity in NF1 creates an abnormally high basal activity in the BDNF signaling pathway, leading to the dysregulation of BDNFmediated physiological functions underlying normal leaming and memory. This will be tested by examining BDNF signaling in geneticallymodified neurons lacking NF. Although BDNF, via its cognate receptor, trkB, is known to activate multiple downstream pathways, not all of these should be affected by the loss of NF. Immunoprecipitation and proteomic analysis will be used to identify and characterize functional signaling complexes containing NF and trkB. If this hypothesis withstands the critical tests outlined in this proposal, the BDNF/trkB signaling pathway will emerge as a potential target for pharmacological or other therapies that could selectively treat the cognitive symptoms of NF1; the neurofibromas may be more effectively treated with a separate therapeutic strategy. In addition to testing this hypothesis, elucidation the components of the NF signaling complex will provide new insight into the normal function of NF and may provide additional clues to potential molecular targets for the treatment of NF1.
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Project Title: NF CENTER: FROM ANIMAL MODELS TO THERAPEUTICS Principal Investigator & Institution: Parada, Luis F.; Director; Cell Biology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2005; Project Start 20-SEP-2005; Project End 30-APR-2010 Description (provided by applicant): Inactivation of the NF1 gene is the underlying cause for one of the most common genetic diseases of the nervous system, neurofibromatosis type 1. Neurofibromin, the gene product of NF1encodes for a 3000 amino acid protein that contains a rasGTPase activating domain (rasGAP), a negative
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regulator of the ras pathway. To date, prevailing evidence indicates that all pathologies associated with neurofibromatosis are the consequence of deregulation of ras signaling. The most common tumor pathologies in afflicted individuals are neurofibromas (100% incidence), malignant peripheral nerve sheath tumors (15% incidence), optic gliomas (pilocytic astrocytomas; 20% incidence), and astrocytomas (<1% incidence). We have attempted to model these tumors in mice as a means of understanding the origin, molecular details of progression, and to develop potential therapies. Initial development of mouse knockout models yielded considerable information on NF1 in development, the null phenotype resulted in embryonic lethality thus limiting our ability to examine NF1 as a tumor suppressor (Brannan et al., 1994). The genetic trick of combining germline mutations at the NF1 and p53 tumor suppressors resulted in mice that developed MPNSTs with 100% penetrance. This result provided the first indication that mutations in the mouse NF1 genes could mimic the human tumor condition effectively (Vogel et al., 1998). To achieve better control of the NF1 modeling, we have developed tissue specific mutations by use of cre/lox technology (Zhu et al., 2000). Using conditional knockouts, we have successfully modeled formation of plexiform neurofibromas, thus identifying the local cell of tumor origin and the importance of a distant partner in tumor development. Much of this application focuses on our conviction that the distant partner is a mast cell. In addition we have new models that exhibit tumors of the CNS: namely optic tract gliomas and astrocytomas. In the present application we propose to develop a greater understanding of the genesis of optic gliomas. In addition, we will interface with our colleagues Dr. Clapp and Dr. Ingram in molecular studies of mast cell contribution to neurofibroma formation. •
Project Title: OSSEOUS ABNORMALITIES IN NEUROFIBROMATOSIS TYPE 1 Principal Investigator & Institution: Stevenson, David Andrew.; Pediatrics; University of Utah 75 South 2000 East Salt Lake City, Ut 84112 Timing: Fiscal Year 2005; Project Start 16-AUG-2005; Project End 31-MAR-2010 Summary: (provided by applicant): Neurofibromatosis type 1 (NF1) is a common genetic disorder with a high degree of variability of clinical expression, including skeletal abnormalities in over 1/3 of patients. These osseous manifestations are unpredictable, and the pathogenesis, natural history and clinical outcome remain relatively obscure. I propose to test the hypothesis that NF1 is a constitutional disorder of bone with generalized osseous abnormalities by addressing 3 Specific Aims. The first Specific Aim is to determine the differences in bone health variables between NF1 individuals and individuals without NF1, and between NF1 individuals with and without osseous abnormalities. Bone-health measurements from imaging modalities [dual energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT)], and biochemical markers of bone metabolism including urinary pyridinium cross-links will be used to test the hypothesis that there are subtle bone abnormalities in NF1 compared to the general population. The second Specific Aim is to determine genotype-phenotype correlations of the NF1 gene and osseous abnormalities. High-throughput DNA sequencing will be used to determine if a specific mutation class contributes to the NF1 osseous phenotype. In addition, a cohort of NF1 families will be recruited to assess osseous phenotypes through sib-pair and parent-child analyses, including NF1 haplotype analysis. The third Specific Aim is to assess health status and health-related quality of life (HRQL) in children and adolescents with NF1 and scoliosis. Utilizing a 1:3 case-control design through a multi-center collaborative network, HRQL measures from a battery of questionnaire instruments between NF1 individuals with and without scoliosis will be obtained and analyzed. The principal investigator has developed an interdisciplinary plan utilizing mentors, a scientific advisory committee,
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Neurofibromatosis Type 1
didactic courses and resources at the University of Utah, General Clinical Research Center in order to become an independent researcher. •
Project Title: PHENOTYPING & GENOTYPE-PHENOTYPE CORRELATIONS IN NF1 Principal Investigator & Institution: Korf, Bruce R.; Professor and Chair; Genetics; University of Alabama at Birmingham 1530 3Rd Avenue South Birmingham, Al 35294 Timing: Fiscal Year 2005; Project Start 15-SEP-2002; Project End 31-JUL-2007 Summary: (provided by the applicant): Neurofibromatosis type 1 is an autosomal dominant disorder whose hallmark feature is the occurrence of benign tumors of the nerve sheath, neurofibromas. The disorder is a paradigmatic example of variable expression, including variability both within and between families. Possible contributors include allelic heterogeneity of the NF1 gene mutations, which differ among different affected individuals, modifying genes, and stochastic factors. In this study, we intend to identify genetic modifiers of NF1 using the most readily determined NF1 phenotypes, cutaneous neurofibromas and cafe-au-lait spots, while simultaneously carrying out a detailed quantitative assessment of the variability of NF1 phenotypes and its relationship to NF1 mutation type. We will test whether the nature of the NF1 mutation differs in individuals in the top and bottom 10% for neurofibroma number. We will also use a discordant sib-pair strategy for identification of modifier loci, using polymorphic microsatellite markers to test whether the wild-type NF1 allele acts as a genetic modifier of the effects of its mutant counterpart, and analyzing candidate loci by single nucleotide polymorphism (SNP) analysis. In parallel, we will perform comprehensive quantitative phenotyping of a cohort of independent individuals with NF1. We will gather detailed data concerning numbers of dermal neurofibromas, number of café-au-lait spots, and number and location of internal plexiform neurofibromas and spinal neurofibromas, in addition to any other notable NF1 phenotypes. These data will provide the basis for defining the relationship between different NF1 phenotypes and the contribution of NF1 mutation, NF1 wild-type allele and modifier genes to variation in phenotype. The products of these studies, including clinical data, results of genetic modifier analyses, permanent cell-lines from the NF1 patients, and any available tumor material will be made available to the research community. Elucidation of genetic modifiers, phenotype-phenotype correlations, and genotype-phenotype correlations would all be of clinical importance in NF1, providing the potential to predict individuals at risk of specific complications, or to avoid agents that increase risk of disease progression, and identifying new cellular targets for therapy.
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Project Title: RAC2 IN HEMATOPOIETIC PROLIFERATION Principal Investigator & Institution: Williams, David A.; Professor of Pediatrics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2005 Summary: Members of the small GTPase family, including Ras and Rho-like proteins, function as key cellular relays of signals emanating from cell membrane receptors, by cycling between inactive GDP-bound and active GTP-bound sates. Rho GTPases are regulators of a wide spectrum of cellular functions in eukaryotic cells, including cytoskeletal organization, gene transcription and cell cycle progression. In addition, Rho GTPases have also been shown to play a role in kinase signaling which appear to be parallel if not independent of their roles in actin organization. Rac2-deficient mice have been generated by homologous recombination and manifest defects in neutrophil
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chemotaxis, superoxide production, shear-dependent L-selectin-mediated capture on endothelial substrates Glycam-1, and F-actin generation. However, it has recently become clear that phenotypic abnormalities of Rac2-/- mice are not confined to the neutrophil lineage, since Rac2-deficient mast cells demonstrate significant actin-based functional defects in vitro, including defective adhesion via integrin receptors and are deficient in vivo in Rac2-/- mice, and Rac proteins also appear critical in lymphocyte differentiation. Indirect evidence from other laboratories suggest that Rac may be involved in Ras hyperactivity characteristic of cells deficient in the Ras GAP protein, neurofibromin, and in the abnormalities associated with expression of the BCR/ABL kinase seen in CM transformed myeloid cells. In this grant application, we propose to utilize a genetic approach to examine the involvement of Rac in signaling in BCR/ABLinduced abnormal cell behavior and NF-1-mediated hyperproliferation. We will utilize genetic crosses between Nf-1 and Rac2 mutant mice to address the role of Rac2 in Ras signaling in primary cells. In addition, we will utilize retrovirus-mediated gene transfer and expression of p210/BC4/ABL in Rac2-deficient myeloid cells to assess the role of Rac2 signaling in BCR/ABL-mediated cell phenotype changes in vitro and development of myeloproliferative disease in vivo. As a result of the proposed studies we will directly determine if Ras proteins are involved in abnormal hematopoiesis characteristics of these two genetic conditions. •
Project Title: RAS-PI3K PATHWAY IN NF1-/-HEMATOPOIESIS AND LEUKEMIA Principal Investigator & Institution: Ingram, David A.; Pediatrics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2005; Project Start 27-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations in the NF1 tumor suppressor gene. Children with NF1 are predisposed to developing juvenile myelomonocytic leukemia (JMML). Neurofibromin, the protein product of NF1, is a negative regulator of p21ras activity. Though Nf1 -/mice die in utero, mice reconstituted with Nf1 -/- fetal stem cells develop a myeloproliferative disease (MPD) similar to JMML in NF1 patients. However, alterations in p21ras signaling pathways in NF1 deficient cells responsible for MPD are unknown. Utilizing PI-3 kinase (PI3K) inhibitors, we have preliminary data implicating hyperactivation of the p21ras-PI3K pathway as responsible for the hyperproliferation and increased survival of Nf1 -/- cells. However, interpretation of results using PI3K inhibitors is limited because there are four classes of PI3K, and inhibitors inactivate all classes. Here we propose genetic experiments to determine whether hyperactivation of class IAPI3K alters the growth of Nf1 -/- hematopoietic cells. Our rationale for studying class IAPI3K in Nf1-/- cells is twofold. First, in contrast to other PI3Ks, all class IAPI3K catalytic subunits contain a p21ras-binding domain. Second, p21ras interacts with these subunits to augment kinase activity in vitro, and no evidence exists to show that p21ras augments the activity of other PI3K classes. Recently, a p85alpha (a regulatory subunit of class IAPI3K) knockout strain was generated which results in a 97% reduction in class IAPI3K activity in myeloid cells. We hypothesize that hyperactivation of the p21rasclass IAPI3K pathway, alters the proliferation and survival of Nf1 -/- hematopoietic cells and contributes to the progression of MPD in mice transplanted with Nf1 -/- cells. To test this hypothesis, we will conduct experiments utilizing a genetic intercross of Nf1 +/- and p85alpha knockout mice. The aims are: 1) To test whether hyperactivation of class IAPI3K contributes to MPD in mice reconstituted with Nf1 -/- stem cells by altering specific signaling pathways, 2) To examine how genetic inactivation of class IAPI3K alters the proliferation and survival of committed, multipotential, and primitive Nf1 +/+ and Nf1 -/- progenitor cells, 3) To examine how neurofibromin and class
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Neurofibromatosis Type 1
IAPI3K regulate cell cycle progression and survival of phenotypically defined hematopoietic cells in vivo. •
Project Title: ROLE OF NEUREGULIN-1 IN SCHWANN CELL NEOPLASIA Principal Investigator & Institution: Carroll, Steven L.; Associate Professor; Pathology; University of Alabama at Birmingham 1530 3Rd Avenue South Birmingham, Al 35294 Timing: Fiscal Year 2005; Project Start 15-SEP-2004; Project End 30-APR-2009 Summary: (provided by applicant): Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell neoplasms that occur in patients with neurofibromatosis type 1 (NF1), the most common genetic disease affecting the nervous system. Nf1 and p53 tumor suppressor gene mutations occur commonly in MPNSTs and epigenetic factors such as stimulation by growth factors likely cooperate with these mutations to promote MPNST tumorigenesis. We hypothesized that proteins in the neuregulin-1 (NRG-1) family of growth and differentiation factors promote MPNST tumorigenesis. To test this hypothesis, we generated transgenic mice expressing the NRG-1 isoform glial growth factor-(3 (GGF133) in Schwann cells (P0-GGF(3 mice). P0GGF(3 mice demonstrate prominent Schwann cell hyperplasia, preneoplastic lesions in peripheral ganglia and MPNST-like Schwann cell neoplasms. Our preliminary studies of MPNSTs arising in P0-GGF(3 mice indicate that neurofibromin, the product of the Nf1 gene, is not expressed in these neoplasms and that their p53 expression is also altered. Human MPNSTs likewise co express multiple NRG-1 isoforms and erbB receptors and we have found that the proliferation of 2 human MPNST cell lines is dependent on erbB signaling. As MPNST formation in P0-GGF(3 mice results from altered growth factor expression, these mice represent a transgenic model distinct from all others previously described and provide a unique opportunity to examine interactions between epigenetic factors and tumor suppressors during in vivo MPNST formation. In this proposal, we will partner the P0-GGF(3 mouse model with mouse and human MPNST cell lines to critically test the hypothesis that constitutive activation of the NRG-1/erbB signaling pathway and mutations of the Nf1 and p53 tumor suppressor genes cooperate to promote MPNST pathogenesis. Specifically, we will test the hypotheses that: 1) Specific NRG-1 isoforms and erbB membrane tyrosine kinases are individually necessary for MPNST proliferation, survival and/or migration in vitro and that constitutive activation of the NRG-1/erbB signaling pathway is necessary for MPNST tumorigenesis in vivo; 2) loss of NJ7 and p53 tumor suppressor gene function is associated with MPNST tumorigenesis in P0-GGF(3 mice and 3) constitutive activation of the NRG-1/erbB signaling pathway and null mutations of the Nf1 and/or p53 tumor suppressor genes cooperate to accelerate MPNST tumorigenesis in vivo. These studies will provide important insights into the mechanisms promoting MPNST formation and establish the NRG-1/erbB signaling pathway as a novel therapeutic target in MPNSTs.
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Project Title: SPINAL ABNORMALITIES IN NEUROFIBOMATOSIS TYPE 1 Principal Investigator & Institution: Viskochil, David H.; Professor; Pediatrics; University of Utah 75 South 2000 East Salt Lake City, Ut 84112 Timing: Fiscal Year 2006; Project Start 01-JUL-2006; Project End 31-MAR-2011 Summary: (provided by applicant): Neurofibromatosis type 1 (NF1) is a common genetic disorder with a high degree of variability of clinical expression, including skeletal abnormalities in over 1/3 of patients. This disorder is associated with spinal abnormalities, long bone dysplasia, and sphenoid wing dysplasia. These osseous manifestations are unpredictable, and the pathogenesis, natural history, and clinical outcome remain relatively obscure. The spinal abnormalities are varied and include
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scoliosis (common and dystrophic forms), neurofibromas, dural ectasias, meningoceles, and vertebral defects. The primary objectives of this clinical study are to determine the incidence and clinical history of NF1-related spinal abnormalities in a prepubertal cohort of 120 children with NF1 over 3 years. Secondary objectives are to determine the efficacy of various radiographic screening tools as predictors for dystrophic scoliosis. These goals will be accomplished in 3 specific aims. Aim 1 is to identify associations of spinal cord dural ectasias, spinal neurofibromas, and meningoceles with dysplastic osseous abnormalities and dystrophic scoliosis. Spine radiographs and MRI will be used to test the hypothesis that NF1 patients with certain manifestations are more likely to develop dystrophic scoliosis. Aim 2 is to define the clinical history and short-term outcome of dystrophic scoliosis and spine abnormalities with respect to various radiographic indices. It tests the hypothesis that there are quantitative differences in vertebral scalloping and spinal canal and vertebral body cross-sectional areas when there is an associated additional dystrophic abnormality and these differences are prognostic indicators for dystrophic scoliosis. Aim 3 is to determine the differences in bone health variables between NF1 patients and individuals without NF1, and between NF1 individuals without dystrophic scoliosis versus NF1 individuals who develop dystrophic scoliosis. Dual energy x-ray absorptiometry (DXA) and peripheral quantitative computerized tomography (pQCT) will be used to test the hypothesis that there-are subtle bone abnormalities of bone mineral density, bone area, bone mass, muscle-to-bone ratios, and cortical thickness in NF1. Urinary Dyridinium cross-links will be measured to detect differences in bone resorption. Spinal abnormalities in NF1 are not well understood, and dystrophic scoliosis is a highly morbid condition. This proposal will identify variables in patients with NF1 as prognostic factors for dystrophic scoliosis to improve clinical management. •
Project Title: TARGETING VASCULOGENESIS HYPERTENSION IN NEUROFIBROMATOSIS TYPE1
AND
INTERSTITIAL
Principal Investigator & Institution: Ozerdem, Ugur; Assistant Professor; La Jolla Inst for Molecular Medicine 4570 Executive Dr, Ste 100 San Diego, Ca 921213074 Timing: Fiscal Year 2006; Project Start 01-AUG-2006; Project End 31-JUL-2008 Summary: (provided by applicant): This is a resubmission of an R21 application. Malignant peripheral nerve sheath tumors (MPNST) are the most common malignant tumor, and the leading cause of mortality in neurofibromatosis type 1 (NF1). Two critical issues in MPNST are neovascularization and high interstitial fluid pressure (IFP). The NG2 proteoglycan, Nf1 haploinsufficiency (Nf1+/-), and accelerated response of neovascular cells to neovascular stimuli are fundamental to both issues. The underlying hypothesis for this proposal is that neovascularization and interstitial fluid hypertension in MPNST can be counteracted by inhibiting both NG2 proteoglycan and Nf1 haploinsufficiency. We propose to establish both vasculogenic and angiogenic pericytes as targets to reduce interstitial fluid pressure and neovascularization in MPNST. Specific Aim 1. Characterize the accelerated contribution of Nf1+/- bone marrow-derived pericytes and endothelial cells to pathological vasculogenesis in NF1 mouse model. We will test whether bone marrow transplantation from wild type mice (Nf1+/+) to Nf1+/mice reduces vasculogenesis and improves survival in MPNST. Specific Aim 2. Characterize the roles for NG2 in modulation of NF1-driven neovascularization, and in interstitial hypertension. We will determine the extent to which pericyte-NG2 contributes to neovascularization and interstitial hypertension in MPNST. We will test whether the combined inhibition of NG2 and Nf1 haploinsufficiency will maximally inhibit neovascularization due to synergy between NG2, and Nf1 haploinsufficiency. Specific Aim 3. Reveal the role for NG2 in accelerated response of Nf1 haploinsufficient
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neovascular cells to bFGF. Previous investigations identified bFGF hypersensitivity as a cause of excessive cell proliferation in Nf1 haploinsufficiency. We propose to determine whether there is a bFGF-driven synergistic mechanism linking Nf1 haploinsufficiency and NG2. Specific Aim 4. Identify the origin of high interstitial fluid pressure in MPNST in the NF1 mouse model. We will test whether inhibition of NG2 results in a decrease in interstitial fluid pressure due to decreasing compressive contractile forces within the tumor by decreasing the abnormal number of pericytes and their abnormal contraction properties. •
Project Title: TRANSLATIONAL INVESTIGATION OF NF1 IN MYELOID LUEKEMIA Principal Investigator & Institution: Shannon, Kevin M.; Professor and Director, Hematopoietic Ma; Pediatrics; University of California San Francisco 3333 California St., Ste. 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2005; Project Start 15-FEB-1997; Project End 31-JAN-2007 Summary: (provided by applicant) Children with the common inherited disorder neurofibromatosis, type 1 (NF1) are predisposed to myeloid leukemia, particularly juvenile chronic myelomonocytic leukemia (JMML). The NF1 gene (NF1) encodes a GTPase activating protein (GAP) called neurofibromin that stimulates GTP hydrolysis on the p21ras (Ras) family of signaling proteins. We have shown that NF1 functions as a tumor suppressor gene in myeloid cells by negatively regulating Ras. In the current period of support, we have exploited a murine model to investigate mechanistic questions related to the role of NF1 in myeloid growth control and to perform preclinical studies of rational therapeutics. These studies strongly implicate the growth factor GM-CSF as playing a central role in the aberrant growth of murine NF1 mutant cells and in human JMML. In the competing renewal of this translational research project, we will extend these studies using expertise and reagents developed during the past 4 years. This application has 4 specific aims. The experiments proposed under aim 1 involve detailed mechanistic studies of the effects of NF1 inactivation on signal transduction, apoptosis, and cell cycle control in myeloid lineage cells. We will also take a genetic approach to test the role of GM-C SF signaling in a myeloproliferative disorder (MPD) that arises in JunB mutant mice. In aim 2, we propose studies to elucidate the role of GM-CSF in fetal liver cell engraftment that might be relevant to the pathogenesis of JMML. Our third aim proposes a combination of in vivo and in vitro approaches to contrast the effects of expressing oncogenic Ras and inactivating NF1 in myeloid cells. These studies will exploit a novel mouse model developed by our collaborator Tyler Jacks. In aim 4, we examine how the adapter molecule p62DOK regulates myeloid growth by interacting with the Ras GTPase activating protein p12OGAP. Together, these studies will provide new insights into how Ras signaling is normally regulated in myeloid cells, and how hyperactive Ras contributes to leukemogenesis.
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Project Title: LEUKEMIA
TRANSLATIONAL
STUDIES
OF
ALKYLATOR
INDUCED
Principal Investigator & Institution: Weiss, Brian D.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2005; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Applicant's Description): Our laboratory recently discovered a high incidence of myeloid malignancies in heterozygous Nf1 mutant (Nf1 +/-) mice treated with the commonly used chemotherapeutic agent cyclophosphamide (CP). The subject of this application is to utilize this novel murine model for translational and mechanistic
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studies of CP-induced myeloid leukemia. These goals will be pursued through three specific aims. In aim 1, we will test the hypotheses (a) that increasing CP dose intensity will increase the incidence of t-ML in Nf1 +/- mice, and (b) that the chemopreventive agent amifostine will partially protect CP-treated Nf1 +/- mice from t-ML. Aim 2 will test the hypothesis that inactivation of the normal Nf1 allele correlates with clinical evidence of t-ML in Nf in mutant mice, and will perform molecular analyses to characterize the mechanism of Np inactivation in CP- treated mice. We will also determine the frequency of Hprt gene inactivation in lymphocytes from control mice and from mice that have been treated with CP, amifostine, or with both agents. These experiments will allow us to ascertain if Hprt mutation rates provide a useful surrogate marker. CP is metabolized to acrolein and to phosphoramide mustard (PM). While PM is responsible for the anti-tumor effects of CP, recent data implicate acrolein as contributing to its leukemogenic properties. Resolving this question has important implications for designing cytotoxic agents with reduced mutagenic potential. Therefore, our final aim will involve determining the incidence of leukemia in cohorts of Nf1+/- mice treated with CP, with an analog that produces only acrolein, or with an analog that generates only PM. In addition, we will perform correlative studies as described under aim 2. These experiments will allow us to compare the leukemogenic effects of these two major metabolites of CP, as well as the type(s) of genetic lesions which occur at Nf1 in hematopoietic cells from mice that received these agents. NTIS (National Technical Information Service) The NTIS (www.ntis.gov), a service of the U.S. Department of Commerce, has published the following information on sponsored studies related to neurofibromatosis type 1: •
"Dissection of the Pathogenesis of Neurofibromatosis type 1-Associated Myeloid Leukemia. - Annual rept. 18 Sep 1999-18 Sep 2000," published in October 2000. Sponsored by: Florida Univ., Gainesville. Written by: C. I. Brannan. Abstract: Although most of the tumors associated with Neurofibromatosis type 1 (NF1) are benign in nature, malignant transformation of a subset of NF1 tumors is a serious complication, often leading to the death of the patient. This is true for NF 1-associated juvenile myelomonocytic leukemia (JMML), known to progress into acute myeloid leukemia (AML). Previously, we have shown that loss of Nfl in the hematopoetic lineage results in JMML. The goal of this grant is to identify the genetic events which lead to the transformation and leukemic progression of NF1 - associated JMML using a mouse model. This model system takes advantage of transgenic mice that harbor one mutant allele of the Nfl gene, but require further mutations for transformation. We have backcrossed this mutant Nfl allele for three generations to a strain of mouse that expresses a murine leukemia virus (MuLV). In this system, the MuLV acts as a mutagen to activate cooperating cellular proto-oncogenes or inactivate tumor suppressor genes, resulting in accelerated tumor development. So far, by cloning sites of somatic MuLV integration from tumor DNAs obtained from these backcrossed mice, we have identified three loci that appear to cooperate with the loss of Nfl to cause to AML.
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"Magnetic Resonance Spectroscopy Imaging and Functional Magnetic Resonance Imaging of Neurofibromatosis type 1: In Vivo Pathophysiology, Brain- Behavior Relationships and Reading Disabilities. - Annual rept. 1 Oct 2001-30 Sep 2002," published in October 2002.
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Sponsored by: KENNEDY KRIEGER RESEARCH INST INC BALTIMORE MD. Written by: L. E. Cutting, P. Barker, A. Horska, W. Kaufmann and C. W. Koth. Abstract: The purpose of this research is oriented towards understanding the reading, language, and articulation deficits associated with Neurofibromatosis type 1 (NF-1) and relating these deficits to the underlying pathophysiology of NF-1 as revealed by Magnetic Resonance Spectroscopy Imaging (MRSI). A second goal is to determine how differences in activation, as measured by functional Magnetic Resonance Imaging (fMRI), are linked to the cognitive/academic impairments associated with NF-1. A third goal is to further understand how T-2 weighted hyperintensities on Magnetic Resonance Imaging (MRI) scans are related to cognitive/academic impairments associated with NF-1. •
"Profile of the Neurofibromatosis type 1 (NF1) Phenotype: Natural History, Neuropsychological and Psychosocial Aspects. - Annual rept. 1 Sep 2000-31 Aug 2001," published in September 2001. Sponsored by: New Childrens Hospital, Parramatta (Australia). Research and Development. Written by: K. North. Abstract: The natural history of both cognitive functioning and T2- hyperintensities is being examined in a longitudinal study of a cohort of 32 patients with NF1 and 11 controls. Follow-up neuropsychological assessments and cranial MRIs were performed after an 8-year period. Preliminary data analysis suggests that there is no improvement in cognitive function over time. MRI T2- hyperintensities decrease in size, intensity and number over time. However lesions in the basal ganglia behave differently from lesions in the cortex and brainstem, suggesting different underlying pathogenetic mechanisms. The timing of the MRI scan appears important in terms of its ability to predict cognitive deficits. In addition, we are conducting a comprehensive neuropsychological study of a cohort of 80 children with NF1 and 50 sibling controls. Patient ascertainment and testing is still in progress. These children (8-16 years) will undergo intensive cognitive assessments and MRIs. The relationship between T2- hyperintensities on cranial MRI and neuropsychological functioning will be examined by determining whether the number, size, or sites of these lesions are predictive of general or specific neuropsychological deficits. A multicentre study is also being conducted to characterise the distribution of IQ scores in a large international cohort of patients with NF1 and to determine whether any clinical or demographic variables are associated with lowering of IQ.
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 6
PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction 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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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 neurofibromatosis type 1, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type neurofibromatosis type 1 (or synonyms) into the search box, and click Go. The following is the type of output you can expect from PubMed for neurofibromatosis type 1 (hyperlinks lead to article summaries): •
A case of intra-dural malignant peripheral nerve sheath tumor in thoracic spine associated with neurofibromatosis type 1. Author(s): Albayrak BS, Gorgulu A, Kose T. Source: Journal of Neuro-Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16598431&query_hl=6&itool=pubmed_docsum
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A large deletion (1.5 Mb) encompassing the neurofibromatosis type 1 (NF1) gene in a patient with sporadic NF1 associated with dysmorphism, mental retardation, and unusual ocular and skeletal features. Author(s): Oktenli C, Saglam M, Demirbas S, Thompson P, Upadhyaya M, Consoli C, Ulucan H, Koz C, Durukan AH, Bozkurt A, Koc B, Kocar IH, Gul D. Source: Clinical Dysmorphology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14564162&query_hl=6&itool=pubmed_docsum
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A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1. Author(s): Garza R, Hudson RA 3rd, McMahan CA, Walter CA, Vogel KS. Source: Mutation Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17208258&query_hl=6&itool=pubmed_docsum
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A neurofibromatosis type 1 patient with severe kyphoscoliosis and intrathoracic meningocele. Author(s): Ebara S, Yuzawa Y, Kinoshita T, Takahashi J, Nakamura I, Hirabayashi H, Kitahara J, Yamada M, Takaoka K. Source: Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12637072&query_hl=6&itool=pubmed_docsum
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A new insight into our understanding of neurofibromatosis type 1? Author(s): Chimenti S. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15096131&query_hl=6&itool=pubmed_docsum
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A novel bipartite phospholipid-binding module in the neurofibromatosis type 1 protein. Author(s): D'Angelo I, Welti S, Bonneau F, Scheffzek K. Source: Embo Reports. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16397625&query_hl=6&itool=pubmed_docsum
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A patient with Marfan's syndrome and neurofibromatosis type 1 with polyneuropathy. Author(s): Hartlapp I, Buhring U, Dichgans J, Isenmann S. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15379745&query_hl=6&itool=pubmed_docsum
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A patient with optic pathway glioma, scoliosis, Chiari type I malformation and syringomyelia: is it Neurofibromatosis type 1? Author(s): Chakravarty A, Bhargava A, Nandy S. Source: Neurology India. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12577114&query_hl=6&itool=pubmed_docsum
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A possible paracrine hedgehog signalling pathway in neurofibromas from patients with neurofibromatosis type 1. Author(s): Endo H, Utani A, Matsumoto F, Kuroki T, Yoshimoto S, Ichinose M, Shinkai H. Source: The British Journal of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12588389&query_hl=6&itool=pubmed_docsum
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A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Author(s): Walker L, Thompson D, Easton D, Ponder B, Ponder M, Frayling I, Baralle D. Source: British Journal of Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16786042&query_hl=6&itool=pubmed_docsum
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A quadricuspid aortic valve in a patient with neurofibromatosis type 1. Author(s): Coulston J, Thekkudan J, Ibrahim MF. Source: J Heart Valve Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16245514&query_hl=6&itool=pubmed_docsum
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Absence of a sphenoid wing in neurofibromatosis type 1 disease: imaging with multidetector computed tomography. Author(s): Onbas O, Aliagaoglu C, Calikoglu C, Kantarci M, Atasoy M, Alper F. Source: Korean Journal of Radiology : Official Journal of the Korean Radiological Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16549958&query_hl=6&itool=pubmed_docsum
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Absence of Lisch nodules in sporadic neurofibromatosis type 1 may reflect somatic mosaicism. Author(s): Vabres P, Bonneau D, Larregue M. Source: Archives of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12056976&query_hl=6&itool=pubmed_docsum
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Acquired cerebellar cavernous angioma following childhood radiotherapy in a patient with neurofibromatosis type 1. Author(s): Van Calenbergh F, Demaerel P, Sciot R, van Loon J. Source: Acta Neurol Belg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12892005&query_hl=6&itool=pubmed_docsum
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Altered calcium-mediated cell signaling in keratinocytes cultured from patients with neurofibromatosis type 1. Author(s): Korkiamaki T, Yla-Outinen H, Koivunen J, Karvonen SL, Peltonen J. Source: American Journal of Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12057903&query_hl=6&itool=pubmed_docsum
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Ampullary ganglioneuroma: an unusual feature of neurofibromatosis type 1--a case report. Author(s): Shojaie M, Abbas Z, Luck NH, Mubarak M. Source: J Pak Med Assoc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16108515&query_hl=6&itool=pubmed_docsum
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Assessment of sacrum scalloping in neurofibromatosis type 1 caused by a giant cell lesion of the sacrum. Author(s): Lee HC, Cho DY. Source: Surgical Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16427426&query_hl=6&itool=pubmed_docsum
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Assessment of vertebral scalloping in neurofibromatosis type 1 with plain radiography and MRI. Author(s): Tsirikos AI, Ramachandran M, Lee J, Saifuddin A. Source: Clinical Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15488850&query_hl=6&itool=pubmed_docsum
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Asymptomatic massive dural ectasia associated with neurofibromatosis type 1 threatening spinal column support: treatment by anterior vascularized fibula graft. Author(s): de Kleuver M, van Jonbergen JP, Langeloo DD. Source: Journal of Spinal Disorders & Techniques. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15570129&query_hl=6&itool=pubmed_docsum
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Atypical meningioma and extensive calvarium defects in neurofibromatosis type 1. Author(s): Simsek E, Yavuz C, Ustundag N. Source: Pediatric Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12719945&query_hl=6&itool=pubmed_docsum
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Bathing trunk naevus and neurofibromatosis type 1: a unique association of Friedrich's ataxia. Author(s): Shah PA, Hassan I, Nafee A. Source: J Indian Med Assoc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15636042&query_hl=6&itool=pubmed_docsum
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Behavioural, academic and neuropsychological profile of normally gifted Neurofibromatosis type 1 children. Author(s): Descheemaeker MJ, Ghesquiere P, Symons H, Fryns JP, Legius E. Source: Journal of Intellectual Disability Research : Jidr. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15634310&query_hl=6&itool=pubmed_docsum
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Benign and malignant pathology in neurofibromatosis type 1. Author(s): Walker M, Gabikian P. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17000953&query_hl=6&itool=pubmed_docsum
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Benign metastasizing leiomyomatosis with massive brachial plexus involvement mimicking neurofibromatosis type 1. Author(s): de Ruiter GC, Scheithauer BW, Amrami KK, Spinner RJ. Source: Clin Neuropathol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17140158&query_hl=6&itool=pubmed_docsum
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Bilateral retinal macroaneurysms with neurofibromatosis type 1. Author(s): Koyama Y, Shibuya Y, Ohira A. Source: Acta Ophthalmologica Scandinavica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12752065&query_hl=6&itool=pubmed_docsum
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Bilateral testicular tumour in neurofibromatosis type 1. Author(s): Kume H, Tachikawa T, Teramoto S, Isurugi K, Kitamura T. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11211029&query_hl=6&itool=pubmed_docsum
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Blood expression profiles for tuberous sclerosis complex 2, neurofibromatosis type 1, and Down's syndrome. Author(s): Tang Y, Schapiro MB, Franz DN, Patterson BJ, Hickey FJ, Schorry EK, Hopkin RJ, Wylie M, Narayan T, Glauser TA, Gilbert DL, Hershey AD, Sharp FR. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15562430&query_hl=6&itool=pubmed_docsum
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Bone deformity showing a deep coronoid notch of the mandible in a patient with neurofibromatosis type 1. Author(s): Hisatomi M, Asaumi J, Konouchi H, Yanagi Y, Kishi K. Source: Dento Maxillo Facial Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16227483&query_hl=6&itool=pubmed_docsum
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Bone mineral density in children and adolescents with neurofibromatosis type 1. Author(s): Stevenson DA, Moyer-Mileur LJ, Murray M, Slater H, Sheng X, Carey JC, Dube B, Viskochil DH. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17188620&query_hl=6&itool=pubmed_docsum
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Bony orbital morphology in neurofibromatosis type 1 (NF1). Author(s): Kaste SC, Pivnick EK. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9719366&query_hl=6&itool=pubmed_docsum
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Bowel perforation due to gastrointestinal autonomic nerve tumour associated with neurofibromatosis type 1. Author(s): Odeh M, Misselevich I, Oliven A. Source: European Journal of Gastroenterology & Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11711789&query_hl=6&itool=pubmed_docsum
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Brachial plexopathy due to malignant peripheral nerve sheath tumor in neurofibromatosis type 1: case report and subject review. Author(s): Pacelli J, Whitaker CH. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16323217&query_hl=6&itool=pubmed_docsum
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Brain apparent diffusion coefficient evaluation in pediatric patients with neurofibromatosis type 1. Author(s): Tognini G, Ferrozzi F, Garlaschi G, Piazza P, Patti A, Virdis R, Bertolino C, Bertolino G, Manfredini D, Zompatori M, Crisi G. Source: Journal of Computer Assisted Tomography. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15891494&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis Type 1
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Brain morphometry, T2-weighted hyperintensities, and IQ in children with neurofibromatosis type 1. Author(s): Greenwood RS, Tupler LA, Whitt JK, Buu A, Dombeck CB, Harp AG, Payne ME, Eastwood JD, Krishnan KR, MacFall JR. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16344348&query_hl=6&itool=pubmed_docsum
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Brain stem involvement in children with neurofibromatosis type 1: role of magnetic resonance imaging and spectroscopy in the distinction from diffuse pontine glioma. Author(s): Broniscer A, Gajjar A, Bhargava R, Langston JW, Heideman R, Jones D, Kun LE, Taylor J. Source: Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9007866&query_hl=6&itool=pubmed_docsum
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Brain tumors predominantly express the neurofibromatosis type 1 gene transcripts containing the 63 base insert in the region coding for GTPase activating proteinrelated domain. Author(s): Suzuki Y, Suzuki H, Kayama T, Yoshimoto T, Shibahara S. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1662505&query_hl=6&itool=pubmed_docsum
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Brain volume in children with neurofibromatosis type 1: relation to neuropsychological status. Author(s): Moore BD 3rd, Slopis JM, Jackson EF, De Winter AE, Leeds NE. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10690986&query_hl=6&itool=pubmed_docsum
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Brainstem tumors in patients with neurofibromatosis type 1: a distinct clinical entity. Author(s): Molloy PT, Bilaniuk LT, Vaughan SN, Needle MN, Liu GT, Zackai EH, Phillips PC. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7477989&query_hl=6&itool=pubmed_docsum
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Brief report: the association of neurofibromatosis type 1 and autism. Author(s): Williams PG, Hersh JH. Source: Journal of Autism and Developmental Disorders. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9932243&query_hl=6&itool=pubmed_docsum
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Cafe-au-lait spots in neurofibromatosis type 1 and in healthy control individuals: hyperpigmentation of a different kind? Author(s): De Schepper S, Boucneau J, Vander Haeghen Y, Messiaen L, Naeyaert JM, Lambert J. Source: Archives of Dermatological Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16479403&query_hl=6&itool=pubmed_docsum
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Capsule endoscopy revealing small-intestinal lymphangiectasia and GI stromal tumor polyps in neurofibromatosis type 1. Author(s): Calabrese C, Pironi L, Di Febo G. Source: Gastrointestinal Endoscopy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16813823&query_hl=6&itool=pubmed_docsum
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Case-control study of the muscular compartments and osseous strength in neurofibromatosis type 1 using peripheral quantitative computed tomography. Author(s): Stevenson DA, Moyer-Mileur LJ, Carey JC, Quick JL, Hoff CJ, Viskochil DH. Source: J Musculoskelet Neuronal Interact. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15951630&query_hl=6&itool=pubmed_docsum
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Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1. Author(s): Naidich MJ, Walker MT, Gottardi-Littell NR, Han G, Chandler JP. Source: Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15289955&query_hl=6&itool=pubmed_docsum
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Cerebrovascular abnormalities in a population of children with neurofibromatosis type 1. Author(s): Rosser TL, Vezina G, Packer RJ. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15699396&query_hl=6&itool=pubmed_docsum
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Cervicothoracic malignant peripheral nerve sheath tumor in a 12-year-old girl with neurofibromatosis type 1. Author(s): Imazu M, Nakamura Y, Nakatani H, Kaneda H, Okamura K, Sato O, Hayase Y. Source: European Journal of Pediatric Surgery : Official Journal of Austrian Association of Pediatric Surgery. [et Al] = Zeitschrift Fur Kinderchirurgie. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16981098&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis Type 1
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Characteristics of Lisch nodules in patients with neurofibromatosis type 1. Author(s): Nichols JC, Amato JE, Chung SM. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14560838&query_hl=6&itool=pubmed_docsum
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Cherubism associated with neurofibromatosis type 1, and multiple osteolytic lesions of both femurs: a previously undescribed association of findings. Author(s): Martinez-Tello FJ, Manjon-Luengo P, Martin-Perez M, Montes-Moreno S. Source: Skeletal Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16096755&query_hl=6&itool=pubmed_docsum
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Chiari I malformation and neurofibromatosis type 1. Author(s): Tubbs RS, Rutledge SL, Kosentka A, Bartolucci AA, Oakes WJ. Source: Pediatric Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15087107&query_hl=6&itool=pubmed_docsum
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Choroidal ganglioneuroma in a patient with neurofibromatosis type 1: a case report. Author(s): Shome D, Vemuganti GK, Honavar SG. Source: Eye (London, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16557286&query_hl=6&itool=pubmed_docsum
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Circulating growth factor levels are associated with tumorigenesis in neurofibromatosis type 1. Author(s): Mashour GA, Driever PH, Hartmann M, Drissel SN, Zhang T, Scharf B, Felderhoff-Muser U, Sakuma S, Friedrich RE, Martuza RL, Mautner VF, Kurtz A. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15355893&query_hl=6&itool=pubmed_docsum
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c-Kit receptor expression in normal human Schwann cells and Schwann cell lines derived from neurofibromatosis type 1 tumors. Author(s): Dang I, Nelson JK, DeVries GH. Source: Journal of Neuroscience Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16235251&query_hl=6&itool=pubmed_docsum
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Clinical and genetic characteristics of patients with neurofibromatosis type 1 and pheochromocytoma. Author(s): Bausch B, Borozdin W, Neumann HP; European-American Pheochromocytoma Study Group. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16790714&query_hl=6&itool=pubmed_docsum
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Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype. Author(s): Stevenson DA, Viskochil DH, Rope AF, Carey JC. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16542390&query_hl=6&itool=pubmed_docsum
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Clinical manifestations and management of neurofibromatosis type 1. Author(s): Tonsgard JH. Source: Semin Pediatr Neurol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16818170&query_hl=6&itool=pubmed_docsum
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Clinicopathological study of neurofibromatosis type 1: an experience in Nigeria. Author(s): Odebode TO, Afolayan EA, Adigun IA, Daramola OO. Source: International Journal of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15689208&query_hl=6&itool=pubmed_docsum
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Cognitive profile of neurofibromatosis type 1. Author(s): Levine TM, Materek A, Abel J, O'Donnell M, Cutting LE. Source: Semin Pediatr Neurol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16818171&query_hl=6&itool=pubmed_docsum
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Congenital intrahepatic portosystemic venous shunt: an unusual feature in LEOPARD syndrome and in neurofibromatosis type 1. Author(s): Digilio MC, Capolino R, Marino B, Sarkozy A, Dallapiccola B. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15669093&query_hl=6&itool=pubmed_docsum
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Cutaneous malignant melanoma and neurofibromatosis type 1. Author(s): Guillot B, Dalac S, Delaunay M, Baccard M, Chevrant-Breton J, Dereure O, Machet L, Sassolas B, Zeller J, Bernard P, Bedane C, Wolkenstein P; French Group of Cutaneous Oncology. Source: Melanoma Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15057048&query_hl=6&itool=pubmed_docsum
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Cutaneous melanoma with neurofibromatosis type 1: rare association? A case report and review of the literature. Author(s): Salvi PF, Lombardi A, Puzzovio A, Stagnitti F, Tisba M, Gaudinieri A, Pappalardo G. Source: Ann Ital Chir. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15283396&query_hl=6&itool=pubmed_docsum
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Debrisoquine hydroxylase gene polymorphism in neurofibromatosis type 1. Author(s): Wundrack I, Sasiadek M, Blin N. Source: Anticancer Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9494560&query_hl=6&itool=pubmed_docsum
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Decreased bone mineral density and content in neurofibromatosis type 1: lowest local values are located in the load-carrying parts of the body. Author(s): Kuorilehto T, Poyhonen M, Bloigu R, Heikkinen J, Vaananen K, Peltonen J. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15551055&query_hl=6&itool=pubmed_docsum
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Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Author(s): Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, et al. Source: Cell. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1694727&query_hl=6&itool=pubmed_docsum
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Deletions spanning the neurofibromatosis type 1 gene: implications for genotypephenotype correlations in neurofibromatosis type 1? Author(s): Cnossen MH, van der Est MN, Breuning MH, van Asperen CJ, BreslauSiderius EJ, van der Ploeg AT, de Goede-Bolder A, van den Ouweland AM, Halley DJ, Niermeijer MF. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9143927&query_hl=6&itool=pubmed_docsum
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Desert hedgehog signalling pathway is involved in the proliferation of a malignant peripheral nerve sheath tumour-derived cell line from neurofibromatosis type 1. Author(s): Endo H, Utani A, Shinkai H. Source: The British Journal of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12366446&query_hl=6&itool=pubmed_docsum
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Diagnosis and management of neurofibromatosis type 1. Author(s): Korf BR. Source: Curr Neurol Neurosci Rep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11898512&query_hl=6&itool=pubmed_docsum
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Diagnosis of neurofibromatosis type 1 using RFLPs tightly linked to gene. Author(s): Vivarelli R, Bartalani G, Berardi A, Calistri L, Balestri P, Fois A. Source: Child's Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8104099&query_hl=6&itool=pubmed_docsum
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Diagnostic delay in neurofibromatosis type 1. Author(s): Cnossen MH, Smit FJ, de Goede-Bolder A, Frets PG, Duivenvoorden HJ, Niermeijer MF. Source: European Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9208248&query_hl=6&itool=pubmed_docsum
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Differential contribution of M(r) 120 kDa rasGTPase-activating protein and neurofibromatosis type 1 gene product during the transition from growth phase to arrested state in human fibroblasts accompanied by a unique rasGTPase-activating activity. Author(s): Kobayashi M, Hashimoto N, Hoshino M, Hattori S, Iwashita S. Source: Febs Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8335107&query_hl=6&itool=pubmed_docsum
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Diffuse-type tenosynovial giant cell tumor in association with neurofibromatosis type 1-Noonan syndrome: possibly more than a chance relationship. Author(s): Posligua L, McDonald DJ, Dehner LP. Source: The American Journal of Surgical Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16723851&query_hl=6&itool=pubmed_docsum
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Diffusion MRI in neurofibromatosis type 1: ADC evaluations of the optic pathways, and a comparison with normal individuals. Author(s): Sener RN. Source: Computerized Medical Imaging and Graphics : the Official Journal of the Computerized Medical Imaging Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11818185&query_hl=6&itool=pubmed_docsum
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Diffusion of information about neurofibromatosis type 1 DNA testing. Author(s): Hofman KJ. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8209889&query_hl=6&itool=pubmed_docsum
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Diffusion property in a hamartomatous lesion of neurofibromatosis type 1. Author(s): Mori H, Abe O, Okubo T, Hayashi N, Yoshikawa T, Kunimatsu A, Yamada H, Aoki S, Ohtomo K. Source: Journal of Computer Assisted Tomography. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11473182&query_hl=6&itool=pubmed_docsum
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Discordant puberty in monozygotic twin sisters with neurofibromatosis type 1 (NF1). Author(s): Kelly TE, Sproul GT, Huerta MG, Rogol AD. Source: Clinical Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9597296&query_hl=6&itool=pubmed_docsum
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Discrete and confluent Lisch nodules in neurofibromatosis type 1. Author(s): Saxena S, Saxena RC. Source: Ann Ophthalmol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8198365&query_hl=6&itool=pubmed_docsum
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DNA testing for neurofibromatosis type 1. Author(s): Karasik JB, Marion RW, Javed AA. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1359047&query_hl=6&itool=pubmed_docsum
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Duodenal somatostatinoma and gastrointestinal stromal tumor associated with neurofibromatosis type 1: diagnosis with PET/CT. Author(s): Juergens KU, Weckesser M, Bettendorf O, Wormanns D. Source: Ajr. American Journal of Roentgenology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16861519&query_hl=6&itool=pubmed_docsum
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Dural ectasia of the optic nerve sheath in neurofibromatosis type 1: CT and MR features. Author(s): Lovblad KO, Remonda L, Ozdoba C, Huber P, Schroth G. Source: Journal of Computer Assisted Tomography. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8089320&query_hl=6&itool=pubmed_docsum
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Dural ectasia of the optic nerve sheath in neurofibromatosis type 1: MRI manifestations. Author(s): Doi J, Uchino A, Kato A, Koga T, Kudo S. Source: Radiat Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9278380&query_hl=6&itool=pubmed_docsum
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Dysembryoplastic neuroepithelial tumors in two children with neurofibromatosis type 1. Author(s): Lellouch-Tubiana A, Bourgeois M, Vekemans M, Robain O. Source: Acta Neuropathologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8525807&query_hl=6&itool=pubmed_docsum
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Early cardiac morphologic and functional changes in neurofibromatosis type 1 hypertensives: an echocardiographic and tissue Doppler study. Author(s): Tedesco MA, Di Salvo G, Natale F, Graziano L, Grassia C, Calabro R, Lama G. Source: International Journal of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15882671&query_hl=6&itool=pubmed_docsum
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Early spontaneous regression of a hypothalamic/chiasmatic mass in neurofibromatosis type 1: MR findings. Author(s): Zuccoli G, Ferrozzi F, Sigorini M, Virdis R, Bassi P, Bellomi M. Source: European Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11003401&query_hl=6&itool=pubmed_docsum
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Effects of activin A on the growth of neurofibroma-derived cells from a patient with neurofibromatosis type 1. Author(s): Kotsuji T, Imakado S, Ichikawa E, Otsuka F. Source: Dermatology (Basel, Switzerland). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11096207&query_hl=6&itool=pubmed_docsum
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Electro-oculogram in patients with neurofibromatosis type 1. Author(s): Lubinski W, Zajaczek S, Sych Z, Penkala K, Palacz O, Lubinski J. Source: Documenta Ophthalmologica. Advances in Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11720259&query_hl=6&itool=pubmed_docsum
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Endotracheal neurofibroma in neurofibromatosis type 1: an unusual manifestation. Author(s): Willmann JK, Weishaupt D, Kestenholz PB, von Smekal A, Marincek B. Source: European Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11868097&query_hl=6&itool=pubmed_docsum
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Enlarging tongue masses in neurofibromatosis type 1: MR findings of two cases. Author(s): Zuccoli G, Ferrozzi F, Tognini G, Troiso A. Source: Clinical Imaging. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11566089&query_hl=6&itool=pubmed_docsum
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Epidemiology of neurofibromatosis type 1 (NF1) in northern Finland. Author(s): Poyhonen M, Kytola S, Leisti J. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10991696&query_hl=6&itool=pubmed_docsum
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Epidemiology of neurofibromatosis type 1. Author(s): Friedman JM. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10469430&query_hl=6&itool=pubmed_docsum
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Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. Author(s): DeClue JE, Heffelfinger S, Benvenuto G, Ling B, Li S, Rui W, Vass WC, Viskochil D, Ratner N. Source: The Journal of Clinical Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10791998&query_hl=6&itool=pubmed_docsum
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Epidermodysplasia verruciformis associated with neurofibromatosis type 1: coincidental association or model for understanding the underlying mechanism of the disease? Author(s): Alpsoy E, Ciftcioglu MA, Keser I, De Villiers EM, Zouboulis CC. Source: The British Journal of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11952554&query_hl=6&itool=pubmed_docsum
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Epigastric pain in a patient with neurofibromatosis type 1. Author(s): Leung VK, Lee SW, Yuen NW, Kung NN, Loke TK. Source: Hong Kong Medical Journal = Xianggang Yi Xue Za Zhi / Hong Kong Academy of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15951589&query_hl=6&itool=pubmed_docsum
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Establishment and characterization of a novel malignant astrocytoma cell line derived from a tumor removed in a patient with neurofibromatosis type 1. Author(s): Kurimoto M, Hirashima Y, Ogiichi T, Hamada H, Kamiyama H, Endo S. Source: Journal of Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11213969&query_hl=6&itool=pubmed_docsum
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Evaluation of genotype-phenotype correlations in neurofibromatosis type 1. Author(s): Castle B, Baser ME, Huson SM, Cooper DN, Upadhyaya M. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14569132&query_hl=6&itool=pubmed_docsum
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Evaluation of primary haemostasis in people with neurofibromatosis type 1. Author(s): Favaloro EJ, Zafer M, Nair SC, Hertzberg M, North K. Source: Clinical and Laboratory Haematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15485464&query_hl=6&itool=pubmed_docsum
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EVI2B, a gene lying in an intron of the neurofibromatosis type 1 (NF1) gene, is as the NF1 gene involved in differentiation of melanocytes and keratinocytes and is overexpressed in cells derived from NF1 neurofibromas. Author(s): Kaufmann D, Gruener S, Braun F, Stark M, Griesser J, Hoffmeyer S, Bartelt B. Source: Dna and Cell Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10360836&query_hl=6&itool=pubmed_docsum
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Expression patterns of cell cycle components in sporadic and neurofibromatosis type 1-related malignant peripheral nerve sheath tumors. Author(s): Agesen TH, Florenes VA, Molenaar WM, Lind GE, Berner JM, Plaat BE, Komdeur R, Myklebost O, van den Berg E, Lothe RA. Source: Journal of Neuropathology and Experimental Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15715087&query_hl=6&itool=pubmed_docsum
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Expression, purification and preliminary crystallographic characterization of a novel segment from the neurofibromatosis type 1 protein. Author(s): Bonneau F, D'Angelo I, Welti S, Stier G, Ylanne J, Scheffzek K. Source: Acta Crystallographica. Section D, Biological Crystallography. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15583390&query_hl=6&itool=pubmed_docsum
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Extensively high load of internal tumors determined by whole body MRI scanning in a patient with neurofibromatosis type 1 and a non-LCR-mediated 2-Mb deletion in 17q11.2. Author(s): Kehrer-Sawatzki H, Kluwe L, Funsterer C, Mautner VF. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15776250&query_hl=6&itool=pubmed_docsum
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Extensor digitorum brevis manus muscle in a patient with neurofibromatosis type 1. Author(s): Onesti MG, Gargano F, Spalvieri C. Source: Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery / Nordisk Plastikkirurgisk Forening [and] Nordisk Klubb for Handkirurgi. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15328779&query_hl=6&itool=pubmed_docsum
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Extracranial vertebral artery aneurysm ruptured into the thoracic cavity with neurofibromatosis type 1: case report. Author(s): Miyazaki T, Ohta F, Daisu M, Hoshii Y. Source: Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15157311&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis Type 1
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Familial cafe au lait spots: a variant of neurofibromatosis type 1. Author(s): Abeliovich D, Gelman-Kohan Z, Silverstein S, Lerer I, Chemke J, Merin S, Zlotogora J. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8825931&query_hl=6&itool=pubmed_docsum
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Familial neurofibromatosis type 1 associated with an overgrowth syndrome resembling Weaver syndrome. Author(s): van Asperen CJ, Overweg-Plandsoen WC, Cnossen MH, van Tijn DA, Hennekam RC. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9598729&query_hl=6&itool=pubmed_docsum
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Familial neurofibromatosis type 1: clinical experience with DNA testing. Author(s): Hofman KJ, Boehm CD. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1347082&query_hl=6&itool=pubmed_docsum
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Familial reciprocal translocation t(17;19) (q11.2;q13.2) associated with neurofibromatosis type 1, including one patient with non-Hodgkin lymphoma and an additional t(14;20) in B lymphocytes. Author(s): Fahsold R, Habash T, Trautmann U, Haustein A, Pfeiffer RA. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7607657&query_hl=6&itool=pubmed_docsum
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Fetal antigen 1, a member of the epidermal growth factor superfamily, in neurofibromas and serum from patients with neurofibromatosis type 1. Author(s): Jensen CH, Schroder HD, Teisner B, Laursen I, Brandrup F, Rasmussen HB. Source: The British Journal of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10354070&query_hl=6&itool=pubmed_docsum
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Fibroblasts of neurofibromatosis type 1 showed no abnormality in p21ras-mediated response to serum in culture. Author(s): Kitano Y, Saito K, Okamoto E, Hashizume K. Source: Journal of Dermatological Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8060920&query_hl=6&itool=pubmed_docsum
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Follow-up of optic pathway gliomas in children with neurofibromatosis type 1. Author(s): Kuenzle C, Weissert M, Roulet E, Bode H, Schefer S, Huisman T, Landau K, Boltshauser E. Source: Neuropediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7770126&query_hl=6&itool=pubmed_docsum
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Four frameshift mutations in neurofibromatosis type 1 caused by small insertions. Author(s): Colman SD, Abernathy CR, Ho VT, Wallace MR. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9222967&query_hl=6&itool=pubmed_docsum
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Frequency of choroidal abnormalities in neurofibromatosis type 1. Author(s): Yasunari T, Shiraki K, Hattori H, Miki T. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11041400&query_hl=6&itool=pubmed_docsum
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Frequency of incidental intracranial aneurysms in neurofibromatosis type 1. Author(s): Schievink WI, Riedinger M, Maya MM. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15690406&query_hl=6&itool=pubmed_docsum
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From the archives of the AFIP: abdominal neoplasms in patients with neurofibromatosis type 1: radiologic-pathologic correlation. Author(s): Levy AD, Patel N, Dow N, Abbott RM, Miettinen M, Sobin LH. Source: Radiographics : a Review Publication of the Radiological Society of North America, Inc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15798063&query_hl=6&itool=pubmed_docsum
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Functional analysis of polymorphic variation within the promoter and 5' untranslated region of the neurofibromatosis type 1 (NF1) gene. Author(s): Horan MP, Osborn M, Cooper DN, Upadhyaya M. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15523626&query_hl=6&itool=pubmed_docsum
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Functional splicing assay shows a pathogenic intronic mutation in neurofibromatosis type 1 (NF1) due to intronic sequence exonization. Author(s): Raponi M, Upadhyaya M, Baralle D. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16470740&query_hl=6&itool=pubmed_docsum
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Ganglioneuroma and adenocarcinoma associated with neurofibromatosis type 1 in the colorectal region. Author(s): Tomita H, Miya K, Tanaka H, Shimokawa K. Source: International Journal of Colorectal Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15660267&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis Type 1
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Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation. Author(s): Gallinger S, Aronson M, Shayan K, Ratcliffe EM, Gerstle JT, Parkin PC, Rothenmund H, Croitoru M, Baumann E, Durie PR, Weksberg R, Pollett A, Riddell RH, Ngan BY, Cutz E, Lagarde AE, Chan HS. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14762794&query_hl=6&itool=pubmed_docsum
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Generalized nerve sheath tumors in neurofibromatosis type 1 (NF1). A case report. Author(s): Pascual-Castroviejo I, Pascual-Pascual SI, Viano J, Martinez V. Source: Neuropediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11071148&query_hl=6&itool=pubmed_docsum
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Genetic and cellular defects contributing to benign tumor formation in neurofibromatosis type 1. Author(s): Rutkowski JL, Wu K, Gutmann DH, Boyer PJ, Legius E. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10767330&query_hl=6&itool=pubmed_docsum
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Genetic and clinical mosaicism in a patient with neurofibromatosis type 1. Author(s): Vandenbroucke I, van Doorn R, Callens T, Cobben JM, Starink TM, Messiaen L. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14605872&query_hl=6&itool=pubmed_docsum
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Genetic and phenotypic characterization of tumor cells derived from malignant peripheral nerve sheath tumors of neurofibromatosis type 1 patients. Author(s): Frahm S, Mautner VF, Brems H, Legius E, Debiec-Rychter M, Friedrich RE, Knofel WT, Peiper M, Kluwe L. Source: Neurobiology of Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15207265&query_hl=6&itool=pubmed_docsum
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Genomic characterization of the Neurofibromatosis Type 1 gene of Fugu rubripes. Author(s): Kehrer-Sawatzki H, Maier C, Moschgath E, Elgar G, Krone W. Source: Gene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9813292&query_hl=6&itool=pubmed_docsum
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GI stromal tumor diagnosed by capsule endoscopy in a patient with neurofibromatosis type 1. Author(s): Jung SW, Kim CD, Chun HR, Kim YS, Jeen YT, Lee HS, Chun HJ, Um SH, Lee SW, Choi JH, Ryu HS, Hyun JH. Source: Gastrointestinal Endoscopy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16813821&query_hl=6&itool=pubmed_docsum
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Giant aneurysm of the vertebral artery in neurofibromatosis type 1: report of a case and review of the literature. Author(s): Hoffmann KT, Hosten N, Liebig T, Schwarz K, Felix R. Source: Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9592796&query_hl=6&itool=pubmed_docsum
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Giant cafe-au-lait macule in neurofibromatosis type 1. Author(s): Thappa DM, Jeevankumar B, Karthikeyan K. Source: The Journal of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11280470&query_hl=6&itool=pubmed_docsum
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Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1). Author(s): Gutmann DH, Rasmussen SA, Wolkenstein P, MacCollin MM, Guha A, Inskip PD, North KN, Poyhonen M, Birch PH, Friedman JM. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12221173&query_hl=6&itool=pubmed_docsum
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Gonosomal mosaicism for a nonsense mutation (R1947X) in the NF1 gene in segmental neurofibromatosis type 1. Author(s): Consoli C, Moss C, Green S, Balderson D, Cooper DN, Upadhyaya M. Source: The Journal of Investigative Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16117786&query_hl=6&itool=pubmed_docsum
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Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. Author(s): Upadhyaya M, Ruggieri M, Maynard J, Osborn M, Hartog C, Mudd S, Penttinen M, Cordeiro I, Ponder M, Ponder BA, Krawczak M, Cooper DN. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9654211&query_hl=6&itool=pubmed_docsum
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Growth and pubertal disorders in neurofibromatosis type 1. Author(s): Virdis R, Street ME, Bandello MA, Tripodi C, Donadio A, Villani AR, Cagozzi L, Garavelli L, Bernasconi S. Source: J Pediatr Endocrinol Metab. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12729406&query_hl=6&itool=pubmed_docsum
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Growth curve analyses of neuropsychological profiles in children with neurofibromatosis type 1: specific cognitive tests remain "spared" and "impaired" over time. Author(s): Cutting LE, Huang GH, Zeger S, Koth CW, Thompson RE, Denckl MB. Source: Journal of the International Neuropsychological Society : Jins. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12240748&query_hl=6&itool=pubmed_docsum
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Growth hormone deficiency in children with neurofibromatosis type 1 without suprasellar lesions. Author(s): Vassilopoulou-Sellin R, Klein MJ, Slopis JK. Source: Pediatric Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10913726&query_hl=6&itool=pubmed_docsum
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Growth hormone excess in a child with neurofibromatosis type 1 and optic pathway tumor: a patient report. Author(s): Fuqua JS, Berkovitz GD. Source: Clinical Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9864651&query_hl=6&itool=pubmed_docsum
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Growth, puberty, and endocrine functions in patients with sporadic or familial neurofibromatosis type 1: a longitudinal study. Author(s): Carmi D, Shohat M, Metzker A, Dickerman Z. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10353939&query_hl=6&itool=pubmed_docsum
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Gynecomastia with pseudoangiomatous stromal hyperplasia and multinucleated giant cells. Association with neurofibromatosis type 1. Author(s): Zamecnik M, Michal M, Gogora M, Mukensnabl P, Dobias V, Vano M. Source: Virchows Archiv : an International Journal of Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12111205&query_hl=6&itool=pubmed_docsum
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Hamartoma involving the pseudarthrosis site in patients with neurofibromatosis type 1. Author(s): Mariaud-Schmidt RP, Rosales-Quintana S, Bitar E, Fajardo D, Chiapa-Robles G, Gonzalez-Mendoza A, Barros-Nunez P. Source: Pediatric and Developmental Pathology : the Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15719206&query_hl=6&itool=pubmed_docsum
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Headache in patients with neurofibromatosis type 1. Author(s): Clementi M, Battistella PA, Rizzi L, Boni S, Tenconi R. Source: Headache. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8666529&query_hl=6&itool=pubmed_docsum
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Hearing loss in neurofibromatosis type 1: report of two cases. Author(s): Shamboul K, Grundfast K. Source: East Afr Med J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10442137&query_hl=6&itool=pubmed_docsum
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Heart rhythm in patients with neurofibromatosis type 1. Author(s): Malmcrona R, Zoller M, Rembeck B. Source: Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8793163&query_hl=6&itool=pubmed_docsum
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Heavily lipidized, calcified giant cell glioblastoma in an 8-year-old patient, associated with neurofibromatosis type 1 (NF1): report of a case with long-term survival. Author(s): Kroh H, Matyja E, Marchel A, Bojarski P. Source: Clin Neuropathol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15584213&query_hl=6&itool=pubmed_docsum
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High frequencies of plexiform neurofibromas, mental retardation, learning difficulties, and scoliosis in Brazilian patients with neurofibromatosis type 1. Author(s): Trovo-Marqui AB, Goloni-Bertollo EM, Valerio NI, Pavarino-Bertelli EC, Muniz MP, Teixeira MF, Antonio JR, Tajara EH. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16138229&query_hl=6&itool=pubmed_docsum
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High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene. Author(s): Kehrer-Sawatzki H, Kluwe L, Sandig C, Kohn M, Wimmer K, Krammer U, Peyrl A, Jenne DE, Hansmann I, Mautner VF. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15257518&query_hl=6&itool=pubmed_docsum
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High-intensity lesion on T1-weighted MR images in neurofibromatosis type 1: a case of premalignant lesion. Author(s): Miaux Y, Guermazi A, Cornu P, Mokhtari K, Singer B, Chiras J, BlanchetBardon C. Source: Acta Neurochirurgica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9442225&query_hl=6&itool=pubmed_docsum
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Hippocampal involvement in identical twins with neurofibromatosis type 1. Author(s): Tubridy N, Schon F, Moss A, Clarke A, Cox T, Ferner R. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11439966&query_hl=6&itool=pubmed_docsum
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HNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1. Author(s): Raevaara TE, Gerdes AM, Lonnqvist KE, Tybjaerg-Hansen A, Abdel-Rahman WM, Kariola R, Peltomaki P, Nystrom-Lahti M. Source: Genes, Chromosomes & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15139004&query_hl=6&itool=pubmed_docsum
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Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. Author(s): Side L, Taylor B, Cayouette M, Conner E, Thompson P, Luce M, Shannon K. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9180088&query_hl=6&itool=pubmed_docsum
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How children with neurofibromatosis type 1 differ from "typical" learning disabled clinic attenders: nonverbal learning disabilities revisited. Author(s): Cutting LE, Koth CW, Denckla MB. Source: Developmental Neuropsychology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10916573&query_hl=6&itool=pubmed_docsum
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Human blood genomics: distinct profiles for gender, age and neurofibromatosis type 1. Author(s): Tang Y, Lu A, Ran R, Aronow BJ, Schorry EK, Hopkin RJ, Gilbert DL, Glauser TA, Hershey AD, Richtand NW, Privitera M, Dalvi A, Sahay A, Szaflarski JP, Ficker DM, Ratner N, Sharp FR. Source: Brain Research. Molecular Brain Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15582155&query_hl=6&itool=pubmed_docsum
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Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Author(s): Ricciardone MD, Ozcelik T, Cevher B, Ozdag H, Tuncer M, Gurgey A, Uzunalimoglu O, Cetinkaya H, Tanyeli A, Erken E, Ozturk M. Source: Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9927033&query_hl=6&itool=pubmed_docsum
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Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. Author(s): Yang FC, Chen S, Robling AG, Yu X, Nebesio TD, Yan J, Morgan T, Li X, Yuan J, Hock J, Ingram DA, Clapp DW. Source: The Journal of Clinical Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17053831&query_hl=6&itool=pubmed_docsum
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Hyperactive Ras as a therapeutic target in neurofibromatosis type 1. Author(s): Weiss B, Bollag G, Shannon K. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10469432&query_hl=6&itool=pubmed_docsum
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Hypermethylation of the neurofibromatosis type 1 (NF1) gene promoter is not a common event in the inactivation of the NF1 gene in NF1-specific tumours. Author(s): Horan MP, Cooper DN, Upadhyaya M. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10982032&query_hl=6&itool=pubmed_docsum
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Hypokalemic rhabdomyolysis due to WDHA syndrome caused by VIP-producing composite pheochromocytoma: a case in neurofibromatosis type 1. Author(s): Onozawa M, Fukuhara T, Minoguchi M, Takahata M, Yamamoto Y, Miyake T, Kanagawa K, Kanda M, Maekawa I. Source: Japanese Journal of Clinical Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16027147&query_hl=6&itool=pubmed_docsum
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Hypopituitarism associated with neurofibromatosis type 1: report of one case. Author(s): Wang CY, Young C, Chu LW, Tsai WY. Source: Acta Paediatr Taiwan. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15264708&query_hl=6&itool=pubmed_docsum
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Hypothalamic hamartoma as a cause of precocious puberty in neurofibromatosis type 1: patient report. Author(s): Biswas K, Kapoor A, Jain S, Ammini AC. Source: J Pediatr Endocrinol Metab. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10777001&query_hl=6&itool=pubmed_docsum
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Identification and characterization of four novel large deletions in the human neurofibromatosis type 1 (NF1) gene. Author(s): Fang LJ, Vidaud D, Vidaud M, Thirion JP. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11748857&query_hl=6&itool=pubmed_docsum
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Identification of an insertion and accompanying deletion in exon 31 of the neurofibromatosis type 1 gene. Author(s): Skuse GR. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9452038&query_hl=6&itool=pubmed_docsum
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Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1. Author(s): Lee MJ, Su YN, You HL, Chiou SC, Lin LC, Yang CC, Lee WC, Hwu WL, Hsieh FJ, Stephenson DA, Yu CL. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16835897&query_hl=6&itool=pubmed_docsum
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Identification of growth hormone receptor in localised neurofibromas of patients with neurofibromatosis type 1. Author(s): Cunha KS, Barboza EP, Da Fonseca EC. Source: Journal of Clinical Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14514779&query_hl=6&itool=pubmed_docsum
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Identification of two novel frame shift mutations of the NF1 gene in Korean patients with neurofibromatosis type 1. Author(s): Park KC, Choi HO, Han WS, Hwang JH, Park KH, Kim KH, Chung JH, Eun HC. Source: Journal of Korean Medical Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11068991&query_hl=6&itool=pubmed_docsum
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Identification of two novel mutations (1448delA and Q682X) in the NF1 gene and analysis for nonsense mutations in patients with neurofibromatosis type 1. Author(s): Horiuchi T, Hatta N, Watanabe I, Kobayashi Y, Wallace MR, Shirakata Y, Ohtsuka H, Fujita S. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9452037&query_hl=6&itool=pubmed_docsum
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Increased brain apparent diffusion coefficient in children with neurofibromatosis type 1. Author(s): Eastwood JD, Fiorella DJ, MacFall JF, Delong DM, Provenzale JM, Greenwood RS. Source: Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11323456&query_hl=6&itool=pubmed_docsum
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Increased noise as an effect of haploinsufficiency of the tumor-suppressor gene neurofibromatosis type 1 in vitro. Author(s): Kemkemer R, Schrank S, Vogel W, Gruler H, Kaufmann D. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12368469&query_hl=6&itool=pubmed_docsum
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Infantile spasms in patients with neurofibromatosis type 1. Author(s): Fois A, Tine A, Pavone L. Source: Child's Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8044814&query_hl=6&itool=pubmed_docsum
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Infrequent involvement of mutations on neurofibromatosis type 1, H-ras, K-ras and N-ras in urothelial tumors. Author(s): Uchida T, Wada C, Ishida H, Egawa S, Ao T, Yokoyama E, Koshiba K. Source: Urologia Internationalis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8533197&query_hl=6&itool=pubmed_docsum
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Inhibition of Ras/Raf interaction by anti-oncogenic mutants of neurofibromin, the neurofibromatosis type 1 (NF1) gene product, in cell-free systems. Author(s): Mori S, Satoh T, Koide H, Nakafuku M, Villafranca E, Kaziro Y. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7499408&query_hl=6&itool=pubmed_docsum
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Intelligence in individuals with a neurofibromatosis type 1 microdeletion. Author(s): Descheemaeker MJ, Roelandts K, De Raedt T, Brems H, Fryns JP, Legius E. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15472997&query_hl=6&itool=pubmed_docsum
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Intestinal mesenteric involvement with plexiform neurofibroma in neurofibromatosis type 1. Author(s): Imamoglu M, Cay A, Yaris N, Yayla S, Sarihan H. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16732807&query_hl=6&itool=pubmed_docsum
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Intracranial abnormalities associated with facial plexiform neurofibromas in neurofibromatosis type 1. Author(s): Boltshauser E, Stocker H, Sailer H, Valavanis A. Source: Neurofibromatosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2518508&query_hl=6&itool=pubmed_docsum
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Intracranial gliomas in neurofibromatosis type 1. Author(s): Listernick R, Charrow J, Gutmann DH. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10469435&query_hl=6&itool=pubmed_docsum
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Intramedullary spinal cord tumour associated with neurofibromatosis type 1. Author(s): Yagi T, Ohata K, Haque M, Hakuba A. Source: Acta Neurochirurgica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9442220&query_hl=6&itool=pubmed_docsum
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Intrathoracic peripheral nerve sheath tumors in patients with neurofibromatosis type 1 (von Recklinghausen disease). Author(s): Patel VS, St Louis JD, Oduntan O, Landolfo KP. Source: The Journal of Thoracic and Cardiovascular Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16515934&query_hl=6&itool=pubmed_docsum
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Ionic currents in normal and neurofibromatosis type 1-affected human Schwann cells: induction of tumor cell K current in normal Schwann cells by cyclic AMP. Author(s): Fieber LA. Source: Journal of Neuroscience Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9822160&query_hl=6&itool=pubmed_docsum
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Is Jaffe-Campanacci syndrome just a manifestation of neurofibromatosis type 1? Author(s): Colby RS, Saul RA. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14556247&query_hl=6&itool=pubmed_docsum
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Is the distribution of dermal neurofibromas in neurofibromatosis type 1 (NF1) related to the pattern of the skin surface temperature? Author(s): Kaufmann D, Tinschert S, Algermissen B. Source: European Journal of Dermatology : Ejd. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11701400&query_hl=6&itool=pubmed_docsum
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Jaw malformations plus displacement and numerical aberrations of teeth in neurofibromatosis type 1: a descriptive analysis of 48 patients based on panoramic radiographs and oral findings. Author(s): Friedrich RE, Giese M, Schmelzle R, Mautner VF, Scheuer HA. Source: Journal of Cranio-Maxillo-Facial Surgery : Official Publication of the European Association for Cranio-Maxillo-Facial Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12553919&query_hl=6&itool=pubmed_docsum
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Ki-67 proliferation-index (MIB-1) of neurofibromas in neurofibromatosis type 1 patients. Author(s): Friedrich RE, Hagel C, Brehme Z, Kluwe L, Mautner VF. Source: Anticancer Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12820329&query_hl=6&itool=pubmed_docsum
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Knowledge without truth: screening for complications of neurofibromatosis type 1 in childhood. Author(s): Listernick R, Charrow J. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15150769&query_hl=6&itool=pubmed_docsum
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Learning disabilities in children with neurofibromatosis type 1: subtypes, cognitive profile, and attention-deficit-hyperactivity disorder. Author(s): Hyman SL, Arthur Shores E, North KN. Source: Developmental Medicine and Child Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17109785&query_hl=6&itool=pubmed_docsum
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Lethal manifestations of neurofibromatosis type 1 in childhood. Author(s): Koszyca B, Moore L, Byard RW. Source: Pediatr Pathol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8247955&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis Type 1
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Letter to the editor: neurofibromatosis type 1 (NF 1) associated with embryonal rhabdomyosarcoma of the orbit. Author(s): Hadjistilianou T, Mastrangelo D, Gragnoli A, Capretti MC, De Francesco S, Galluzzi P. Source: Medical and Pediatric Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11984810&query_hl=6&itool=pubmed_docsum
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Life expectancy, mortality and prognostic factors in neurofibromatosis type 1. A twelve-year follow-up of an epidemiological study in Goteborg, Sweden. Author(s): Zoller M, Rembeck B, Akesson HO, Angervall L. Source: Acta Dermato-Venereologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7604643&query_hl=6&itool=pubmed_docsum
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Linkage analysis of neurofibromatosis type 1. Study of a homogeneous North Italian population with five DNA markers of chromosome 17. Author(s): Clementi M, Murgia A, Anglani F, Tenconi R, Turolla L, Picci L, Zacchello F. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1674720&query_hl=6&itool=pubmed_docsum
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Lisch nodule asymmetry in a patient with neurofibromatosis type 1. Author(s): Nichol JC, Amato JE, Chung SM. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12908541&query_hl=6&itool=pubmed_docsum
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Lisch nodules and skin manifestation in neurofibromatosis type 1. Author(s): Otsuka F, Kawashima T, Imakado S, Usuki Y, Hon-Mura S. Source: Archives of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11176707&query_hl=6&itool=pubmed_docsum
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Lisch nodules in neurofibromatosis type 1. Author(s): Lubs ML, Bauer MS, Formas ME, Djokic B. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1901624&query_hl=6&itool=pubmed_docsum
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Lisch nodules of the iris in neurofibromatosis type 1. Author(s): Richetta A, Giustini S, Recupero SM, Pezza M, Carlomagno V, Amoruso G, Calvieri S. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15096151&query_hl=6&itool=pubmed_docsum
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Lisch spots in neurofibromatosis type 1. Author(s): Saxena RC, Saxena S. Source: Indian J Ophthalmol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1810882&query_hl=6&itool=pubmed_docsum
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Localised megacolon complicating neurofibromatosis type 1. Author(s): Duxbury MS, Brodribb AJ. Source: Digestive Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15010589&query_hl=6&itool=pubmed_docsum
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Localization of the 17q breakpoint of a constitutional 1;17 translocation in a patient with neuroblastoma within a 25-kb segment located between the ACCN1 and TLK2 genes and near the distal breakpoints of two microdeletions in neurofibromatosis type 1 patients. Author(s): Van Roy N, Vandesompele J, Berx G, Staes K, Van Gele M, De Smet E, De Paepe A, Laureys G, van der Drift P, Versteeg R, Van Roy F, Speleman F. Source: Genes, Chromosomes & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12203774&query_hl=6&itool=pubmed_docsum
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Localized unilateral hyperhidrosis and neurofibromatosis type 1: case report of a new association. Author(s): Baskan EB, Karli N, Baykara M, Cikman S, Tunali S. Source: Dermatology (Basel, Switzerland). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16205077&query_hl=6&itool=pubmed_docsum
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Longitudinal evaluation of apparent diffusion coefficient in children with neurofibromatosis type 1. Author(s): Sheikh SF, Kubal WS, Anderson AW, Mutalik P. Source: Journal of Computer Assisted Tomography. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14501358&query_hl=6&itool=pubmed_docsum
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Loss of heterozygosity of NF1 gene in juvenile chronic myelogenous leukemia with neurofibromatosis type 1. Author(s): Kai S, Sumita H, Fujioka K, Takahashi H, Hanzawa N, Funabiki T, Ikuta K, Sasaki H. Source: International Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9713168&query_hl=6&itool=pubmed_docsum
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Losses in chromosomes 17, 19, and 22q in neurofibromatosis type 1 and sporadic neurofibromas: a comparative genomic hybridization analysis. Author(s): Koga T, Iwasaki H, Ishiguro M, Matsuzaki A, Kikuchi M. Source: Cancer Genetics and Cytogenetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12237234&query_hl=6&itool=pubmed_docsum
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Lumbar region intra-spinal primitive neuroectodermal tumour (PNET) combined with neurofibromatosis type 1. Author(s): Bohn Sarmiento U, Aguiar Bujanda D, Camacho Galan R, Rivero Vera JC, Aguiar Morales J. Source: Clin Transl Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16373056&query_hl=6&itool=pubmed_docsum
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Malignant peripheral nerve sheath tumors (MPNST) in neurofibromatosis type 1 (NF1): diagnostic findings on magnetic resonance images and mutation analysis of the NF1 gene. Author(s): Friedrich RE, Kluwe L, Funsterer C, Mautner VF. Source: Anticancer Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16033085&query_hl=6&itool=pubmed_docsum
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Malignant peripheral nerve sheath tumour of the cervical vagus nerve in a neurofibromatosis type 1 patient. Author(s): Molina AR, Brasch H, Tan ST. Source: J Plast Reconstr Aesthet Surg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17113542&query_hl=6&itool=pubmed_docsum
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Management of head and neck plexiform neurofibromas in pediatric patients with neurofibromatosis type 1. Author(s): Wise JB, Cryer JE, Belasco JB, Jacobs I, Elden L. Source: Archives of Otolaryngology--Head & Neck Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16103304&query_hl=6&itool=pubmed_docsum
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Manifestations of the tongue in Neurofibromatosis type 1. Author(s): Bongiorno MR, Pistone G, Arico M. Source: Oral Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16476032&query_hl=6&itool=pubmed_docsum
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Math learning disability and math LD subtypes: evidence from studies of Turner syndrome, fragile X syndrome, and neurofibromatosis type 1. Author(s): Mazzocco MM. Source: Journal of Learning Disabilities. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15503567&query_hl=6&itool=pubmed_docsum
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Methylation analysis of the neurofibromatosis type 1 (NF1) promoter in peripheral nerve sheath tumours. Author(s): Harder A, Rosche M, Reuss DE, Holtkamp N, Uhlmann K, Friedrich R, Mautner VF, von Deimling A. Source: European Journal of Cancer (Oxford, England : 1990). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15571966&query_hl=6&itool=pubmed_docsum
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Misdiagnosis of neurofibromatosis type 1 as Proteus syndrome. Author(s): Biesecker LG, Cohen MM Jr. Source: Panminerva Medica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16462730&query_hl=6&itool=pubmed_docsum
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Mitotic recombination as evidence of alternative pathogenesis of gastrointestinal stromal tumours in neurofibromatosis type 1. Author(s): Stewart DR, Corless CL, Rubin BP, Heinrich MC, Messiaen LM, Kessler LJ, Zhang PJ, Brooks DG. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17209131&query_hl=6&itool=pubmed_docsum
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Modeling neurofibromatosis type 1 tumors in the mouse for therapeutic intervention. Author(s): Parada LF, Kwon CH, Zhu Y. Source: Cold Spring Harb Symp Quant Biol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16869751&query_hl=6&itool=pubmed_docsum
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Molecular genetic analyses in neurofibromatosis type 1 patients with tumors. Author(s): Oguzkan S, Terzi YK, Cinbis M, Anlar B, Aysun S, Ayter S. Source: Cancer Genetics and Cytogenetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16527612&query_hl=6&itool=pubmed_docsum
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Molecular profiles of neurofibromatosis type 1-associated plexiform neurofibromas: identification of a gene expression signature of poor prognosis. Author(s): Levy P, Bieche I, Leroy K, Parfait B, Wechsler J, Laurendeau I, Wolkenstein P, Vidaud M, Vidaud D. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15173083&query_hl=6&itool=pubmed_docsum
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Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR. Author(s): Levy P, Vidaud D, Leroy K, Laurendeau I, Wechsler J, Bolasco G, Parfait B, Wolkenstein P, Vidaud M, Bieche I. Source: Molecular Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15255999&query_hl=6&itool=pubmed_docsum
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Molecular targets for emerging anti-tumor therapies for neurofibromatosis type 1. Author(s): Dilworth JT, Kraniak JM, Wojtkowiak JW, Gibbs RA, Borch RF, Tainsky MA, Reiners JJ Jr, Mattingly RR. Source: Biochemical Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16797490&query_hl=6&itool=pubmed_docsum
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MR imaging of abdominopelvic involvement in neurofibromatosis type 1: a review of 43 patients. Author(s): Zacharia TT, Jaramillo D, Poussaint TY, Korf B. Source: Pediatric Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15517232&query_hl=6&itool=pubmed_docsum
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MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1. Author(s): Mautner VF, Hartmann M, Kluwe L, Friedrich RE, Funsterer C. Source: Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16432718&query_hl=6&itool=pubmed_docsum
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MRI investigation for neurofibromatosis type 1 lesions during pregnancy--a case report. Author(s): Stefanidis K, Solomou E, Lagona E, Pilalis A, Makris N, Loutradis D, Antsaklis A. Source: Clin Exp Obstet Gynecol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17211977&query_hl=6&itool=pubmed_docsum
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Multicentric pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1. Case report and review of the literature. Author(s): Saikali S, Le Strat A, Heckly A, Stock N, Scarabin JM, Hamlat A. Source: Journal of Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15739569&query_hl=6&itool=pubmed_docsum
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Multiple gastrointestinal stromal tumors of the ileum and neurofibromatosis type 1. Author(s): Beltran MA, Cruces KS, Barria C, Verdugo G. Source: Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16455465&query_hl=6&itool=pubmed_docsum
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Multiple malignant melanomas in association with neurofibromatosis type 1. Author(s): Barringer CB, Gorse SJ, Rigby HS, Reid CD. Source: J Plast Reconstr Aesthet Surg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17113519&query_hl=6&itool=pubmed_docsum
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Multiple myofibromas and an epidermal verrucous nevus in a child with neurofibromatosis type 1. Author(s): De Schepper S, Janssens S, Messiaen L, Van den Broecke C, Naeyaert JM. Source: Dermatology (Basel, Switzerland). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15459537&query_hl=6&itool=pubmed_docsum
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Neurocognitive deficits in children with neurofibromatosis type 1. Author(s): Packer RJ. Source: Curr Neurol Neurosci Rep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16522264&query_hl=6&itool=pubmed_docsum
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Neurofibroma of the breast in a boy with neurofibromatosis type 1. Author(s): Murat A, Kansiz F, Kabakus N, Kazez A, Ozercan R. Source: Clinical Imaging. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15531141&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1 - a model for nervous system tumour formation? Author(s): Rubin JB, Gutmann DH. Source: Nature Reviews. Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16069817&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1 and hereditary non-polyposis colorectal cancer: is there a link? Author(s): Barbaric D, Stevens M, Dalla-Pozza L. Source: Pediatric Blood & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15468301&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1 and masses of the appendix: a case report. Author(s): Rosenberg E, Sheiner E, Holcberg G. Source: J Reprod Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16913550&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1 and multiple primary malignancies. Author(s): Duzovali O. Source: Pediatric Blood & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15514918&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1 associated with central nervous system lymphoma. Author(s): Zein G, Yu E, Tawansy K, Berta A, Foster CS. Source: Ophthalmic Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15255115&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1 gene haploinsufficiency reduces AP-1 gene expression without abrogating the anabolic effect of parathyroid hormone. Author(s): Yu X, Milas J, Watanabe N, Rao N, Murthy S, Potter OL, Wenning MJ, Clapp WD, Hock JM. Source: Calcified Tissue International. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16525748&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1 in a pediatric population: Ste-Justine's experience. Author(s): Boulanger JM, Larbrisseau A. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16018159&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1 in pregnancy. Author(s): Kosec V, Marton I. Source: Coll Antropol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16617607&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1 presenting with Horner's syndrome. Author(s): Cackett P, Vallance J, Bennett H. Source: Eye (London, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15272289&query_hl=6&itool=pubmed_docsum
Studies
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Neurofibromatosis type 1 protein and amyloid precursor protein interact in normal human melanocytes and colocalize with melanosomes. Author(s): De Schepper S, Boucneau JM, Westbroek W, Mommaas M, Onderwater J, Messiaen L, Naeyaert JM, Lambert JL. Source: The Journal of Investigative Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16374483&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1. Author(s): Page TZ, Franklin J. Source: School Nurse News. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15563097&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1: diffusion weighted imaging findings of brain. Author(s): Alkan A, Sigirci A, Kutlu R, Ozcan H, Erdem G, Aslan M, Ates O, Yakinci C, Egri M. Source: European Journal of Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15963674&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1: new insights into neurocognitive issues. Author(s): Acosta MT, Gioia GA, Silva AJ. Source: Curr Neurol Neurosci Rep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16522267&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis type 1: spinal manifestations of a systemic disease. Author(s): Restrepo CS, Riascos RF, Hatta AA, Rojas R. Source: Journal of Computer Assisted Tomography. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16012314&query_hl=6&itool=pubmed_docsum
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Neuroimaging findings in neurofibromatosis type 1 and 2. Author(s): Rodriguez D, Young Poussaint T. Source: Neuroimaging Clin N Am. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15182813&query_hl=6&itool=pubmed_docsum
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Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Author(s): De Luca A, Schirinzi A, Buccino A, Bottillo I, Sinibaldi L, Torrente I, Ciavarella A, Dottorini T, Porciello R, Giustini S, Calvieri S, Dallapiccola B. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15146469&query_hl=6&itool=pubmed_docsum
70
Neurofibromatosis Type 1
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Novel mutation of neurofibromatosis type 1 in a patient with cerebral vasculopathy and fatal ischemic stroke. Author(s): Tang SC, Lee MJ, Jeng JS, Yip PK. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16414076&query_hl=6&itool=pubmed_docsum
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Novel NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor. Author(s): Nemoto H, Tate G, Schirinzi A, Suzuki T, Sasaya S, Yoshizawa Y, Midorikawa T, Mitsuya T, Dallapiccola B, Sanada Y. Source: Journal of Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16741618&query_hl=6&itool=pubmed_docsum
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Occult retinal and choroidal lesions in neurofibromatosis type 1. Author(s): Ishiko S, Yoshida A, Kato Y, Kagokawa H. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16854838&query_hl=6&itool=pubmed_docsum
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Ocular findings in neurofibromatosis type 1. Author(s): Sippel KC. Source: International Ophthalmology Clinics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11198145&query_hl=6&itool=pubmed_docsum
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Omental liposarcoma; a rare complication in neurofibromatosis type 1. Author(s): Imai A, Onogi K, Sugiyama Y. Source: Journal of Obstetrics and Gynaecology : the Journal of the Institute of Obstetrics and Gynaecology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16753705&query_hl=6&itool=pubmed_docsum
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Ophthalmological manifestations in segmental neurofibromatosis type 1. Author(s): Ruggieri M, Pavone P, Polizzi A, Di Pietro M, Scuderi A, Gabriele A, Spalice A, Iannetti P. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15489488&query_hl=6&itool=pubmed_docsum
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Optic gliomas in children with neurofibromatosis type 1. Author(s): Listernick R, Charrow J, Greenwald MJ, Esterly NB. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2497236&query_hl=6&itool=pubmed_docsum
Studies
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Optic pathway gliomas in neurofibromatosis type 1: the effect of presenting symptoms on outcome. Author(s): King A, Listernick R, Charrow J, Piersall L, Gutmann DH. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12955759&query_hl=6&itool=pubmed_docsum
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Optic-nerve gliomas, chiasmal gliomas and neurofibromatosis type 1. Author(s): Sylvester CL, Drohan LA, Sergott RC. Source: Current Opinion in Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16436918&query_hl=6&itool=pubmed_docsum
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Orbit deformities in craniofacial neurofibromatosis type 1. Author(s): Jacquemin C, Bosley TM, Svedberg H. Source: Ajnr. American Journal of Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=13679291&query_hl=6&itool=pubmed_docsum
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Orbital optic nerve gliomas in children with neurofibromatosis type 1. Author(s): Zeid JL, Charrow J, Sandu M, Goldman S, Listernick R. Source: Journal of Aapos : the Official Publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17189147&query_hl=6&itool=pubmed_docsum
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Ossifying subperiosteal hematoma associated with neurofibromatosis type 1. Diagnostic hesitation: a case report and literature review. Author(s): Herrera-Soto JA, Crawford AH, Loveless EA. Source: Journal of Pediatric Orthopaedics. Part B / European Paediatric Orthopaedic Society, Pediatric Orthopaedic Society of North America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15577308&query_hl=6&itool=pubmed_docsum
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Osteosarcoma in a patient with neurofibromatosis type 1: a case report and review of the literature. Author(s): Hatori M, Hosaka M, Watanabe M, Moriya T, Sasano H, Kokubun S. Source: The Tohoku Journal of Experimental Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16565597&query_hl=6&itool=pubmed_docsum
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Outcomes of systematic screening for optic pathway tumors in children with Neurofibromatosis Type 1. Author(s): Blazo MA, Lewis RA, Chintagumpala MM, Frazier M, McCluggage C, Plon SE. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15150770&query_hl=6&itool=pubmed_docsum
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Neurofibromatosis Type 1
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Pancreatic endocrine tumors are a rare manifestation of the neurofibromatosis type 1 phenotype: molecular analysis of a malignant insulinoma in a NF-1 patient. Author(s): Perren A, Wiesli P, Schmid S, Montani M, Schmitt A, Schmid C, Moch H, Komminoth P. Source: The American Journal of Surgical Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16861979&query_hl=6&itool=pubmed_docsum
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Pathophysiology of neurofibromatosis type 1. Author(s): Theos A, Korf BR; American College of Physicians; American Physiological Society. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16754926&query_hl=6&itool=pubmed_docsum
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Pegvisomant treatment in a 4-year-old girl with neurofibromatosis type 1. Author(s): Main KM, Sehested A, Feldt-Rasmussen U. Source: Hormone Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16269873&query_hl=6&itool=pubmed_docsum
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Phase II trial of pirfenidone in adults with neurofibromatosis type 1. Author(s): Babovic-Vuksanovic D, Ballman K, Michels V, McGrann P, Lindor N, King B, Camp J, Micic V, Babovic N, Carrero X, Spinner R, O'Neill B. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17035676&query_hl=6&itool=pubmed_docsum
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Pheochromocytoma in von Hippel-Lindau disease and neurofibromatosis type 1. Author(s): Opocher G, Conton P, Schiavi F, Macino B, Mantero F. Source: Familial Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15883705&query_hl=6&itool=pubmed_docsum
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Pigment cell-related manifestations in neurofibromatosis type 1: an overview. Author(s): De Schepper S, Boucneau J, Lambert J, Messiaen L, Naeyaert JM. Source: Pigment Cell Research / Sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15649148&query_hl=6&itool=pubmed_docsum
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Preimplantation genetic diagnosis for neurofibromatosis type 1. Author(s): Spits C, De Rycke M, Van Ranst N, Joris H, Verpoest W, Lissens W, Devroey P, Van Steirteghem A, Liebaers I, Sermon K. Source: Molecular Human Reproduction. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15833774&query_hl=6&itool=pubmed_docsum
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Prenatal diagnosis of neurofibromatosis type 1: sonographic and MRI findings. Author(s): McEwing RL, Joelle R, Mohlo M, Bernard JP, Hillion Y, Ville Y. Source: Prenatal Diagnosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16981221&query_hl=6&itool=pubmed_docsum
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Primary malignant peripheral nerve sheath tumor of the lung in a young child without neurofibromatosis type 1. Author(s): Muwakkit SA, Rodriguez-Galindo C, El Samra AI, Khoury R, Akel SR, Mroueh S, Razzouk B, Abboud MR. Source: Pediatric Blood & Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16544294&query_hl=6&itool=pubmed_docsum
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Psychological disturbance and sleep disorders in children with neurofibromatosis type 1. Author(s): Johnson H, Wiggs L, Stores G, Huson SM. Source: Developmental Medicine and Child Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15832546&query_hl=6&itool=pubmed_docsum
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Quality of life and psychological adjustment in children and adolescents with neurofibromatosis type 1. Author(s): Graf A, Landolt MA, Mori AC, Boltshauser E. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16939745&query_hl=6&itool=pubmed_docsum
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Quality-of-life impairment in neurofibromatosis type 1: a cross-sectional study of 128 cases. Author(s): Wolkenstein P, Zeller J, Revuz J, Ecosse E, Leplege A. Source: Archives of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11708944&query_hl=6&itool=pubmed_docsum
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Quantitative analysis of NF1 and OMGP gene transcripts in sporadic gliomas, sporadic meningiomas and neurofibromatosis type 1-associated plexiform neurofibromas. Author(s): Peters N, Waha A, Wellenreuther R, Friedrich RE, Mautner VF, Hoffmeyer S, Lenartz D, Schramm J, Wiestler OD, von Deimling A. Source: Acta Neuropathologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10378372&query_hl=6&itool=pubmed_docsum
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Radiology case of the month. Cafe-au-lait spots. Neurofibromatosis type 1. Author(s): Gupta A, Neitzschman HR, Schroder M. Source: J La State Med Soc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12440746&query_hl=6&itool=pubmed_docsum
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Rapid development of optic glioma in a patient with hybrid phakomatosis: neurofibromatosis type 1 and tuberous sclerosis. Author(s): Erbay SH, Oljeski SA, Bhadelia R. Source: Ajnr. American Journal of Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14729526&query_hl=6&itool=pubmed_docsum
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Reassessment of sphenoid dysplasia associated with neurofibromatosis type 1. Author(s): Jacquemin C, Bosley TM, Liu D, Svedberg H, Buhaliqa A. Source: Ajnr. American Journal of Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11950659&query_hl=6&itool=pubmed_docsum
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Recent advances in neurofibromatosis type 1. Author(s): Arun D, Gutmann DH. Source: Current Opinion in Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15021234&query_hl=6&itool=pubmed_docsum
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Recurrent malignant schwannoma of the parapharyngeal space in neurofibromatosis type 1. Author(s): Gallo A, Suriano M, Simonelli M, Ralli G, de Vincentiis M. Source: Ear, Nose, & Throat Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14661436&query_hl=6&itool=pubmed_docsum
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Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. Author(s): Ars E, Kruyer H, Morell M, Pros E, Serra E, Ravella A, Estivill X, Lazaro C. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12807981&query_hl=6&itool=pubmed_docsum
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Response to imatinib in KIT- and PDGFRA-wild type gastrointestinal stromal associated with neurofibromatosis type 1. Author(s): Lee JL, Kim JY, Ryu MH, Kang HJ, Chang HM, Kim TW, Lee H, Park JH, Kim HC, Kim JS, Kang YK. Source: Digestive Diseases and Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16865565&query_hl=6&itool=pubmed_docsum
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Retinal vascular abnormalities in neurofibromatosis type 1. Author(s): Karadimas P, Hatzispasou E, Bouzas EA. Source: Journal of Neuro-Ophthalmology : the Official Journal of the North American Neuro-Ophthalmology Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14663309&query_hl=6&itool=pubmed_docsum
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Retrospective analysis of patients attending a neurofibromatosis type 1 clinic. Author(s): Noble F, Kornberg AJ, Elder JE, Delatycki MB. Source: Journal of Paediatrics and Child Health. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17207057&query_hl=6&itool=pubmed_docsum
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Serial MR imaging and 1H-MR spectroscopy of unidentified bright objects in a case of neurofibromatosis type 1. Author(s): Imamura A, Matsuo N, Okuda M, Morita H, Iwata M, Yamazaki Y, Takahashi Y. Source: Brain & Development. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15878248&query_hl=6&itool=pubmed_docsum
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Severe pulmonary involvement and pheochromocytoma in atypical patient with neurofibromatosis type 1. Author(s): Gursoy A, Erdogan MF. Source: Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16939950&query_hl=6&itool=pubmed_docsum
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Simultaneous occurrence of neurofibromatosis type 1 and tuberous sclerosis in a young girl. Author(s): Wheeler PG, Sadeghi-Nejad A. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15637706&query_hl=6&itool=pubmed_docsum
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Single-sperm analysis for haplotype construction of de-novo paternal mutations: application to PGD for neurofibromatosis type 1. Author(s): Altarescu G, Brooks B, Kaplan Y, Eldar-Geva T, Margalioth EJ, Levy-Lahad E, Renbaum P. Source: Human Reproduction (Oxford, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16740526&query_hl=6&itool=pubmed_docsum
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Somatic deletion of the NF1 gene in a neurofibromatosis type 1-associated malignant melanoma demonstrated by digital PCR. Author(s): Rubben A, Bausch B, Nikkels A. Source: Molecular Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16961930&query_hl=6&itool=pubmed_docsum
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Spontaneous rupture of recurrent gastrointestinal stromal tumor associated with neurofibromatosis type 1. Author(s): Wang SM, Chiang RA, Tzen CY, Cheng SP, Liu TP. Source: J Chin Med Assoc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16323399&query_hl=6&itool=pubmed_docsum
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Sudden cardiac death in young children with neurofibromatosis type 1. Author(s): Kanter RJ, Graham M, Fairbrother D, Smith SV. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17095352&query_hl=6&itool=pubmed_docsum
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Superficial neurofibroma: a lesion with unique MRI characteristics in patients with neurofibromatosis type 1. Author(s): Lim R, Jaramillo D, Poussaint TY, Chang Y, Korf B. Source: Ajr. American Journal of Roentgenology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15728625&query_hl=6&itool=pubmed_docsum
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Surgical treatment of scoliosis caused by neurofibromatosis type 1. Author(s): Shen JX, Qiu GX, Wang YP, Zhao Y, Ye QB, Wu ZK. Source: Chinese Medical Sciences Journal = Chung-Kuo I Hsueh K'o Hsueh Tsa Chih / Chinese Academy of Medical Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16075744&query_hl=6&itool=pubmed_docsum
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Synchronous optic and pineal pilocytic astrocytomas in a paediatric patient with neurofibromatosis type 1. Author(s): Ogura T, Adachi J, Nishikawa R, Hirose T, Matsutani M. Source: Pediatric Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15821362&query_hl=6&itool=pubmed_docsum
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TATA-binding protein (TBP)-like factor (TLF) is a functional regulator of transcription: reciprocal regulation of the neurofibromatosis type 1 and c-fos genes by TLF/TRF2 and TBP. Author(s): Chong JA, Moran MM, Teichmann M, Kaczmarek JS, Roeder R, Clapham DE. Source: Molecular and Cellular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15767669&query_hl=6&itool=pubmed_docsum
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The course of neurofibromatosis type 1 on immunosuppression after lung transplantation: report of 2 cases. Author(s): Merlo CA, Studer SM, Conte JV, Yang SC, Sonnett J, Orens JB. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15366441&query_hl=6&itool=pubmed_docsum
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The mechanism of epidermal hyperpigmentation in cafe-au-lait macules of neurofibromatosis type 1 (von Recklinghausen's disease) may be associated with dermal fibroblast-derived stem cell factor and hepatocyte growth factor. Author(s): Okazaki M, Yoshimura K, Suzuki Y, Uchida G, Kitano Y, Harii K, Imokawa G. Source: The British Journal of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12752125&query_hl=6&itool=pubmed_docsum
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The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Author(s): Hyman SL, Shores A, North KN. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16217056&query_hl=6&itool=pubmed_docsum
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The neurofibromatosis type 1 gene product neurofibromin enhances cell motility by regulating actin filament dynamics via the Rho-ROCK-LIMK2-cofilin pathway. Author(s): Ozawa T, Araki N, Yunoue S, Tokuo H, Feng L, Patrakitkomjorn S, Hara T, Ichikawa Y, Matsumoto K, Fujii K, Saya H. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16169856&query_hl=6&itool=pubmed_docsum
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The Ras inhibitor farnesylthiosalicylic acid as a potential therapy for neurofibromatosis type 1. Author(s): Barkan B, Starinsky S, Friedman E, Stein R, Kloog Y. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17000690&query_hl=6&itool=pubmed_docsum
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The soft-tissue manifestations of neurofibromatosis type 1. Author(s): Hillier JC, Moskovic E. Source: Clinical Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16124977&query_hl=6&itool=pubmed_docsum
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The spectrum of NF1 mutations in Korean patients with neurofibromatosis type 1. Author(s): Jeong SY, Park SJ, Kim HJ. Source: Journal of Korean Medical Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16479075&query_hl=6&itool=pubmed_docsum
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The strange association between achondroplasia and neurofibromatosis type 1: molecular analysis of a new patient and review of the literature. Author(s): Margari L, Presicci A, Ventura P, Bacca SM, Tota T, Perniola T, Gentile M. Source: Genet Couns. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16970043&query_hl=6&itool=pubmed_docsum
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Two neurofibromatosis type 1 cases associated with rhabdomyosarcoma of bladder, one with a large deletion in the NF1 gene. Author(s): Oguzkan S, Terzi YK, Guler E, Derbent M, Agras PI, Saatci U, Ayter S. Source: Cancer Genetics and Cytogenetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16434322&query_hl=6&itool=pubmed_docsum
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Unusual association of neurofibromatosis type 1 and coeliac disease in a single patient. Author(s): Biagi F, Campanella J, Alvisi C, Versino M, Corazza GR. Source: Funct Neurol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15948566&query_hl=6&itool=pubmed_docsum
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Unusual features in a patient with neurofibromatosis type 1: multiple subcutaneous lipomas, a juvenile polyp in ascending colon, congenital intrahepatic portosystemic venous shunt, and horseshoe kidney. Author(s): Oktenli C, Gul D, Deveci MS, Saglam M, Upadhyaya M, Thompson P, Consoli C, Kocar IH, Pilarski R, Zhou XP, Eng C. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15150783&query_hl=6&itool=pubmed_docsum
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Unusual form of recurrent giant cell granuloma of the mandible and lower extremities in a patient with neurofibromatosis type 1. Author(s): Ruggieri M, Pavone V, Polizzi A, Albanese S, Magro G, Merino M, Duray PH. Source: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9927083&query_hl=6&itool=pubmed_docsum
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Use of 2-tracer PET to diagnose gastrointestinal stromal tumour and pheochromocytoma in patients with Carney triad and neurofibromatosis type 1. Author(s): Bumming P, Nilsson B, Sorensen J, Nilsson O, Ahlman H. Source: Scandinavian Journal of Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16638708&query_hl=6&itool=pubmed_docsum
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Usefulness of contrast material in MR of patients with neurofibromatosis type 1. Author(s): Bonawitz C, Castillo M, Chin CT, Mukherji SK, Barkovich AJ. Source: Ajnr. American Journal of Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9541315&query_hl=6&itool=pubmed_docsum
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Usefulness of screening investigations in neurofibromatosis type 1. A study of 152 patients. Author(s): Wolkenstein P, Freche B, Zeller J, Revuz J. Source: Archives of Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8915311&query_hl=6&itool=pubmed_docsum
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Utility of multimodal evoked potentials study in neurofibromatosis type 1 of childhood. Author(s): Ammendola A, Ciccone G, Ammendola E. Source: Pediatric Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16638501&query_hl=6&itool=pubmed_docsum
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Venous aneurysm, arterial dysplasia, and near-fatal hemorrhages in neurofibromatosis type 1. Author(s): Nopajaroonsri C, Lurie AA. Source: Human Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8816897&query_hl=6&itool=pubmed_docsum
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Vertebral scalloping in neurofibromatosis type 1: a quantitative approach. Author(s): Kwok ES, Sawatzky B, Birch P, Friedman JM, Tredwell SJ. Source: Canadian Journal of Surgery. Journal Canadien De Chirurgie. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12067169&query_hl=6&itool=pubmed_docsum
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Visual evoked potentials in children with neurofibromatosis type 1. Author(s): Iannaccone A, McCluney RA, Brewer VR, Spiegel PH, Taylor JS, Kerr NC, Pivnick EK. Source: Documenta Ophthalmologica. Advances in Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12152804&query_hl=6&itool=pubmed_docsum
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Visual loss in children with neurofibromatosis type 1 and optic pathway gliomas: relation to tumor location by magnetic resonance imaging. Author(s): Balcer LJ, Liu GT, Heller G, Bilaniuk L, Volpe NJ, Galetta SL, Molloy PT, Phillips PC, Janss AJ, Vaughn S, Maguire MG. Source: American Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11292406&query_hl=6&itool=pubmed_docsum
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Von Recklinghausen's neurofibromatosis: neurofibromatosis type 1. Author(s): Reynolds RM, Browning GG, Nawroz I, Campbell IW. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12737880&query_hl=6&itool=pubmed_docsum
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Whole-spine magnetic resonance imaging in patients with neurofibromatosis type 1 and spinal deformity. Author(s): Ramachandran M, Tsirikos AI, Lee J, Saifuddin A. Source: Journal of Spinal Disorders & Techniques. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15570119&query_hl=6&itool=pubmed_docsum
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Zollinger-Ellison syndrome associated with neurofibromatosis type 1: a case report. Author(s): Lee WS, Koh YS, Kim JC, Park CH, Joo YE, Kim HS, Cho CK, Choi SK, Rew JS, Kim SJ. Source: Bmc Cancer [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16042772&query_hl=6&itool=pubmed_docsum
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CHAPTER 2. ALTERNATIVE MEDICINE AND NEUROFIBROMATOSIS TYPE 1 Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to neurofibromatosis type 1. 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 neurofibromatosis type 1 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 neurofibromatosis type 1 (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 neurofibromatosis type 1: •
A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Author(s): Silva AJ, Frankland PW, Marowitz Z, Friedman E, Laszlo GS, Cioffi D, Jacks T, Bourtchuladze R. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9054942&query_hl=1&itool=pubmed_docsum
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Acupuncture in a patient with neurofibromatosis. Author(s): Zarnegar R, Jenner C, Filshie J. Source: Acupuncture in Medicine : Journal of the British Medical Acupuncture Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12924851&query_hl=1&itool=pubmed_docsum
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Acute promyelocytic leukemia after treatment of malignant glioma in a patient with von Recklinghausen's disease: case report and review of the literature. Author(s): Wiernik PH, Muse IM. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8558926&query_hl=1&itool=pubmed_docsum
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Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. Author(s): Packer RJ, Ater J, Allen J, Phillips P, Geyer R, Nicholson HS, Jakacki R, Kurczynski E, Needle M, Finlay J, Reaman G, Boyett JM. Source: Journal of Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9126887&query_hl=1&itool=pubmed_docsum
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Characterization and chemosensitivity of two human malignant peripheral nerve sheath tumour cell lines derived from a patient with neurofibromatosis type 1. Author(s): Imaizumi S, Motoyama T, Ogose A, Hotta T, Takahashi HE. Source: Virchows Archiv : an International Journal of Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9849858&query_hl=1&itool=pubmed_docsum
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Congenital “pseudarthroses” of the tibia: treatment with pulsing electromagnetic fields. Author(s): Bassett CA, Caulo N, Kort J. Source: Clin Orthop Relat Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6781806&query_hl=1&itool=pubmed_docsum
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Differences in the interaction of p21c-Ha-ras-GMP-PNP with full-length neurofibromin and GTPase-activating protein. Author(s): DiBattiste D, Golubic M, Stacey D, Wolfman A. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8437847&query_hl=1&itool=pubmed_docsum
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Differential modulation of malignant peripheral nerve sheath tumor growth by omega-3 and omega-6 fatty acids. Author(s): Mashour GA, Drissel SN, Frahm S, Farassati F, Martuza RL, Mautner VF, Kindler-Rohrborn A, Kurtz A. Source: Oncogene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15735744&query_hl=1&itool=pubmed_docsum
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Enigmatic statue. Author(s): Gourevitch D, Grmek MD.
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Source: Nature. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7969466&query_hl=1&itool=pubmed_docsum •
Gender response to neurofibromatosis 1. Author(s): Ablon J. Source: Social Science & Medicine (1982). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8745111&query_hl=1&itool=pubmed_docsum
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Growth hormone hypersecretion in a girl with neurofibromatosis type 1 and an optic nerve glioma: resolution following chemotherapy. Author(s): Drake AJ, Lowis SP, Bouffet E, Crowne EC. Source: Hormone Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11146372&query_hl=1&itool=pubmed_docsum
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High response rate to cisplatin/etoposide regimen in childhood low-grade glioma. Author(s): Massimino M, Spreafico F, Cefalo G, Riccardi R, Tesoro-Tess JD, Gandola L, Riva D, Ruggiero A, Valentini L, Mazza E, Genitori L, Di Rocco C, Navarria P, Casanova M, Ferrari A, Luksch R, Terenziani M, Balestrini MR, Colosimo C, Fossati-Bellani F. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12377964&query_hl=1&itool=pubmed_docsum
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Mediastinal atypical carcinoid and neurofibromatosis type 1. Author(s): Mathew P, Roberts JA, Zwischenberger J, Haque AK. Source: Archives of Pathology & Laboratory Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10656749&query_hl=1&itool=pubmed_docsum
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Monosomy 7 syndrome in an infant with neurofibromatosis. Author(s): Kelleher JF, Carbone TV. Source: Am J Pediatr Hematol Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1793161&query_hl=1&itool=pubmed_docsum
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Myeloid malignancies induced by alkylating agents in Nf1 mice. Author(s): Mahgoub N, Taylor BR, Le Beau MM, Gratiot M, Carlson KM, Atwater SK, Jacks T, Shannon KM. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10339466&query_hl=1&itool=pubmed_docsum
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Neurofibromatosis I and unexplained iron deficiency in two patients: is iron depletion related to neurofibroma growth? Author(s): Moczygemba C, Bhattacharjee M.
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Source: Journal of Neuro-Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16283447&query_hl=1&itool=pubmed_docsum •
Neurofibromatosis type 1 (NF1): knowledge, experience, and reproductive decisions of affected patients and families. Author(s): Benjamin CM, Colley A, Donnai D, Kingston H, Harris R, Kerzin-Storrar L. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8411029&query_hl=1&itool=pubmed_docsum
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Neurofibromatosis type 1-associated unusual pleomorphic astrocytoma displaying continual malignant progression. Author(s): Yokoo H, Kamiya M, Sasaki A, Hirato J, Nakazato Y, Kurachi H. Source: Pathology International. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11472572&query_hl=1&itool=pubmed_docsum
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Neurofibromatosis type I: clinical and imaging features of Von Recklinghausen's disease. Author(s): Gajeski BL, Kettner NW, Awwad EE, Boesch RJ. Source: Journal of Manipulative and Physiological Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12584510&query_hl=1&itool=pubmed_docsum
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Neurofibromatosis: looking at LINK. Author(s): Bureau E. Source: Nursing Standard : Official Newspaper of the Royal College of Nursing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2494531&query_hl=1&itool=pubmed_docsum
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Neurological disorders with autosomal dominant transmission. Author(s): Simpson JM. Source: J Neurosurg Nurs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6239015&query_hl=1&itool=pubmed_docsum
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Parents' responses to their child's diagnosis of neurofibromatosis 1. Author(s): Ablon J. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10869117&query_hl=1&itool=pubmed_docsum
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Recent advances in neuroblastoma. Author(s): Finklestein JZ, Gilchrist GS.
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Source: Calif Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=4622580&query_hl=1&itool=pubmed_docsum •
Recurrent retroperitoneal malignant nerve sheath tumor associated with neurofibromatosis type 1 responding to carboplatin and etoposide combined chemotherapy. Author(s): Kinebuchi Y, Noguchi W, Igawa Y, Nishizawa O. Source: International Journal of Clinical Oncology / Japan Society of Clinical Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16247664&query_hl=1&itool=pubmed_docsum
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Sichuan pepper extracts block the PAK1/cyclin D1 pathway and the growth of NF1deficient cancer xenograft in mice. Author(s): Hirokawa Y, Nheu T, Grimm K, Mautner V, Maeda S, Yoshida M, Komiyama K, Maruta H. Source: Cancer Biology & Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16418572&query_hl=1&itool=pubmed_docsum
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Statue enigma. Author(s): Linden DE. Source: Nature. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8008065&query_hl=1&itool=pubmed_docsum
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The different forms of neurofibromatosis. Author(s): Huson SM. Source: British Medical Journal (Clinical Research Ed.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3107717&query_hl=1&itool=pubmed_docsum
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'The Elephant Man' as 'self' and 'other': the psycho-social costs of a misdiagnosis. Author(s): Ablon J. Source: Social Science & Medicine (1982). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7667653&query_hl=1&itool=pubmed_docsum
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The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD184352 (CI-1040) selectively induces apoptosis in malignant schwannoma cell lines. Author(s): Mattingly RR, Kraniak JM, Dilworth JT, Mathieu P, Bealmear B, Nowak JE, Benjamins JA, Tainsky MA, Reiners JJ Jr. Source: The Journal of Pharmacology and Experimental Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16239399&query_hl=1&itool=pubmed_docsum
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Traumatic pseudoaneurysm of ascending cervical artery in neurofibromatosis: complication of chiropractic manipulation. Author(s): Lennington BR, Laster DW, Moody DM, Ball MR. Source: Ajnr. American Journal of Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6779604&query_hl=1&itool=pubmed_docsum
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Treatment of neurofibromatosis with Chinese herbal drugs. Author(s): Zhou X, Wang H, Yuan Q. Source: J Tradit Chin Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11263277&query_hl=1&itool=pubmed_docsum
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Treatments for astrocytic tumors in children: current and emerging strategies. Author(s): Burzynski SR. Source: Paediatric Drugs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16774296&query_hl=1&itool=pubmed_docsum
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Visual pathway glioma in children treated with chemotherapy. Author(s): Demaerel P, de Ruyter N, Casteels I, Renard M, Uyttebroeck A, van Gool S. Source: European Journal of Paediatric Neurology : Ejpn : Official Journal of the European Paediatric Neurology Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12374587&query_hl=1&itool=pubmed_docsum
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Visual pathway glioma: an erratic tumour with therapeutic dilemmas. Author(s): Shuper A, Horev G, Kornreich L, Michowiz S, Weitz R, Zaizov R, Cohen IJ. Source: Archives of Disease in Childhood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9135269&query_hl=1&itool=pubmed_docsum
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Von Recklinghausen Gesellschaft: the German lay organization for patients with neurofibromatosis. Author(s): Mautner VF, Friedrich RE. Source: Anticancer Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12820366&query_hl=1&itool=pubmed_docsum
Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://health.aol.com/healthyliving/althealth
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com®: http://www.drkoop.com/naturalmedicine.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Alternative/
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 3. BOOKS ON NEUROFIBROMATOSIS TYPE 1 Overview This chapter provides bibliographic book references relating to neurofibromatosis type 1. In addition to online booksellers such as www.amazon.com and www.bn.com, the National Library of Medicine is an excellent source for book titles on neurofibromatosis type 1. 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 neurofibromatosis type 1 at online booksellers’ Web sites, you may discover non-medical books that use the generic term “neurofibromatosis type 1” (or a synonym) in their titles. The following is indicative of the results you might find when searching for neurofibromatosis type 1 (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
Living with Genetic Disorder: The Impact of Neurofibromatosis 1 Joan Ablon (1999); ISBN: 0865692874; http://www.amazon.com/exec/obidos/ASIN/0865692874/icongroupinterna
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Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (Bilateral acoustic neurofibromatosis) : an upate (SuDoc HE 20.3002:N 39/4) U.S. Dept of Health and Human Services; ISBN: B000107HC8; http://www.amazon.com/exec/obidos/ASIN/B000107HC8/icongroupinterna
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The child with neurofibromatosis 1 Bruce R Korf (1991); ISBN: B0006R5TUS; http://www.amazon.com/exec/obidos/ASIN/B0006R5TUS/icongroupinterna
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The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select LocatorPlus. Once you are in the search area, simply type neurofibromatosis type 1 (or synonyms) into the search box, and select the Quick Limit Option for Keyword, Title, or Journal Title Search: Books. From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine7: •
Neurofibromatosis type 1: from genotype to phenotype Author: Upadhyaya, M. (Meena); Year: 1998; Oxford; Washington, DC: Bios Scientific, 1998; ISBN: 9781859961 http://www.amazon.com/exec/obidos/ASIN/9781859961/icongroupinterna
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Neurofibromatosis type 1 in childhood Author: North, Kathryn.; Year: 1997; London, England: Mac Keith Press, for the International Child Neurology Association, 1997; ISBN: 9781898683 http://www.amazon.com/exec/obidos/ASIN/9781898683/icongroupinterna
7 In addition to LocatorPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a Books button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.
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APPENDIX A. HELP ME UNDERSTAND GENETICS Overview This appendix presents basic information about genetics in clear language and provides links to online resources.8
The Basics: Genes and How They Work This section gives you information on the basics of cells, DNA, genes, chromosomes, and proteins. What Is a Cell? Cells are the basic building blocks of all living things. The human body is composed of trillions of cells. They provide structure for the body, take in nutrients from food, convert those nutrients into energy, and carry out specialized functions. Cells also contain the body’s hereditary material and can make copies of themselves. Cells have many parts, each with a different function. Some of these parts, called organelles, are specialized structures that perform certain tasks within the cell. Human cells contain the following major parts, listed in alphabetical order: •
Cytoplasm: The cytoplasm is fluid inside the cell that surrounds the organelles.
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Endoplasmic reticulum (ER): This organelle helps process molecules created by the cell and transport them to their specific destinations either inside or outside the cell.
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Golgi apparatus: The golgi apparatus packages molecules processed by the endoplasmic reticulum to be transported out of the cell.
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Lysosomes and peroxisomes: These organelles are the recycling center of the cell. They digest foreign bacteria that invade the cell, rid the cell of toxic substances, and recycle worn-out cell components.
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This appendix is an excerpt from the National Library of Medicine’s handbook, Help Me Understand Genetics. For the full text of the Help Me Understand Genetics handbook, see http://ghr.nlm.nih.gov/handbook.
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Mitochondria: Mitochondria are complex organelles that convert energy from food into a form that the cell can use. They have their own genetic material, separate from the DNA in the nucleus, and can make copies of themselves.
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Nucleus: The nucleus serves as the cell’s command center, sending directions to the cell to grow, mature, divide, or die. It also houses DNA (deoxyribonucleic acid), the cell’s hereditary material. The nucleus is surrounded by a membrane called the nuclear envelope, which protects the DNA and separates the nucleus from the rest of the cell.
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Plasma membrane: The plasma membrane is the outer lining of the cell. It separates the cell from its environment and allows materials to enter and leave the cell.
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Ribosomes: Ribosomes are organelles that process the cell’s genetic instructions to create proteins. These organelles can float freely in the cytoplasm or be connected to the endoplasmic reticulum. What Is DNA?
DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA). The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences. DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder. An important property of DNA is that it can replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.
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DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone. What Is Mitochondrial DNA? Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Each cell contains hundreds to thousands of mitochondria, which are located in the fluid that surrounds the nucleus (the cytoplasm). Mitochondria produce energy through a process called oxidative phosphorylation. This process uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell’s main energy source. A set of enzyme complexes, designated as complexes I-V, carry out oxidative phosphorylation within mitochondria. In addition to energy production, mitochondria play a role in several other cellular activities. For example, mitochondria help regulate the self-destruction of cells (apoptosis). They are also necessary for the production of substances such as cholesterol and heme (a component of hemoglobin, the molecule that carries oxygen in the blood). Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. The remaining genes provide instructions for making molecules called transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), which are chemical cousins of
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DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins. What Is a Gene? A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules called proteins. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes. Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features.
Genes are made up of DNA. Each chromosome contains many genes. What Is a Chromosome? In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled many times around proteins called histones that support its structure. Chromosomes are not visible in the cell’s nucleus—not even under a microscope—when the cell is not dividing. However, the DNA that makes up chromosomes becomes more tightly packed during cell division and is then visible under a microscope. Most of what researchers know about chromosomes was learned by observing chromosomes during cell division. Each chromosome has a constriction point called the centromere, which divides the chromosome into two sections, or “arms.” The short arm of the chromosome is labeled the “p arm.” The long arm of the chromosome is labeled the “q arm.” The location of the centromere on each chromosome gives the chromosome its characteristic shape, and can be used to help describe the location of specific genes.
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DNA and histone proteins are packaged into structures called chromosomes. How Many Chromosomes Do People Have? In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46. Twentytwo of these pairs, called autosomes, look the same in both males and females. The 23rd pair, the sex chromosomes, differ between males and females. Females have two copies of the X chromosome, while males have one X and one Y chromosome.
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The 22 autosomes are numbered by size. The other two chromosomes, X and Y, are the sex chromosomes. This picture of the human chromosomes lined up in pairs is called a karyotype. How Do Geneticists Indicate the Location of a Gene? Geneticists use maps to describe the location of a particular gene on a chromosome. One type of map uses the cytogenetic location to describe a gene’s position. The cytogenetic location is based on a distinctive pattern of bands created when chromosomes are stained with certain chemicals. Another type of map uses the molecular location, a precise description of a gene’s position on a chromosome. The molecular location is based on the sequence of DNA building blocks (base pairs) that make up the chromosome. Cytogenetic Location Geneticists use a standardized way of describing a gene’s cytogenetic location. In most cases, the location describes the position of a particular band on a stained chromosome: 17q12 It can also be written as a range of bands, if less is known about the exact location: 17q12-q21 The combination of numbers and letters provide a gene’s “address” on a chromosome. This address is made up of several parts: •
The chromosome on which the gene can be found. The first number or letter used to describe a gene’s location represents the chromosome. Chromosomes 1 through 22 (the autosomes) are designated by their chromosome number. The sex chromosomes are designated by X or Y.
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•
The arm of the chromosome. Each chromosome is divided into two sections (arms) based on the location of a narrowing (constriction) called the centromere. By convention, the shorter arm is called p, and the longer arm is called q. The chromosome arm is the second part of the gene’s address. For example, 5q is the long arm of chromosome 5, and Xp is the short arm of the X chromosome.
•
The position of the gene on the p or q arm. The position of a gene is based on a distinctive pattern of light and dark bands that appear when the chromosome is stained in a certain way. The position is usually designated by two digits (representing a region and a band), which are sometimes followed by a decimal point and one or more additional digits (representing sub-bands within a light or dark area). The number indicating the gene position increases with distance from the centromere. For example: 14q21 represents position 21 on the long arm of chromosome 14. 14q21 is closer to the centromere than 14q22.
Sometimes, the abbreviations “cen” or “ter” are also used to describe a gene’s cytogenetic location. “Cen” indicates that the gene is very close to the centromere. For example, 16pcen refers to the short arm of chromosome 16 near the centromere. “Ter” stands for terminus, which indicates that the gene is very close to the end of the p or q arm. For example, 14qter refers to the tip of the long arm of chromosome 14. (“Tel” is also sometimes used to describe a gene’s location. “Tel” stands for telomeres, which are at the ends of each chromosome. The abbreviations “tel” and “ter” refer to the same location.)
The CFTR gene is located on the long arm of chromosome 7 at position 7q31.2.
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Molecular Location The Human Genome Project, an international research effort completed in 2003, determined the sequence of base pairs for each human chromosome. This sequence information allows researchers to provide a more specific address than the cytogenetic location for many genes. A gene’s molecular address pinpoints the location of that gene in terms of base pairs. For example, the molecular location of the APOE gene on chromosome 19 begins with base pair 50,100,901 and ends with base pair 50,104,488. This range describes the gene’s precise position on chromosome 19 and indicates the size of the gene (3,588 base pairs). Knowing a gene’s molecular location also allows researchers to determine exactly how far the gene is from other genes on the same chromosome. Different groups of researchers often present slightly different values for a gene’s molecular location. Researchers interpret the sequence of the human genome using a variety of methods, which can result in small differences in a gene’s molecular address. For example, the National Center for Biotechnology Information (NCBI) identifies the molecular location of the APOE gene as base pair 50,100,901 to base pair 50,104,488 on chromosome 19. The Ensembl database identifies the location of this gene as base pair 50,100,879 to base pair 50,104,489 on chromosome 19. Neither of these addresses is incorrect; they represent different interpretations of the same data. For consistency, Genetics Home Reference presents data from NCBI for the molecular location of genes. What Are Proteins and What Do They Do? Proteins are large, complex molecules that play many critical roles in the body. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs. Proteins are made up of hundreds or thousands of smaller units called amino acids, which are attached to one another in long chains. There are 20 different types of amino acids that can be combined to make a protein. The sequence of amino acids determines each protein’s unique 3-dimensional structure and its specific function.
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Examples of Protein Functions Proteins can be described according to their large range of functions in the body, listed in alphabetical order: Function Antibody
Description Antibodies bind to specific foreign particles, such as viruses and bacteria, to help protect the body.
Example Immunoglobulin G (IgG)
Enzyme
Enzymes carry out almost all of the thousands of chemical reactions that take place in cells. They also assist with the formation of new molecules by reading the genetic information stored in DNA.
Phenylalanine hydroxylase
Messenger
Messenger proteins, such as some types of hormones, transmit signals to coordinate biological processes between different cells, tissues, and organs.
Growth hormone
Structural component
These proteins provide structure and support for cells. On a larger scale, they also allow the body to move. These proteins bind and carry atoms and small molecules within cells and throughout the body.
Actin
Transport/storage
Ferritin
How Does a Gene Make a Protein? Most genes contain the information needed to make functional molecules called proteins. (A few genes produce other molecules that help the cell assemble proteins.) The journey from gene to protein is complex and tightly controlled within each cell. It consists of two major steps: transcription and translation. Together, transcription and translation are known as gene expression. During the process of transcription, the information stored in a gene’s DNA is transferred to a similar molecule called RNA (ribonucleic acid) in the cell nucleus. Both RNA and DNA are made up of a chain of nucleotide bases, but they have slightly different chemical properties. The type of RNA that contains the information for making a protein is called messenger RNA (mRNA) because it carries the information, or message, from the DNA out of the nucleus into the cytoplasm. Translation, the second step in getting from a gene to a protein, takes place in the cytoplasm. The mRNA interacts with a specialized complex called a ribosome, which “reads” the sequence of mRNA bases. Each sequence of three bases, called a codon, usually codes for
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one particular amino acid. (Amino acids are the building blocks of proteins.) A type of RNA called transfer RNA (tRNA) assembles the protein, one amino acid at a time. Protein assembly continues until the ribosome encounters a “stop” codon (a sequence of three bases that does not code for an amino acid). The flow of information from DNA to RNA to proteins is one of the fundamental principles of molecular biology. It is so important that it is sometimes called the “central dogma.”
Through the processes of transcription and translation, information from genes is used to make proteins.
Can Genes Be Turned On and Off in Cells? Each cell expresses, or turns on, only a fraction of its genes. The rest of the genes are repressed, or turned off. The process of turning genes on and off is known as gene regulation. Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments. Although we know that the regulation of genes is critical for life, this complex process is not yet fully understood. Gene regulation can occur at any point during gene expression, but most commonly occurs at the level of transcription (when the information in a gene’s DNA is transferred to mRNA). Signals from the environment or from other cells activate proteins called transcription factors. These proteins bind to regulatory regions of a gene and increase or decrease the level of transcription. By controlling the level of transcription, this process can determine the amount of protein product that is made by a gene at any given time.
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How Do Cells Divide? There are two types of cell division: mitosis and meiosis. Most of the time when people refer to “cell division,” they mean mitosis, the process of making new body cells. Meiosis is the type of cell division that creates egg and sperm cells. Mitosis is a fundamental process for life. During mitosis, a cell duplicates all of its contents, including its chromosomes, and splits to form two identical daughter cells. Because this process is so critical, the steps of mitosis are carefully controlled by a number of genes. When mitosis is not regulated correctly, health problems such as cancer can result. The other type of cell division, meiosis, ensures that humans have the same number of chromosomes in each generation. It is a two-step process that reduces the chromosome number by half—from 46 to 23—to form sperm and egg cells. When the sperm and egg cells unite at conception, each contributes 23 chromosomes so the resulting embryo will have the usual 46. Meiosis also allows genetic variation through a process of DNA shuffling while the cells are dividing.
Mitosis and meiosis, the two types of cell division. How Do Genes Control the Growth and Division of Cells? A variety of genes are involved in the control of cell growth and division. The cell cycle is the cell’s way of replicating itself in an organized, step-by-step fashion. Tight regulation of this process ensures that a dividing cell’s DNA is copied properly, any errors in the DNA are repaired, and each daughter cell receives a full set of chromosomes. The cycle has checkpoints (also called restriction points), which allow certain genes to check for mistakes and halt the cycle for repairs if something goes wrong.
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If a cell has an error in its DNA that cannot be repaired, it may undergo programmed cell death (apoptosis). Apoptosis is a common process throughout life that helps the body get rid of cells it doesn’t need. Cells that undergo apoptosis break apart and are recycled by a type of white blood cell called a macrophage. Apoptosis protects the body by removing genetically damaged cells that could lead to cancer, and it plays an important role in the development of the embryo and the maintenance of adult tissues. Cancer results from a disruption of the normal regulation of the cell cycle. When the cycle proceeds without control, cells can divide without order and accumulate genetic defects that can lead to a cancerous tumor.
Genetic Mutations and Health This section presents basic information about gene mutations, chromosomal changes, and conditions that run in families.9 What Is a Gene Mutation and How Do Mutations Occur? A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome. Gene mutations occur in two ways: they can be inherited from a parent or acquired during a person’s lifetime. Mutations that are passed from parent to child are called hereditary mutations or germline mutations (because they are present in the egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person’s life in virtually every cell in the body. Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder. Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person’s life. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation. Mutations may also occur in a single cell within an early embryo. As all the cells divide during growth and development, the individual will have some cells with the mutation and some cells without the genetic change. This situation is called mosaicism. Some genetic changes are very rare; others are common in the population. Genetic changes that occur in more than 1 percent of the population are called polymorphisms. They are common enough to be considered a normal variation in the DNA. Polymorphisms are 9
This section has been adapted from the National Library of Medicine’s handbook, Help Me Understand Genetics, which presents basic information about genetics in clear language and provides links to online resources: http://ghr.nlm.nih.gov/handbook.
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responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects on a person’s health, some of these variations may influence the risk of developing certain disorders. How Can Gene Mutations Affect Health and Development? To function correctly, each cell depends on thousands of proteins to do their jobs in the right places at the right times. Sometimes, gene mutations prevent one or more of these proteins from working properly. By changing a gene’s instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirely. When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical condition. A condition caused by mutations in one or more genes is called a genetic disorder. In some cases, gene mutations are so severe that they prevent an embryo from surviving until birth. These changes occur in genes that are essential for development, and often disrupt the development of an embryo in its earliest stages. Because these mutations have very serious effects, they are incompatible with life. It is important to note that genes themselves do not cause disease—genetic disorders are caused by mutations that make a gene function improperly. For example, when people say that someone has “the cystic fibrosis gene,” they are usually referring to a mutated version of the CFTR gene, which causes the disease. All people, including those without cystic fibrosis, have a version of the CFTR gene. Do All Gene Mutations Affect Health and Development? No, only a small percentage of mutations cause genetic disorders—most have no impact on health or development. For example, some mutations alter a gene’s DNA base sequence but do not change the function of the protein made by the gene. Often, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed (makes a protein). Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, DNA repair is an important process by which the body protects itself from disease. A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment. For example, a beneficial mutation could result in a protein that protects the organism from a new strain of bacteria. For More Information about DNA Repair and the Health Effects of Gene Mutations •
The University of Utah Genetic Science Learning Center provides information about genetic disorders that explains why some mutations cause disorders but others do not. (Refer to the questions in the far right column.) See http://learn.genetics.utah.edu/units/disorders/whataregd/.
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Additional information about DNA repair is available from the NCBI Science Primer. In the chapter called “What Is A Cell?”, scroll down to the heading “DNA Repair Mechanisms.” See http://www.ncbi.nlm.nih.gov/About/primer/genetics_cell.html. What Kinds of Gene Mutations Are Possible?
The DNA sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health, depending on where they occur and whether they alter the function of essential proteins. The types of mutations include: •
Missense mutation: This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene.
•
Nonsense mutation: A nonsense mutation is also a change in one DNA base pair. Instead of substituting one amino acid for another, however, the altered DNA sequence prematurely signals the cell to stop building a protein. This type of mutation results in a shortened protein that may function improperly or not at all.
•
Insertion: An insertion changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly.
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Deletion: A deletion changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the resulting protein(s).
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Duplication: A duplication consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein.
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Frameshift mutation: This type of mutation occurs when the addition or loss of DNA bases changes a gene’s reading frame. A reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts the grouping of these bases and changes the code for amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.
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Repeat expansion: Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated. This type of mutation can cause the resulting protein to function improperly. Can Changes in Chromosomes Affect Health and Development?
Changes that affect entire chromosomes or segments of chromosomes can cause problems with growth, development, and function of the body’s systems. These changes can affect many genes along the chromosome and alter the proteins made by those genes. Conditions caused by a change in the number or structure of chromosomes are known as chromosomal disorders. Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell. A change in the number of chromosomes leads to a chromosomal disorder. These changes can occur during the formation of reproductive cells (eggs and sperm) or in early fetal development. A gain or loss of chromosomes from the normal 46 is called aneuploidy.
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The most common form of aneuploidy is trisomy, or the presence of an extra chromosome in each cell. “Tri-” is Greek for “three”; people with trisomy have three copies of a particular chromosome in each cell instead of the normal two copies. Down syndrome is an example of a condition caused by trisomy—people with Down syndrome typically have three copies of chromosome 21 in each cell, for a total of 47 chromosomes per cell. Monosomy, or the loss of one chromosome from each cell, is another kind of aneuploidy. “Mono-” is Greek for “one”; people with monosomy have one copy of a particular chromosome in each cell instead of the normal two copies. Turner syndrome is a condition caused by monosomy. Women with Turner syndrome are often missing one copy of the X chromosome in every cell, for a total of 45 chromosomes per cell. Chromosomal disorders can also be caused by changes in chromosome structure. These changes are caused by the breakage and reunion of chromosome segments when an egg or sperm cell is formed or in early fetal development. Pieces of DNA can be rearranged within one chromosome, or transferred between two or more chromosomes. The effects of structural changes depend on their size and location. Many different structural changes are possible; some cause medical problems, while others may have no effect on a person’s health. Many cancer cells also have changes in their chromosome number or structure. These changes most often occur in somatic cells (cells other than eggs and sperm) during a person’s lifetime. Can Changes in Mitochondrial DNA Affect Health and Development? Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body’s systems. These mutations disrupt the mitochondria’s ability to generate energy efficiently for the cell. Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues that require a lot of energy (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision. Mitochondrial DNA is also prone to noninherited (somatic) mutations. Somatic mutations occur in the DNA of certain cells during a person’s lifetime, and typically are not passed to future generations. Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time. A buildup of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person’s lifetime may play a role in the normal process of aging.
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What Are Complex or Multifactorial Disorders? Researchers are learning that nearly all conditions and diseases have a genetic component. Some disorders, such as sickle cell anemia and cystic fibrosis, are caused by mutations in a single gene. The causes of many other disorders, however, are much more complex. Common medical problems such as heart disease, diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. By 2010, however, researchers predict they will have found the major contributing genes for many common complex disorders. What Information about a Genetic Condition Can Statistics Provide? Statistical data can provide general information about how common a condition is, how many people have the condition, or how likely it is that a person will develop the condition. Statistics are not personalized, however—they offer estimates based on groups of people. By taking into account a person’s family history, medical history, and other factors, a genetics professional can help interpret what statistics mean for a particular patient. Common Statistical Terms Some statistical terms are commonly used when describing genetic conditions and other disorders. These terms include: Statistical Term Incidence
Description The incidence of a gene mutation or a genetic disorder is the number of people who are born with the mutation or disorder in a specified group per year. Incidence is often written in the form “1 in [a number]” or as a total number of live births.
Examples About 1 in 200,000 people in the United States are born with syndrome A each year. An estimated 15,000 infants with syndrome B were born last year worldwide.
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Prevalence
The prevalence of a gene mutation or a genetic disorder is the total number of people in a specified group at a given time who have the mutation or disorder. This term includes both newly diagnosed and preexisting cases in people of any age. Prevalence is often written in the form “1 in [a number]” or as a total number of people who have a condition.
Approximately 1 in 100,000 people in the United States have syndrome A at the present time. About 100,000 children worldwide currently have syndrome B.
Mortality
Mortality is the number of deaths from a particular disorder occurring in a specified group per year. Mortality is usually expressed as a total number of deaths.
An estimated 12,000 people worldwide died from syndrome C in 2002.
Lifetime risk
Lifetime risk is the average risk of developing a particular disorder at some point during a lifetime. Lifetime risk is often written as a percentage or as “1 in [a number].” It is important to remember that the risk per year or per decade is much lower than the lifetime risk. In addition, other factors may increase or decrease a person’s risk as compared with the average.
Approximately 1 percent of people in the United States develop disorder D during their lifetimes. The lifetime risk of developing disorder D is 1 in 100.
Naming Genetic Conditions Genetic conditions are not named in one standard way (unlike genes, which are given an official name and symbol by a formal committee). Doctors who treat families with a particular disorder are often the first to propose a name for the condition. Expert working groups may later revise the name to improve its usefulness. Naming is important because it allows accurate and effective communication about particular conditions, which will ultimately help researchers find new approaches to treatment. Disorder names are often derived from one or a combination of sources: •
The basic genetic or biochemical defect that causes the condition (for example, alpha-1 antitrypsin deficiency)
•
One or more major signs or symptoms of the disorder (for example, sickle cell anemia)
•
The parts of the body affected by the condition (for example, retinoblastoma)
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The name of a physician or researcher, often the first person to describe the disorder (for example, Marfan syndrome, which was named after Dr. Antoine Bernard-Jean Marfan)
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A geographic area (for example, familial Mediterranean fever, which occurs mainly in populations bordering the Mediterranean Sea)
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The name of a patient or family with the condition (for example, amyotrophic lateral sclerosis, which is also called Lou Gehrig disease after a famous baseball player who had the condition).
Disorders named after a specific person or place are called eponyms. There is debate as to whether the possessive form (e.g., Alzheimer’s disease) or the nonpossessive form (Alzheimer disease) of eponyms is preferred. As a rule, medical geneticists use the nonpossessive form, and this form may become the standard for doctors in all fields of medicine. Genetics Home Reference uses the nonpossessive form of eponyms. Genetics Home Reference consults with experts in the field of medical genetics to provide the current, most accurate name for each disorder. Alternate names are included as synonyms. Naming genes The HUGO Gene Nomenclature Committee (HGNC) designates an official name and symbol (an abbreviation of the name) for each known human gene. Some official gene names include additional information in parentheses, such as related genetic conditions, subtypes of a condition, or inheritance pattern. The HGNC is a non-profit organization funded by the U.K. Medical Research Council and the U.S. National Institutes of Health. The Committee has named more than 13,000 of the estimated 20,000 to 25,000 genes in the human genome. During the research process, genes often acquire several alternate names and symbols. Different researchers investigating the same gene may each give the gene a different name, which can cause confusion. The HGNC assigns a unique name and symbol to each human gene, which allows effective organization of genes in large databanks, aiding the advancement of research. For specific information about how genes are named, refer to the HGNC’s Guidelines for Human Gene Nomenclature. Genetics Home Reference describes genes using the HGNC’s official gene names and gene symbols. Genetics Home Reference frequently presents the symbol and name separated with a colon (for example, FGFR4: Fibroblast growth factor receptor 4).
Inheriting Genetic Conditions This section gives you information on inheritance patterns and understanding risk. What Does It Mean If a Disorder Seems to Run in My Family? A particular disorder might be described as “running in a family” if more than one person in the family has the condition. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited (passed down from parent to child). Other conditions that appear to run in families are not inherited. Instead, environmental factors
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such as dietary habits or a combination of genetic and environmental factors are responsible for these disorders. It is not always easy to determine whether a condition in a family is inherited. A genetics professional can use a person’s family history (a record of health information about a person’s immediate and extended family) to help determine whether a disorder has a genetic component.
Some disorders are seen in more than one generation of a family. Why Is It Important to Know My Family Medical History? A family medical history is a record of health information about a person and his or her close relatives. A complete record includes information from three generations of relatives,
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including children, brothers and sisters, parents, aunts and uncles, nieces and nephews, grandparents, and cousins. Families have many factors in common, including their genes, environment, and lifestyle. Together, these factors can give clues to medical conditions that may run in a family. By noticing patterns of disorders among relatives, healthcare professionals can determine whether an individual, other family members, or future generations may be at an increased risk of developing a particular condition. A family medical history can identify people with a higher-than-usual chance of having common disorders, such as heart disease, high blood pressure, stroke, certain cancers, and diabetes. These complex disorders are influenced by a combination of genetic factors, environmental conditions, and lifestyle choices. A family history also can provide information about the risk of rarer conditions caused by mutations in a single gene, such as cystic fibrosis and sickle cell anemia. While a family medical history provides information about the risk of specific health concerns, having relatives with a medical condition does not mean that an individual will definitely develop that condition. On the other hand, a person with no family history of a disorder may still be at risk of developing that disorder. Knowing one’s family medical history allows a person to take steps to reduce his or her risk. For people at an increased risk of certain cancers, healthcare professionals may recommend more frequent screening (such as mammography or colonoscopy) starting at an earlier age. Healthcare providers may also encourage regular checkups or testing for people with a medical condition that runs in their family. Additionally, lifestyle changes such as adopting a healthier diet, getting regular exercise, and quitting smoking help many people lower their chances of developing heart disease and other common illnesses. The easiest way to get information about family medical history is to talk to relatives about their health. Have they had any medical problems, and when did they occur? A family gathering could be a good time to discuss these issues. Additionally, obtaining medical records and other documents (such as obituaries and death certificates) can help complete a family medical history. It is important to keep this information up-to-date and to share it with a healthcare professional regularly. What Are the Different Ways in which a Genetic Condition Can Be Inherited? Some genetic conditions are caused by mutations in a single gene. These conditions are usually inherited in one of several straightforward patterns, depending on the gene involved: Inheritance Pattern Autosomal dominant
Description One mutated copy of the gene in each cell is sufficient for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. Autosomal dominant disorders tend to occur in every generation of an affected family.
Examples Huntington disease, neurofibromatosis type 1
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Autosomal recessive
Two mutated copies of the gene are present in each cell when a person has an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Autosomal recessive disorders are typically not seen in every generation of an affected family.
cystic fibrosis, sickle cell anemia
X-linked dominant
X-linked dominant disorders are caused by mutations in genes on the X chromosome. Females are more frequently affected than males, and the chance of passing on an X-linked dominant disorder differs between men and women. Families with an X-linked dominant disorder often have both affected males and affected females in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).
fragile X syndrome
X-linked recessive
X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. Families with an X-linked recessive disorder often have affected males, but rarely affected females, in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).
hemophilia, Fabry disease
Codominant
In codominant inheritance, two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein. Both alleles influence the genetic trait or determine the characteristics of the genetic condition.
ABO blood group, alpha-1 antitrypsin deficiency
Mitochondrial
This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Mitochondria, which are structures in each cell that convert molecules into energy, each contain a small amount of DNA. Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children.
Leber hereditary optic neuropathy (LHON)
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Many other disorders are caused by a combination of the effects of multiple genes or by interactions between genes and the environment. Such disorders are more difficult to analyze because their genetic causes are often unclear, and they do not follow the patterns of inheritance described above. Examples of conditions caused by multiple genes or gene/environment interactions include heart disease, diabetes, schizophrenia, and certain types of cancer. Disorders caused by changes in the number or structure of chromosomes do not follow the straightforward patterns of inheritance listed above. Other genetic factors can also influence how a disorder is inherited. If a Genetic Disorder Runs in My Family, What Are the Chances That My Children Will Have the Condition? When a genetic disorder is diagnosed in a family, family members often want to know the likelihood that they or their children will develop the condition. This can be difficult to predict in some cases because many factors influence a person’s chances of developing a genetic condition. One important factor is how the condition is inherited. For example: •
Autosomal dominant inheritance: A person affected by an autosomal dominant disorder has a 50 percent chance of passing the mutated gene to each child. The chance that a child will not inherit the mutated gene is also 50 percent.
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Autosomal recessive inheritance: Two unaffected people who each carry one copy of the mutated gene for an autosomal recessive disorder (carriers) have a 25 percent chance with each pregnancy of having a child affected by the disorder. The chance with each pregnancy of having an unaffected child who is a carrier of the disorder is 50 percent, and the chance that a child will not have the disorder and will not be a carrier is 25 percent.
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X-linked dominant inheritance: The chance of passing on an X-linked dominant condition differs between men and women because men have one X chromosome and one Y chromosome, while women have two X chromosomes. A man passes on his Y chromosome to all of his sons and his X chromosome to all of his daughters. Therefore, the sons of a man with an X-linked dominant disorder will not be affected, but all of his daughters will inherit the condition. A woman passes on one or the other of her X chromosomes to each child. Therefore, a woman with an X-linked dominant disorder has a 50 percent chance of having an affected daughter or son with each pregnancy.
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X-linked recessive inheritance: Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder also differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. With each pregnancy, a woman who carries an X-linked recessive disorder has a 50 percent chance of having sons who are affected and a 50 percent chance of having daughters who carry one copy of the mutated gene.
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Codominant inheritance: In codominant inheritance, each parent contributes a different version of a particular gene, and both versions influence the resulting genetic trait. The chance of developing a genetic condition with codominant inheritance, and the characteristic features of that condition, depend on which versions of the gene are passed from parents to their child.
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Mitochondrial inheritance: Mitochondria, which are the energy-producing centers inside cells, each contain a small amount of DNA. Disorders with mitochondrial inheritance result from mutations in mitochondrial DNA. Although mitochondrial
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disorders can affect both males and females, only females can pass mutations in mitochondrial DNA to their children. A woman with a disorder caused by changes in mitochondrial DNA will pass the mutation to all of her daughters and sons, but the children of a man with such a disorder will not inherit the mutation. It is important to note that the chance of passing on a genetic condition applies equally to each pregnancy. For example, if a couple has a child with an autosomal recessive disorder, the chance of having another child with the disorder is still 25 percent (or 1 in 4). Having one child with a disorder does not “protect” future children from inheriting the condition. Conversely, having a child without the condition does not mean that future children will definitely be affected. Although the chances of inheriting a genetic condition appear straightforward, factors such as a person’s family history and the results of genetic testing can sometimes modify those chances. In addition, some people with a disease-causing mutation never develop any health problems or may experience only mild symptoms of the disorder. If a disease that runs in a family does not have a clear-cut inheritance pattern, predicting the likelihood that a person will develop the condition can be particularly difficult. Estimating the chance of developing or passing on a genetic disorder can be complex. Genetics professionals can help people understand these chances and help them make informed decisions about their health. Factors that Influence the Effects of Particular Genetic Changes Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern. Reduced Penetrance Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop. Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person’s family medical history and predict the risk of passing a genetic condition to future generations. Variable Expressivity Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and
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symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely— some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience lifethreatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1). As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose. What Do Geneticists Mean by Anticipation? The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. This phenomenon is called anticipation. Anticipation is most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. Anticipation typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row. DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation. Most genetic disorders have signs and symptoms that differ among affected individuals, including affected people in the same family. Not all of these differences can be explained by anticipation. A combination of genetic, environmental, and lifestyle factors is probably responsible for the variability, although many of these factors have not been identified. Researchers study multiple generations of affected family members and consider the genetic cause of a disorder before determining that it shows anticipation. What Is Genomic Imprinting? Genomic imprinting is a factor that influences how some genetic conditions are inherited. People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or “turned on,” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting. In genes that undergo genomic imprinting, the parent of origin is often marked, or “stamped,” on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. These molecules identify which copy of a gene was inherited
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from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes. Only a small percentage of all human genes undergo genomic imprinting. Researchers are not yet certain why some genes are imprinted and others are not. They do know that imprinted genes tend to cluster together in the same regions of chromosomes. Two major clusters of imprinted genes have been identified in humans, one on the short (p) arm of chromosome 11 (at position 11p15) and another on the long (q) arm of chromosome 15 (in the region 15q11 to 15q13). What Is Uniparental Disomy? Uniparental disomy is a factor that influences how some genetic conditions are inherited. Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development. In many cases, UPD likely has no effect on health or development. Because most genes are not imprinted, it doesn’t matter if a person inherits both copies from one parent instead of one copy from each parent. In some cases, however, it does make a difference whether a gene is inherited from a person’s mother or father. A person with UPD may lack any active copies of essential genes that undergo genomic imprinting. This loss of gene function can lead to delayed development, mental retardation, or other medical problems. Several genetic disorders can result from UPD or a disruption of normal genomic imprinting. The most well-known conditions include Prader-Willi syndrome, which is characterized by uncontrolled eating and obesity, and Angelman syndrome, which causes mental retardation and impaired speech. Both of these disorders can be caused by UPD or other errors in imprinting involving genes on the long arm of chromosome 15. Other conditions, such as Beckwith-Wiedemann syndrome (a disorder characterized by accelerated growth and an increased risk of cancerous tumors), are associated with abnormalities of imprinted genes on the short arm of chromosome 11. Are Chromosomal Disorders Inherited? Although it is possible to inherit some types of chromosomal abnormalities, most chromosomal disorders (such as Down syndrome and Turner syndrome) are not passed from one generation to the next. Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body’s cells.
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Changes in chromosome structure can also cause chromosomal disorders. Some changes in chromosome structure can be inherited, while others occur as random accidents during the formation of reproductive cells or in early fetal development. Because the inheritance of these changes can be complex, people concerned about this type of chromosomal abnormality may want to talk with a genetics professional. Some cancer cells also have changes in the number or structure of their chromosomes. Because these changes occur in somatic cells (cells other than eggs and sperm), they cannot be passed from one generation to the next. Why Are Some Genetic Conditions More Common in Particular Ethnic Groups? Some genetic disorders are more likely to occur among people who trace their ancestry to a particular geographic area. People in an ethnic group often share certain versions of their genes, which have been passed down from common ancestors. If one of these shared genes contains a disease-causing mutation, a particular genetic disorder may be more frequently seen in the group. Examples of genetic conditions that are more common in particular ethnic groups are sickle cell anemia, which is more common in people of African, African-American, or Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur among people of Ashkenazi (eastern and central European) Jewish or French Canadian ancestry. It is important to note, however, that these disorders can occur in any ethnic group.
Genetic Consultation This section presents information on finding and visiting a genetic counselor or other genetics professional. What Is a Genetic Consultation? A genetic consultation is a health service that provides information and support to people who have, or may be at risk for, genetic disorders. During a consultation, a genetics professional meets with an individual or family to discuss genetic risks or to diagnose, confirm, or rule out a genetic condition. Genetics professionals include medical geneticists (doctors who specialize in genetics) and genetic counselors (certified healthcare workers with experience in medical genetics and counseling). Other healthcare professionals such as nurses, psychologists, and social workers trained in genetics can also provide genetic consultations. Consultations usually take place in a doctor’s office, hospital, genetics center, or other type of medical center. These meetings are most often in-person visits with individuals or families, but they are occasionally conducted in a group or over the telephone.
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Why Might Someone Have a Genetic Consultation? Individuals or families who are concerned about an inherited condition may benefit from a genetic consultation. The reasons that a person might be referred to a genetic counselor, medical geneticist, or other genetics professional include: •
A personal or family history of a genetic condition, birth defect, chromosomal disorder, or hereditary cancer.
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Two or more pregnancy losses (miscarriages), a stillbirth, or a baby who died.
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A child with a known inherited disorder, a birth defect, mental retardation, or developmental delay.
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A woman who is pregnant or plans to become pregnant at or after age 35. (Some chromosomal disorders occur more frequently in children born to older women.)
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Abnormal test results that suggest a genetic or chromosomal condition.
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An increased risk of developing or passing on a particular genetic disorder on the basis of a person’s ethnic background.
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People related by blood (for example, cousins) who plan to have children together. (A child whose parents are related may be at an increased risk of inheriting certain genetic disorders.)
A genetic consultation is also an important part of the decision-making process for genetic testing. A visit with a genetics professional may be helpful even if testing is not available for a specific condition, however. What Happens during a Genetic Consultation? A genetic consultation provides information, offers support, and addresses a patient’s specific questions and concerns. To help determine whether a condition has a genetic component, a genetics professional asks about a person’s medical history and takes a detailed family history (a record of health information about a person’s immediate and extended family). The genetics professional may also perform a physical examination and recommend appropriate tests. If a person is diagnosed with a genetic condition, the genetics professional provides information about the diagnosis, how the condition is inherited, the chance of passing the condition to future generations, and the options for testing and treatment. During a consultation, a genetics professional will: •
Interpret and communicate complex medical information.
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Help each person make informed, independent decisions about their health care and reproductive options.
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Respect each person’s individual beliefs, traditions, and feelings.
A genetics professional will NOT: •
Tell a person which decision to make.
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Advise a couple not to have children.
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Recommend that a woman continue or end a pregnancy.
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Tell someone whether to undergo testing for a genetic disorder. How Can I Find a Genetics Professional in My Area?
To find a genetics professional in your community, you may wish to ask your doctor for a referral. If you have health insurance, you can also contact your insurance company to find a medical geneticist or genetic counselor in your area who participates in your plan. Several resources for locating a genetics professional in your community are available online: •
GeneTests from the University of Washington provides a list of genetics clinics around the United States and international genetics clinics. You can also access the list by clicking on “Clinic Directory” at the top of the GeneTests home page. Clinics can be chosen by state or country, by service, and/or by specialty. State maps can help you locate a clinic in your area. See http://www.genetests.org/.
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The National Society of Genetic Counselors offers a searchable directory of genetic counselors in the United States. You can search by location, name, area of practice/specialization, and/or ZIP Code. See http://www.nsgc.org/resourcelink.cfm.
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The National Cancer Institute provides a Cancer Genetics Services Directory, which lists professionals who provide services related to cancer genetics. You can search by type of cancer or syndrome, location, and/or provider name at the following Web site: http://cancer.gov/search/genetics_services/.
Genetic Testing This section presents information on the benefits, costs, risks, and limitations of genetic testing. What Is Genetic Testing? Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins. Most of the time, testing is used to find changes that are associated with inherited disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed. Genetic testing is voluntary. Because testing has both benefits and limitations, the decision about whether to be tested is a personal and complex one. A genetic counselor can help by providing information about the pros and cons of the test and discussing the social and emotional aspects of testing. What Are the Types of Genetic Tests? Genetic testing can provide information about a person’s genes and chromosomes. Available types of testing include:
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•
Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. Millions of babies are tested each year in the United States. All states currently test infants for phenylketonuria (a genetic disorder that causes mental retardation if left untreated) and congenital hypothyroidism (a disorder of the thyroid gland). Most states also test for other genetic disorders.
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Diagnostic testing is used to identify or rule out a specific genetic or chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical signs and symptoms. Diagnostic testing can be performed before birth or at any time during a person’s life, but is not available for all genes or all genetic conditions. The results of a diagnostic test can influence a person’s choices about health care and the management of the disorder.
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Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder. This type of testing is offered to individuals who have a family history of a genetic disorder and to people in certain ethnic groups with an increased risk of specific genetic conditions. If both parents are tested, the test can provide information about a couple’s risk of having a child with a genetic condition.
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Prenatal testing is used to detect changes in a fetus’s genes or chromosomes before birth. This type of testing is offered during pregnancy if there is an increased risk that the baby will have a genetic or chromosomal disorder. In some cases, prenatal testing can lessen a couple’s uncertainty or help them make decisions about a pregnancy. It cannot identify all possible inherited disorders and birth defects, however.
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Preimplantation testing, also called preimplantation genetic diagnosis (PGD), is a specialized technique that can reduce the risk of having a child with a particular genetic or chromosomal disorder. It is used to detect genetic changes in embryos that were created using assisted reproductive techniques such as in-vitro fertilization. In-vitro fertilization involves removing egg cells from a woman’s ovaries and fertilizing them with sperm cells outside the body. To perform preimplantation testing, a small number of cells are taken from these embryos and tested for certain genetic changes. Only embryos without these changes are implanted in the uterus to initiate a pregnancy.
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Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no features of the disorder themselves at the time of testing. Predictive testing can identify mutations that increase a person’s risk of developing disorders with a genetic basis, such as certain types of cancer. Presymptomatic testing can determine whether a person will develop a genetic disorder, such as hemochromatosis (an iron overload disorder), before any signs or symptoms appear. The results of predictive and presymptomatic testing can provide information about a person’s risk of developing a specific disorder and help with making decisions about medical care.
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Forensic testing uses DNA sequences to identify an individual for legal purposes. Unlike the tests described above, forensic testing is not used to detect gene mutations associated with disease. This type of testing can identify crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people (for example, paternity).
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How Is Genetic Testing Done? Once a person decides to proceed with genetic testing, a medical geneticist, primary care doctor, specialist, or nurse practitioner can order the test. Genetic testing is often done as part of a genetic consultation. Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. The sample is sent to a laboratory where technicians look for specific changes in chromosomes, DNA, or proteins, depending on the suspected disorder. The laboratory reports the test results in writing to a person’s doctor or genetic counselor. Newborn screening tests are done on a small blood sample, which is taken by pricking the baby’s heel. Unlike other types of genetic testing, a parent will usually only receive the result if it is positive. If the test result is positive, additional testing is needed to determine whether the baby has a genetic disorder. Before a person has a genetic test, it is important that he or she understands the testing procedure, the benefits and limitations of the test, and the possible consequences of the test results. The process of educating a person about the test and obtaining permission is called informed consent. What Is Direct-to-Consumer Genetic Testing? Traditionally, genetic tests have been available only through healthcare providers such as physicians, nurse practitioners, and genetic counselors. Healthcare providers order the appropriate test from a laboratory, collect and send the samples, and interpret the test results. Direct-to-consumer genetic testing refers to genetic tests that are marketed directly to consumers via television, print advertisements, or the Internet. This form of testing, which is also known as at-home genetic testing, provides access to a person’s genetic information without necessarily involving a doctor or insurance company in the process. If a consumer chooses to purchase a genetic test directly, the test kit is mailed to the consumer instead of being ordered through a doctor’s office. The test typically involves collecting a DNA sample at home, often by swabbing the inside of the cheek, and mailing the sample back to the laboratory. In some cases, the person must visit a health clinic to have blood drawn. Consumers are notified of their results by mail or over the telephone, or the results are posted online. In some cases, a genetic counselor or other healthcare provider is available to explain the results and answer questions. The price for this type of at-home genetic testing ranges from several hundred dollars to more than a thousand dollars. The growing market for direct-to-consumer genetic testing may promote awareness of genetic diseases, allow consumers to take a more proactive role in their health care, and offer a means for people to learn about their ancestral origins. At-home genetic tests, however, have significant risks and limitations. Consumers are vulnerable to being misled by the results of unproven or invalid tests. Without guidance from a healthcare provider, they may make important decisions about treatment or prevention based on inaccurate, incomplete, or misunderstood information about their health. Consumers may also experience an invasion of genetic privacy if testing companies use their genetic information in an unauthorized way.
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Genetic testing provides only one piece of information about a person’s health—other genetic and environmental factors, lifestyle choices, and family medical history also affect a person’s risk of developing many disorders. These factors are discussed during a consultation with a doctor or genetic counselor, but in many cases are not addressed by athome genetic tests. More research is needed to fully understand the benefits and limitations of direct-to-consumer genetic testing. What Do the Results of Genetic Tests Mean? The results of genetic tests are not always straightforward, which often makes them challenging to interpret and explain. Therefore, it is important for patients and their families to ask questions about the potential meaning of genetic test results both before and after the test is performed. When interpreting test results, healthcare professionals consider a person’s medical history, family history, and the type of genetic test that was done. A positive test result means that the laboratory found a change in a particular gene, chromosome, or protein of interest. Depending on the purpose of the test, this result may confirm a diagnosis, indicate that a person is a carrier of a particular genetic mutation, identify an increased risk of developing a disease (such as cancer) in the future, or suggest a need for further testing. Because family members have some genetic material in common, a positive test result may also have implications for certain blood relatives of the person undergoing testing. It is important to note that a positive result of a predictive or presymptomatic genetic test usually cannot establish the exact risk of developing a disorder. Also, health professionals typically cannot use a positive test result to predict the course or severity of a condition. A negative test result means that the laboratory did not find a change in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic mutation, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder. Further testing may be required to confirm a negative result. In some cases, a negative result might not give any useful information. This type of result is called uninformative, indeterminate, inconclusive, or ambiguous. Uninformative test results sometimes occur because everyone has common, natural variations in their DNA, called polymorphisms, that do not affect health. If a genetic test finds a change in DNA that has not been associated with a disorder in other people, it can be difficult to tell whether it is a natural polymorphism or a disease-causing mutation. An uninformative result cannot confirm or rule out a specific diagnosis, and it cannot indicate whether a person has an increased risk of developing a disorder. In some cases, testing other affected and unaffected family members can help clarify this type of result. What Is the Cost of Genetic Testing, and How Long Does It Take to Get the Results? The cost of genetic testing can range from under $100 to more than $2,000, depending on the nature and complexity of the test. The cost increases if more than one test is necessary or if multiple family members must be tested to obtain a meaningful result. For newborn
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screening, costs vary by state. Some states cover part of the total cost, but most charge a fee of $15 to $60 per infant. From the date that a sample is taken, it may take a few weeks to several months to receive the test results. Results for prenatal testing are usually available more quickly because time is an important consideration in making decisions about a pregnancy. The doctor or genetic counselor who orders a particular test can provide specific information about the cost and time frame associated with that test. Will Health Insurance Cover the Costs of Genetic Testing? In many cases, health insurance plans will cover the costs of genetic testing when it is recommended by a person’s doctor. Health insurance providers have different policies about which tests are covered, however. A person interested in submitting the costs of testing may wish to contact his or her insurance company beforehand to ask about coverage. Some people may choose not to use their insurance to pay for testing because the results of a genetic test can affect a person’s health insurance coverage. Instead, they may opt to pay out-of-pocket for the test. People considering genetic testing may want to find out more about their state’s privacy protection laws before they ask their insurance company to cover the costs. What Are the Benefits of Genetic Testing? Genetic testing has potential benefits whether the results are positive or negative for a gene mutation. Test results can provide a sense of relief from uncertainty and help people make informed decisions about managing their health care. For example, a negative result can eliminate the need for unnecessary checkups and screening tests in some cases. A positive result can direct a person toward available prevention, monitoring, and treatment options. Some test results can also help people make decisions about having children. Newborn screening can identify genetic disorders early in life so treatment can be started as early as possible. What Are the Risks and Limitations of Genetic Testing? The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a procedure that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but real risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus. Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. The possibility of genetic discrimination in employment or insurance is also a concern.
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Genetic testing can provide only limited information about an inherited condition. The test often can’t determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed. A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision. What Is Genetic Discrimination? Genetic discrimination occurs when people are treated differently by their employer or insurance company because they have a gene mutation that causes or increases the risk of an inherited disorder. People who undergo genetic testing may be at risk for genetic discrimination. The results of a genetic test are normally included in a person’s medical records. When a person applies for life, disability, or health insurance, the insurance company may ask to look at these records before making a decision about coverage. An employer may also have the right to look at an employee’s medical records. As a result, genetic test results could affect a person’s insurance coverage or employment. People making decisions about genetic testing should be aware that when test results are placed in their medical records, the results might not be kept private. Fear of discrimination is a common concern among people considering genetic testing. Several laws at the federal and state levels help protect people against genetic discrimination; however, genetic testing is a fast-growing field and these laws don’t cover every situation. How Does Genetic Testing in a Research Setting Differ from Clinical Genetic Testing? The main differences between clinical genetic testing and research testing are the purpose of the test and who receives the results. The goals of research testing include finding unknown genes, learning how genes work, and advancing our understanding of genetic conditions. The results of testing done as part of a research study are usually not available to patients or their healthcare providers. Clinical testing, on the other hand, is done to find out about an inherited disorder in an individual patient or family. People receive the results of a clinical test and can use them to help them make decisions about medical care or reproductive issues. It is important for people considering genetic testing to know whether the test is available on a clinical or research basis. Clinical and research testing both involve a process of informed consent in which patients learn about the testing procedure, the risks and benefits of the test, and the potential consequences of testing.
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Gene Therapy This section presents information on experimental techniques, safety, ethics, and availability of gene therapy. What Is Gene Therapy? Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient’s cells instead of using drugs or surgery. Researchers are testing several approaches to gene therapy, including: •
Replacing a mutated gene that causes disease with a healthy copy of the gene.
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Inactivating, or “knocking out,” a mutated gene that is functioning improperly.
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Introducing a new gene into the body to help fight a disease.
Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be safe and effective. Gene therapy is currently only being tested for the treatment of diseases that have no other cures. How Does Gene Therapy Work? Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein. A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they can’t cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome. The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where it is taken up by individual cells. Alternately, a sample of the patient’s cells can be removed and exposed to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the treatment is successful, the new gene delivered by the vector will make a functioning protein. Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body.
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A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.
Is Gene Therapy Safe? Gene therapy is under study to determine whether it could be used to treat disease. Current research is evaluating the safety of gene therapy; future studies will test whether it is an effective treatment option. Several studies have already shown that this approach can have very serious health risks, such as toxicity, inflammation, and cancer. Because the techniques are relatively new, some of the risks may be unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research is as safe as possible. Comprehensive federal laws, regulations, and guidelines help protect people who participate in research studies (called clinical trials). The U.S. Food and Drug Administration (FDA) regulates all gene therapy products in the United States and oversees research in this area. Researchers who wish to test an approach in a clinical trial must first obtain permission from the FDA. The FDA has the authority to reject or suspend clinical trials that are suspected of being unsafe for participants. The National Institutes of Health (NIH) also plays an important role in ensuring the safety of gene therapy research. NIH provides guidelines for investigators and institutions (such as universities and hospitals) to follow when conducting clinical trials with gene therapy. These guidelines state that clinical trials at institutions receiving NIH funding for this type of research must be registered with the NIH Office of Biotechnology Activities. The protocol, or plan, for each clinical trial is then reviewed by the NIH Recombinant DNA Advisory Committee (RAC) to determine whether it raises medical, ethical, or safety issues that warrant further discussion at one of the RAC’s public meetings.
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An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must approve each gene therapy clinical trial before it can be carried out. An IRB is a committee of scientific and medical advisors and consumers that reviews all research within an institution. An IBC is a group that reviews and approves an institution’s potentially hazardous research studies. Multiple levels of evaluation and oversight ensure that safety concerns are a top priority in the planning and carrying out of gene therapy research. What Are the Ethical Issues surrounding Gene Therapy? Because gene therapy involves making changes to the body’s set of basic instructions, it raises many unique ethical concerns. The ethical questions surrounding gene therapy include: •
How can “good” and “bad” uses of gene therapy be distinguished?
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Who decides which traits are normal and which constitute a disability or disorder?
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Will the high costs of gene therapy make it available only to the wealthy?
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Could the widespread use of gene therapy make society less accepting of people who are different?
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Should people be allowed to use gene therapy to enhance basic human traits such as height, intelligence, or athletic ability?
Current gene therapy research has focused on treating individuals by targeting the therapy to body cells such as bone marrow or blood cells. This type of gene therapy cannot be passed on to a person’s children. Gene therapy could be targeted to egg and sperm cells (germ cells), however, which would allow the inserted gene to be passed on to future generations. This approach is known as germline gene therapy. The idea of germline gene therapy is controversial. While it could spare future generations in a family from having a particular genetic disorder, it might affect the development of a fetus in unexpected ways or have long-term side effects that are not yet known. Because people who would be affected by germline gene therapy are not yet born, they can’t choose whether to have the treatment. Because of these ethical concerns, the U.S. Government does not allow federal funds to be used for research on germline gene therapy in people. Is Gene Therapy Available to Treat My Disorder? Gene therapy is currently available only in a research setting. The U.S. Food and Drug Administration (FDA) has not yet approved any gene therapy products for sale in the United States. Hundreds of research studies (clinical trials) are under way to test gene therapy as a treatment for genetic conditions, cancer, and HIV/AIDS. If you are interested in participating in a clinical trial, talk with your doctor or a genetics professional about how to participate. You can also search for clinical trials online. ClinicalTrials.gov, a service of the National Institutes of Health, provides easy access to information on clinical trials. You can search for specific trials or browse by condition or trial sponsor. You may wish to refer to a list of gene therapy trials that are accepting (or will accept) patients.
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The Human Genome Project and Genomic Research This section presents information on the goals, accomplishments, and next steps in understanding the human genome. What Is a Genome? A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome—more than 3 billion DNA base pairs—is contained in all cells that have a nucleus. What Was the Human Genome Project and Why Has It Been Important? The Human Genome Project was an international research effort to determine the sequence of the human genome and identify the genes that it contains. The Project was coordinated by the National Institutes of Health and the U.S. Department of Energy. Additional contributors included universities across the United States and international partners in the United Kingdom, France, Germany, Japan, and China. The Human Genome Project formally began in 1990 and was completed in 2003, 2 years ahead of its original schedule. The work of the Human Genome Project has allowed researchers to begin to understand the blueprint for building a person. As researchers learn more about the functions of genes and proteins, this knowledge will have a major impact in the fields of medicine, biotechnology, and the life sciences. What Were the Goals of the Human Genome Project? The main goals of the Human Genome Project were to provide a complete and accurate sequence of the 3 billion DNA base pairs that make up the human genome and to find all of the estimated 20,000 to 25,000 human genes. The Project also aimed to sequence the genomes of several other organisms that are important to medical research, such as the mouse and the fruit fly. In addition to sequencing DNA, the Human Genome Project sought to develop new tools to obtain and analyze the data and to make this information widely available. Also, because advances in genetics have consequences for individuals and society, the Human Genome Project committed to exploring the consequences of genomic research through its Ethical, Legal, and Social Implications (ELSI) program. What Did the Human Genome Project Accomplish? In April 2003, researchers announced that the Human Genome Project had completed a high-quality sequence of essentially the entire human genome. This sequence closed the gaps from a working draft of the genome, which was published in 2001. It also identified the locations of many human genes and provided information about their structure and
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organization. The Project made the sequence of the human genome and tools to analyze the data freely available via the Internet. In addition to the human genome, the Human Genome Project sequenced the genomes of several other organisms, including brewers’ yeast, the roundworm, and the fruit fly. In 2002, researchers announced that they had also completed a working draft of the mouse genome. By studying the similarities and differences between human genes and those of other organisms, researchers can discover the functions of particular genes and identify which genes are critical for life. The Project’s Ethical, Legal, and Social Implications (ELSI) program became the world’s largest bioethics program and a model for other ELSI programs worldwide. What Were Some of the Ethical, Legal, and Social Implications Addressed by the Human Genome Project? The Ethical, Legal, and Social Implications (ELSI) program was founded in 1990 as an integral part of the Human Genome Project. The mission of the ELSI program was to identify and address issues raised by genomic research that would affect individuals, families, and society. A percentage of the Human Genome Project budget at the National Institutes of Health and the U.S. Department of Energy was devoted to ELSI research. The ELSI program focused on the possible consequences of genomic research in four main areas: •
Privacy and fairness in the use of genetic information, including the potential for genetic discrimination in employment and insurance.
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The integration of new genetic technologies, such as genetic testing, into the practice of clinical medicine.
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Ethical issues surrounding the design and conduct of genetic research with people, including the process of informed consent.
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The education of healthcare professionals, policy makers, students, and the public about genetics and the complex issues that result from genomic research. What Are the Next Steps in Genomic Research?
Discovering the sequence of the human genome was only the first step in understanding how the instructions coded in DNA lead to a functioning human being. The next stage of genomic research will begin to derive meaningful knowledge from the DNA sequence. Research studies that build on the work of the Human Genome Project are under way worldwide. The objectives of continued genomic research include the following: •
Determine the function of genes and the elements that regulate genes throughout the genome.
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Find variations in the DNA sequence among people and determine their significance. These variations may one day provide information about a person’s disease risk and response to certain medications.
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Discover the 3-dimensional structures of proteins and identify their functions.
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Explore how DNA and proteins interact with one another and with the environment to create complex living systems.
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Develop and apply genome-based strategies for the early detection, diagnosis, and treatment of disease.
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Sequence the genomes of other organisms, such as the rat, cow, and chimpanzee, in order to compare similar genes between species.
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Develop new technologies to study genes and DNA on a large scale and store genomic data efficiently.
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Continue to explore the ethical, legal, and social issues raised by genomic research. What Is Pharmacogenomics?
Pharmacogenomics is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup. Many drugs that are currently available are “one size fits all,” but they don’t work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects (called adverse drug reactions). Adverse drug reactions are a significant cause of hospitalizations and deaths in the United States. With the knowledge gained from the Human Genome Project, researchers are learning how inherited differences in genes affect the body’s response to medications. These genetic differences will be used to predict whether a medication will be effective for a particular person and to help prevent adverse drug reactions. The field of pharmacogenomics is still in its infancy. Its use is currently quite limited, but new approaches are under study in clinical trials. In the future, pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, Alzheimer disease, cancer, HIV/AIDS, and asthma.
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APPENDIX B. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.
NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute10: •
National Institutes of Health (NIH); guidelines consolidated across agencies available at http://health.nih.gov/
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/Publications/FactSheets.htm
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancertopics/pdq
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/health/
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/HealthInformation/Publications/
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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/Publications/
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These publications are typically written by one or more of the various NIH Institutes.
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidcr.nih.gov/HealthInformation/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/healthinformation/index.cfm
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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
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National Institute of Biomedical Imaging and Bioengineering; general information at http://www.nibib.nih.gov/HealthEdu
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.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
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Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html).
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citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine12: •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/index.html
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Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
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Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
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See http://www.nlm.nih.gov/databases/index.html.
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The NLM 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 neurofibromatosis type 1 (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 6305 49 73 0 0 6427
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 neurofibromatosis type 1 (or synonyms) at the following Web site: http://text.nlm.nih.gov. 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. 13
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
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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. 18 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
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Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.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: •
MD Consult: Access to electronic clinical resources, see http://www.mdconsult.com/.
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Medical Matrix: Lists over 6000 medical Web sites and links to over 1.5 million documents with clinical content, see http://www.medmatrix.org/.
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Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
19
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 C. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called Fact Sheets or Guidelines. They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on neurofibromatosis type 1 can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.
Patient Guideline Sources This section directs you to sources which either publish fact sheets or can help you find additional guidelines on topics related to neurofibromatosis type 1. 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 neurofibromatosis type 1. 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 neurofibromatosis type 1:
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Acoustic Neuroma http://www.nlm.nih.gov/medlineplus/acousticneuroma.html Birth Defects http://www.nlm.nih.gov/medlineplus/birthdefects.html Brain Cancer http://www.nlm.nih.gov/medlineplus/braincancer.html Childhood Brain Tumors http://www.nlm.nih.gov/medlineplus/childhoodbraintumors.html Genetic Disorders http://www.nlm.nih.gov/medlineplus/geneticdisorders.html Neurofibromatosis http://www.nlm.nih.gov/medlineplus/neurofibromatosis.html Neurologic Diseases http://www.nlm.nih.gov/medlineplus/neurologicdiseases.html Peripheral Nerve Disorders http://www.nlm.nih.gov/medlineplus/peripheralnervedisorders.html Soft Tissue Sarcoma http://www.nlm.nih.gov/medlineplus/softtissuesarcoma.html Speech and Communication Disorders http://www.nlm.nih.gov/medlineplus/speechandcommunicationdisorders.html Taste and Smell Disorders http://www.nlm.nih.gov/medlineplus/tasteandsmelldisorders.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click Search. This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •
geneticalliance.org Source: www.geneticalliance.org http://www.geneticalliance.org/ws_display.asp?filter=resources_family_history& char=V&s_Diseases=
Patient Resources
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NORD - National Organization for Rare Disorders, Inc. Source: www.rarediseases.org http://www.rarediseases.org/search/rdblist.html?query_start=801
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TSC Alert 2004 Feb/Mar Source: tsalliance.easycgi.com http://tsalliance.easycgi.com/pages.aspx?content=238
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TSC Alert 2004-Jan Source: tsalliance.easycgi.com http://tsalliance.easycgi.com/pages.aspx?content=220 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 neurofibromatosis type 1. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://health.nih.gov/index.asp. Under Search Health Topics, type neurofibromatosis type 1 (or synonyms) into the search box, and click Search. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
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WebMD®Health: http://www.webmd.com/diseases_and_conditions/default.htm
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Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to neurofibromatosis type 1. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with neurofibromatosis type 1. 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 neurofibromatosis type 1. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://sis.nlm.nih.gov/dirline.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. Simply type in neurofibromatosis type 1 (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://healthhotlines.nlm.nih.gov/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type neurofibromatosis type 1 (or a synonym) into the search box, and click Submit Query.
Patient Resources
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Resources for Patients and Families The following are organizations that provide support and advocacy for patient with genetic conditions and their families21: •
Genetic Alliance: http://geneticalliance.org
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Genetic and Rare Diseases Information Center: http://rarediseases.info.nih.gov/html/resources/info_cntr.html
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Madisons Foundation: http://www.madisonsfoundation.org/
•
March of Dimes: http://www.marchofdimes.com
•
National Organization for Rare Disorders (NORD): http://www.rarediseases.org/ For More Information on Genetics
The following publications offer detailed information for patients about the science of genetics: •
What Is a Genome?: http://www.ncbi.nlm.nih.gov/About/primer/genetics_genome.html
•
A Science Called Genetics: http://publications.nigms.nih.gov/genetics/science.html
•
Genetic Mapping: http://www.genome.gov/10000715
21
Adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/ghr/resource/patients.
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
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MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
•
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/
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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
•
Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/archive//20040831/nichsr/ta101/ta10108.html
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
•
Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
•
Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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NEUROFIBROMATOSIS DICTIONARY
TYPE
1
The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablation: The removal of an organ by surgery. [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 leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [NIH]
Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH]
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Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] 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] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alkaline: Having the reactions of an alkali. [EU] 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] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alternative Splicing: A process whereby multiple protein isoforms are generated from a single gene. Alternative splicing involves the splicing together of nonconsecutive exons during the processing of some, but not all, transcripts of the gene. Thus a particular exon may be connected to any one of several alternative exons to form messenger RNA. The alternative forms produce proteins in which one part is common while the other part is different. [NIH]
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Alveolar Process: The thickest and spongiest part of the maxilla and mandible hollowed out into deep cavities for the teeth. [NIH] Amifostine: A phosphorothioate proposed as a radiation-protective agent. It causes splenic vasodilation and may block autonomic ganglia. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]
Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Anabolic: Relating to, characterized by, or promoting anabolism. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angioma: A tumor composed of lymphatic or blood vessels. [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
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or other tissues are called xenograft models. [NIH] Anterior chamber: The space in front of the iris and behind the cornea. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]
Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Aortic Valve: The valve between the left ventricle and the ascending aorta which prevents backflow into the left ventricle. [NIH] Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH]
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Aqueous: Having to do with water. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articulation: The relationship of two bodies by means of a moveable joint. [NIH] Ascending Colon: The part of the colon on the right side of the abdomen. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, star-shaped cells called astrocytes. [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] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] 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] Axilla: The underarm or armpit. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH]
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Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Benign tumor: A noncancerous growth that does not invade nearby tissue or spread to other parts of the body. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] 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] 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]
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Blood Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone Remodeling: The continuous turnover of bone matrix and mineral that involves first, an increase in resorption (osteoclastic activity) and later, reactive bone formation (osteoblastic activity). The process of bone remodeling takes place in the adult skeleton at discrete foci. The process ensures the mechanical integrity of the skeleton throughout life and plays an important role in calcium homeostasis. An imbalance in the regulation of bone remodeling's two contrasting events, bone resorption and bone formation, results in many of the metabolic bone diseases, such as osteoporosis. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small 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] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Plexus: The large network of nerve fibers which distributes the innervation of the upper extremity. The brachial plexus extends from the neck into the axilla. In humans, the nerves of the plexus usually originate from the lower cervical and the first thoracic spinal cord segments (C5-C8 and T1), but variations are not uncommon. [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] Bromodeoxyuridine: A nucleoside that substitutes for thymidine in DNA and thus acts as an antimetabolite. It causes breaks in chromosomes and has been proposed as an antiviral and antineoplastic agent. It has been given orphan drug status for use in the treatment of primary brain tumors. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Cafe-au-Lait Spots: Light brown pigmented macules associated with neurofibromatosis and Albright's syndrome (see fibrous dysplasia, polyostotic). [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal
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functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Carbohydrates: The largest class of organic compounds, including starches, glycogens, cellulose, gums, and simple sugars. Carbohydrates are composed of carbon, hydrogen, and oxygen in a ratio of Cn(H2O)n. [NIH] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoid: A type of tumor usually found in the gastrointestinal system (most often in the appendix), and sometimes in the lungs or other sites. Carcinoid tumors are usually benign. [NIH]
Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Cardiac: Having to do with the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular Abnormalities: Congenital structural abnormalities of the cardiovascular system. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [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] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and
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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 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] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Centromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is
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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] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] Chemotaxis: The movement of cells or organisms toward or away from a substance in response to its concentration gradient. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chiasmatic: A subarachnoid space between the pituitary body and the optic chiasm. [NIH] Child Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders in children. [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] Chiropractic: A system of treating bodily disorders by manipulation of the spine and other parts, based on the belief that the cause is the abnormal functioning of a nerve. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chromosome Fragility: Susceptibility of chromosomes to breakage and translocation or other aberrations. Chromosome fragile sites are regions that show up in karyotypes as a gap (uncondensed stretch) on the chromatid arm. They are associated with chromosome break sites and other aberrations. A fragile site on the X chromosome is associated with fragile X syndrome. Fragile sites are designated by the letters "FRA" followed by the designation for the specific chromosome and a letter which refers to the different fragile sites on a chromosome (e.g. FRAXA). [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic granulocytic leukemia: A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic myeloid leukemia. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH]
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Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] C-kit receptor: A protein on the surface of some cells that binds to stem cell factor (a substance that causes certain types of cells to grow). Altered forms of this receptor may be associated with some types of cancer. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH]
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Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] 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
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machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Concentric: Having a common center of curvature or symmetry. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] 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] Consciousness: Sense of awareness of self and of the environment. [NIH] Consolidation: The healing process of a bone fracture. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial
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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] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Death Certificates: Official records of individual deaths including the cause of death certified by a physician, and any other required identifying information. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Demyelinating Diseases: Diseases characterized by loss or dysfunction of myelin in the
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central or peripheral nervous system. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Developmental Biology: The field of biology which deals with the process of the growth and differentiation of an organism. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] 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] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the
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back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Double Outlet Right Ventricle: Incomplete transposition of the great vessels in which both the aorta and the pulmonary artery arise from the right ventricle, often associated with a subaortic ventricular septal defect. [NIH] Duct: A tube through which body fluids pass. [NIH] 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] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophic: Pertaining to toxic habitats low in nutrients. [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] 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] Elastin: The protein that gives flexibility to tissues. [NIH] Electrolytes: Substances that break up into ions (electrically charged particles) when they are dissolved in body fluids or water. Some examples are sodium, potassium, chloride, and calcium. Electrolytes are primarily responsible for the movement of nutrients into cells, and the movement of wastes out of cells. [NIH] Electromagnetic Fields: Fields representing the joint interplay of electric and magnetic forces. [NIH] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]
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] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocardium: The innermost layer of the heart, comprised of endothelial cells. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the
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body. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermal growth factor receptor: EGFR. The protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide. It is found at abnormally high levels on the surface of many types of cancer cells, so these cells may divide excessively in the presence of epidermal growth factor. Also known as ErbB1 or HER1. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] 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
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anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythroid Progenitor Cells: Committed, erythroid stem cells derived from myeloid stem cells. The progenitor cells develop in two phases: erythroid burst-forming units (BFU-E) followed by erythroid colony-forming units (CFU-E). BFU-E differentiate into CFU-E on stimulation by erythropoietin, and then further differentiate into erythroblasts when stimulated by other factors. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Etoposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [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] 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] Excrete: To get rid of waste from the body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] 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] Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. [EU]
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Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Eye Color: Color of the iris. [NIH] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Facial: Of or pertaining to the face. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [NIH] Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [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] Fibula: The bone of the lower leg lateral to and smaller than the tibia. In proportion to its length, it is the most slender of the long bones. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] 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] Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH]
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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] 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]
Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal stromal tumor: GIST. A type of tumor that usually begins in cells in the wall of the gastrointestinal tract. It can be benign or malignant. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Products, rev: Trans-acting nuclear proteins whose functional expression are required for HIV viral replication. Specifically, the rev gene products are required for processing and translation of the HIV gag and env mRNAs, and thus rev regulates the expression of the viral structural proteins. rev can also regulate viral regulatory proteins. A cis-acting antirepression sequence (CAR) in env, also known as the rev-responsive element (RRE), is responsive to the rev gene product. rev is short for regulator of virion. [NIH] Gene 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] Genes, env: DNA sequences that form the coding region for the viral envelope (env) proteins in retroviruses. The env genes contain a cis-acting RNA target sequence for the rev protein (= gene products, rev), termed the rev-responsive element (RRE). [NIH] Genes, Neurofibromatosis 2: Tumor suppressor genes located on the long arm of human chromosome 22. Mutation or loss of these genes causes neurofibromatosis 2. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of
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heredity. [NIH] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]
Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germline mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; germline mutations are passed on from parents to offspring. Also called hereditary mutation. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gifted: As used in child psychiatry, this term is meant to refer to a child whose intelligence is in the upper 2 per cent of the total population of his age. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioblastoma: A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. They may arise in any region of the central nervous system, with a predilection for the cerebral hemispheres, basal ganglia, and commissural pathways. Clinical presentation most frequently occurs in the fifth or sixth decade of life with focal neurologic signs or seizures. [NIH] Glioblastoma multiforme: A type of brain tumor that forms from glial (supportive) tissue of the brain. It grows very quickly and has cells that look very different from normal cells. Also called grade IV astrocytoma. [NIH] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH] Gliosis: The production of a dense fibrous network of neuroglia; includes astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion. [NIH] 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] 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]
Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] 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] Granule: A small pill made from sucrose. [EU] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH]
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Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [NIH] Groin: The external junctural region between the lower part of the abdomen and the thigh. [NIH]
Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Haemostasis: The arrest of bleeding, either by the physiological properties of vasoconstriction and coagulation or by surgical means. [EU] Hair Color: Color of hair or fur. [NIH] Hamartoma: A focal malformation resembling a neoplasm, composed of an overgrowth of mature cells and tissues that normally occur in the affected area. [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] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Hematoma: An extravasation of blood localized in an organ, space, or tissue. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Hemicrania: An ache or a pain in one side of the head, as in migraine. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH]
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Hemophilia: Refers to a group of hereditary disorders in which affected individuals fail to make enough of certain proteins needed to form blood clots. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hepatocyte: A liver cell. [NIH] Hepatocyte Growth Factor: Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is proto-oncogene protein C-met. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Hereditary mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; hereditary mutations are passed on from parents to offspring. Also called germline mutation. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] 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] Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] 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] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of
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water. [NIH] 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] Hyperhidrosis: Excessive sweating. In the localized type, the most frequent sites are the palms, soles, axillae, inguinal folds, and the perineal area. Its chief cause is thought to be emotional. Generalized hyperhidrosis may be induced by a hot, humid environment, by fever, or by vigorous exercise. [NIH] Hyperpigmentation: Excessive pigmentation of the skin, usually as a result of increased melanization of the epidermis rather than as a result of an increased number of melanocytes. Etiology is varied and the condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersecretion: Excessive secretion. [EU] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypoglycemia: Abnormally low blood sugar [NIH] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Ileum: The lower end of the small intestine. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] 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] Immunosuppressant: An agent capable of suppressing immune responses. [EU] 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
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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] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In 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] Incidental: 1. Small and relatively unimportant, minor; 2. Accompanying, but not a major part of something; 3. (To something) Liable to occur because of something or in connection with something (said of risks, responsibilities, .) [EU] Incision: A cut made in the body during surgery. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Inguinal: Pertaining to the inguen, or groin. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [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] Inorganic: Pertaining to substances not of organic origin. [EU]
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Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intracellular: Inside a cell. [NIH] Intracranial Aneurysm: A saclike dilatation of the walls of a blood vessel, usually an artery. [NIH]
Intracranial tumors: Tumors that occur in the brain. [NIH] Intrahepatic: Within the liver. [NIH] Intravenous: IV. Into a vein. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
Involuntary: Reaction occurring without intention or volition. [NIH] 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] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Ischemic stroke: A condition in which the blood supply to part of the brain is cut off. Also called "plug-type" strokes. Blocked arteries starve areas of the brain controlling sight, speech, sensation, and movement so that these functions are partially or completely lost. Ischemic stroke is the most common type of stroke, accounting for 80 percent of all strokes. Most ischemic strokes are caused by a blood clot called a thrombus, which blocks blood flow
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in the arteries feeding the brain, usually the carotid artery in the neck, the major vessel bringing blood to the brain. When it becomes blocked, the risk of stroke is very high. [NIH] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] 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. 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] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] 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] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]
Leukemia: Cancer of blood-forming tissue. [NIH]
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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] Linkages: 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] Liposarcoma: A rare cancer of the fat cells. [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] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Long-Term Potentiation: A persistent increase in synaptic efficacy, usually induced by appropriate activation of the same synapses. The phenomenological properties of long-term potentiation suggest that it may be a cellular mechanism of learning and memory. [NIH] 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] Loss of Heterozygosity: The loss of one allele at a specific locus, caused by a deletion mutation; or loss of a chromosome from a chromosome pair. It is detected when heterozygous markers for a locus appear monomorphic because one of the alleles was deleted. When this occurs at a tumor suppressor gene locus where one of the alleles is already abnormal, it can result in neoplastic transformation. [NIH] Lung Transplantation: The transference of either one or both of the lungs from one human or animal to another. [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] Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Malformation: A morphologic developmental process. [EU]
defect
resulting
from
an
intrinsically
abnormal
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] Mammary: Pertaining to the mamma, or breast. [EU] Mammography: Radiographic examination of the breast. [NIH] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mastication: The act and process of chewing and grinding food in the mouth. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work
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properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Meatus: A canal running from the internal auditory foramen through the petrous portion of the temporal bone. It gives passage to the facial and auditory nerves together with the auditory branch of the basilar artery and the internal auditory veins. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] 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] Medulloblastoma: A malignant brain tumor that begins in the lower part of the brain and can spread to the spine or to other parts of the body. Medulloblastomas are sometimes called primitive neuroectodermal tumors (PNET). [NIH] Megacolon: Pathological enlargement of the colon. [NIH] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Megalencephaly: A condition in which there is an abnormally large, heavy, and usually malfunctioning brain. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melanophores: Chromatophores (large pigment cells of fish, amphibia, reptiles and many invertebrates) which contain melanin. Short term color changes are brought about by an active redistribution of the melanophores pigment containing organelles (melanosomes). Mammals do not have melanophores; however they have retained smaller pigment cells known as melanocytes. [NIH] Melanosomes: Melanin-containing organelles found in melanocytes and melanophores. [NIH]
Membrane: A very thin layer of tissue that covers a surface. [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] Meningeal: Refers to the meninges, the tissue covering the brain and spinal cord. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningioma: A type of tumor that occurs in the meninges, the membranes that cover and protect the brain and spinal cord. Meningiomas usually grow slowly. [NIH] Meningocele: A congenital or acquired protrusion of the meninges, unaccompanied by neural tissue, through a bony defect in the skull or vertebral column. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU]
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Mental Health: The state wherein the person is well adjusted. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]
Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the second trimester. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitogen-Activated Protein Kinase Kinases: A serine-threonine protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate mitogen-activated protein kinases and are themselves phosphorylated by MAP kinase kinase kinases. JNK kinases (also known as SAPK kinases) are a subfamily. EC 2.7.10.- [NIH] Mitogen-Activated Protein Kinases: A superfamily of protein-serine-threonine kinases that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by mitogen-activated protein kinase kinases which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP kinase kinase kinases). Families of these mitogen-activated protein kinases (MAPKs) include extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs) (also known as c-jun terminal kinases (JNKs)), and p38-mitogen-activated protein kinases. EC 2,7,1.- [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]
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Mitotic: Cell resulting from mitosis. [NIH] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] 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] 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] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]
Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Motility: The ability to move spontaneously. [EU] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Mustard Gas: Severe irritant and vesicant of skin, eyes, and lungs. It may cause blindness and lethal lung edema and was formerly used as a war gas. The substance has been proposed as a cytostatic and for treatment of psoriasis. It has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP-85-002, 1985) (Merck, 11th ed). [NIH] Mutagen: Any agent, such as X-rays, gamma rays, mustard gas, TCDD, that can cause abnormal mutation in living cells; having the power to cause mutations. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Myelin: The fatty substance that covers and protects nerves. [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
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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] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [NIH] Myeloid Progenitor Cells: One of the two stem cells derived from hematopoietic stem cells the other being the lymphoid progenitor cell. Derived from these myeloid progenitor cells are the erythroid progenitor cells and the myeloid cells (monocytes and granulocytes). [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Naevus: A circumscribed area of pigmentation or vascularization, usually in the form of a congenital benign neoplasm occurring in the skin or in various ocular tissues. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephrectomy: Surgery to remove a kidney. Radical nephrectomy removes the kidney, the adrenal gland, nearby lymph nodes, and other surrounding tissue. Simple nephrectomy removes only the kidney. Partial nephrectomy removes the tumor but not the entire kidney. [NIH]
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 Sheath Tumors: Tumors arising from nerve sheaths formed by schwann cells in the peripheral nervous system and by oligodendrocytes in the central nervous system. Malignant peripheral nerve sheath tumors, neurofibroma, and neurilemmoma are relatively common tumors in this category. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis,
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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] Neuregulin-1: A peptide factor originally identified by its ability to stimulate the phosphorylation the erbB-2 receptor. It is a ligand for the erbB-3 receptor and the erbB-4 receptor. Variant forms of neuregulin-1 occur through alternative splicing of its mRNA. [NIH]
Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurofibroma: A fibrous tumor, usually benign, arising from the nerve sheath or the endoneurium. [NIH] Neurofibromatosis 2: An autosomal dominant disorder characterized by a high incidence of bilateral acoustic neuromas as well as other benign intracranial tumors including meningiomas, ependymomas, spinal neurofibromas, and gliomas. The disease has been linked to mutations of the NF2 gene (genes, neurofibromatosis 2) on chromosome 22 (22q12) and usually presents clinically in the first or second decade of life. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neuronal Plasticity: The capacity of the nervous system to change its reactivity as the result of successive activations. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neurotrophins: A nerve growth factor. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Nevus: A benign growth on the skin, such as a mole. A mole is a cluster of melanocytes and surrounding supportive tissue that usually appears as a tan, brown, or flesh-colored spot on the skin. The plural of nevus is nevi (NEE-vye). [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14.
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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] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Envelope: The membrane system of the cell nucleus that surrounds the nucleoplasm. It consists of two concentric membranes separated by the perinuclear space. The structures of the envelope where it opens to the cytoplasm are called the nuclear pores (nuclear pore). [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [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] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] 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]
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Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]
Optic 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] Orbit: One of the two cavities in the skull which contains an eyeball. Each eye is located in a bony socket or orbit. [NIH] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU] 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] Osteoblasts: Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. [NIH] Osteolytic: Causing the breakdown of bone. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] Paediatric: Of or relating to the care and medical treatment of children; belonging to or concerned with paediatrics. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [NIH] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH]
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Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Paternity: Establishing the father relationship of a man and a child. [NIH] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] PDQ: Physician Data Query. PDQ is an online database developed and maintained by the National Cancer Institute. Designed to make the most current, credible, and accurate cancer information available to health professionals and the public, PDQ contains peer-reviewed summaries on cancer treatment, screening, prevention, genetics, and supportive care; a registry of cancer clinical trials from around the world; and directories of physicians, professionals who provide genetics services, and organizations that provide cancer care. Most of this information is available on the CancerNet Web site, and more specific information about PDQ can be found at http://cancernet.nci.nih.gov/pdq.html. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] Pericytes: Smooth muscle cell that wraps around normal blood vessels. [NIH] Perineal: Pertaining to the perineum. [EU] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or
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glycerophosphatidates. EC 3.1.-. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pigmentation: Coloration or discoloration of a part by a pigment. [NIH] Pilocytic: Made up of cells that look like fibers when viewed under a microscope. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] 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] Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [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
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sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyp: A growth that protrudes from a mucous membrane. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Pontine: A brain region involved in the detection and processing of taste. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-synaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Precipitating Factors: Factors associated with the definitive onset of a disease, illness, accident, behavioral response, or course of action. Usually one factor is more important or more obviously recognizable than others, if several are involved, and one may often be regarded as "necessary". Examples include exposure to specific disease; amount or level of an infectious organism, drug, or noxious agent, etc. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [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]
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Premalignant: A term used to describe a condition that may (or is likely to) become cancer. Also called precancerous. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [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] Primitive neuroectodermal tumors: PNET. A type of bone cancer that forms in the middle (shaft) of large bones. Also called Ewing's sarcoma/primitive neuroectodermal tumor. [NIH] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] 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] Promyelocytic leukemia: A type of acute myeloid leukemia, a quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. [NIH]
Prone: Having the front portion of the body downwards. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] 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 Kinase C: An enzyme that phosphorylates proteins on serine or threonine residues in the presence of physiological concentrations of calcium and membrane phospholipids. The additional presence of diacylglycerols markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by phorbol esters and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. EC 2.7.1.-. [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]
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Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors. EC 2.7.10. [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 formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychic: Pertaining to the psyche or to the mind; mental. [EU] 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] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a
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machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioactivity: The quality of emitting or the emission of corpuscular or electromagnetic radiations consequent to nuclear disintegration, a natural property of all chemical elements of atomic number above 83, and possible of induction in all other known elements. [EU] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] 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] 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] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Registries: The systems and processes involved in the establishment, support, management, and operation of registers, e.g., disease registers. [NIH] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a
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specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [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] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] 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] Retroperitoneal: Having to do with the area outside or behind the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rhabdomyolysis: Necrosis or disintegration of skeletal muscle often followed by myoglobinuria. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [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
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of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [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] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schwann: A neurilemmal cell from the sheath of a peripheral nerve fiber. [NIH] Schwann Cells: Neuroglial cells of the peripheral nervous system which form the insulating myelin sheaths of peripheral axons. [NIH] Schwannoma: A tumor of the peripheral nervous system that begins in the nerve sheath (protective covering). It is almost always benign, but rare malignant schwannomas have been reported. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Scoliosis: A lateral curvature of the spine. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast
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cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segmentation: The process by which muscles in the intestines move food and wastes through the body. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Shunt: A surgically created diversion of fluid (e.g., blood or cerebrospinal fluid) from one area of the body to another area of the body. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH]
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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] Social Work: The use of community resources, individual case work, or group work to promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Sphenoid: An unpaired cranial bone with a body containing the sphenoid sinus and forming the posterior part of the medial walls of the orbits. [NIH] Sphenoid Sinus: One of the paired paranasal sinuses, located in the body of the sphenoid bone and communicating with the highest meatus of the nasal cavity on the same side. [NIH]
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Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinal 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] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Spotting: A slight discharge of blood via the vagina, especially as a side-effect of oral contraceptives. [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]
Status Epilepticus: Repeated and prolonged epileptic seizures without recovery of consciousness between attacks. [NIH] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cell Factor: Hematopoietic growth factor and the ligand of the c-kit receptor CD117 (proto-oncogene protein C-kit). It is expressed during embryogenesis and provides a key signal in multiple aspects of mast-cell differentiation and function. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] 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.
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Neurofibromatosis Type 1
These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclavian: The direct continuation of the axillary vein at the lateral border of the first rib. It passes medially to join the internal jugular vein and form the brachiocephalic vein on each side. [NIH] Subclavian Artery: Artery arising from the brachiocephalic trunk on the right side and from the arch of the aorta on the left side. It distributes to the neck, thoracic wall, spinal cord, brain, meninges, and upper limb. [NIH] 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] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [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] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU]
Dictionary 189
Syringomyelia: The presence in the spinal cord of elongated central fluid containing cavities surrounded by gliosis. [NIH] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Talus: The second largest of the tarsal bones and occupies the middle and upper part of the tarsus. [NIH] Tamoxifen: A first generation selective estrogen receptor modulator (SERM). It acts as an agonist for bone tissue and cholesterol metabolism but is an estrogen antagonist in mammary and uterine. [NIH] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Tendon: A discrete band of connective tissue mainly composed of parallel bundles of collagenous fibers by which muscles are attached, or two muscles bellies joined. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] 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] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH]
190
Neurofibromatosis Type 1
Thoracic: Having to do with the chest. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]
Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Tibia: The second longest bone of the skeleton. It is located on the medial side of the lower leg, articulating with the fibula laterally, the talus distally, and the femur proximally. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [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] 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
Dictionary 191
(pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Triad: Trivalent. [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] Trinucleotide Repeat Expansion: DNA region comprised of a variable number of repetitive, contiguous trinucleotide sequences. The presence of these regions is associated with diseases such as Fragile X Syndrome and myotonic dystrophy. Many chromosome fragile sites (chromosome fragility) contain expanded trinucleotide repeats. [NIH] Trinucleotide Repeats: Microsatellite repeats consisting of three nucleotides dispersed in the euchromatic arms of chromosomes. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]
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] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor model: A type of animal model which can be 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] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumorigenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH]
Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ultraviolet radiation: Invisible rays that are part of the energy that comes from the sun. UV radiation can damage the skin and cause melanoma and other types of skin cancer. UV radiation that reaches the earth's surface is made up of two types of rays, called UVA and UVB rays. UVB rays are more likely than UVA rays to cause sunburn, but UVA rays pass deeper into the skin. Scientists have long thought that UVB radiation can cause melanoma and other types of skin cancer. They now think that UVA radiation also may add to skin damage that can lead to skin cancer and cause premature aging. For this reason, skin specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. [NIH]
192
Neurofibromatosis Type 1
Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] 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] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vagus Nerve: The 10th cranial nerve. The vagus is a mixed nerve which contains somatic afferents (from skin in back of the ear and the external auditory meatus), visceral afferents (from the pharynx, larynx, thorax, and abdomen), parasympathetic efferents (to the thorax and abdomen), and efferents to striated muscle (of the larynx and pharynx). [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Vertebral Artery: The first branch of the subclavian artery with distribution to muscles of the neck, vertebrae, spinal cord, cerebellum and interior of the cerebrum. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [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
Dictionary 193
alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Proteins: Proteins found in any species of virus. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Afferents: The sensory fibers innervating the viscera. [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] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
194
INDEX 3 3-dimensional, 98, 129, 141 A Abdomen, 141, 145, 162, 166, 168, 177, 183, 187, 192, 193 Abdominal, 51, 171, 176, 177, 183 Aberrant, 20, 32 Ablation, 21 Abscess, 185 Acetylcholine, 174 Acetylgalactosamine, 161 Acetylglucosamine, 161 Acid, 143, 161, 175 Acoustic, 88, 174 Actin, 28, 77, 173 Acute Disease, 16 Acute leukemia, 19 Acute myelogenous leukemia, 141 Acute myeloid leukemia, 16, 18, 33, 141, 180 Acute nonlymphocytic leukemia, 141 Adaptability, 148, 149 Adaptation, 178 Adenine, 92, 141, 181 Adenocarcinoma, 51 Adenosine, 93, 141, 142, 178 Adenosine Triphosphate, 93, 142, 178 Adenovirus, 125 Adjustment, 73, 141 Administration, iv, 11, 15, 17, 19, 125, 126, 133 Adolescence, 142 Adrenal Medulla, 157 Adrenergic, 157 Adverse Effect, 185 Aerobic, 171 Afferent, 179 Affinity, 142, 145 Agonist, 189 Algorithms, 146 Alkaline, 147, 189 Alkalosis, 189 Alkylating Agents, 83 Alleles, 111, 168 Allergen, 155 Alopecia, 154 Alpha Particles, 142, 181 Alpha-1, 107, 111 Alpha-helix, 167
Alternative medicine, 152 Alternative Splicing, 174 Alveolar Process, 183 Amifostine, 33 Amino Acid Sequence, 144, 158 Amino Acid Substitution, 11 Amino acids, 94, 98, 104, 143, 151, 177, 179, 180, 184, 191 Amino Acids, 94, 98, 104, 143, 151, 177, 179, 180, 184, 191 Amnion, 143 Amniotic Fluid, 120, 122, 143 Amygdala, 146, 168, 189 Amyloid, 69 Anabolic, 68 Anaesthesia, 165 Anal, 168 Analog, 33 Analogous, 191 Anaphylatoxins, 152 Anatomical, 150, 165, 184 Anemia, 106, 107, 110, 111, 116 Anesthetics, 158 Aneuploidy, 104, 105 Aneurysm, 49, 53, 79, 192 Angioma, 37 Animal model, 12, 48, 191 Anions, 166 Anomalies, 189 Anterior chamber, 166 Antibacterial, 186 Antibiotic, 186 Antibodies, 12, 144, 164, 178, 182 Antibody, 144, 152, 163, 164, 165, 182 Anticoagulant, 180 Antigen, 50, 144, 152, 163, 164, 165 Antigen-Antibody Complex, 152 Antigens, 144, 164 Anti-inflammatory, 17 Antilymphocyte Serum, 169 Antimetabolite, 147 Antineoplastic, 142, 147, 148, 154, 178, 192 Antineoplastic Agents, 142, 192 Antiviral, 147 Anuria, 167 Anus, 143, 151 Aorta, 144, 156, 188, 192 Aortic Valve, 36 Aponeurosis, 160
Index 195
Apoptosis, 13, 32, 85, 93, 102 Aqueous, 146, 154 Archaea, 171 Arginine, 163 Arterial, 79, 164, 180, 189 Arteries, 144, 145, 147, 153, 166 Arterioles, 147 Arteriosus, 181 Artery, 86, 143, 145, 166, 167, 184 Articulation, 34 Ascending Colon, 78 Ascorbic Acid, 164 Aseptic, 187 Assay, 12, 51 Astigmatism, 182 Astrocytes, 145, 161 Astrocytoma, 13, 48, 84, 161 Ataxia, 38, 145, 189 Atrium, 192 Attenuation, 16 Atypical, 75, 83, 115 Auditory, 170, 179, 192 Auditory nerve, 170 Autonomic Nervous System, 145, 177, 188 Axilla, 147 Axillary, 188 Axillary Vein, 188 Axons, 12, 20, 155, 172, 173, 175, 176, 183, 184 B Bacteria, 91, 99, 103, 144, 159, 171, 186, 190, 192 Bacterial Infections, 149 Bacterial Physiology, 141 Barbiturates, 181 Basal Ganglia, 34, 145, 146, 160, 161, 168 Basal Ganglia Diseases, 145 Base, 40, 92, 93, 96, 98, 102, 103, 104, 127, 141, 154, 155, 159, 167, 189 Base Sequence, 103, 159 Basement Membrane, 158 Basilar Artery, 170 Basophils, 161 Benign, 12, 20, 23, 24, 28, 33, 52, 148, 160, 162, 173, 174, 182, 184 Benign tumor, 28, 52 Beta Rays, 156 Beta-pleated, 143 Bewilderment, 153 Bilateral, 174 Bile, 146, 168 Bile Acids, 146
Bile Acids and Salts, 146 Binding Sites, 19 Biochemical, 15, 21, 23, 25, 27, 107, 142, 144, 146, 167 Biological response modifier, 146 Biological therapy, 162 Biological Transport, 155 Biotechnology, 127 Bladder, 78, 192 Blastocyst, 153 Blood Coagulation, 146, 148, 190 Blood Coagulation Factors, 146 Blood Glucose, 162, 166 Blood Platelets, 170 Blood pressure, 110, 148, 164, 172 Blood urea, 167 Blood vessel, 114, 143, 147, 148, 149, 150, 157, 166, 168, 169, 171, 177, 186, 187, 190, 192 Blood Vessels, 114, 143, 148, 149, 150, 157, 169, 171, 177, 186, 192 Body Fluids, 156 Bone Marrow, 23, 31, 56, 126, 141, 147, 150, 160, 169, 170, 172, 173, 180, 186, 187 Bone Marrow Cells, 23, 56, 170 Bone Marrow Transplantation, 31 Bone Remodeling, 24, 147 Bone Resorption, 24, 31, 147 Bone scan, 184 Bowel, 143, 166, 177, 187 Bowel Movement, 187 Brachial, 38, 147 Brachial Plexus, 38, 147 Brachiocephalic Trunk, 188 Brachytherapy, 182 Brain Hypoxia, 189 Brain Neoplasms, 189 Brain Stem, 149 Bromodeoxyuridine, 17 Bronchi, 157, 190 Buccal, 120, 122, 147 C Cafe-au-Lait Spots, 28 Caffeine, 181 Calcium, 37, 147, 152, 156, 169, 176, 180, 185, 189 Callus, 156 Capillary, 192 Carbohydrate, 179 Carbohydrates, 149 Carboplatin, 85 Carcinogen, 172
196
Neurofibromatosis Type 1
Carcinogenesis, 150 Carcinogenic, 12, 142, 165, 175, 180, 191 Carcinogens, 175 Carcinoid, 83 Carcinoma, 148 Cardiac, 24, 47, 76, 157, 173 Cardiovascular, 24, 25, 129, 148 Cardiovascular Abnormalities, 25 Cardiovascular disease, 129 Cardiovascular System, 148 Carotene, 183 Case report, 37, 39, 42, 43, 49, 52, 63, 66, 68, 71, 80, 82, 148, 151 Case series, 148, 151 Cathode, 156 Cations, 166 Caudal, 164, 179 Caudate Nucleus, 146 Cause of Death, 154 Cecum, 167 Cell Cycle, 28, 30, 32, 49, 101, 102, 151, 154, 158 Cell Death, 102, 144, 158, 173 Cell Differentiation, 185, 187 Cell Division, 21, 94, 101, 102, 114, 115, 145, 148, 149, 154, 158, 162, 170, 171, 178, 180, 185 Cell Lineage, 23 Cell membrane, 28, 146, 155, 173 Cell motility, 77, 163 Cell proliferation, 17, 20, 32, 185 Cell Respiration, 171 Cell Survival, 162 Central Nervous System, 13, 17, 68, 145, 149, 160, 161, 162, 173, 175, 176 Central Nervous System Infections, 162 Centrioles, 180 Centromere, 94, 97 Cerebellar, 21, 37, 145, 182 Cerebellar Diseases, 145 Cerebellum, 21, 149, 182, 192 Cerebral, 70, 145, 147, 149, 157, 158, 159, 161, 189 Cerebral Cortex, 145, 158, 159 Cerebral hemispheres, 145, 147, 149, 161, 189 Cerebrospinal, 185 Cerebrospinal fluid, 185 Cerebrovascular, 146, 148, 189 Cerebrovascular Disorders, 189 Cerebrum, 149, 189, 191, 192 Cervical, 64, 86, 147, 149
Cervix, 149 Chemopreventive, 33 Chemotactic Factors, 152 Chemotaxis, 29 Chemotherapeutic agent, 32 Chemotherapy, 13, 82, 83, 85, 86 Chiasma, 154 Chiasmatic, 47 Child Psychiatry, 161 Chin, 170 Chiropractic, 86 Cholesterol, 93, 146, 153, 189 Choroid, 183 Chromatin, 144, 157, 169 Chromosomal, 18, 102, 104, 115, 116, 117, 119, 143, 150, 163, 172, 183, 184 Chromosomal Proteins, Non-Histone, 150 Chromosome, 3, 16, 62, 94, 95, 96, 97, 98, 101, 102, 104, 105, 111, 112, 115, 116, 121, 124, 143, 149, 150, 160, 167, 168, 172, 174, 184, 185, 191 Chromosome Fragility, 191 Chronic, 16, 32, 63, 150, 155, 165, 167, 168, 188 Chronic granulocytic leukemia, 150 Chronic myelogenous leukemia, 63, 150 Cirrhosis, 162 CIS, 150, 160, 183 Cisplatin, 83, 151 C-kit receptor, 23, 187 Clamp, 13 Clinical Medicine, 128, 179 Clinical Protocols, 14 Clinical study, 31 Clinical trial, 11, 125, 126, 129, 132, 151, 177, 181, 182 Clinical Trials, 125, 126, 129, 132, 151, 177 Cloning, 33, 146 Coagulation, 162 Codon, 99, 151 Codon, Terminator, 151 Codons, 151 Cofactor, 180, 190 Cognition, 23 Collagen, 20, 24, 151, 158, 159, 169, 180 Colloidal, 156 Colon, 108, 145, 151, 152, 167, 170 Colonoscopy, 110 Colorectal, 51, 67, 152 Colorectal Cancer, 67, 152 Complement, 152, 160, 167
Index 197
Complementary and alternative medicine, 81, 87 Complementary medicine, 81 Computational Biology, 132 Computed tomography, 27, 36, 41, 153, 184 Computerized axial tomography, 152, 153, 184 Computerized tomography, 31, 152, 153 Concentric, 175 Conception, 101, 159, 186, 187 Conduction, 173 Cones, 183 Confusion, 108, 155, 192 Conjugated, 154 Conjunctiva, 191 Connective tissue, 147, 151, 153, 159, 160, 169, 171, 181, 187, 189 Connective Tissue, 147, 151, 153, 159, 160, 169, 171, 181, 187, 189 Connective Tissue Cells, 153 Consciousness, 154, 187 Consolidation, 12 Constitutional, 27, 63 Constriction, 94, 97, 166, 184, 192 Constriction, Pathologic, 192 Consultation, 116, 117, 120, 121 Contraindications, ii Contralateral, 176, 182 Conus, 181 Coordination, 149 Cornea, 144, 187 Corneum, 157 Coronary, 148, 153 Coronary heart disease, 148 Cortex, 19, 34, 153 Cortical, 31, 158, 179, 185, 189 Cranial, 34, 149, 154, 162, 174, 176, 177, 186, 192 Cranial Nerves, 154 Craniocerebral Trauma, 146, 162, 189 Creatinine, 167 Cricoid Cartilage, 193 Crossing-over, 182 Curative, 189 Cutaneous, 28 Cyclic, 60, 184 Cyclin, 85 Cyclophosphamide, 32 Cytochrome, 176 Cytogenetics, 184 Cytokines, 165
Cytoplasm, 91, 92, 93, 99, 144, 146, 149, 157, 169, 172, 175, 184 Cytosine, 92, 181 Cytostatic, 172 Cytotoxic, 33, 165, 182, 185 Cytotoxicity, 151 D De novo, 102 Death Certificates, 110 Degenerative, 161 Deletion, 35, 49, 58, 75, 78, 104, 144, 168 Dementia, 105 Demyelinating Diseases, 173 Dendrites, 155, 174 Dendritic, 13, 170, 183 Dentate Gyrus, 163 Deoxyribonucleic, 92, 184 Deoxyribonucleic acid, 92, 184 Deoxyribonucleotides, 155 Depolarization, 185 Desensitization, 164 Deuterium, 163 Developmental Biology, 26 Diabetes Mellitus, 162, 166 Dialyzer, 162 Diastole, 155 Diastolic, 164 Diastolic pressure, 164 Diffusion, 39, 59, 63, 69, 146 Digestion, 146, 166, 168, 187, 192 Digestive tract, 186 Dilatation, Pathologic, 192 Dilation, 192 Diploid, 143, 172, 178, 191 Direct, iii, 120, 121, 122, 151, 182, 188 Discrete, 147, 189 Discrimination, 122, 123, 128 Disease Progression, 16, 28 Diseases, 64, 74, 131, 136, 137, 139, 140, 146, 154, 189 Disorientation, 153 Distal, 63, 181 Dopamine, 174, 177 Dorsal, 17, 21, 174, 179, 187 Dorsum, 155, 160 Double Outlet Right Ventricle, 24 Duct, 169, 187 Duodenum, 146, 187 Dyes, 143, 146 Dysplasia, 30, 74, 79, 147 Dystrophic, 31
198
Neurofibromatosis Type 1
E Ectoderm, 174 Edema, 172 Effector, 23, 152 Efficacy, 31, 156, 168 Elastin, 151, 158 Electrocoagulation, 151 Electrolyte, 167 Electrolytes, 146, 167 Electromagnetic Fields, 82 Electrons, 146, 156, 166, 181, 182 Electrophoresis, 11 Elementary Particles, 156, 174, 181 Embryo, 101, 102, 103, 111, 143, 146, 148, 149, 156, 165 Embryogenesis, 156, 187 Enamel, 167 Endemic, 187 Endocardium, 25 Endocrine Glands, 176 Endogenous, 21 Endorphins, 174 Endoscopy, 41, 53 Endothelial cell, 25, 26, 31, 156, 190 Endothelial cells, 25, 26, 31, 156, 190 Endothelium, 25, 157 Endothelium, Lymphatic, 157 Endothelium, Vascular, 157 Endotoxins, 152 Enhancer, 18 Enkephalins, 174 Entorhinal Cortex, 163 Environmental Exposure, 175 Environmental Health, 131, 132 Enzymatic, 148, 152, 183 Enzyme, 93, 143, 156, 157, 160, 178, 180, 181, 185, 190, 193 Enzymes, 93, 103, 142, 169, 173, 176, 177, 180, 181 Eosinophils, 161 Epidemic, 187 Epidemiological, 62 Epidermal, 20, 50, 67, 77, 157, 167 Epidermal Growth Factor, 20, 50, 157 Epidermal growth factor receptor, 20 Epidermis, 157, 164, 167 Epigastric, 176 Epinephrine, 174, 191 Epithalamus, 168 Epithelial, 25, 141, 146, 157, 158, 163 Epithelial Cells, 157, 158, 163 Epithelium, 157, 166
Erythroblasts, 158 Erythrocytes, 143, 147, 158 Erythroid Progenitor Cells, 173 Erythropoietin, 158 Esophagus, 177, 187 Estrogen, 185, 189 Estrogen receptor, 185 Ethnic Groups, 116, 119 Etoposide, 83, 85 Eukaryotic Cells, 28, 176 Evoke, 187 Excitation, 174 Excitatory, 19, 161 Excrete, 144, 167 Exocrine, 176 Exogenous, 156, 158 Exon, 58, 142 Exons, 142, 158 External-beam radiation, 182 Extracellular, 20, 85, 143, 145, 153, 158, 159, 169, 171, 176, 189 Extracellular Matrix, 153, 158, 159, 169, 176 Extracellular Matrix Proteins, 169 Extracellular Space, 158 Extravasation, 162 Extremity, 147 Eye Color, 103 Eye Infections, 142 F Facial, 60, 170 Family Planning, 132 Fast Neutrons, 174 Fat, 147, 148, 153, 168, 186 Fathers, 111 Fats, 146, 150, 159 Fatty acids, 82 Feces, 187 Femur, 190 Fetus, 119, 120, 122, 126, 180, 187, 192 Fibrin, 146, 190 Fibrinogen, 190 Fibroblasts, 20, 45 Fibronectins, 158 Fibrosis, 20, 103, 106, 110, 111, 184 Fibula, 37, 190 Filtration, 15, 167 Fissure, 155, 179 Flatus, 160 Fold, 14, 17, 159, 171 Foramen, 150, 170 Forearm, 147
Index 199
Fossa, 149 Fractionation, 15 Frameshift, 51, 104 Frameshift Mutation, 51, 104 Frontal Lobe, 179 G Gallbladder, 141, 159 Gamma Rays, 172, 181, 182 Ganglia, 17, 25, 30, 143, 173, 177, 188 Ganglion, 17, 22, 174, 183 Gas, 155, 163, 172, 175, 188 Gastric, 157 Gastrin, 163 Gastrointestinal, 39, 46, 65, 67, 70, 74, 76, 78, 148, 157, 160 Gastrointestinal stromal tumor, 46, 67, 70, 76 Gastrointestinal tract, 160 Gene Expression, 16, 18, 65, 68, 99, 100, 160 Gene Products, rev, 160 Gene Therapy, 124, 125, 126, 142, 160 Genes, env, 110 Genes, Neurofibromatosis 2, 174 Genetic Code, 175 Genetic Engineering, 146, 151 Genetic testing, 113, 117, 118, 119, 120, 121, 122, 123, 128 Genetic transcription, 190 Genetics, 91, 102, 103, 104, 106, 108, 109, 113, 116, 117, 118, 123, 126, 127, 128, 139, 154, 177 Genomics, 57, 129 Genotype, 27, 28, 44, 48, 89, 177 Germ Cells, 102, 126, 170, 186, 189 Germ Layers, 156 Germline mutation, 27, 102, 161, 163 Gestation, 24 Gifted, 38 Gland, 25, 169, 173, 176, 185, 187, 188, 190 Glioblastoma, 13, 55 Glioblastoma multiforme, 13 Glioma, 36, 40, 74, 82, 83, 86 Gliosis, 189 Globus Pallidus, 146 Glomerular, 167 Glomerular Filtration Rate, 167 Glucose, 155, 162, 166 Glucose Intolerance, 155 Glutamate, 161 Glutamic Acid, 174, 180 Glycine, 174
Glycoprotein, 190 Glycosaminoglycans, 158, 181 Governing Board, 179 Government Agencies, 179 Grade, 13, 82, 83, 161 Graft, 37 Grafting, 165 Granule, 21, 155, 184 Granulocyte, 23 Granulocytes, 161, 167, 173, 185, 193 Granuloma, 78 Groin, 165 Growth factors, 17, 23, 30, 162 Guanine, 92, 181 Gyrus Cinguli, 168 H Haemostasis, 49 Hair Color, 103 Hamartoma, 58 Haploid, 178 Headache, 16, 162 Headache Disorders, 17, 162 Health Status, 27 Heart attack, 148 Helminthiasis, 149 Hematoma, 71 Hematopoiesis, 19, 29 Hematopoietic Stem Cells, 19, 173 Hematopoietic tissue, 147 Hemicrania, 162 Hemochromatosis, 119 Hemodialysis, 167 Hemoglobin, 93, 143, 158, 162 Hemoglobinopathies, 160 Hemophilia, 111 Hemorrhage, 16, 154, 162, 187 Hepatocyte, 77 Hepatocyte Growth Factor, 77 Hepatocytes, 163 Hereditary, 16, 67, 91, 92, 102, 111, 117, 161, 163, 183 Hereditary mutation, 102, 161, 163 Heredity, 94, 160, 161 Heterogeneity, 20, 28, 163 Hippocampus, 19, 155, 163, 168, 188 Histone Deacetylase, 18 Histones, 94, 150, 163 Homeostasis, 147 Homogeneous, 62 Homologous, 28, 142, 154, 160, 185, 188 Hormone, 54, 58, 83, 99, 157, 160, 166, 176, 184, 185, 190
200
Neurofibromatosis Type 1
Hormones, 99, 158, 161, 163, 185, 189 Horny layer, 157 Hybrid, 74, 163 Hybridization, 64, 163 Hydrogen, 146, 148, 158, 163, 172, 174, 175, 181 Hydrogen Bonding, 175 Hydrolysis, 32, 151, 177, 179, 181 Hydroxylysine, 151 Hydroxyproline, 151, 164 Hyperhidrosis, 63, 164 Hyperopia, 182 Hyperpigmentation, 41, 77 Hyperplasia, 17, 25, 30, 54 Hyperreflexia, 189 Hypersecretion, 83 Hypersensitivity, 14, 32, 155 Hypertension, 31, 148 Hypertrophy, 164 Hypoglycemia, 16 Hypothalamic, 47 Hypothalamus, 145, 164, 168 I Ileum, 67 Imaging procedures, 190 Immune response, 144, 164, 193 Immune system, 146, 164, 165, 169, 192, 193 Immunofluorescence, 15 Immunohistochemistry, 17 Immunologic, 182 Immunosuppressant, 142 Immunosuppression, 76, 165 Immunosuppressive, 154, 164 Immunosuppressive Agents, 164 Immunotherapy, 146, 155 Immunotoxins, 182 Impairment, 24, 73, 159, 165, 171 Implant radiation, 182 Implantation, 153 In vitro, 11, 12, 14, 23, 29, 30, 32, 59, 160, 165 In vivo, 12, 15, 17, 19, 21, 22, 23, 24, 29, 30, 32, 160, 165, 169 Incidental, 51 Incision, 166 Induction, 21, 60, 182 Infancy, 129 Infection, 12, 16, 146, 161, 165, 168, 169, 174, 188, 193 Infections, 124, 144, 149 Inflammation, 125, 144, 159
Informed Consent, 120, 123, 128 Infusion, 17, 165 Ingestion, 189 Inguinal, 164 Initiation, 190 Innervation, 147 Inorganic, 151 Inositol, 184 Insight, 26, 35 Insulator, 172 Insulin, 16, 166 Insulin-dependent diabetes mellitus, 166 Interleukins, 165 Intermittent, 168 Internal radiation, 182 Interstitial, 31 Intestinal, 41, 148 Intestine, 152, 167, 186 Intestines, 141, 160, 166, 185 Intracellular, 165, 184, 185 Intracranial Aneurysm, 51 Intracranial Hemorrhages, 189 Intracranial Hypertension, 162 Intracranial tumors, 174 Intrahepatic, 43, 78 Intravenous, 165 Invasive, 13, 169 Invertebrates, 170 Involuntary, 146, 173 Ion Channels, 145 Ionization, 166 Ionizing, 142, 182 Ions, 146, 156, 163 Ipsilateral, 182 Iris, 62, 144, 159, 166 Ischemia, 16 Ischemic stroke, 70, 166 K Karyotype, 96 Karyotypes, 150 Kb, 63 Keratin, 167 Keratinocytes, 37, 49, 167 Keratolytic, 178 Kidney Failure, 105, 167 Kidney Failure, Acute, 167 Kidney Failure, Chronic, 167 Kidney Transplantation, 167 Kinetic, 166 L Labile, 152 Laminin, 158
Index 201
Large Intestine, 152, 166, 167, 182, 186 Larynx, 190, 192 Latent, 179 Lenses, 182 Lesion, 37, 46, 56, 76, 161, 162, 168 Lethal, 23, 25, 172 Leucocyte, 142 Leukemia, 14, 16, 19, 23, 29, 32, 33, 141, 150, 160, 180 Ligaments, 153 Limbic, 179 Limbic System, 179 Linkages, 161, 162, 163 Lipid, 166, 172 Liposarcoma, 70 Liver, 32, 100, 141, 146, 150, 154, 159, 162, 163, 166, 168, 184 Liver scan, 184 Localization, 15, 25, 164 Localized, 162, 164, 165, 178 Locomotion, 178 Longitudinal study, 34, 54 Long-Term Care, 18 Long-Term Potentiation, 19, 168 Loop, 15, 168 Loss of Heterozygosity, 14 Lung Transplantation, 76 Lymph, 149, 157, 169, 173, 188 Lymph node, 149, 169, 173 Lymph nodes, 149, 169, 173 Lymphatic, 143, 157, 165, 168, 169, 171, 178, 186 Lymphatic system, 168, 186 Lymphocyte Depletion, 164 Lymphocytes, 33, 50, 144, 167, 169, 193 Lymphoid, 144, 167, 169, 173 Lymphoma, 50, 68 Lysine, 163, 164 M Macrophage, 23, 102 Magnetic Resonance Imaging, 40, 79, 80, 184 Malformation, 36, 42, 162 Malignancy, 57 Malignant, 12, 13, 18, 20, 21, 23, 24, 27, 31, 33, 35, 38, 39, 41, 43, 44, 48, 49, 52, 56, 66, 67, 72, 73, 74, 75, 82, 84, 85, 141, 144, 160, 161, 170, 173, 182, 183, 184 Malignant tumor, 12, 21, 23, 24, 31, 183 Mammary, 189 Mammography, 110 Mandible, 39, 78, 143, 150, 183
Manifest, 28 Mastication, 191 Matrix metalloproteinase, 18 Meatus, 186, 192 Medial, 176, 186, 190 Medical Records, 110, 123 MEDLINE, 132 Medulloblastoma, 21 Megacolon, 63 Megakaryocytes, 147 Megalencephaly, 22 Meiosis, 101, 188 Melanin, 166, 170, 177, 191 Melanocytes, 49, 69, 164, 170, 174 Melanoma, 43, 67, 75, 191 Melanophores, 170 Melanosomes, 69, 170 Membrane, 15, 30, 92, 143, 145, 149, 152, 153, 155, 158, 167, 175, 176, 179, 180, 183, 185, 191 Membranes, 170, 175, 178, 183, 191 Memory, 12, 19, 26, 81, 154, 168, 170 Meningeal, 17 Meninges, 149, 154, 170, 188 Meningioma, 38 Meningocele, 35 Mental, 35, 55, 70, 115, 117, 119, 149, 150, 151, 153, 154, 155, 170, 181, 184, 192 Mental Disorders, 150 Mental Health, 181 Mental Retardation, 35, 55, 115, 117, 119 Mentors, 18, 27 Mesencephalic, 182 Mesenchymal, 25, 157 Mesenteric, 60 Mesentery, 171, 177 Metastasis, 15, 170 Metastasize, 184 Metastatic, 184 Microbe, 190 Microbiology, 141, 145 Microglia, 145 Microorganism, 151, 193 Microscopy, 13 Migration, 15, 20, 22, 25, 30 Miscarriage, 122 Mitochondria, 92, 93, 105, 111, 176 Mitochondrial Swelling, 173 Mitogen-Activated Protein Kinase Kinases, 171 Mitogen-Activated Protein Kinases, 20, 171
202
Neurofibromatosis Type 1
Mitosis, 101, 144, 172 Mitotic, 158 Modeling, 27 Modification, 160, 181 Modulator, 185 Molecular, 13, 15, 17, 18, 20, 21, 24, 26, 27, 33, 43, 72, 78, 96, 98, 100, 132, 134, 146, 152, 154, 155, 188 Molecule, 15, 17, 25, 32, 92, 93, 94, 99, 144, 146, 152, 156, 163, 172, 175, 181, 182, 185, 190, 192 Monitor, 175 Monoclonal, 182 Monocytes, 173 Mononuclear, 162, 172 Monosomy, 105, 143 Morphogenesis, 13 Morphological, 13, 156, 170 Morphology, 13, 39 Morula, 146 Mosaicism, 37, 52, 53, 56, 102 Motility, 149 Motor Cortex, 182 Movement Disorders, 189 Mucinous, 160 Mucosa, 188 Mucositis, 190 Mucus, 172 Muscle Fibers, 173 Mustard Gas, 172 Mutagen, 33 Mutagenesis, 16 Mutagenic, 33, 142 Mutagens, 159, 172 Mycoplasma, 149 Mycoplasma Infections, 149 Myelin, 154, 172, 175, 184 Myelin Sheath, 172, 175, 184 Myelogenous, 141, 150 Myeloid Cells, 29, 32, 173 Myeloid Progenitor Cells, 23, 173 Myocardium, 24 Myopia, 182 Myosin, 18 Myotonic Dystrophy, 114, 191 N Naevus, 38 Nasal Cavity, 186 Nausea, 192 NCI, 150, 177 Necrosis, 144, 161 Neoplasm, 162, 173, 191
Neoplasms, 13, 30, 51, 144, 182 Nephrectomy, 173 Nerve Fibers, 147 Nerve Growth Factor, 17, 174 Nerve Sheath Tumors, 12, 18, 20, 27, 30, 31, 49, 52, 60, 64, 66, 173 Nervous System, 17, 20, 26, 30, 67, 114, 142, 145, 149, 174, 175, 177 Networks, 21 Neural, 12, 13, 21, 24, 25, 142, 170, 174 Neural Crest, 21, 24, 25, 174 Neuregulin-1, 30, 174 Neuroblastoma, 63, 84 Neurodegenerative Diseases, 146 Neuroectodermal tumor, 180 Neuroectodermal Tumors, 180 Neurofibroma, 20, 27, 28, 47, 60, 76, 83, 173 Neurofibromatosis 2, 88, 160 Neuroglia, 161 Neurologic, 161 Neuronal, 12, 22 Neuronal Plasticity, 12 Neurons, 13, 19, 21, 26, 155, 158, 160, 173, 174, 188 Neuropathy, 111 Neurophysiology, 155 Neurosurgery, 13 Neurotransmitter, 141, 142, 161, 174, 184, 185 Neurotrophins, 17 Neutrons, 142, 174, 181 Neutrophil, 28 Nevus, 67, 174 Niacin, 191 Nitrogen, 154, 158, 167, 191 Norepinephrine, 174 Nuclear, 25, 92, 145, 156, 158, 159, 160, 161, 168, 173, 175, 182, 183, 189 Nuclear Envelope, 92, 175 Nuclear Pore, 175 Nuclear Proteins, 160, 175 Nuclei, 142, 156, 160, 163, 169, 171, 174, 176, 178, 181 Nucleic acid, 146, 154, 163, 175, 181, 184 Nucleic Acid Hybridization, 163 Nucleic Acids, 146, 154, 163, 175, 181, 184 Nucleus, 92, 93, 94, 99, 105, 124, 127, 144, 146, 150, 154, 157, 158, 159, 169, 170, 172, 174, 175, 179, 180, 181, 187, 189 Nurse Practitioners, 120
Index 203
O Ocular, 35, 173 Odds Ratio, 175, 183 Oligodendroglia, 173 Oliguria, 167 Oncogene, 163, 175, 187 Oncogenes, 33 Oncogenic, 21, 32, 59 Operon, 183 Opsin, 183 Optic Chiasm, 150, 164, 176 Optic Nerve, 46, 71, 83, 176, 183 Orbit, 62, 176 Orbital, 39 Organelles, 91, 92, 154, 170, 172, 178 Organizations, 138 Osteoblasts, 24 Osteolytic, 42 Osteoporosis, 147, 176 Ovaries, 119, 176, 185 Ovary, 176, 188 Ovulation, 176 Ovum, 161, 193 Oxidation, 154 Oxidative Phosphorylation, 93 P Paediatric, 76 Palliative, 189 Pancreas, 141, 162, 166 Paranasal Sinuses, 186 Parathyroid, 68, 176, 189 Parathyroid Glands, 176 Parathyroid hormone, 68, 176 Parietal, 177 Paroxysmal, 162 Particle, 190 Patch, 13, 177 Paternity, 119 Pathologic, 51, 144, 153, 164, 183 Pathologic Processes, 144 Pathologies, 27 Pathophysiology, 34 PDQ, 130, 177 Peduncle, 182 Pelvis, 141, 176, 192 Peptide, 167, 174, 179, 180, 181 Perforation, 39 Pericytes, 31 Perineal, 164 Perineum, 177 Peripheral Nerves, 187
Peripheral Nervous System, 12, 22, 26, 155, 172, 173, 174, 177, 184 Peritoneum, 171, 177, 183 Perivascular, 175 Pharmacologic, 21, 190 Pharynx, 192 Phenotype, 19, 20, 25, 27, 28, 29, 35, 43, 44, 48, 72, 89, 177 Phenotypes, 24, 27, 28 Phenylalanine, 191 Phorbol, 180 Phorbol Esters, 180 Phospholipases, 185 Phospholipids, 159, 166, 180 Phosphorus, 147, 176, 178 Phosphorylate, 171 Phosphorylated, 15, 171 Phosphorylates, 180 Phosphorylation, 15, 93, 171, 174, 181 Photocoagulation, 151 Photoreceptor, 183 Photoreceptors, 153 Physical Examination, 117 Physiologic, 142, 178, 182, 183 Pigment, 170, 178 Pigmentation, 164, 173 Pigments, 148, 178, 183 Pilocytic, 27, 76 Plants, 161, 172, 190 Plasma, 15, 92, 144, 149, 157, 162, 167, 178 Plasma cells, 144 Plasma protein, 157 Plasticity, 13, 19, 178 Plastids, 176 Platelet Activation, 185 Platelets, 178 Pleated, 146, 167 Pleomorphic, 41, 66, 84 Plexus, 147 Pneumonia, 153 Podophyllotoxin, 158 Polymerase, 178, 183 Polymorphic, 28, 51, 155 Polymorphism, 28, 44, 121 Polyp, 78 Polypeptide, 143, 151, 157, 163, 193 Polyposis, 67, 152 Polysaccharide, 144, 181 Pons, 147 Pontine, 40 Posterior, 143, 145, 149, 156, 166, 176, 186 Postmenopausal, 176
204
Neurofibromatosis Type 1
Postnatal, 22, 187 Postsynaptic, 185 Post-synaptic, 19 Post-traumatic, 162 Potassium, 156 Potentiation, 185 Practice Guidelines, 133 Precancerous, 150, 180 Precipitating Factors, 162 Preclinical, 32 Precursor, 21, 69, 156, 157, 177, 191 Predisposition, 14, 20 Prefrontal Cortex, 19, 179 Premalignant, 56, 179 Prenatal, 119, 122, 156 Presynaptic, 174 Prevalence, 11, 107, 175 Primitive neuroectodermal tumors, 170 Prion, 149 Prognostic factor, 31, 62 Progression, 16, 17, 18, 27, 28, 29, 33, 84, 143, 191 Progressive, 16, 24, 82, 105, 150, 154, 167, 173, 178, 191 Projection, 176, 179, 182 Proline, 21, 151, 164 Promoter, 18, 51, 57, 65 Promyelocytic leukemia, 82 Prone, 105, 114 Prophase, 188 Prosencephalon, 189 Prospective study, 36, 168 Protein Conformation, 143, 167 Protein Isoforms, 142 Protein Kinase C, 171 Protein Kinases, 171 Proteins, 11, 12, 15, 17, 28, 30, 32, 91, 92, 94, 95, 99, 100, 103, 104, 118, 120, 127, 129, 142, 143, 144, 149, 150, 151, 152, 158, 160, 163, 167, 169, 172, 175, 177, 178, 180, 181, 184, 185, 190 Protein-Serine-Threonine Kinases, 171 Proteoglycan, 31 Proteoglycans, 158 Proteolytic, 12, 142, 152 Prothrombin, 190 Protocol, 14, 125 Protons, 142, 163, 166, 181 Protozoa, 171 Protozoan, 149 Protozoan Infections, 149 Proximal, 155, 185
Psoriasis, 172 Psychic, 170, 185 Puberty, 46, 54, 58 Public Health, 11 Public Policy, 132 Pulmonary, 75, 147, 156, 167, 192 Pulmonary Artery, 147, 156, 192 Pulmonary Edema, 167 Pulse, 172 Purines, 146 Putamen, 146 Pyramidal Cells, 155 Pyrimidines, 146 Q Quality, iv, 11, 73, 133, 154, 181 Quality of Life, 27, 188 R Race, 167, 171 Radiation, 13, 141, 143, 159, 164, 181, 182, 184, 191, 193 Radiation therapy, 141, 159, 182 Radioactive, 147, 163, 165, 168, 175, 182, 184, 191 Radioactivity, 11 Radiography, 37 Radioimmunotherapy, 182 Radioisotope, 190 Radiolabeled, 182 Radiotherapy, 37, 182 Randomized, 156 Receptor, 17, 26, 42, 48, 58, 108, 141, 144, 151, 157, 163, 174, 180, 182, 185 Recombinant, 19, 21, 192 Recombination, 28, 56, 65, 160 Rectum, 144, 151, 152, 160, 167 Red Nucleus, 145 Refer, 1, 97, 101, 108, 126, 147, 152, 161, 168, 174, 182 Refraction, 186 Regimen, 83, 151, 156 Registries, 14 Relative risk, 14, 183 Repressor, 18, 175 Reproductive cells, 104, 115, 116, 161, 163 Resorption, 24, 147 Respiration, 172 Response rate, 83 Retina, 153, 176, 183, 184 Retinal, 38, 70, 176, 183 Retinal Ganglion Cells, 176 Retinoblastoma, 107 Retinoids, 183
Index 205
Retinol, 183 Retroperitoneal, 85 Retroviral vector, 160 Retrovirus, 16, 29 Rhabdomyolysis, 57 Rhabdomyosarcoma, 62, 78 Rhodopsin, 176, 183 Ribonucleic acid, 99 Ribose, 141 Ribosome, 99, 191 Rigidity, 178 Risk factor, 180, 183 Rod, 151 Rods, 183 S Salivary, 188 Sarcoma, 180 Satellite, 17, 175 Scans, 34, 184 Scatter, 191 Schizophrenia, 112 Schwann, 173 Schwann Cells, 173 Schwannoma, 21, 74, 85 Sclera, 153 Scleroproteins, 167 Sclerosis, 108 Scoliosis, 27, 31, 36, 55, 76 Screening, 12, 31, 61, 71, 79, 110, 119, 120, 122, 151, 177 Second Messenger Systems, 17, 184 Secondary tumor, 171, 185 Secretion, 157, 164, 166, 184, 185, 192 Segmental, 53, 70 Segmentation, 185 Segregation, 182 Seizures, 161, 177, 185, 187 Selective estrogen receptor modulator, 189 Sella, 156 Sella Turcica, 156 Semisynthetic, 158 Senile, 176 Sensibility, 143 Sensory loss, 189 Septal, 156, 168 Septal Nuclei, 168 Sequencing, 12, 27, 127 Serine, 171, 180, 181 Serotonin, 174, 191 Serous, 157 Serum, 50, 152, 167, 185
Sex Characteristics, 142, 181, 185 Shunt, 43, 78 Side effect, 126, 129, 142, 146, 154, 188, 190 Side effects, 126, 129, 146, 188, 190 Signal Transduction, 12, 14, 32, 166, 185 Signs and Symptoms, 113, 114, 119 Skeletal, 24, 27, 30, 35, 151, 183 Skeleton, 24, 141, 147, 159, 186, 190 Skull, 154, 170, 176, 189 Small intestine, 163, 164, 166 Smooth muscle, 18, 25 Social Environment, 181 Social Work, 116 Sodium, 156 Soft tissue, 147, 186 Solid tumor, 13 Solitary Nucleus, 145 Soma, 186 Somatic, 14, 16, 33, 37, 56, 102, 105, 116, 142, 156, 168, 170, 171, 177, 179, 192 Somatic cells, 102, 105, 116, 170, 171 Somatic mutations, 105 Sound wave, 153 Spasm, 189 Specialist, 120, 138 Species, 129, 157, 163, 167, 170, 171, 181, 186, 188, 193 Spectrum, 28, 77 Sperm, 75, 101, 102, 104, 105, 114, 115, 116, 119, 126, 150, 161, 163, 183, 186 Sphenoid, 30, 36, 74, 186 Sphenoid Sinus, 186 Sphincter, 167 Spinal cord, 17, 31, 60, 145, 147, 149, 150, 160, 170, 173, 174, 177, 187, 188, 189, 192 Spinal Nerves, 177 Spinous, 157, 167 Spleen, 169 Sporadic, 18, 35, 37, 49, 54, 64, 73, 183 Spotting, 23 Staging, 184 Status Epilepticus, 16 Steel, 151 Stem Cell Factor, 23, 77, 151 Stem Cells, 13, 16, 22, 29, 158, 173 Stenosis, 24, 187 Sterile, 176 Sterility, 154 Stillbirth, 117 Stimulus, 165, 190 Stomach, 141, 160, 163, 177, 186 Stool, 151, 167
206
Neurofibromatosis Type 1
Strand, 92, 178 Stress, 145, 171, 179 Stricture, 187 Stridor, 189 Stroke, 110, 148, 166 Stroma, 166 Stromal, 41, 53, 54, 65, 74, 78, 147, 160 Stromal Cells, 147 Subacute, 165 Subarachnoid, 150, 162 Subclavian, 192 Subclavian Artery, 192 Subclinical, 165, 185 Subcutaneous, 78 Subiculum, 163 Submandibular, 188 Submaxillary, 157 Subspecies, 186 Suction, 159 Sulfur, 158 Superoxide, 29 Supportive care, 177 Suppression, 14 Sympathetic Nervous System, 145, 174, 188 Sympathomimetic, 157 Symphysis, 150 Symptomatic, 37 Synapse, 13, 188 Synapses, 168 Synapsis, 188 Synaptic, 13, 168, 174, 179, 185 Synergistic, 32 Syringomyelia, 36 System, 12, 15, 17, 20, 33, 87, 133, 135, 136, 148, 150, 151, 152, 157, 164, 169, 175, 176, 177, 185, 188 Systemic, 69, 144, 147, 157, 165 Systemic disease, 69 Systolic, 164 T Talus, 190 Tamoxifen, 25 Tarsal Bones, 189 Tarsus, 189 Telencephalon, 145, 149, 189 Temporal, 162, 163, 170 Tendon, 160 Teratogenic, 142 Terminalis, 189 Testicular, 38 Testis, 189
Tetany, 176 Thalamic, 145 Thalamic Diseases, 145 Thalamus, 168, 179, 189 Theophylline, 181 Therapeutics, 14, 17, 32 Thermal, 174 Thigh, 162 Third Ventricle, 164, 189 Thoracic, 35, 49, 147, 169, 188, 193 Threonine, 171, 180, 181 Threshold, 164, 190 Thrombin, 180, 190 Thrombomodulin, 180 Thrombosis, 180, 187 Thymidine, 147 Thymus, 169 Thyroid, 119, 176, 190, 191 Thyroid Gland, 119, 176, 190 Thyroid Hormones, 190, 191 Thyroxine, 177 Tibia, 82, 159 Tissue, 13, 25, 27, 47, 77, 120, 122, 124, 141, 144, 146, 151, 156, 157, 158, 159, 161, 162, 164, 166, 167, 169, 170, 171, 172, 173, 174, 178, 183, 185, 186, 187, 189, 191, 193 Tolerance, 141 Tomography, 152, 153 Tooth Preparation, 141 Toxic, 91, 142, 154, 156, 174, 178, 190 Toxicity, 125 Toxicology, 132 Toxins, 144, 165, 182 Tracer, 78 Trachea, 167, 177, 190 Traction, 151 Transcriptase, 183 Transcription Factors, 100 Transduction, 13, 14, 185 Transfection, 146, 160 Translation, 12, 14, 99, 100, 160 Translational, 14, 32 Translocation, 18, 44, 50, 63, 150 Transmitter, 145 Transplantation, 169 Trauma, 173 Triad, 78 Trigeminal, 17 Trinucleotide Repeat Expansion, 114 Trinucleotide Repeats, 191 Trisomy, 105, 143
Index 207
Trypsin, 193 Tryptophan, 151 Tuberous Sclerosis, 39, 74, 75 Tumor model, 17 Tumor suppressor gene, 15, 23, 29, 30, 32, 33, 168 Tumorigenic, 20 Tumour, 38, 39, 44, 60, 64, 67, 78, 82, 86, 160 Tyrosine, 23, 30 U Ultraviolet radiation, 102 Uracil, 181 Urea, 192 Uremia, 167 Urethra, 192 Urinary, 27, 175 Urine, 144, 146, 157, 167, 175, 192 Uterus, 119, 150, 176, 192 V Vaccine, 181 Vaccines, 193 Vacuoles, 176 Vagina, 150, 187 Vagus Nerve, 64 Vascular, 25, 74, 157, 162, 165, 190 Vasoconstriction, 157, 162 Vasodilation, 143 Vector, 124, 125, 183, 190 Vein, 20, 143, 166, 175, 184, 188 Veins, 147, 170, 178, 192 Venous, 43, 78, 180 Ventral, 187 Ventricle, 144, 156, 163, 181, 189, 192 Ventricles, 149 Ventricular, 156 Venules, 147, 157 Vertebrae, 187, 192 Vertebral, 31, 37, 49, 53, 170 Vertebral Artery, 49, 53
Veterinary Medicine, 132 Vinca Alkaloids, 193 Vincristine, 82 Viral, 12, 16, 124, 160, 175, 183, 190, 191 Viral Proteins, 12 Viral Regulatory Proteins, 160 Viral Structural Proteins, 160 Virion, 160 Virulence, 190 Virus, 12, 33, 124, 149, 157, 160, 183, 190, 193 Viruses, 99, 124, 142, 144, 159, 171, 183, 192, 193 Viscera, 171, 186, 193 Visceral, 145, 168, 177, 192 Visceral Afferents, 145, 192 Visual field, 176 Vitreous, 183 Vitreous Body, 183 Vitro, 11, 12, 29, 119, 165 Vivo, 12, 19, 29, 30, 165, 169 Volition, 166 W War, 172 Warts, 178 White blood cell, 102, 144, 150, 161, 169, 174, 178 Windpipe, 177, 190 Womb, 192 Wound Healing, 170 X Xenograft, 85, 144, 191 X-ray, 27, 31, 152, 153, 159, 175, 181, 182, 184 X-Rays, 159, 175, 181, 182 Y Yeasts, 177, 193 Z Zygote, 153, 172 Zymogen, 180, 193
