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

DWARFISM A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES J AMES N. P...

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

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2003 by ICON Group International, Inc. Copyright 2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Dwarfism: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83896-8 1. Dwarfism-Popular works. I. Title.

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

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

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on dwarfism. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON DWARFISM ................................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Dwarfism ...................................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 32 The National Library of Medicine: PubMed ................................................................................ 34 CHAPTER 2. NUTRITION AND DWARFISM ...................................................................................... 51 Overview...................................................................................................................................... 51 Finding Nutrition Studies on Dwarfism ..................................................................................... 51 Federal Resources on Nutrition ................................................................................................... 52 Additional Web Resources ........................................................................................................... 53 CHAPTER 3. ALTERNATIVE MEDICINE AND DWARFISM ................................................................ 55 Overview...................................................................................................................................... 55 National Center for Complementary and Alternative Medicine.................................................. 55 Additional Web Resources ........................................................................................................... 61 General References ....................................................................................................................... 62 CHAPTER 4. DISSERTATIONS ON DWARFISM .................................................................................. 63 Overview...................................................................................................................................... 63 Dissertations on Dwarfism .......................................................................................................... 63 Keeping Current .......................................................................................................................... 63 CHAPTER 5. CLINICAL TRIALS AND DWARFISM ............................................................................. 65 Overview...................................................................................................................................... 65 Recent Trials on Dwarfism .......................................................................................................... 65 Keeping Current on Clinical Trials ............................................................................................. 67 CHAPTER 6. PATENTS ON DWARFISM ............................................................................................. 69 Overview...................................................................................................................................... 69 Patents on Dwarfism ................................................................................................................... 69 Patent Applications on Dwarfism................................................................................................ 70 Keeping Current .......................................................................................................................... 73 CHAPTER 7. BOOKS ON DWARFISM ................................................................................................ 75 Overview...................................................................................................................................... 75 Book Summaries: Federal Agencies.............................................................................................. 75 Book Summaries: Online Booksellers........................................................................................... 76 The National Library of Medicine Book Index ............................................................................. 76 Chapters on Dwarfism ................................................................................................................. 77 CHAPTER 8. MULTIMEDIA ON DWARFISM ...................................................................................... 79 Overview...................................................................................................................................... 79 Bibliography: Multimedia on Dwarfism ...................................................................................... 79 CHAPTER 9. PERIODICALS AND NEWS ON DWARFISM ................................................................... 81 Overview...................................................................................................................................... 81 News Services and Press Releases................................................................................................ 81 Academic Periodicals covering Dwarfism.................................................................................... 83 APPENDIX A. PHYSICIAN RESOURCES ............................................................................................ 87 Overview...................................................................................................................................... 87 NIH Guidelines............................................................................................................................ 87 NIH Databases............................................................................................................................. 89 Other Commercial Databases....................................................................................................... 91 The Genome Project and Dwarfism ............................................................................................. 91 APPENDIX B. PATIENT RESOURCES ................................................................................................. 99 Overview...................................................................................................................................... 99

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Patient Guideline Sources............................................................................................................ 99 Finding Associations.................................................................................................................. 102 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 105 Overview.................................................................................................................................... 105 Preparation................................................................................................................................. 105 Finding a Local Medical Library................................................................................................ 105 Medical Libraries in the U.S. and Canada ................................................................................. 105 ONLINE GLOSSARIES................................................................................................................ 111 Online Dictionary Directories ................................................................................................... 112 DWARFISM DICTIONARY ........................................................................................................ 115 INDEX .............................................................................................................................................. 165

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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 dwarfism 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 dwarfism, 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 dwarfism, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on dwarfism. 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 dwarfism, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on dwarfism. The Editors

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

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

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

Dental Findings in Morquio Syndrome (Mucopolysaccharidoses Type IVa) Source: Journal of Dentistry for Children. 67(6): 431-433. November-December 2000. Contact: Available from American Society of Dentistry for Children. John Hancock Center, 875 North Michigan Avenue, Suite 4040, Chicago, IL 60611-1901. (312) 943-1244. Summary: Morquio syndrome is a genetic disorder of mucopolysaccharide metabolism characterized by skeletal deformities (including dwarfism and general osteoporosis), neurological symptoms, facial features of short nose and broad mouth, muscle weakness and hyperextensible joints, corneal opacities, progressive deafness, normal intelligence, and dental manifestations. This article reports the case of dental findings in a 2 year old male with suspected Morquio syndrome. The authors report how the dental findings helped with the diagnosis of Morquio syndrome and then discuss the child's dental

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follow up over the next 10 years. Dental treatment has been confined to preventive regimens involving dietary analysis and advice, tooth brush instruction, systemic and topical fluorides, and fissure sealants. The authors discuss the dental manifestations of Morquio syndrome, which are usually confined to enamel defects (the enamel is described as thin, with a tendency to fracture and flake off); tooth discoloration can be greyish or yellowish which probably reflects normal color variation in the dentin which underlies the thin translucent enamel. The authors note that the dental findings are similar to those found in hypoplastic amelogenesis imperfecta. 3 figures. 15 references. •

Esthetic Overdenture for a Patient with Possible Seckel Syndrome Source: SCD. Special Care in Dentistry. 16(5): 210-213. September-October 1996. Summary: This article presents a case report of a 21-year-old with possible Seckel syndrome (bird-headed dwarfism), micrognathia, microdontia, severe bony undercuts, and periodontal disease who sought treatment at a university dental clinic. Treatment included extractions, periodontal therapy, retention of premolars with sealants, and overdentures with resilient soft liners. The authors include a limited review of the literature on Seckel syndrome. The authors also discuss the modification of existing dental materials and procedures required for successful functional and esthetic results in this patient. 7 figures. 18 references. (AA-M).

Federally Funded Research on Dwarfism The U.S. Government supports a variety of research studies relating to dwarfism. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to dwarfism. 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 dwarfism. The following is typical of the type of information found when searching the CRISP database for dwarfism: •

Project Title: A PANHYPOPITUITARY MOUSE MUTATION Principal Investigator & Institution: Camper, Sally A.; Professor; Human Genetics; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 01-APR-1993; Project End 31-MAR-2002 Summary: (Adapted from the Investigator's Abstract): This is a renewal application requesting five years of funding to continue Dr. Camper s research program to

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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positionally clone and functionally characterize the mouse Ames dwarf (df) gene. The df mutation arose in descendants of an X-irradiated male mouse at Iowa State University in Ames, Iowa. Df is a recessive mutation that produces severe proportional dwarfism, hypothyroidism and infertility. The growth insufficiency results from a lack of thyroid stimulating hormone (TSH) and growth hormone (GH), and a lack of prolactin (PRL) contributes to the infertility of females. The Ames dwarf mice, like the Snell (Pitdw) dwarf mice, exhibit severe hypocellularity due to a deficiency in the three pituitary cells that produce PRL, GH, and TSH: lactotropes, somatotropes, and thyrotropes, respectively. The simultaneous loss of these three cell types suggest that they derive from a common precursor cell, and the similarity of the phenotypes of the non-allelic df and dw mutants suggests that the two mutated genes are involved in the proliferation and/or differentiation of this precursor cell. The dw mutation has been shown to result from defects in the Pit-1 transcription factor gene. In Specific Aim 1 Camper proposes to clone the df gene. The df critical region will be physically mapped and the 3.5 Mb YAC and P1 contig encompassing the 635 kb df critical region will be completed. Exon trapping and cDNA selection will be applied to identify transcripts within the df critical region. Full length cDNA clones will be generated for the identified transcripts and these clones will be used in Northern analyses, and if necessary RNase protection and RT-PCR assays, to determine the tissue distribution of the cloned transcripts. These studies will allow Camper to prioritize transcripts as products of possible candidate df genes. Candidate gene sequences will then be compared in normal and df mutant mice to detect mutations in the putative df gene. In Specific Aim 2, Camper will characterize the intron/exon structure and 5 end of the candidate df gene. In addition, df gene expression gene will be characterized by immunostaining of tissue sections, RT-PCR, RNase protection, in situ hybridization, and Northern analysis of pituitary cell lines. Confirmation that a mutation in a candidate gene is responsible for the df phenotype will be obtained in Specific Aim 3 by transgene correction, the generation of gain of function alleles, and the production of loss of function mutations. These studies will also begin to probe df gene function. Camper proposes in Specific Aim 4 to clone and chromosomally map the human df gene and to assess the association of df with human pituitary tumors and families of short stature. Specific Aim 5 will establish the role of the df gene within the hierarchy of genes regulating pituitary development by comparing the expression of early pituitary markers in df and dw and by examining df gene expression in other mouse mutants with pituitary defects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ABNORMALITIES OF GONADAL/PUBERTAL DEVELOPMENT USING LHRH ANALOG Principal Investigator & Institution: Lee, Peter A.; Children's Hosp Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 15213 Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 30-NOV-2001 Summary: Assessment of efficacy and dosage of treatment of central precocious puberty and growth hormone deficient patients with GnRH analogue, depot leuprolide acetate. Studies include efffect upon pubertal development, adult height and bone mineral density. Post treatment outcome including adult height and gonadal function are being monitored. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHRONIC SOMATOTROPIN ON BONE MINERAL DENSITY IN GH DEFICIENCY Principal Investigator & Institution: Arafah, Baha M.; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001 Summary: Clinical studies have established that deficiency of growth hormone (GH), also known as somatotropin in adults is associated with higher adiposity, reduced lean body mass, lower bone mineral density, and decreased quality of life ratings in a wide range of areas. Somatotropin deficiency is associated with decreased bone mineral content and density in patients with childhood or adult-onset disease. While delayed bone maturation and unachieved peak bone mass might explain reduced bone mineral density (BMD) in patients afflicted with GH deficiency as children, the pathophysiology of low BMD in patients with adult-onset somatotropin deficiency is less clear. Recent research suggests that chronic somatotropin therapy can reverse some of the bony changes associated with adult-onset somatotropin deficiency. Unfortunately, the studies conducted thus far have lacked sufficient control measures to be regarded as "definitive." The aim of the present study is to investigate, in a randomized placebocontrolled design, the effect of chronic somatotropin treatment on BMD in patients diagnosed with adult-onset somatotropin deficiency. The primary objective is to test the hypothesis that patients with adult-onset growth hormone deficiency who are treated with somatotropin will have a greater bone mineral density of the spine and the femoral neck, than those who are treated with placebo at the end of 2 years of treatment. The secondary objectives of the study are as follows: 1) to test the hypothesis that patients with adult-onset growth hormone deficiency who are treated with somatotropin will demonstrate increased bone formation and decreased bone breakdown, as assessed by serum and urinary markers, than those treated with placebo. 2) to assess adverse events associated with 2 years of somatotropin treatment in patients with adult-onset growth hormone deficiency. 3) to collect data on a new health-related quality of life questionnaire for Somatotropin Deficiency Syndrome (SDS). This will be a multi-center, parallel, double-blind, placebo-controlled study involving 72 patients diagnosed with somatotropin deficiency syndrome. Approximately 9-10 patients will be recruited for the study at our institution. Patients fulfilling the entry criteria will be randomized at Visit 2 to either somatotropin therapy or placebo. Clinical assessment of randomized patients will take place at 1,2,3,4,6,7,12,18, and 24 months after treatment is initiated. Clinical assessment will consist of BMD measurements using Dual Energy X-ray Absorptiometry (DEXA) and laboratory tests (n-telopeptide, creatinine, and alkaline phosphatase) for bone turnover. BMD assessment and the latter laboratory tests will be done before treatment and at 6,12,18 and 24 months. Patients who are nutritionally deficient, based on a nutritional assessment at Visit 2, will be given supplements for optimal calcium and vitamin D levels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL & HORMONAL EFFECTS OF GHRP 2 ADMINISTERED BY INFUSION FOR 30 Principal Investigator & Institution: Bowers, Cyril; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2001 Summary: GHRP's (GHRP-2, hexarelin, peptidomimetic growth hormone secretagogueGHS) administered chronically to short stature children with various degrees of GH

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deficiency or to obese subjects have produced anabolic effects by increasing the rate of body growth in children and increasing fat-free mass as determined by analysis of body composition with dual photon x-ray absorptometry (DEXA). These results were analogous to and predicted from results obtained from chronic administration of rhGH to elderly subjects. Furthermore, when rhGH was administered chronically to abdominally obese men, the abdominal fat mass decreased and lipoprotein and glucose metabolism improved. In addition, diastolic blood pressure was reduced. The route of administration of rhGH, daily injections or continuous infusion, also influenced the results in that rhGH administered continuously to GH deficient adults induced a greater reduction in total body fat than sc injections. A positive relationship between cortisol secretion and fat distribution in obese (especially visceral obesity) premenopausal women has been described. GHRPs in certain dosages and by specific routes of administration slightly and transiently raise serum cortisol levels. Also, GHRP may transiently impair glucose homeostasis which over time becomes negligible possibly because lean body mass is increased. The latter may represent increased skeletal muscle and perhaps an added route for glucose disposal. In reference to pulsatile GH secretion, the studies by Veldhuis et al indicate a dual defect in GH secretion and clearance in GH deficient adults. Also, these investigators have defined the differential impacts of age, sex steroid hormones and obesity on basal versus pulsatile GH secretion. Hartman et al demonstrated that low euglycemic dosages of recombinant IGF-I rapidly suppressed the fasting enhanced pulsatile release of GH. The objective of this study will be to determine the 24 hour pulsatile growth hormone levels and the IGF-1/IGFBP-3 levels after a 30 day chronic infusion of GHRP-2 to normal older men and women with decreased secretion of GH. In addition, effects on the following parameters will be studies: 1) body composition; 2) thyroid; 3) adrenal function; 4) serum PRL, cortisol; 5) serum lipoproteins; 6) glucose-insulin levels after an oral glucose tolerance test; 7) PTH; 8) osteocalcin; 9) C-terminal collagen propeptide (Prolagen-C); 10) Leptin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONSTITUTIVELY ACTIVE PTH/PTHRP RECEPTORS IN VIVO Principal Investigator & Institution: Jueppner, Harald W.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-MAY-1996; Project End 31-JAN-2004 Summary: (Verbatim from the Applicant): After the molecular cloning of the PTH/PTHrP receptor (PTH1R) and its gene, we identified activating mutations in Jansen's metaphyseal chondrodysplasia (JMC), a genetic disorder characterized by short-limbed dwarfism and severe PTH-/PTHrP-independent hypercalcemia. Since the PTH1R is abundantly expressed in kidney, bone and growth plates, expression of mutant PTH1Rs in these tissues provided a plausible explanation for the characteristic laboratory and radiological findings in JMC, and the transgenic expression of mutant PTH1Rs (type II collagen promoter) in mice confirmed that the metaphyseal changes are indeed caused by constitutively active receptors. Surprisingly, trabecular bone volume appears to be increased in JMC patients, while cortical bone is unchanged or diminished; equivalent findings were made in transgenic mice expressing the mutant PTH1R under the control of the type I collagen promoter. Taken together these findings indicate that endosteal and periosteal bone formation are differently regulated. To further explore the PTH1Rs role in bone formation, we now propose to pursue the following Specific Aims. In Aim 1, we propose to develop a mouse model of Jansen's disease by replacing the wild-type PTH1R gene with a mutant gene containing an activating mutation (i.e. the H223R/M226L mutation, or other mutations with higher

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constitutive activity). This animal will allow us to explore, in more detail than is possible in patients, the impact of activated PTH1Rs on mineral ion homeostasis, bone metabolism, and growth plate development. In Aim 2, we will determine whether inverse agonists can reduce the constitutive activity of the mutant PTH1R in kidney and bone. Besides providing further confirmation that persistent receptor activation is indeed responsible for all JMC-specific changes, the "Jansen" mouse will thus provide a model to explore details of the PTH1R's role in bone metabolism, and to determine its biological role(s) in other tissues. In Aim 3, we plan to search for additional PTH1R mutations in JMC patients and to assess in these and previously characterized individuals the changes in trabecular and cortical bone formation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--ANIMAL AND ADMINISTRATION Principal Investigator & Institution: Sonntag, William E.; Professor; Wake Forest University 2240 Reynolda Rd Winston-Salem, Nc 27106 Timing: Fiscal Year 2003; Project Start 01-DEC-2002; Project End 30-NOV-2007 Summary: The goal of the Administrative/Animal Core is to provide support for each of the projects funded in the Program Project. The Administrative/Animal Core has multiple aims: 1. The Core will provide administrative assistance in record keeping, personnel management, library services, and preparation of manuscripts. This includes organizing weekly meetings of the Project Leaders, organizing seminars relevant to the goals of the program project, and facilitating interactions with senior consultants to the program project. One consultant will be invited each year to review progress on the goals of the PPG and provide advice on future directions. 2. The Core will procure and maintain animals used by program investigators and meet all AAALAC and institutional standards for animal care in the satellite facilities. The Core will maintain a breeding colony of dw/dw and dw/+ Lewis rats and provide offspring (dw/+, dwldw +/- GH, dw/dw+saline) to be used for the model of adult-onset growth hormone deficiency. The Core personnel will assess basic parameters of aging animals (general health and body weight), monitor sentinel and experimental animals for the presence of disease and provide these data to project investigators. Finally, Core personnel will be responsible for conducting peripheral cardiovascular measurements using telemetry and conducting behavioral analyses on animals as requested by the program project investigators. 3. The Core will conduct studies of alterations in gene expression using large scale DNA macroarrays and smaller custom arrays for genes determined to be of interest to project investigators. 4. The Core will provide support in the design, data management, and statistical analyses of within project and between project results with the assistance of Dr. Walter Ambrosius, Statistician for the program. The Administrative/Animal Core is an essential aspect of the Program Project ensuring effective management of limited resources, smooth interactions between projects and the use of animal models that have been validated for studies of the biology of aging. The availability of the Administrative/Animal Core has been a key part of the success of our program to date and will perform responsibilities that are essential to meet the scientific objectives of the program project in the next funding period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DISPROPORTIONATE DWARFISM IN THE MOUSE MUTANT RHIZOMELIA Principal Investigator & Institution: Bergstrom, David E.; Research Scientist; Jackson Laboratory 600 Main St Bar Harbor, Me 04609

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Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): The vertebrate skeleton is an important anatomical system providing structural support for a motile body, protection for vital internal organs, and a hospitable environment for the hematopoetic system. The set of processes by which these bony structures develop is known as skeletal morphogenesis. Defects in skeletal morphogenesis are manifested as osteochondrodysplasias, a large group of statural disorders affecting more than 1 person in 5000 in the human population and observed in nearly one percent of perinatal deaths. These conditions range in seriousness from relatively mild to severe. The more mild conditions may affect such quality of life issues as stature, mobility, activity and sexuality. Moderate conditions may include neurological and orthopedic complications. The most severe cases can result in perinatal lethality. The purpose of this proposal is to study the molecular genetic basis of disproportionate dwarfism seen in mice carrying the rhizomelia (rzm) mutation, rzm is a novel, transgene-induced mutation that causes skeletal growth aberrations in both the axial and appendicular skeleton including shortened humeri and femora, narrowed thoracic cavity, shortened tail, and craniofacial defects. The specific aims of this proposal are focused at understanding the molecular genetic basis of the rzm phenotype. First, experiments will be performed to determine whether the rzm phenotype results from a gain-of-function (GoF) or loss-of-function (LoF) mechanism. Using an embryonic stem (ES) cell-based approach, a deletion (delta) will be constructed which spans the rzm locus. After creating deletion-bearing mice, genetic crosses will be used to place rzm in trans to the encompassing deletion (rzm/A). Assessment of the resulting phenotype should allow one to discriminate between the GoF and LoF hypotheses. Second, molecular studies will be performed to clone the genomic region flanking the transgene insertion and to assess the expression of linked candidate genes and other critical players implicated in skeletal morphogenesis. The ultimate goal of this and subsequent studies is to use this unique animal and the molecular tag provided by the transgene itself as a means of entry into the network of structural and regulatory genes that coordinate skeletal development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DNA REPAIR AND ITS RELATIONSHIP TO CARCINOGENESIS Principal Investigator & Institution: Friedberg, Errol C.; Professor and Chair; Pathology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 01-AUG-1979; Project End 28-FEB-2003 Summary: These studies will utilize the yeast Saccharomyces cerevisiae as a model to investigate the molecular mechanism of nucleotide excision repair (NER) of DNA in eukaryotic cells. Since yeast NER genes are conserved in all eukaryotes thus far investigated, including mammalian cells, these studies are expected to provide considerable information on the molecular basis of the human cancer-prone, hereditary repair-defective diseases xeroderma pigmentosum (XP) and the disease Cockayne syndrome (CS) which is believed to be defective in a transcription-dependent NER mode. Multiple cloned genes required for or involved in NER are now available, as are multiple cloned genes that participate in both NER and RNA polymerase II transcription. Recent evidence suggests that the Rad proteins required for NER as well as the subunits of TFIIH are preassembled into a large NER machine that has been designated as the nucleotide excision repairosome. It is proposed to characterize the structure and function of this multi-protein complex in greater detail and to establish a fully reconstituted NER system in vitro. It is also proposed to determine whether other transcription factors participate in NER and to establish the role(s) of DNA replication

10

Dwarfism

accessory proteins such as RFA, RFC and PCNA in NER in yeast. The NER mode which operates in the in vitro system is independent of RNA polymerase II transcription. There is evidence that the yeast RAD7 and RAD16 genes are required for this process. Their role appears to be one of modulating chromatin structure to provide access of the repairosome to sites of base damage. It is proposed to isolate and characterize a putative Rad7/Rad16 chromatin-modulating complex. In addition to transcription-independent NER there is a particular interest in exploring the possibility that a transcriptiondependent NER mode also operates in yeast. At least two candidate genes for this process designated RAD26 and RAD28 [the yeast homologues of the human Cockayne syndrome group A (CSA) and group B (CSB) genes, respectively] have been identified. There is reason to believe that the proteins encoded by these genes operate in a different chromatin-modulating complex, and it is proposed to isolate and characterize this putative complex as well. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DOES CR ALTER THE METABOLIC RATE OF SPECIFIC TISSUES Principal Investigator & Institution: Mccarter, Roger J.; Professor; Physiology; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: Decreased metabolic rate (MR) is widely believed to play a major role in the anti-aging effects of caloric restriction (CR). Such a role is consistent with the Rate of Living theory and with evidence demonstrating reduced MR in response to CR. However, studies of whole animal metabolism indicate the reduced MR is transient and does not persist over the lifespan. These studies do not exclude sustained reduction in MR of specific tissues. This is important because homeothermic animals must expend energy to maintain body temperature. The two most robust models of extended longevity in mammals (calorie restriction of rodents and dwarfism in mice) both involve high rates of heat loss associated with high surface/volume ratios. Thus is it possible that MR of key tissues such as the brain is reduced while MR of tissues regulating body temperature such as brown fat or skeletal muscle is increased. Technical limitations have thus far prevented measurement of MR of specific rodent tissues in vivo. The recent development of micro Positron Emission Tomography (PET) devices now makes it possible for the first time to establish MR of specific rodent tissues non-invasively. Using PET measurements together with magnetic resonance imaging and indirect calorimetry, we propose to provide the first test of the Hypothesis: The extended longevity of caloric restriction and of dwarfism in laboratory rodents is associated with altered metabolic rates of specific tissues. In particular, specific metabolic rates of key maintenance tissues such as the brain are decreased and specific metabolic rates of heat generating tissues such as skeletal muscle are increased. The hypothesis will be tested by executing the following Specific Aims: 1. To measure specific metabolic rates of skeletal muscle, brown adipose tissue, brain, heart, kidneys, liver and of the whole animal in male Fischer 344 rats fed ad libitum and fed 40 percent less than ad libitum. 2. To measure specific metabolic rates of skeletal muscle, brown adipose tissue, brain, heart, kidneys, liver and whole body in male C57BL/6 mice fed ad libitum or fed 40 percent less than ad libitum. 3. To measure the specific metabolic rates of skeletal muscle, brown adipose tissue, brain, heart, kidneys, liver and whole animal in male Ames dwarf mice fed ad libitum. The measurements will provide a definitive test of the involvement of reduced metabolic rate in the mechanism by which CR retards aging processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DOSAGE ACCORDING TO IGF1 RESPONSE IN GROWTH HORMONE DEFI Principal Investigator & Institution: Inzucchi, Silvio E.; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001 Summary: The primary objective of this study is to test whether a fixed weight-based regimen of Somatropin (recombinant human growth hormone (rhGH) (Humatrope), starting with 4.0 ug/kg/day for four months and increasing to 8 ug/kg/day for two months, followed by 12 ug/kg/day for another two months, is equivalent or superior to an individualized Humatrope dose regimen, starting with 200 ug/day and adjusted by 200 ug/day increments at two-monthly intervals based on IGF-1 response for a further six months. Efficacy will primarily be assessed from changes in body composition determined from the results of fat mass measurements obtained by dual-energy x-ray absorptiometry (DXA) scanning performed at baseline and at the 8 month endpoint. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECT OF CHRONIC SOMATROPIN TREATMENT ON BONE MINERAL DENSITY Principal Investigator & Institution: Snyder, Peter J.; Professor; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECT DEVELOPMENT

OF

COMP

MUTATION

ON

MUSCULOSKELETAL

Principal Investigator & Institution: Di Cesare, Paul E.; Associate Professor; Hospital for Joint Diseases Ortho Inst Orthopaedic Institute New York, Ny 10003 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2003 Summary: (Adapted from the Applicant's Abstract): The ability to identify and characterize mechanisms affecting longitudinal growth and articular cartilage extracellular architecture carries with it the potential for fashioning novel techniques of early diagnosis and intervention. The focus of the proposed studies, cartilage oligomeric matrix protein (COMP), is a previously little-studied noncollagenous protein that appears to have a profound influence on musculoskeletal growth and function, as illustrated by the recent identification of mutations in COMP gene in two types of inherited chondrodysplasias and osteoarthrotic phenotypes, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), conditions characterized by disrupted longitudinal growth and early-onset arthritis. The hypothesis of this proposal is that mutations in the calcium-binding molecular domains of COMP alter its threedimensional structure and function in such a way as to impede appendicular longitudinal growth and compromise cartilaginous extracellular matrix integrity. Studies will be undertaken to (1) examine how a point mutation in the calcium-binding domains of COMP disrupts known COMP functions; and (2) determine, utilizing a transgenic model, how this process results in PSACH and MED. Identifying the functions, synthesis, interactions, tissue distribution and expression of COMP is critical to understanding its influence on growth during endochondral ossification and articular cartilage structure and function.

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Dwarfism

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

Project Title: EFFECT OF RHGH ON ENDURANCE AND CARDIOPULMONARY FUNCTION IN GH DEFICIENT ADULTS Principal Investigator & Institution: Kleinberg, David; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FGF3 RECEPTOR/BMP4: PATHWAYS REGULATING SKELETAL GROWTH Principal Investigator & Institution: Naski, Michael C.; Pathology; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2001; Project Start 15-JUL-2000; Project End 30-JUN-2004 Summary: Fibroblast growth factor receptor 3 (FGFR3) is a chief regulator of endochondral bone growth, as evidenced by the discovery that the most common genetic cause of dwarfism, achondroplasia, results from mutations in FGFR3. This implies that pathways downstream of FGFR3 are central to the control of skeletal growth. Our goals are to understand the signaling pathways used by FGFR3 to control cell proliferation and differentiation during skeletal growth and development. Understanding these pathways will lead to novel interventions for the control of skeletal growth and suggest approaches for promoting cartilage repair and regeneration. We hypothesize that FGFR3 inhibits cell proliferation by accelerating pathways of cell senescence and inhibits cell differentiation by repressing BMP4 expression. These hypotheses are a direct consequence of our preliminary data showing that FGFR3 reduces the number of chondrocytes in S-phase and slows the rate of chondrocyte and osteoprogenitor cell differentiation. Intriguingly, FGFR3 represses the expression of bone morphogenetic protein 4 (BMP4) both in chondrocytes and perichondrial osteoprogenitor cells, suggesting that FGFR3 may synchronize bone growth in the perichondrium with the growth of the epiphyseal growth plate by modulating BMP4 expression. Despite this knowledge, much remains to be learned about how FGFR3 inhibits skeletal growth. Specifically, what are the pathways used by FGFR3 to inhibit cell proliferation and what are the mediators downstream of FGFR3 that inhibit perichondrial and chondrocyte differentiation? Without understanding these fundamental questions there is little hope of designing interventional treatments for dwarfing conditions such as achondroplasia. We will address these questions and test our hypotheses by pursuing the following specific aims: 1) Investigate how FGFR3 inhibits chondrocyte proliferation by testing the hypothesis that FGFR3 accelerates cell cycle senescence; 2a) Determine how BMP4 acts as a mediator of FGFR3 signaling by targeting the expression of BMP4 to cartilage of transgenic mice and 2b) Using a cre-lox system to express BMP4 in transgenic mice, investigate the separate and combined roles of BMP4 in cartilage and the perichondrium. These studies will utilize unique reagents, including FGFR3 transgenic mice, created during our preliminary studies. Using these reagents we can directly test what effects of FGFR3 are consequences of altered BMP4 expression. These studies will fundamentally advance our understanding of the communication of the growth plate and the perichondrium and unravel novel growth regulatory pathways of FGFR3 and BMP4. We anticipate these studies will suggest new ways to control skeletal growth and to promote cartilage repair and regeneration.

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Project Title: GENETIC ANALYSIS USING SPERM TYPING Principal Investigator & Institution: Arnheim, Norman; Professor; Biological Sciences; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-SEP-1985; Project End 31-MAR-2006 Summary: This proposal seeks to study fundamental questions concerning mutation and recombination events that lead to human disease. One aim is to determine whether expansions of the CAT/CTG tracts found in Huntington disease patients occur in germline mitotic cells or following the initiation of meiosis. Studies are also proposed to examine whether the proximity or orientation of a CAG/CTG tract relative to an origin of DNA replication influences expansion size or frequency and whether this accounts for the marked inter-locus variation in expansion mutation susceptibility. Two other aims also focus on mutation. One aim will examine human sperm to determine whether the mutation that causes achondroplasia, the most common cause of dwarfism, increases with the age of the father as predicted by population studies. Another will examine the role played by members of the MutL DNA repair protein family on mononucleotide repeat slippage mutations. In humans this kind of mutation has been shown to inactivate important genes in many tumors from patients with the a familial colon cancer (HNPCC). The last aim seeks to directly measure the effects of sequence length and sequence similarity on the frequency of unequal recombination between repeated sequences in the human genome. Such events have been shown to lead to a variety of human disease syndromes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SIGNALING

GENETIC

BIOCHEMICAL

STUDIES

OF

PLANT

STEROID

Principal Investigator & Institution: Wang, Zhiyong; Carnegie Institution of Washington, Dc 1530 P St Nw Washington, Dc 20005 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Both animals and plants use steroids as signaling molecules (hormones) for physiological and developmental regulation. In plants, brassinosteroids (BRs) have growth-promoting activity and are essential for normal growth and development. Deficiencies in BR biosynthesis and responsiveness cause dramatic developmental alterations that include dwarfism due to reduced cell elongation and expansion, male sterility, delayed reproductive development, and development of light-grown morphology in the dark. BRs are perceived by the cell surface receptor kinase BAIl. How the BR signal is transduced from BRI1 on the plasma membrane to other cellular and nuclear responses remains unknown. This proposal aims at obtaining a molecular understanding of the BR signaling pathways in the model plant Arabidopsis thaliana, using approaches of molecular genetics, biochemistry, and cell biology. First, we have found that the BRI1 receptor kinase is in a large protein complex, and we hypothesize that other proteins associated with BRI1 in the receptor complex are required for the receptor function. We plan to identify the proteins associated with BRI1 using affinity purification and to characterize the functions of these proteins using reverse-genetic and molecular approaches. Second, we have isolated and carried out preliminary studies of a new BR-signaling mutant bzr1-1 D and the corresponding gene BZR1. Based on these studies, we hypothesize that BZR1 functions as a positive regulator in the BR response pathway downstream of BRI1. We plan to

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further characterize the BZR1 gene by identifying loss-of-function alleles of bzrl and bzr2, by analyzing the interaction of BZR1 with other genes of the BR signaling pathway, and by determining the biochemical activity of the BZR1 protein. We also plan to identify and characterize BZR1 interacting proteins and perform genetic studies of intragenic and extragenic mutations that suppress or enhance the bzr1 -1 D mutant phenotype. Finally, we have screened and isolated additional mutants associated with BR signaling. We have cloned the gene corresponding to one of these mutants, BZR6, which encodes a small protein. We hypothesize that BZR6 may function as a peptide ligand antagonizing BR signaling or as one of the secondary signals for the BR response. We plan to determine the functions of BZR6 and its homologue BZL1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENOTROPIN ADOLESCENTS

USE

IN

GROWTH

HORMONE

DEFICIENT

Principal Investigator & Institution: Moshang, Thomas; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GH ALTERNATIVE SPLICING: MECHANISMS AND DISEASE Principal Investigator & Institution: Phillips, John A.; Director, Division of Genetics; Pediatrics; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-1984; Project End 31-MAR-2005 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GH/IGF AXIS AND BONE TURNOVER IN CHILDREN WITH CRF AND ESRD Principal Investigator & Institution: Johnson, Valerie; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2001 Summary: Children with chronic renal failure (CRF) and end-stage renal disease (ESRD) have growth retardation and do not achieve expected height based on genetic potential despite adequate caloric supplementation, and more recently recombinant human growth hormone (GH) treatment. This study is designed to allow more efficacious use of GH and better understanding its mechanism of action. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GROWTH HORMONE DEFICIENT ADULTS--IFG1 DOSE REGIMEN Principal Investigator & Institution: Phillips, Lawrence S.; Professor; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001; Project Start 01-OCT-1974; Project End 30-NOV-2004 Summary: The purpose of this project is to show that patients are growth-hormone deficient prior to their randomization into a study in which they will receive growth hormone (humatrope). Due to the strict enrollment window, it is not anticipated that further patients will be enrolled.

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Project Title: GROWTH HORMONE IN PITUITARY DISORDERS Principal Investigator & Institution: Underwood, Louis; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GROWTH HORMONE REPLACEMENT IN CHILDHOOD ONSET GHD TREATED TO FINAL HEIGHT Principal Investigator & Institution: Brown, David; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001 Summary: This study is designed to describe the effects of Humotrope (GH) on bone mineral content and density (assessed by Dual Energy X-ray Absorptiometry (DEXA)), lean body mass, insulin-like-growth factors, bone markers, lipids, and Quality of Life in childhood-onset growth hormone-deficient (GHD) patients treated for two years after attainment of final height. A randomized, open-label, three-arm comparative, multinational trial of 24-months duration, this investigation will be performed in childhoodonset GHD patients who had previously attained a final adult height while on growth hormone (GH) replacement therapy. Patients will be randomized to recieve one of two GH therapy doses, or no treatment (control group). Approximately 150 patients will participate at sites in the U.S. Up to five patients will participate at the University of Minnesota. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GROWTH HORMONE REPLACEMENT THERAPY IN CHILDHOOD ONSET GROWTH HORMONE DEF Principal Investigator & Institution: Gordon, Catherine; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2001 Summary: International multi-center randomized controlled trial to examine the effect of growth hormone replacement (hGH) in adolescent and young adult patients with childhood onset growth hormone deficient (GHD)previously treated to final height. Previous data obtained from adult GHD patients of childhood onset treated with hGH until epiphyseal closure indicate that in spite of satisfactory final height results, other developmental milestone may not have been achieved in these individuals. Evidence suggests that the attainment of adult body shape and of peak bone mass are usually not reached until after epiphyseal closure, i.e. after final height has been reached. Thus, patients only treated to final height often have a lower than normal lean body mass, and a lower than normal bone mineral content (BMC) and bone mineral density (BMD). This clinical study will test the hypothesis that continuing hGH replacement therapy for two years after epiphyseal closure will result in increased lean body mass, BMC, and BMD. The accepted daily replacement dosage for adults (0.017-0.034IU/kg/day) will also be evaluated to see if it is significant enough to cover the developmental phase following epiphyseal closure in young adults, or if a larger dosage closer to that used in children

16

Dwarfism

(0.070-0.100 IU/kg/day) is more appropriate. Three treatment arms will be included; pediatric dosage, adult dosage, and no treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HORMONAL AND DEVELOPMENTAL REGULATION OF GENE EXPRESSION Principal Investigator & Institution: Rosenfeld, Michael G.; Professor; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 01-JUN-1977; Project End 31-MAR-2006 Summary: Understanding the molecular mechanisms by which specific cell types develop from a common primordium in the anterior pituitary gland represents a basic question in molecular and developmental biology. Under this Grant, we analyzed the roles of Pit-1, cloned and characterized Prop-1 as the hypomorphic allele causing the Ames genetic dwarfism, and identified disease alleles in human pituitary combined hormone deficiency syndrome; identified the signaling molecules from ventral diencephalon and opposing signaling gradients that dictated the positional commitments of organ and cell-type determination events, and provided the initial evidence of the roles of induced transcription factors as the "molecular memory" of the transient signaling gradients. In this competitive renewal application, we propose to investigate the role of a series of transcription factors, including the members of the Six, Pax, GATA and Pitx families, and of specific co-activators, in nearly and late developmental events. The roles of specific protein-protein interactions, and coactivators and co-repressors, on their actions will be considered, and we propose to identify artificial target genes that mediate their biological actions. The role of signaling factors, including Shh, BMP, Wnt and retinoic acid, will be further explored using in vivo and in vitro approaches. The mechanism of Pit-1 lineage determination will be explored, with experiments directed at understanding the activation of the early Pit-1 gene enhancer, regulation of the Pit-1 lineage by Prop-1, and the mechanisms of control by Pit-1 of the terminal differentiation of three pituitary cell types. The allosteric effects of cognate Pit-1 DNA binding sites on these events will be explored structurally, and in vitro, and the role of co-repressor complex assembly will be investigated. This research proposal extends the approach used over the current grant period, which has been the most successful in our 22 years under this grant, combining biochemical and genetic approaches to investigate potentially important regulatory proteins, and systematically exploring the functional role of the novel proteins. We believe that these experimental approaches will provide insights into the intriguing problems of organ and cell-type differentiation, and cell-specific patterns of gene activation, with clear implications for human diseases that are caused by abnormalities of these developmental events. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HYPOPHYSIOTROPIC NEURON DIFFERENTIATION--TARGET FEEDBACK Principal Investigator & Institution: Phelps, Carol J.; Professor; Anatomy; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2001; Project Start 01-DEC-1988; Project End 30-JUN-2003 Summary: The proposed studies are designed to test the hypothesis that anterior pituitary hormones act as developmental neurotrophic signals for hypothalamic pituitary-regulating (hypophysiotropic) neurons. The broad, long-term objective of the research is to elucidate the mechanisms by which these endocrine signals affect

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hypophysiotropic neuron survival, differentiation, and axon terminal guidance. The studies will be conducted using two types of dwarf mouse with spontaneous pituitary transcription factor mutations that result in failure to produce growth hormone (GH) and prolactin (PRL), and which show concomitant abnormalities in neurons that produce GH-regulating somatostatin and GH-releasing hormone, and PRL-inhibiting DA. Thus, the effect of absent signal during development may be assessed without experimentation, and hormone treatments may be selective and specific. The general experimental design is evaluation of developmental events in the absence of target feedback, and of effects of hormone replacement on these events. The specific aims are to determine, in naive and hormone-treated dwarf mice, 1) the extent to which hypophysiotropic axons terminate aberrantly outside of or within the hypothalamic median eminence (ME) and whether this pattern is regressive, using anterograde and retrograde tract tracing, immunocytochemistry (ICC) and electron microscopy (EM), including assessment of axonal guidance molecules and structural elements in ME, 2) whether programmed cell death occurs postnatally among hypophysiotropic DA neurons, by ICC of apoptotic gene products, nucleosome end-labeling in situ, and EM, and 3) whether IGF-I and GDNF are respective mediators of GH and PRL effects, by assessing expression of these factors and their receptors using in situ hybridization and testing whether either factor can substitute for hormone replacement. Related to the assessment of mediators is Specific Aim 4, further examination of pathways and mechanisms of GH and PRL effect, by localizing GH and PRL receptors, identifying the JAK/STAT proteins that these receptors activate, measuring the expression of immediate-early gene products after GH or PRL treatment, and identifying the neuronal phenotypes showing receptor or activation, because hypophysiotropic neuron stimulation may be indirect. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYPOPITUITARISM AFTER MODERATE AND SEVERE HEAD INJURY Principal Investigator & Institution: Kelly, Daniel F.; Associate Professor; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 90502 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (Verbatim from applicant's abstract) Pituitary function is rarely considered in the care of patients with traumatic brain injury (TBI). Yet, TBI poses significant risk to pituitary function given the gland's encasement within the sella, its delicate infundibular-hypothalamic structures and vulnerable vascular supply. Autopsy studies of fatal head injury victims confirm that up to one third sustain pituitary necrosis and hundreds of case reports document chronic post-traumatic pituitary failure. The longterm neurobehavioral problems that plague a majority of TBI victims are quite similar to those of patients with hypopituitarism. It is the primary hypothesis of this study that many TBI victims suffer from unrecognized pituitary dysfunction that acutely and chronically compounds the initial brain injury and limits maximal recovery. The major hypotheses being tested in this study are that i) post-traumatic pituitary failure, both acute and chronic, results primarily from a vascular insult to the pituitary gland and/or its hypothalamic-infundibular connections; ii) in the acute phase of TBI such injury can result in acute secondary adrenal insufficiency, iii) in the chronic phase of TBI such injury can result in long-term hypopituitarism, and iv) treatment of pituitary hormone deficiencies will improve neurobehavioral functioning and quality of life in the chronic post-traumatic state. These hypotheses will be tested in a three-phase study. In the first phase, acutely post-injury, subjects will undergo serial determinations of adrenocortical

18

Dwarfism

function to diagnose and treat acute adrenal insufficiency. Patients found to have inappropriately low cortisol levels, will be randomized to placebo or hydrocortisone therapy for 48 hours, and changes in blood pressure and vasopressor requirements will be monitored. Pituitary/hypothalamic MRIs will also be performed at 10 days and 6 months post-injury to assess for acute structural lesions and chronic pituitary volumetric changes. In the second phase, at 2 and 6 months post-injury, pituitary function tests will be performed. Hormone deficient patients will be placed on hormone replacement except for growth hormone (GH) after the 2-month time point. In the third phase, from 6 to 12 months post-injury, TBI patients with GH deficiency or GH insufficiency, who have memory impairment, concentration deficits, depression, anxiety or fatigue will be entered into a double-blind placebo-controlled GH replacement therapy trial to assess changes in these neurobehavioral and quality of life complaints. By diagnosing and treating both acute and chronic traumatic neuroendocrine deficiencies, this study may dramatically improve the lone-term prognosis of many TBI patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYPOPITUITARISM: CHARACTERIZATION

CLINICAL

&

MOLECULAR

Principal Investigator & Institution: Radovick, Sally M.; Section Chief; Pediatrics; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAR-2005 Summary: Pituitary development and hormone expression in mammals is controlled by pituitary-specific transcription factors including: Rpx, Lhx3, Prop-1 and Pit-1. These factors initiate a cascade of development events resulting in mature pituitary cell-types and mutation or deletion of the genes encoding these factors have been shown to result in anterior pituitary hormone deficiency in mammals. A consistent feature of these animal models is GH deficiency associated with either TSH and/or prolactin deficiency. Many patients have been described with complete or partial deficiency of hormone secretion from these cell types. However, in many cases, the pituitary function has not been carefully evaluated and patients are frequently diagnosed as having 'idiopathic' GH deficiency. My laboratory and others have described a genetic basis for combined pituitary hormone deficiency (CPHD) in man due to point mutations in the Pit-1 and Prop-1 genes. We and others have also discovered Pit-1 and Prop-1 mutations in patients with presumed idiopathic GH deficiency. These observations demonstrate that mutations in these genes may be a frequent cause of not only CPHD, but also 'isolated' GH deficiency. In addition, mutation or deletion of other pituitary developmental factors (Rpx, also 'isolated' GH deficiency. In addition, mutation or deletion of other pituitary developmental factors (Rpx, Ptx2 and Lhx3) has been associated with pituitary hormone deficiencies. This proposal will clinically characterize patients with hypopituitarism and investigate the structure of candidate genes. Study of mutations in pituitary transcription factors and their diverse pathophysiological mechanisms should increase our understanding of anterior pituitary gland development and gene regulation in normal and disease states. The candidate is an Associate Professor of Pediatrics at Harvard Medical School and an Associate Physician at Children's Hospital, Boston, where she is the director of the reproductive endocrine unit and endocrine clinical laboratories. She has independent support to study GnRH gene expression (RO1-HD34551) and Pit-1 gene function (R01-DK53977) in mammals. She also directs a CRC protocol to evaluate and categorize patients with hypopituitarism. She actively mentors four BE/BC pediatric endocrinologists, a BE obstetrician-gynecologist, two of whom are funded by the intramural Endocrine training grant (T32HD07277), one

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funded by a mentored grant (K11DK02329), one by a Janeway fellowship award from Children's Hospital mentoring success, in an environment rich with academic opportunities, this award will allow her to increase her mentoring activities and to enhance her own commitment to patient- oriented research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDENTIFICATION OF IMPRINTED GENES ON CHROMOSOME 14 Principal Investigator & Institution: Shaffer, Lisa G.; Molecular and Human Genetics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 28-FEB-2002 Summary: Uniparental disomy (UPD) is the abnormal inheritance of both copies of chromosome from the same parent with no contribution of that particular chromosome from the other parent. UPD has been described for many human chromosomes, resulting in varying clinical outcomes. An abnormal phenotype may result from genes on a chromosome that are subject to genomic imprinting. Genomic imprinting is the molecular mechanism by which there can be differential expression of genes from either the maternally-or paternally inherited chromosome. The clinical description of cases with either maternal and paternal disomy 14 has enable the characterization of distinct syndromes for each. Individuals with paternal disomy 14 present with a more several phenotype with includes mental retardation, skeletal abnormalities that result in a shortlimb dwarfism with narrow thorax, decreased survival due to respiratory difficulties, dysmorphic facies, scoliosis, and short status. This application proposes to identify imprinted genes on human chromosome 14 through two Specific Aims. First, differentially expressed sequences will be identified from maternally- and paternallyderived chromosomes 14. Expressed sequences from cell lines of either maternal disomy 14 or paternal disomy 14 will be compared through direct analysis of known genes, hybridization to arrayed cDNA filters, and suppression subtraction hybridization to identify imprinted genes. Second, differentially expressed sequences will be characterized in order to understand the molecular mechanism of genomic imprinting and the effects of phenotype. The differentially expressed sequences will be sequenced and full length cDNAs will be identified. Sequences will be analyzed for parent-specific methylation and expression to begin to understand the molecular elements used to control the imprinting process. The identification of genes that are subject to genomic imprinting will allow insight into the mechanisms of genomic imprinting in normal and abnormal human development and mental retardation syndromes and may lead to further advances in the diagnosis and molecular understanding of UPD disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IGF-1 AND LONGEVITY IN MAMMALS Principal Investigator & Institution: Sell, Christian; Assistant Professor; Lankenau Institute for Medical Research Wynnewood, Pa 19096 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: A central issue in biogerontology is the nature of the mechanisms that modulate species lifespan. Genetic studies in Caenohabditis elegans and Drosophila melanogaster have identified a cellular pathway that modulates longevity. Mutations that reduce the function of the homolog of the IGF-I/insulin receptors extends lifespan in both nematodes and flies. Similarly, studies in rodents indicate that a reduction in the growth hormone/IGF-I axis leads to an extension in lifespan. These studies suggest that a reduction in IGF-I may extend lifespan in mammals but no direct evidence for this

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hypothesis exists. We propose to test directly the possibility that a reduction in IGF-I levels can increase lifespan using a transgenic mouse model. We have obtained a unique transgenic mouse line that contains an insertion in the igf-1 gene leading to a specific reduction in IGF-I and a dwarf phenotype (IGF-I m/m mice). Specific aim 1 will examine survival of the IGF-I mice relative to controls over the course of this study and Specific aim 2 will examine age related changes in the IGF-I m/m mice such as immune senescence, collagen crosslinking and hormonal changes to determine whether there is any change relative to controls. Our long-term goals are to perform complementation analysis using the IGF-I m/m mice and mice that harbor other mutations that are known to extend lifespan. In this way, we can determine whether these mutations act through separate or common mechanisms to regulate longevity. In parallel to the mouse studies we plan to identify the IGF-I dependent pathways relevant to longevity using cell culture models derived from these mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INHERITED GROWTH HORMONE DEFICIENCY Principal Investigator & Institution: Parks, John S.; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001 Summary: No research subjects are admitted to the GCRC under this protocol. It utilizes the Molecular Cell Biology Lab to transform and store immortal Epstein-Barr virus lymphocyte cell lines from patient samples sent directly to the lab. The cell lines then serve as a permanent DNA/RNA resource, as well as an in vitro model system for molecular genetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INTERACTION OF CALORIC RESTRICTION WITH LONGEVITY GENES Principal Investigator & Institution: Bartke, Andrzej; Professor; Physiology; Southern Illinois University Carbondale 900 S. Normal Carbondale, Il 629014709 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Our long-term objective is to identify the molecular mechanism(s) responsible for delayed aging and prolonged longevity of animals exposed to caloric restriction (CR). We will approach this goal by examining interactions of CR and longevity assurance genes (LAGs) in a mammalian system. Will help identify the unique, intersecting and additive effects of CR and dwarfism upon aging to provide an inferential basis to determine which candidate and novel mechanisms specifically relate to aging in these models. This experimental design is unique and powerful. The proposed domains of phenotypic analysis combine careful study of standard candidates and exploratory use of microarrays. Hormone therapy is proposed as an experimental manipulation to further test the hypotheses. The concept is promising, but the design requires additional controls (revise and add to budget). The environment, investigators and model background provide high confidence for an informative study. Loss-offunction mutations at the Prop1 and Pit1 loci, as well as targeted disruption of the growth hormone receptor (GHR)/binding protein gene, delay aging and greatly prolong life in the mouse. Phenotypic characteristics of these novel models of delayed aging overlap with many of the well-documented effects of CR. We have recently demonstrated that in one of these models, the Ames dwarf (Prop1df) mouse, CR may extend life beyond the limits achievable with CR or dwarfism alone. We believe that

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studying interaction of CR with different LAGs is a powerful approach for identifying those changes in gene expression and in physiological characteristics that are consistently associated with prolonged longevity. These changes can be viewed as potential mechanisms and/or biomarkers of delayed aging. In the proposed studies, we will determine whether CR increases life span in Snell dwarf, in GHR knock out (GHRKO) mice, and in Ames dwarf mice given replacement therapy with thyroid hormone. We will also examine ad libitum (AL) fed and CR dwarfs at 2.0, 2.5 and 3.0 years of age to determine whether extension of life span in Ames dwarfs by 30% CR is associated with delay of aging as assessed by tests of cognitive and immune function. To identify mechanisms of CR action in long-lived mice, we will examine the effects of 6 months of CR on gene expression in the liver and muscle, on plasma glucose, insulin, and corticosterone levels, on activity of antioxidant enzymes, and on body temperature in dwarf and GHR-KO, as compared to normal mice. Gene expression will be assessed by microarrays as in our recent studies of the effects of Ames dwarfism on age-related changes in hepatic gene expression, and results of particular interest will be verified by Northern analysis. The results will be used to determine how CR and LAGs interact to delay aging, and to identify putative mechanisms of action of CR at the molecular and organismal levels. In future studies, we will verify involvement of these mechanisms in the control of normal and delayed aging and examine their potential in designing interventions that prolong health span. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTRACELLULAR ZINC COMPARTMENTALIZATION IN S CEREVISIAE Principal Investigator & Institution: Brown, Nina M.; Chemistry; Northwestern University 633 Clark St Evanston, Il 60208 Timing: Fiscal Year 2001; Project Start 13-AUG-2001 Summary: Zinc is an essential element, and alterations in systemic zinc homeostasis have been linked to diseases such as adolescent nutritional dwarfism, acrodermatitis enteropathica and repression of the immune system. A greater understanding of zinc homeostasis at the cellular and molecular level is essential to human health in that it will directly impact the ability to diagnose and treat zinc related diseases by providing markers by which to assess zinc status and therapeutic targets. Two central questions are addressed in this proposal. Is zinc stored within cells in a bio- available form, and if so, which proteins are involved in zinc transit through these compartments? The research described in the proposal will combine fluorescent microscopy studies with biophysical and proteomic approaches to identify zinc rich cellular compartments and isolate the proteins associated with these vesicles. These studies will resolve several competing hypotheses regarding zinc homeostasis and can potentially reveal a completely novel pathway for trafficking and utilization of this element. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LONGITUDINAL AND RELATED PSYCHOHORMONAL STUDIES Principal Investigator & Institution: Money, John W.; Professor; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2004 Summary: (provided by the applicant): The immediate objective of this proposal is to do the research for and writing of the history of pediatric clinical psychoendocrinology and psychosexology in the Johns Hopkins Pediatric Endocrine Clinic. This Clinic, the first of

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its kind worldwide, was founded by Lawson Wilkins, M.D., in 1946. In 1951 he foresaw the need for psychohormonal research, with special reference to the prevention of unwanted virilization in the CAH (congenital adrenal hyperplasia) syndrome of female pseudohermaphroditism with the newly discovered hormone, cortisol. The person he recruited having been myself, history and autobiography overlap chronologically and will continue to do so, in part, in the book proposed in this present grant application. The necessary information will be retrieved from voluminous records published and unpublished, and from library resources and online data bases. The initial draft of the Table of Contents will be amended and augmented if the writing so dictates. The longterm objective of the book is to provide psychohormonal and psychosexological researchers and health care providers with the information that will enable them to heed Santayana's famous warning to those who do not know their history, namely that they "are condemned to repeat it"-- as, for example, in today's revival of the nature/nurture debate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LRF ANALOG TO DELAY PUBERTY IN PRECOCIOUS PUBERTY, GH DEFICIENCY, SHORT STATURE Principal Investigator & Institution: Crowley, William F.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF MUTAGENISIS IN 'HOT SPOTS' CAUSING CANCER Principal Investigator & Institution: Wright, Barbara E.; Div of Biological Sciences; University of Montana University Hall 202 Missoula, Mt 598124104 Timing: Fiscal Year 2002; Project Start 10-JUL-2002; Project End 30-JUN-2004 Summary: (provided by applicant): In humans, characteristic DNA sequence motifs and 'hot spots' are frequently associated with mutational events leading to genetic diseases such as dwarfism (achondroplasia) and Apert's syndrome. Short sequences of DNA repeats, called microsatellites, generate instability in colon cancer, and T-G repeats and an ATGGTC hexamer are involved in breaks of hybrid genes in liposarcoma and leukemia. Some skin cancer cell lines harbor frameshift mutations in the hRAD30 gene, and over 35% of the transition mutations in haemophilias or retinoblastoma cancers occur at C-G sites at which C-to-T transitions occur. In both humans and microbes these mutations originate preferentially on the single-stranded non-transcribed strand, which is 100-times more vulnerable to mutation than dsDNA. Thus, transcription is implicated as a cause of these mutations. DNA secondary structures are also implicated, since hot spots in microbes and certain cancers are known to be associated with these structures. They are mutagenic precursors because they can contain repeat sequences susceptible to strand slippage (frameshifts) or inverted repeats that tend to form stem-loop structures containing vulnerable mispaired or unpaired bases. Exposure to stresses such as reactive oxygen species, pollutants and heavy metals could cause mutations resulting in cancer via direct effects on supercoiling and secondary structures. We will use a microbial model system to determine the mechanisms by which gene transcription and supercoiling triggered by various forms of stress increase mutation rates specifically in the activated genes. We will determine the effects of activators and supercoiling on

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transcription initiation and pausing, examine predicted stem-loop structures in both transcribed and non-transcribed strands, determine whether antisense DNA to the coding strand will protect genes from mutations, and modify sequences in stem-loop structures to examine predicted effects on mutation rates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF P27KIPL-ASSOCIATED NEOPLASIA Principal Investigator & Institution: Clurman, Bruce E.; Associate Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2001; Project Start 16-FEB-2000; Project End 31-JAN-2005 Summary: The overall goal of this proposal is to characterize the normal regulation of the p27 kip1 protein, and how loss of this regulation contributes to multi-step tumorigenesis. p27kip1 is a member of the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors, which bind to an inhibit CDKs in response to anti-proliferative signals. P27 expression is regulated by physiologic stimuli such as mitogen. Conversely, loss of p27 expression is associated with increased cell division and tumorigenesis. Low p27 expression is associated with increased cell division and tumorigenesis. Low p27 expression correlates with poor outcome in many human cancers, and p27 function as a tumor suppressor in mice. The mechanism of p27 loss in tumors and how this participates in neoplastic transformation is largely unknown. The experiments described in this proposal address both of these issues. P27 abundance is controlled at many levels, including proteolysis, translation, phosphorylation, and subcellular localization. In this proposal, we will define the nuclear transport mechanisms of p27, and how they are integrated with other modes of p27 control to globally regulate p27 abundance and function. We have identified a novel nuclear pore protein, termed PASSTA, that interacts with p27 and created a targeted deletion of PASSTA in mice that causes embryonic lethality, neural tube defects, and dwarfism. We will now test the hypothesis that PASSTA mediates interactions between p27 and the nuclear pore, and determine the mechanisms and physiologic consequences of these interactions in normal and tumor cells. The mechanism of tumor suppression by p27 is not clearly understood. We have established a mouse model to identify genes that cooperate with p27 loss in multistep transformations by using insertional mutagenesis to induce lymphomas in p27 null and wild type mice. P27 null animals exhibit greatly accelerated lymphogenesis. We will now identify the activated genes in these lymphomas, determine how they synergize with p27 loss, and examine if they are similarly involved with human cancer associated with low p27 expression. Ultimately, understanding the mechanisms underlying p27 regulation in normal and neoplastic cells may lead to the identification of novel therapeutic targets for the treatment of cancer and other diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: METABOLIC STUDIES IN GROWTH HORMONE DEFICIENT PATIENTS Principal Investigator & Institution: Sharma, Norali; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001 Summary: This research project investigating the effect of growth hormone replacement therapy on glucose and protein metabolism in growth hormone-deficient adults has a total of 7 patients (1male, 6 female) enrolled. One patient was discontinued from the study due to non-compliance. One patient has completed six months on growth

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hormone therapy without any complications. Two patients have completed their baseline studies and have recently started growth hormone treatment. Three patients are undergoing their base-line studies and will begin growth hormone therapy thereafter. These patients are also receiving clinical and biochemical assessment as needed in the Clinical Studies Unit at the Ben-Taub General Hospital. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METALLOPROTEASES IN SKELETAL DEVELOPMENT AND GROWTH Principal Investigator & Institution: Apte, Suneel; Associate Staff Scientist; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2001; Project Start 15-JUL-2000; Project End 30-JUN-2004 Summary: Cartilage extracellular matrix (ECM) degradation and angiogenesis are critical for skeletal development in general and for endochondral ossification in particular. Matrix metalloproteinases (MMPs) play an important role in these processes. MMP-14 (or MT1-MMP, membrane type I-MMP), an integral membrane MMP, is prominently expressed during skeletal development. In vitro, MMP-14 cleaves ECM molecules such as collagen I and aggrecan. It is the cell surface activator of progelatinase A and collagenase-3, the most active collagen II protease. These observations predicted a significant role for MMP-14 in cartilage ECM proteolysis and skeletal development. We have confirmed this by generation of transgenic null mice lacking MMP-14, via homologous recombination in embryonic stem cells. The abnormalities in MMP-14 deficient mice include defective cartilage resorption, decreased chondrocyte proliferation, delayed formation of secondary ossification centers, and defective angiogenesis. The consequences of these abnormalities are severe dwarfism and early death. The precise molecular pathways leading up to this phenotype are unknown and will be investigated in this proposal. We will address the effects of the transgene on parameters of chondrocyte performance and bone growth, and on expression of genes for stage specific chondrocyte markers and molecules related to angiogenesis. Experiments are described to determine whether MMP-14 directly resorbs cartilage extracellular matrix or whether it acts through activation of other metalloproteases. Since secondary ossification center formation is delayed, we will study angiogenesis using in vitro and in vivo assays in these mice. In view of preliminary studies which suggest interference with the growth hormone-insulin-like growth factor (IGF) axis in these mice, we will investigate a role for MMP-14 in mediating the bioavailability of free IGF via proteolysis of IGF binding proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR BASIS OF NOONAN SYNDROME AND RELATED DISORDERS Principal Investigator & Institution: Gelb, Bruce D.; Professor; Pediatrics; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The applicant proposes to study Noonan syndrome (NS) and related disorders. NS is a relatively common autosomal dominant trait with features that include congenital heart disease (CHD), short stature, dysmorphism, and mental retardation. We recently showed that mutations in the PTPN1 1 gene cause NS. PTPN1 I encodes the protein tyrosine phosphatase, SHP-2, which has two src-homology 2 (SH2) domains. SHP-2 is known to play a critical role in receptor tyrosine kinase-

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mediated signal transduction through MAP kinase. These new findings provide opportunities to understand the role of SHP-2 in CHD as well as to identify additional CHD genes.To test the hypothesis that all PTPN11 mutations causing NS are missense defects affecting residues at the interface of the N-SH2 and phosphatase domains, we will identify and characterize PTPN11 mutations in a large, well-characterized NS cohort. This will establish the range of molecular defects and may permit correlation of genotype with phenotype. To determine whether PTPN1 I mutations cause Noonan-like syndromes and sporadic CHD, cohorts with the latter will be screened as will those with cardiofaciocutaneous and Costello syndromes.To test the hypothesis that PTPN1 1 mutations cause NS by a gain-of-function mechanism, the function of mutant SHP-2 proteins will be tested in cell culture to document that they have increased phosphatase activity, interact with the SHP-2 docking partners, and excessively stimulate receptor tyrosine kinase signaling cascades.To test whether NS mutations perturb the FGFR and EGFR pathways during development through a gain-offunction, NS mutations will be studied in Drosophila and Xenopus. Mutant corkscrew (the SHP-2 orthologue) will be introduced in fly embryos with null or hypomorphic corkscrew alleles. Development of terminal structures (torso pathway), eyes (sevenless pathway), wings (EGFR pathway) and trachea (FGFR pathway) will be assessed. Mutant SHP-2 will be expressed in frog animal caps to assess FGF-mediated mesoderm induction.Since NS is genetically heterogeneous, there are additional NS disease genes. To identify them, we will use candidate gene and positional cloning strategies. For the former, we will focus on genes with biological roles relevant to signaling cascades in which SHP-2 participates. For the latter, a positional cloning/candidacy approach will be used with multiplex NS kindreds whose trait does not link to the PTPN1 I locus.These studies will delineate the molecular diversity of PTPN1 1 mutations underlying NS and related disorders as well as provide insights into the effects of SHP-2 mutants at the biochemical, cellular, and organismal levels. The results will inform future work directed at understanding the pathogenesis of NS and at developing novel therapeutic strategies, such as those ameliorating the progression of cardiac hypertrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR BIOLOGY OF CAMPTOTHECIN INDUCED DNA DAMAGE Principal Investigator & Institution: Snapka, Robert M.; Professor; Radiology; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2001; Project Start 08-MAY-2000; Project End 30-APR-2003 Summary: Camptothecins are a very promising group of strong topoisomerase I poisons that have shown good activity against a variety of human cancers in clinical trials. Several key contributions to our understanding of the cytotoxic mechanisms of camptothecins have been made with studies of simian virus 40 (SV40), a small double strand DNA virus which makes such extensive use of host cell chromosomal proteins and enzymes of DNA replication and transcription that it is considered a "minichromosome" and model for the mammalian replicon. As a model system, SV40 has unique advantages and has made many contributions to our understanding of mammalian DNA replication and transcription. The hypothesis of this proposed study is that our understanding of the molecular biology of camptothecin action can be significantly advanced by two developments of the SV40 model system: (1) the study of camptothecin-resistant mutants of CV-1 host cells for SV40 infections and (2) studies using mutants of SV40 with greatly increased infectivity for human cells. The primary goal of the studies is to understand the structure and processing of camptothecin-

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induced DNA lesions and how these can be modulated by other treatments. The unique advantages of the SV40 system will allow us to analyze disruptions in DNA replication and transcription in unusual molecular detail. Secondary goals include complete characterization of the camptothecin resistant CV-1 cell mutants, studies of camptothecin effects on DNA replication in human genetic instability syndromes hypersensitive to camptothecins and understanding of the roles of topoisomerases I and IIbeta in transcription. The rational for the studies is that improved understanding of camptothecin-induced damage and its processing will provide valuable information for the design of new drugs of this class and for new treatment combinations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR MECHANISMS OF FGFR RELATED SKELETAL DISORDERS Principal Investigator & Institution: Fu, Xin-Yuan; Associate Professor; Pathology; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2003 Summary: Fibroblast growth factor receptors (FGFRs) have crucial functions in differentiation, angiogenesis, cell migration and development. Mutations in FGFRs have been shown to cause dominantly inherited human skeletal abnormalities and other disorders. In particular, the achondroplasia class of chondrodysplasias is comprised of the most common genetic forms of dwarfism in humans. Its members, achondroplasia (ACH), hypochondroplasia (HCH) and thanatoporic dysplasia types I and II (TDI and TDII), are caused by distinct mutations of fibroblast growth factor receptor 3 (FGFR3) which retard skeletal growth and development. The molecular mechanism and mediators of these FGFR3-related growth abnormalities are unclear. We have shown that the mutant TDII FGFR3 has a constitutive tyrosine kinase activity that could specifically activate STAT1 both in vitro and in vivo. Furthermore, TDII FGFR3-induced STAT1 activation was correlated with translocation of STAT1 to the nucleus, expression of cell cycle inhibitor p21WAF1/CIP1 and cell growth arrest in tissue culture cells and in the cartilage cells from the TDII fetus. These results have shown, for the first time, that abnormal STAT activation and p21WAF1/CIP1 expression may be responsible for the TDIIFGFR3-caused bone disease. Based on these discoveries, it is necessary to expand our research work on the detailed molecular mechanisms of FGFR signal transduction, and to further reveal the complicated molecular basis of mutant FGFR- associated abnormalities. In this application, I propose the following specific aims: 1) To investigate the possible programmed cell death (apoptosis) induced by the expression of mutant FGFR3. To determine whether STAT1 activation and p21 expression are involved in the induction of apoptosis. 2) To reveal molecular mechanisms of STAT1 activation by the TDII receptor and search for other possible signaling molecules that may also play a role in the mutant FGFR3 function. 3) To study molecular mechanisms of developmental disorders caused by mutant ACH, HCH, and TDI receptors of FGFR3. We will determine whether the abnormal STAT activation is also involved in these disorders. We will also test whether STAT1 activation is one of the outcomes of constitutive activation of other tyrosine kinases. 4) To generate mouse models using TDII and ACH knock-in technique. These mice will be used for in vivo test for our hypothesis and for potential therapeutic studies. I believe that the experiments proposed in this application represent a novel and important dimension of research that will reveal a molecular basis for FGFR-related genetic disorders. The results from these studies will also contribute to the development of the molecular therapies for these disorders in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR PATHOPHYSIOLOGY OF GROWTH DISORDERS Principal Investigator & Institution: Wajnrajch, Michael P.; Pediatrics; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 30-JUN-2003 Summary: We have undertaken a patient-based study of the role of molecular defects in individuals with growth disorders. We hypothesize that a subset of individuals with familial severe isolated Growth Hormone (GH) deficiency have a mutation in a gene compromising the Growth Hormone axis. Careful phenotyping via a detailed endocrine evaluation, we limit the potential candidate genes to the Growth Hormone Releasing Hormone (GHRH), the GHRH Receptor (GHRHR), the Growth Hormone Secretagogue (GHS), the GHS receptor (GHSR) and Growth Hormone (GH1). We recruit and analyze families for genetic linkage of familial, severe short stature to a region of the genome containing one of the components of the GH axis. The candidate gene is then characterized, exon- by-exon, initially by Single Strand Conformational Analysis (SSCA) and then by direct sequencing of the conformationally unique exon in affected and unaffected members of a family. Confirmation of mutational status is furnished by restriction fragment length (RFLP) analysis which detects sequence variants, including novel restriction sites. This protocol requires knowledge of the genetic position of a candidate gene, and its fine genetic structure. Those genes whose genomic structure is not known (e.g. GHRHR and GHSR) will be fully characterized by us in an effort to enable their screening as above. We are also recruiting individuals with GH-secreting tumors to determine the role of molecular defects in GH excess/acromegaly. We are revere transcribing the total RNA from tumor tissue to obtain cDNA for candidate genes, including the GHRHR, the GHSR and the Growth Hormone Factor-1 (GHF-1, also called the PIT-1 transcription factor). In cases where RNA is not available, we rely on SSCA followed by direct sequencing of genomic DNA to identify activating mutations resulting in GH excess/acromegaly. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MULTI STEP TUMORIGENESIS, CONTROL OF CELL CYCLE ENTRY Principal Investigator & Institution: Land, Hartmut; Director, Center for Cancer Biology; Genetics; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 28-FEB-2006 Summary: Carcinogenesis is caused by multiple co-operating genetic lesions leading to a progressive deregulation of cellular signaling and cell cycle restriction point control. The mutations involved result in oncogene activation or loss of tumor-suppressor gene function. However, the mechanisms by which these mutant genes co-operate in malignant cell transformation are largely unknown. Our laboratory has shown that the co-operation of oncogenic lesions involves integration of multiple signals converging on the regulation of cell cycle-dependent kinase complexes. Here we propose to investigate the molecular mechanisms by which the c-myc oncogene co-operates with activated Ras/Raf signaling. The c-myc oncogene is frequently activated in human cancer and is a potent inducer of proliferation and apoptosis. One essential step in Myc-induced proliferation is the activation of Cyclin E-dependent kinase (Cyclin E/Cdk2). Using genetic and biochemical approaches in tissue culture, we recently made the surprising finding that activation of cyclin E/Cdk2 by c-myc requires the ability of D cyclins to sequester Gl cell cycle inhibitors p27Kip1 and p21Cip1 (Ckis). We now propose to investigate whether the capability of D cyclins to sequester Ckis plays an important role in the induction of cell division by activated c-myc in an intact organism. Moreover, we

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plan to tea the hypothesis that sequestration of Ckis by D cyclins may play a significant role in organ development and during multi-step carcinogenesis. This work will provide insight into developing signaling pathway-based strategies for cancer therapy in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTICENTER STUDY TO EVALUATE SAFETY AND EFFICACY OF GRF Principal Investigator & Institution: Plotnik, Leslie P.; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001 Summary: Growth hormone releasing hormone stimulates the release of growth hormone in normal subjects. This is a Phase III study which aims to identify whether GRF (at 30 mcg/kg) given as a single daily injection, is an effective therapy in growth hormone deficient children. We have had 1 patient in this study since 6/90 who, per protocol, is growing at a rate greater than 5 cm/year above baseline. GEREF was approved in the summer of 1995 by the FDA for lilmited usage. Our patient will continue on GEREF until final adult height, as long has he continues to grow well. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOCTURNAL TSH SURGE IN CENTRAL HYPOTHYROIDISM Principal Investigator & Institution: Rose, Susan R.; University of Tennessee Health Sci Ctr Health Science Center Memphis, Tn 38163 Timing: Fiscal Year 2001 Summary: In this study, 60 children with idiopathic short stature undergo overnight study of their pattern TSH. In addition, 60 children who have undergone treatment of CNS tumor/oncology and 60 children who have survived significant head injury will be studied. Those who are identified as having blunted TSH secretion at night will be eligible to participate in a subsequent placebo-controlled treatment phase." Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOGENESIS OF OSTEOARTHRITIS IN COL2A1 MUTANT MICE Principal Investigator & Institution: Seegmiller, Robert E.; Professor; Physiology/Developmtl Biology; Brigham Young University A-261 Asb Provo, Ut 846021231 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): The application?s major objective is to develop an animal model for osteoarthritis (OA) to provide an understanding of the histopathology and mechanisms involved in the development of articular cartilage disease. Degeneration of synovial joint tissue in the form of OA is one of the leading causes of chronic disability in humans. For the most part, OA is idiopathic and, therefore, animal models are urgently needed for the understanding of the mechanisms involved and to lay the foundation for the development of drug and gene therapies used in the treatment and prevention of this skeletal disease. One class of proteins that plays an essential role in the structure and function of articular cartilage, triple helical collagen, appears to be involved in the pathogenesis of this disease, particularly those types of hereditary OA associated with mild chondrodysplasia. Disproportionate micromelia (Dmm) is a semidominant, type II collagen (Col2a1) mutation in mice that, in the

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heterozygous condition, causes mild dwarfism. Preliminary studies, including small histological studies on knee joints from 6- and 9-month-old mice, indicate the presence of OA as well. The purpose of the proposed research is to expand these preliminary studies to thoroughly characterize the development of OA in Dmm/+ mice. The use of light microscopy will permit examination of cellular changes within knee-joint as well as non-weight-bearing articular cartilages of various aged heterozygous mice. Electron microscopy will permit examination of subcellular and matrix changes in relation to the observed histological changes. Immunohistochemistry will allow documentation of the presence of type I collagen, as well as the appearance of such OA biomarkers as degraded collagen and degraded proteoglycan, and up-regulation of the corresponding metalloproteinases in relation to the time-of-onset of such histopathological changes. The overall objective is to establish Dmm/+ mice as an animal model of OA in which various therapies can be tested to determine whether they prevent OA initiation or progression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE III STUDY OF NUTROPIN THERAPY IN PUBERTAL CHILDREN WITH GH DEFICIENCY Principal Investigator & Institution: Rogol, Alan D.; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RANK/NF-KAPPAB SIGNALING IN CHONDROGENESIS Principal Investigator & Institution: Boyce, Brendan F.; Professor; Pathology and Lab Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 23-SEP-2002; Project End 31-MAY-2004 Summary: (provided by applicant): Most of the skeleton forms by endochondral ossification in a highly regulated process in which skeletal elements are first laid down during embryogenesis in a cartilaginous framework. These cartilage elements are invaded by blood vessels and partly replaced by bone, laid down by bone forming osteoblasts and remodeled by bone destroying osteoclasts at epiphyseal growth plates, which form near the ends of the growing bones and control skeletal growth. Many genes have been identified during the past decade as regulators of this process, and mutation or deletion of them can result in various chondrodysplasias, including dwarfism. RANKL/RANK/NF- B signaling was shown to regulate osteoclastogenesis after deletion of these genes in mice led to osteopetrosis due to failure of osteoclast formation. Surprisingly, these knockout mice also have short limbs, but the role of this signaling pathway in endochondral ossification has not been studied in detail. In this proposal, we plan to obtain preliminary data that will provide definitive evidence of a role for this pathway in chondrogenesis and to develop an assay that will permit in vitro morphologic assessment of manipulation of this and other signaling pathways. Our Specific Aims are: 1) To determine the role of RANKL/RANK/NF- B signaling in chondrogenesis; 2) To determine the effects of absent RANK/NF- B signaling on chondrocyte gene expression. NF- B transcription factors regulate the expression of a variety of genes involved in numerous cell processes, including the early stages of limb development. Delineation of a specific role for these factors in endochondral ossification

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should open up a new field of investigation into the pathogenesis of the many forms of chondrodysplasia that to date do not yet have an identified molecular basis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RHIGF1 IN CHILDREN WITH SHORT STATURE DUE TO GROWTH HORMONE INSENSITIVITY SYNDROM Principal Investigator & Institution: Chernausek, Steven D.; Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2001 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF FGF SIGNALING IN BONE DEVELOPMENT Principal Investigator & Institution: Basilico, Claudio; Professor and Chairman; Microbiology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-DEC-2005 Summary: Skeletal morphogenesis is controlled by a network of signaling molecules that first determine the fate of undifferentiated stem cells of the mesenchymal lineage and then regulate the proliferation and differentiation of committed osteogenic cells. Among the signaling molecules which influence bone morphogenesis, fibroblast growth factors (FGF) and their cognate receptors (FGFR) have been recently shown to play a major role both in endochondral and intramembranous bone formation. Activating mutations in FGFR3 have been shown to be responsible for several genetic forms of human dwarfism, and other activating mutations in FGFR1, FGFR2 and FGFR3 have been linked to many craniosynostosis syndromes. Mouse genetic experiments have confirmed that unregulated FGF signaling causes bone malformations and suggested that FGFs may act as negative regulators of bone growth. However, the molecular mechanisms through which FGFs influence the proliferation of differentiation of osteogenic cells (e.g. chondrocytes and osteoblasts) remain to be elucidated. The goal of this research project is to study the response to FGF signaling of chondrocytes. We have shown that FGF treatment inhibits the proliferation of chondrocytes, and that this inhibition requires activation of the STAT-1 pathway. Using organ cultures of metatarsal bones rudiments of E15 murine embryos we have also shown that FGFs regulate chondrocyte proliferation and bone development and that this effect also requires STAT-1. We wish to understand the molecular mechanisms underlying the growth inhibitory response of chondrocytes to FGF signaling and how FGF signaling affects chondrocyte proliferation and differentiation. We will study 1) the signal transduction pathways activated by FGF receptors in chondrocytes with an emphasis on the mechanisms leading to activation on STAT-1, which plays an essential role in the chondrocyte response to FGF; 2) how the progress of the differentiation program which takes place during organ culture of bone rudiments from murine embryos is affected by FGF treatment or by molecules in the FGF signaling pathways; 3) the effect of modulating FGF signaling on bone morphogenesis in vivo, using transgenic and knockout mice, to verify how STAT-1 influences long bone development and chondrodysplasia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SAFETY AND EFFICACY OF GROWTH HORMONE FROM ADOLESCENCE TO ADULTHOOD Principal Investigator & Institution: Geffner, Mitchell; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SIGNALING RESPONSE TO DNA DAMAGE IN DICTYOSTELIUM Principal Investigator & Institution: Alexander, Stephen; Associate Professor; Biological Sciences; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2002; Project Start 01-APR-1996; Project End 31-AUG-2005 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SKELETAL DYSPLASIAS--INTERNATIONAL REGISTRY Principal Investigator & Institution: Rimoin, David; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 90502 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TRANSGENE OSTEOARTHRITIS

RESCUE

OF

CHONDRODYSPLASIA

AND

Principal Investigator & Institution: Bridgewater, Laura C.; Zoology; Brigham Young University A-261 Asb Provo, Ut 846021231 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-OCT-2002 Summary: Cartilage collagen fibrils are composed of type II, type IX and type XI collagen. Mutations in the genes for any of these collagens produce cartilage disorders, which range in severity from mild dwarfism with osteoarthritis to neonatal lethal chondrodysplasias. In addition to these syndromic cartilage disorders, a growing body of evidence suggests that cartilage collagen mutations also play a role in some of the estimated 20.7 million cases of osteoarthritis in America today. Little is currently known about the etiology of the vast majority of osteoarthritis cases. But in cases where the genetic cause is known, and the mutation is not dominant negative therapeutic expression of a healthy version of the mutant gene in the affected joint may be an effective treatment. The feasibility of such a treatment for cartilage disorders has not yet been tested, but we propose to begin testing it in this project. The chondrodysplasia (cho) mouse line provides a model system in which the rescue of both chondrodysplasia and osteoarthritis by ectopic expression of a gene can be studied. The cho mutation is a single base pair deletion in Col11a1 which leads to premature termination of its protein product, the type XI collagen subunit alpha1 (XI). Mice that are homozygous for the cho mutation have severe abnormalities of all cartilaginous structures and die at birth. Mice that are heterozygous for the mutation appear normal at birth, but develop osteoarthritis within six months. The goal of this proposal is to express a Col11a1 transgene in homozygous and heterozygous cho mice, in an effort to rescue the chondrodysplasia and osteoarthritis phenotypes. Enhancer elements which are capable

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of directing reporter gene expression specifically to cartilage in transgenic mice have already been characterized and tested. These elements will be used to construct a transgene vector that expresses Col11a1 specifically in cartilage and at levels that approximate the expression level of the endogenous Col11a1 gene. The vector will then be used to insert the transgene in homozygous and heterozygous cho mice. Our hypothesis is that the Col11a1 transgene will rescue or ameliorate the neonatal lethal homozygous cho phenotype, allowing mice to survive beyond birth. But whether or not the mice survive beyond birth, they will be thoroughly analyzed by skeletal preparations histology, immunofluorescence, and electron microscopy. Our hypothesis in the case of the heterozygous cho mice which develop osteoarthritis by 6 months of age, is that the Col11a1 transgene will prevent or delay the onset of osteoarthritis. Histological and electron microscopic analyses of articular cartilage and intervertebral discs will be performed to assess the effects of the transgene on these mice. The overall goal of this proposal is to determine whether the chondrodysplasia and osteoarthritis phenotypes in cho mice can be rescued by the ectopic expression of a transgene, and to thereby shed light on the feasibility of one day using gene therapy protocols to treat similar disorders in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: USE OF GROWTH HORMONE FOR OSTEOPOROSIS OF WERNERS SYNDROMEN Principal Investigator & Institution: Rubin, Craig D.; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001 Summary: The purpose of this project is to study the value of the administration of recombinant human growth hormone in the treatment of severe osteoporosis in a patient with Werner's Sundrome and growth hormone deficiency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

3 4

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

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

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A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. by Wang Y, Spatz MK, Kannan K, Hayk H, Avivi A, Gorivodsky M, Pines M, Yayon A, Lonai P, Givol D.; 1999 Apr 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16353

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A Mutation of the Mitochondrial ABC Transporter Sta1 Leads to Dwarfism and Chlorosis in the Arabidopsis Mutant starik. by Kushnir S, Babiychuk E, Storozhenko S, Davey MW, Papenbrock J, De Rycke R, Engler G, Stephan UW, Lange H, Kispal G, Lill R, Van Montagu M.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102216

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A targeted dominant negative mutation of the thyroid hormone [alpha]1 receptor causes increased mortality, infertility, and dwarfism in mice. by Kaneshige M, Suzuki H, Kaneshige K, Cheng J, Wimbrow H, Barlow C, Willingham MC, Cheng SY.; 2001 Dec 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64989

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Blockage of Brassinosteroid Biosynthesis and Sensitivity Causes Dwarfism in Garden Pea. by Nomura T, Nakayama M, Reid JB, Takeuchi Y, Yokota T.; 1997 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=158112

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Chimeras of the native form or achondroplasia mutant (G375C) of human fibroblast growth factor receptor 3 induce ligand-dependent differentiation of PC12 cells. by Thompson LM, Raffioni S, Wasmuth JJ, Bradshaw RA.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232270

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Disruption of PC1 /3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. by Zhu X, Zhou A, Dey A, Norrbom C, Carroll R, Zhang C, Laurent V, Lindberg I, Ugleholdt R, Holst JJ, Steiner DF.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124907

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Dwarfism and age-associated spinal degeneration of heterozygote cmd mice defective in aggrecan. by Watanabe H, Nakata K, Kimata K, Nakanishi I, Yamada Y.; 1997 Jun 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21264

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Dwarfism and early death in mice lacking C-type natriuretic peptide. by Chusho H, Tamura N, Ogawa Y, Yasoda A, Suda M, Miyazawa T, Nakamura K, Nakao K, Kurihara T, Komatsu Y, Itoh H, Tanaka K, Saito Y, Katsuki M, Nakao K.; 2001 Mar 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31171

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Laron Dwarfism and Non-Insulin-Dependent Diabetes Mellitus in the Hnf-1[alpha] Knockout Mouse. by Lee YH, Sauer B, Gonzalez FJ.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110684

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Positional cloning of the gene LIMBIN responsible for bovine chondrodysplastic dwarfism. by Takeda H, Takami M, Oguni T, Tsuji T, Yoneda K, Sato H, Ihara N, Itoh T, Kata SR, Mishina Y, Womack JE, Moritomo Y, Sugimoto Y, Kunieda T.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124971

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Pseudoachondroplasia is caused through both intra- and extracellular pathogenic pathways. by Dinser R, Zaucke F, Kreppel F, Hultenby K, Kochanek S, Paulsson M, Maurer P.; 2002 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150414

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Suppression of the heterotrimeric G protein causes abnormal morphology, including dwarfism, in rice. by Fujisawa Y, Kato T, Ohki S, Ishikawa A, Kitano H, Sasaki T, Asahi T, Iwasaki Y.; 1999 Jun 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22128

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with dwarfism, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “dwarfism” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for dwarfism (hyperlinks lead to article summaries): •

A 17-month-old with extreme prenatal-onset growth delay. Microcephalic osteodysplastic primordial dwarfism type II. Author(s): Tekin M, Ng J, Bodurtha J. Source: European Journal of Pediatrics. 2000 December; 159(12): 926-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11131353&dopt=Abstract

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A familial syndrome of dwarfism, bilateral club feet, premature aging and progressive panhypogammaglobulinemia. Author(s): Lenaerts J, Fryns JP, Westhovens R, Dequeker J. Source: The Journal of Rheumatology. 1994 May; 21(5): 961-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8064743&dopt=Abstract

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A homozygous nonsense mutation of the human growth hormone receptor gene in a Sardinian boy with Laron-type dwarfism. Author(s): Putzolu M, Meloni A, Loche S, Pischedda C, Cao A, Moi P. Source: J Endocrinol Invest. 1997 May; 20(5): 286-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9258809&dopt=Abstract

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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A lethal, unclassifiable form of micromelic dwarfism with posterior cleft palate, multiple cervicothoracal vertebral anomalies and iliac hypoplasia. Author(s): Fryns JP, Moerman P. Source: Genet Couns. 1995; 6(1): 65-7. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7794565&dopt=Abstract

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A lethal, unclassifiable form of micromelic dwarfism with posterior cleft palate, multiple cervicothoracal vertebral anomalies and iliac hypoplasia: evidence for autosomal recessive inheritance. Author(s): Fryns JP, Moerman P. Source: Genet Couns. 1998; 9(1): 61-2. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9555592&dopt=Abstract

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A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors. Author(s): Li C, Chen L, Iwata T, Kitagawa M, Fu XY, Deng CX. Source: Human Molecular Genetics. 1999 January; 8(1): 35-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9887329&dopt=Abstract

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A new lethal neonatal short limb dwarfism. Author(s): al Gazali LI, Devadas K, Hall CM. Source: Clinical Dysmorphology. 1996 April; 5(2): 159-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8723566&dopt=Abstract

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A new Seckel-like syndrome of primordial dwarfism. Author(s): Buebel MS, Salinas CF, Pai GS, Macpherson RI, Greer MK, Perez-Comas A. Source: American Journal of Medical Genetics. 1996 August 23; 64(3): 447-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8862620&dopt=Abstract

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A novel syndrome with dwarfism, poorly muscled build, absent clavicles, humeroradial fusion, slender bones, oligodactyly and micrognathia. Author(s): Faivre L, Cormier-Daire V, Genevieve D, Pinto G, Goulet O, Munnich A, Maroteaux P, Le Merrer M. Source: Clinical Dysmorphology. 2001 July; 10(3): 181-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11446410&dopt=Abstract

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Achondroplasic and GH-deficiency dwarfism. Diego Velasquez (1656). Author(s): Papi G. Source: J Endocrinol Invest. 2002 December; 25(11): 1020. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12553565&dopt=Abstract

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Acromesomelic dwarfism: a new variation. Author(s): Ferraz FG, Maroteaux P, Sousa JP, Alves T, Dias I, Ferraz E, Marques M, Santos L. Source: Journal of Pediatric Orthopaedics. Part B / European Paediatric Orthopaedic Society, Pediatric Orthopaedic Society of North America. 1997 January; 6(1): 27-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9039664&dopt=Abstract

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Acromesomelic dwarfism: report of a family with two affected siblings. Author(s): Danda S, Phadke SR, Agarwal SS. Source: Indian Pediatrics. 1997 December; 34(12): 1127-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9715561&dopt=Abstract

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Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Author(s): Su WC, Kitagawa M, Xue N, Xie B, Garofalo S, Cho J, Deng C, Horton WA, Fu XY. Source: Nature. 1997 March 20; 386(6622): 288-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9069288&dopt=Abstract

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An unusual MR presentation of the neurohypophyseal “bright spot” in pituitary dwarfism. Author(s): Zuccoli G, Ferrozzi F, Troiso A, Ubaldi A, Ghizzoni L. Source: Clinical Imaging. 2001 January-February; 25(1): 9-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11435031&dopt=Abstract

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Anauxetic dysplasia, a spondylometaepiphyseal dysplasia with extreme dwarfism. Author(s): Horn D, Rupprecht E, Kunze J, Spranger J. Source: Journal of Medical Genetics. 2001 April; 38(4): 262-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11370632&dopt=Abstract

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Anesthesia for scoliosis: dwarfism and congenitally absent odontoid process. Author(s): Roberts W, Henson LC. Source: Aana Journal. 1995 August; 63(4): 332-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7676770&dopt=Abstract

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Antenatal diagnosis of short-limb dwarfism: sonographic approach. Author(s): Avni EF, Rypens F, Zappa M, Donner C, Vanregemorter N, Cohen E. Source: Pediatric Radiology. 1996; 26(3): 171-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8599003&dopt=Abstract

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Autopsy case of microcephalic osteodysplastic primordial “dwarfism” type II. Author(s): Fukuzawa R, Sato S, Sullivan MJ, Nishimura G, Hasegawa T, Matsuo N. Source: American Journal of Medical Genetics. 2002 November 15; 113(1): 93-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12400072&dopt=Abstract

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Autosomal recessive severe dwarfism in a Sicilian girl: a new form of osteodysplastic primordial dwarfism? Author(s): Corsello G, Albanese A, Piccione M, Giuffre M, Opitz JM. Source: American Journal of Medical Genetics. 1996 December 18; 66(3): 265-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8985484&dopt=Abstract

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Brachytelephalangic dwarfism due to the loss of ARSE and SHOX genes resulting from an X;Y translocation. Author(s): Seidel J, Schiller S, Kelbova C, Beensen V, Orth U, Vogt S, Claussen U, Zintl F, Rappold GA. Source: Clinical Genetics. 2001 February; 59(2): 115-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11260213&dopt=Abstract

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Case report. Microcephalic osteodysplastic primordial dwarfism type II: a child with unusual symptoms and clinical course. Author(s): Spranger S, Tariverdian G, Albert FK, Sontheimer D, Zoller J, Weber M, Troger J. Source: European Journal of Pediatrics. 1996 September; 155(9): 796-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8874115&dopt=Abstract

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Case report: neonatal platyspondylic dwarfism--a new form. Author(s): Kozlowski K, John E, Masel J, Muralinath S, Vijayalakshmi G. Source: The British Journal of Radiology. 1995 November; 68(815): 1254-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8542237&dopt=Abstract

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Cephaloskeletal dysplasia (Taybi-Linder syndrome: osteodysplastic primordial dwarfism type III): report of two cases and review of the literature. Author(s): Vichi GF, Currarino G, Wasserman RL, Duvina PL, Filippi L. Source: Pediatric Radiology. 2000 September; 30(9): 644-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11009306&dopt=Abstract

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Cervical spine instability and dwarfism: fiberoptic intubations for all. Author(s): Auden SM. Source: Anesthesiology. 1999 August; 91(2): 580. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10443630&dopt=Abstract

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Childhood lichen planus in a patient receiving growth hormone for dwarfism. Author(s): Oono T, Arata J. Source: Dermatology (Basel, Switzerland). 1996; 192(1): 87-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8832965&dopt=Abstract

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Clinical and roentgenographic findings in a patient with primordial microcephalic dwarfism type Caroline Crachami. Author(s): Boscherini B, Colabucci F, Galasso C, Marietti G, Cappa M, Pasquino AM. Source: American Journal of Medical Genetics. 1996 December 18; 66(3): 269-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8985485&dopt=Abstract

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Correction of lumbosacral hyperlordosis in achondroplasia. Author(s): Park HW, Kim HS, Hahn SB, Yang KH, Choi CH, Park JO, Jung SH. Source: Clinical Orthopaedics and Related Research. 2003 September; (414): 242-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12966299&dopt=Abstract

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Diastrophic dwarfism and pregnancy. Author(s): Ayoubi JM, Jouk PS, Pons JC. Source: Lancet. 2001 November 24; 358(9295): 1778. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11734236&dopt=Abstract

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Dominant dwarfism in transgenic rats by targeting human growth hormone (GH) expression to hypothalamic GH-releasing factor neurons. Author(s): Flavell DM, Wells T, Wells SE, Carmignac DF, Thomas GB, Robinson IC. Source: The Embo Journal. 1996 August 1; 15(15): 3871-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8670892&dopt=Abstract

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Dwarfism and gigantism in historical picture postcards. Author(s): Enderle A. Source: Journal of the Royal Society of Medicine. 1998 May; 91(5): 273-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9764085&dopt=Abstract

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Dwarfism in Dexter cattle is not caused by the mutations in FGFR3 responsible for achondroplasia in humans. Author(s): Usha AP, Lester DH, Williams JL. Source: Animal Genetics. 1997 February; 28(1): 55-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9124710&dopt=Abstract

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Dynamic enhancement MRI of anterior lobe in pituitary dwarfism. Author(s): Liu HM, Li YW, Tsai WY, Su CT. Source: Neuroradiology. 1995 August; 37(6): 486-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7477866&dopt=Abstract

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Dysgenesis of corpus callosum in Lenz-Majewski hyperostotic dwarfism. Author(s): Saraiva JM. Source: American Journal of Medical Genetics. 2000 March 20; 91(3): 198-200. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10756342&dopt=Abstract

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Dyssegmental dysplasia: short-trunk, short-limb dwarfism with anisospondyly. A case report. Author(s): Reckling WC, Cheng EY. Source: The Journal of Bone and Joint Surgery. American Volume. 1994 October; 76(10): 1551-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7929504&dopt=Abstract

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Early prenatal diagnosis of polycystic pancreas with narrow thorax and short limb dwarfism. Author(s): Bronstein M, Reichler A, Borochowitz Z, Bejar J, Drugan A. Source: American Journal of Medical Genetics. 1994 January 1; 49(1): 6-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8172252&dopt=Abstract

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Exclusion of the lim homeodomain gene LHX4 as a candidate gene for pituitary dwarfism in German shepherd dogs. Author(s): van Oost BA, Versteeg SA, Imholz S, Kooistra HS. Source: Molecular and Cellular Endocrinology. 2002 November 29; 197(1-2): 57-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12431796&dopt=Abstract

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Familial dwarfism and painful muscle spasms. Author(s): Sica RE, Espinoza R, Benavente O, Sanz OP, Molina H. Source: Medicina (B Aires). 1995; 55(2): 111-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7565047&dopt=Abstract

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Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. Author(s): Salvatori R, Hayashida CY, Aguiar-Oliveira MH, Phillips JA 3rd, Souza AH, Gondo RG, Toledo SP, Conceicao MM, Prince M, Maheshwari HG, Baumann G, Levine MA. Source: The Journal of Clinical Endocrinology and Metabolism. 1999 March; 84(3): 91723. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10084571&dopt=Abstract

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Fetal congenital abnormality (thanatophoric dwarfism) in one of two simultaneous recipients from a single altruistic ovum donor. Author(s): Fraidakis M, Ashworth F, Chapman M, Pearce M, Grudzinskas JG. Source: Human Reproduction (Oxford, England). 1995 November; 10(11): 3055-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8747072&dopt=Abstract

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Fibroblast growth factor receptor 3 mutations in achondroplasia and related forms of dwarfism. Author(s): Horton WA, Lunstrum GP. Source: Reviews in Endocrine & Metabolic Disorders. 2002 December; 3(4): 381-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12424440&dopt=Abstract

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Fibroblast growth factor receptor-3 as a therapeutic target for Achondroplasia--genetic short limbed dwarfism. Author(s): Aviezer D, Golembo M, Yayon A. Source: Current Drug Targets. 2003 July; 4(5): 353-65. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816345&dopt=Abstract

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Fibrotic aortic stenosis in a patient with dwarfism. Author(s): Huang WY, Nanda NC, Miller A, Aaluri SR, McGiffin DC, Reddy V, Yesilbursa D, Kottakota RJ. Source: Echocardiography (Mount Kisco, N.Y.). 2000 October; 17(7): 701-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11107211&dopt=Abstract

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Gastroesophageal reflux disease and progressive nephropathy after improving glycemic control in an adolescent with diabetic dwarfism. Author(s): Wu CJ. Source: Diabetes Care. 2002 February; 25(2): 401-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11815520&dopt=Abstract

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Gene analysis of PROP1 in dwarfism with combined pituitary hormone deficiency. Author(s): Takamura N, Fofanova OV, Kinoshita E, Yamashita S. Source: Growth Hormone & Igf Research : Official Journal of the Growth Hormone Research Society and the International Igf Research Society. 1999 June; 9 Suppl B: 12-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10549300&dopt=Abstract

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Genetic dwarfism with high growth hormone levels--multiple causation of GH nonresponsiveness. Author(s): Shafrir E. Source: Isr J Med Sci. 1993 December; 29(12): 800-1. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8300391&dopt=Abstract

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Genetic mapping of the human pituitary-specific transcriptional factor gene and its analysis in familial panhypopituitary dwarfism. Author(s): Raskin S, Cogan JD, Summar ML, Moreno A, Krishnamani MR, Phillips JA 3rd. Source: Human Genetics. 1996 December; 98(6): 703-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8931705&dopt=Abstract

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Growth hormone insensitivity syndrome (Laron dwarfism). Author(s): Jaruratanasirikul S, Chaichanwatanakul K. Source: Hormone Research. 1998; 49 Suppl 1: 47-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9554471&dopt=Abstract

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Growth hormone-releasing hormone (GHRH) receptor mutation and dwarfism: after the mouse, the human. Author(s): Bertherat J. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 1996 June; 134(6): 684-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8766935&dopt=Abstract

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Historical case of dwarfism: attempted diagnosis. Author(s): Wiedemann HR. Source: American Journal of Medical Genetics. 1993 October 1; 47(5): 805-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8267017&dopt=Abstract

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Hoxa5 overexpression correlates with IGFBP1 upregulation and postnatal dwarfism: evidence for an interaction between Hoxa5 and Forkhead box transcription factors. Author(s): Foucher I, Volovitch M, Frain M, Kim JJ, Souberbielle JC, Gan L, Unterman TG, Prochiantz A, Trembleau A. Source: Development (Cambridge, England). 2002 September; 129(17): 4065-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12163409&dopt=Abstract

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Index of suspicion. Case 3. Diagnosis: failure to thrive due to psychosocial dwarfism. Author(s): Swanson H. Source: Pediatrics in Review / American Academy of Pediatrics. 1994 January; 15(1): 39, 41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8121846&dopt=Abstract

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Infant with thanatophoric dwarfism in triplet pregnancy. Author(s): Oga M, Takai N, Yoshimatsu J, Fujisawa K, Gholbzouri K, Miyakawa I. Source: Gynecologic and Obstetric Investigation. 1995; 39(4): 274-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7635373&dopt=Abstract

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Intrahypothalamic growth hormone feedback: from dwarfism to acromegaly in the rat. Author(s): Pellegrini E, Carmignac DF, Bluet-Pajot MT, Mounier F, Bennett P, Epelbaum J, Robinson IC. Source: Endocrinology. 1997 November; 138(11): 4543-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9348176&dopt=Abstract

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Langer mesomelic dwarfism: ultrasonographic diagnosis of two cases in early midtrimester. Author(s): Roth P, Agnani G, Arbez-Gindre F, Maillet R, Colette C. Source: Prenatal Diagnosis. 1996 March; 16(3): 247-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8710779&dopt=Abstract

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Leg lengthening in Turner dwarfism. Author(s): Trivella GP, Brigadoi F, Aldegheri R. Source: The Journal of Bone and Joint Surgery. British Volume. 1996 March; 78(2): 290-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8666644&dopt=Abstract

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Lenz-Majewski hyperostotic dwarfism: reexamination of the original patient. Author(s): Majewski F. Source: American Journal of Medical Genetics. 2000 August 14; 93(4): 335-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10946362&dopt=Abstract

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Lesions in the sterol delta reductase gene of Arabidopsis cause dwarfism due to a block in brassinosteroid biosynthesis. Author(s): Choe S, Tanaka A, Noguchi T, Fujioka S, Takatsuto S, Ross AS, Tax FE, Yoshida S, Feldmann KA. Source: The Plant Journal : for Cell and Molecular Biology. 2000 March; 21(5): 431-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10758495&dopt=Abstract

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Lethal forms of short limb dwarfism. Author(s): Srinath KS, Bhat BV, Kumar MR. Source: Indian Pediatrics. 1995 September; 32(9): 1011-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8935269&dopt=Abstract

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Little People of America: position statement on genetic discoveries in dwarfism (1996). Author(s): Ricker R. Source: Genetic Resour. 1997; 11(1): 29. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12731507&dopt=Abstract

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Localization of a locus responsible for the bovine chondrodysplastic dwarfism (bcd) on chromosome 6. Author(s): Yoneda K, Moritomo Y, Takami M, Hirata S, Kikukawa Y, Kunieda T. Source: Mammalian Genome : Official Journal of the International Mammalian Genome Society. 1999 June; 10(6): 597-600. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10341093&dopt=Abstract

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Lower limb lengthening in turner dwarfism. Author(s): Hahn SB, Park HW, Park HJ, Seo YJ, Kim HW. Source: Yonsei Medical Journal. 2003 June 30; 44(3): 502-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12833589&dopt=Abstract

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Major central nervous system malformation in “micromelic dwarfism with cone epiphyses, metaphyseal dysplasia and vertebral segmentation defects”. Author(s): Fryns JP. Source: American Journal of Medical Genetics. 1997 January 10; 68(1): 109. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8986289&dopt=Abstract

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Measurement of zinc, copper, manganese, and iron concentrations in hair of pituitary dwarfism patients using flameless atomic absorption spectrophotometry. Author(s): Miki F, Sakai T, Wariishi M, Kaji M. Source: Biological Trace Element Research. 2002 February; 85(2): 127-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11899020&dopt=Abstract

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Meckel-Gruber syndrome associated with short limbed dwarfism. Author(s): Malguria N, Merchant SA, Kiran KV, Verghese SL. Source: Journal of Postgraduate Medicine. 1996 April-June; 42(2): 55-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9715303&dopt=Abstract

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Megalencephaly, hydrocephalus and cortical dysplasia in severe dwarfism mimicking leprechaunism. Author(s): Hayashi M, Kurata K, Suzuki K, Hirasawa K, Nagata J, Morimatsu Y. Source: Acta Neuropathologica. 1998 April; 95(4): 431-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9560023&dopt=Abstract

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Microcephalic osteodysplastic primordial dwarfism Taybi-Linder type: report of four cases and review of the literature. Author(s): Sigaudy S, Toutain A, Moncla A, Fredouille C, Bourliere B, Ayme S, Philip N. Source: American Journal of Medical Genetics. 1998 October 30; 80(1): 16-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9800907&dopt=Abstract

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Microcephalic osteodysplastic primordial dwarfism type II. Author(s): al Gazali LI, Hamada M, Lytle W. Source: Clinical Dysmorphology. 1995 July; 4(3): 234-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7551160&dopt=Abstract

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Microcephalic osteodysplastic primordial dwarfism type II: report of three cases and review. Author(s): Majewski F, Goecke TO. Source: American Journal of Medical Genetics. 1998 October 30; 80(1): 25-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9800908&dopt=Abstract

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Microdontia with severe microcephaly and short stature in two brothers: osteodysplastic primordial dwarfism with dental findings. Author(s): Lin HJ, Sue GY, Berkowitz CD, Brasel JA, Lachman RS. Source: American Journal of Medical Genetics. 1995 August 28; 58(2): 136-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8533804&dopt=Abstract

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Microlissencephaly in microcephalic osteodysplastic primordial dwarfism: a case report and review of the literature. Author(s): Klinge L, Schaper J, Wieczorek D, Voit T. Source: Neuropediatrics. 2002 December; 33(6): 309-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571786&dopt=Abstract

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Micromelic dwarfism with cone epiphyses, metaphyseal dysplasia, and vertebral segmentation defects. Author(s): Fryns JP, Lorenzetti ME, Maroteaux P, Van den Berghe H. Source: American Journal of Medical Genetics. 1996 January 11; 61(2): 164-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8669445&dopt=Abstract

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Micromelic dwarfism--humerus, femur and tibia type. Author(s): Al-Gazali LI, Bakir M, Hamid Z, Nath D, Haas D. Source: Clinical Dysmorphology. 2001 January; 10(1): 24-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11152143&dopt=Abstract

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Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Author(s): Rousseau F, el Ghouzzi V, Delezoide AL, Legeai-Mallet L, Le Merrer M, Munnich A, Bonaventure J. Source: Human Molecular Genetics. 1996 April; 5(4): 509-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8845844&dopt=Abstract

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Moebius syndrome, pituitary dwarfism and hypoplastic optic disc. Author(s): Williams MS. Source: Acta Paediatr Jpn. 1998 June; 40(3): 294-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9695311&dopt=Abstract

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Morphometric appraisal of the skull of Caroline Crachami, the Sicilian “dwarf” 1815?-1824: a contribution to the study of primordial microcephalic dwarfism. Author(s): Jeffery N, Berkovitz BK. Source: American Journal of Medical Genetics. 2002 August 15; 111(3): 260-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12210322&dopt=Abstract

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Mutations in the growth hormone releasing hormone receptor: a new form of dwarfism in humans. Author(s): Baumann G. Source: Growth Hormone & Igf Research : Official Journal of the Growth Hormone Research Society and the International Igf Research Society. 1999 June; 9 Suppl B: 24-9; Discussion 29-30. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10549302&dopt=Abstract

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Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Author(s): Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ. Source: Cell. 1994 July 29; 78(2): 335-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7913883&dopt=Abstract

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Neonatal cholestasis and focal medullary dysplasia of the kidneys in a case of microcephalic osteodysplastic primordial dwarfism. Author(s): Berger A, Haschke N, Kohlhauser C, Amman G, Unterberger U, Weninger M. Source: Journal of Medical Genetics. 1998 January; 35(1): 61-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9475098&dopt=Abstract

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Neonatal lethal dwarfism with distinct skeletal malformations--a separate entity? Author(s): Rosendahl K, Maurseth K, Olsen OE, Halvorsen OJ, Gjelland K, Engebretsen L. Source: Pediatric Radiology. 2001 September; 31(9): 663-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11512011&dopt=Abstract

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Onchocerciasis, epilepsy and hyposexual dwarfism. Author(s): Duke BO. Source: Trans R Soc Trop Med Hyg. 1998 March-April; 92(2): 236. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9764344&dopt=Abstract

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Oral manifestations of severe short-limb dwarfism resembling Grebe chondrodysplasia: report of a case. Author(s): Hattab FN, al-Khateeb T, Mansour M. Source: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 1996 May; 81(5): 550-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8734701&dopt=Abstract

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Osteodysplastic primordial dwarfism (ODPD): notes on brain imaging. Author(s): Corsello G, Giuffre M. Source: American Journal of Medical Genetics. 1998 October 30; 80(1): 90-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9800914&dopt=Abstract

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Osteodysplastic primordial dwarfism type II with normal intellect but delayed central nervous system myelination. Author(s): Halder A, Pahi J, Sharma AK, Bhatia VL, Phadke RV, Gujral R, Agarwal SS. Source: American Journal of Medical Genetics. 1998 October 30; 80(1): 12-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9800906&dopt=Abstract

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Osteodysplastic primordial dwarfism: a case with features of type II. Author(s): Masuno M, Imaizumi K, Nishimura G, Kurosawa K, Makita Y, Shimazaki Y, Kuroki Y. Source: Clinical Dysmorphology. 1995 January; 4(1): 57-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7735506&dopt=Abstract

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Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: Dwarfism of Sindh. Author(s): Maheshwari HG, Silverman BL, Dupuis J, Baumann G. Source: The Journal of Clinical Endocrinology and Metabolism. 1998 November; 83(11): 4065-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9814493&dopt=Abstract

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Phenotypic correction of dwarfism by constitutive expression of growth hormone. Author(s): Hahn TM, Copeland KC, Woo SL. Source: Endocrinology. 1996 November; 137(11): 4988-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8895372&dopt=Abstract

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Pituitary dwarfism in the R271W Pit-1 gene mutation. Author(s): Aarskog D, Eiken HG, Bjerknes R, Myking OL. Source: European Journal of Pediatrics. 1997 November; 156(11): 829-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9392392&dopt=Abstract

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Polyradiculoneuropathy in boy with pituitary dwarfism treated with recombinant growth hormone. Author(s): Sakurai T, Kodama S, Urata R, Komatsu M. Source: Endocrine Journal. 1996 October; 43 Suppl: S127-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9076360&dopt=Abstract

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Positional cloning of the gene LIMBIN responsible for bovine chondrodysplastic dwarfism. Author(s): Takeda H, Takami M, Oguni T, Tsuji T, Yoneda K, Sato H, Ihara N, Itoh T, Kata SR, Mishina Y, Womack JE, Moritomo Y, Sugimoto Y, Kunieda T. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 August 6; 99(16): 10549-54. Epub 2002 July 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12136126&dopt=Abstract

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Prenatal diagnosis of metatropic dwarfism. Author(s): Manouvrier-Hanu S, Devisme L, Zelasko MC, Bourgeot P, Vincent-Delorme C, Valat-Rigot AS, Puech F, Farriaux JP. Source: Prenatal Diagnosis. 1995 August; 15(8): 753-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7479594&dopt=Abstract

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Prenatal diagnosis of thanatophoric dwarfism in second trimester. A case report. Author(s): Yuce MA, Yardim T, Kurtul M, Durukan S, Gucer F. Source: Clin Exp Obstet Gynecol. 1998; 25(4): 149-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9987576&dopt=Abstract

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Prenatal sonographic diagnosis of diastrophic dwarfism. Author(s): Tongsong T, Wanapirak C, Sirichotiyakul S, Chanprapaph P. Source: Journal of Clinical Ultrasound : Jcu. 2002 February; 30(2): 103-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11857516&dopt=Abstract

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Propofol pharmacokinetics in a dwarfism patient. Author(s): Tsubokawa T, Yamamoto K, Komuro A, Ishizuka S, Kobayashi T. Source: Acta Anaesthesiologica Scandinavica. 2003 April; 47(4): 488-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694152&dopt=Abstract

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Radiographic abnormalities in Laron dwarfism. Author(s): Vasil M, Baxova A, Kozlowski K. Source: Pediatric Radiology. 1994; 24(4): 260-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7800446&dopt=Abstract

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Renal tubular leakage complicating microcephalic osteodysplastic primordial dwarfism. Author(s): Eason J, Hall CM, Trounce JQ. Source: Journal of Medical Genetics. 1995 March; 32(3): 234-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7783178&dopt=Abstract

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Reversibility of physiological growth hormone secretion in children with psychosocial dwarfism. Author(s): Albanese A, Hamill G, Jones J, Skuse D, Matthews DR, Stanhope R. Source: Clinical Endocrinology. 1994 May; 40(5): 687-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8013149&dopt=Abstract

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Severe hypertensive sequelae in a child with Seckel syndrome (bird-like dwarfism). Author(s): Sorof JM, Dow-Smith C, Moore PJ. Source: Pediatric Nephrology (Berlin, Germany). 1999 May; 13(4): 343-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10454788&dopt=Abstract

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Short root anomaly in a patient with severe short-limbed dwarfism. Author(s): Shaw L. Source: International Journal of Paediatric Dentistry / the British Paedodontic Society [and] the International Association of Dentistry for Children. 1995 December; 5(4): 24952. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8957839&dopt=Abstract

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Short-limb dwarfism and hypertrophic cardiomyopathy in a patient with paternal isodisomy 14: 45,XY,idic(14)(p11). Author(s): Walter CA, Shaffer LG, Kaye CI, Huff RW, Ghidoni PD, McCaskill C, McFarland MB, Moore CM. Source: American Journal of Medical Genetics. 1996 November 11; 65(4): 259-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8923931&dopt=Abstract

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Short-limbed dwarfism with bowing, combined immune deficiency, and late onset aplastic anaemia caused by novel mutations in the RMPR gene. Author(s): Kuijpers TW, Ridanpaa M, Peters M, de Boer I, Vossen JM, Pals ST, Kaitila I, Hennekam RC. Source: Journal of Medical Genetics. 2003 October; 40(10): 761-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14569125&dopt=Abstract

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Staged lengthening in the prevention of dwarfism in achondroplastic children: a preliminary report. Author(s): Peretti G, Memeo A, Paronzini A, Marzorati S. Source: Journal of Pediatric Orthopaedics. Part B / European Paediatric Orthopaedic Society, Pediatric Orthopaedic Society of North America. 1995; 4(1): 58-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7719836&dopt=Abstract

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Stop codon FGFR3 mutations in thanatophoric dwarfism type 1. Author(s): Rousseau F, Saugier P, Le Merrer M, Munnich A, Delezoide AL, Maroteaux P, Bonaventure J, Narcy F, Sanak M. Source: Nature Genetics. 1995 May; 10(1): 11-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7647778&dopt=Abstract

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Successful pregnancy in a case of pituitary dwarfism complicated by diabetes insipidus and primary amenorrhea. Author(s): Narahara H, Kawano Y, Yoshimatsu J, Miyakawa I. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2000 August; 79(8): 714-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10949242&dopt=Abstract

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Survival and dominant transmission of “lethal” platyspondylic dwarfism of the “West coast” types. Author(s): Omran H, Uhl M, Brandis M, Wolff G. Source: The Journal of Pediatrics. 2000 March; 136(3): 411-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10700704&dopt=Abstract

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The bovine fibroblast growth factor receptor 3 (FGFR3) gene is not the locus responsible for bovine chondrodysplastic dwarfism in Japanese brown cattle. Author(s): Takami M, Yoneda K, Kobayashi Y, Moritomo Y, Kata SR, Womack JE, Kunieda T. Source: Animal Genetics. 2002 October; 33(5): 351-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12354143&dopt=Abstract

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The concurrence of the blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) and Langer type of mesomelic dwarfism in the same patient. Evidence of the location of Langer type of mesomelic dwarfism at 3q22.3-q23? Author(s): Fryns JP. Source: Clinical Genetics. 1995 August; 48(2): 111-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7586651&dopt=Abstract

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The genetic basis of dwarfism. Author(s): Francomano CA. Source: The New England Journal of Medicine. 1995 January 5; 332(1): 58-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7990869&dopt=Abstract

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The surgical treatment of vertebral deformities in achondroplastic dwarfism. Author(s): Parisini P, Greggi T, Casadei R, Martini A, De Zerbi M, Campanacci L, Perozzi M. Source: Chir Organi Mov. 1996 April-June; 81(2): 129-37. English, Italian. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8968116&dopt=Abstract

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Total knee arthroplasty in patients with inherited dwarfism--a report of five knee replacements in two patients with Morquio's disease type A and one with spondyloepiphyseal dysplasia. Author(s): de Waal Malefijt MC, van Kampen A, van Gemund JJ. Source: Archives of Orthopaedic and Trauma Surgery. 2000; 120(3-4): 179-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10738879&dopt=Abstract

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Treatment of atrichia pubis in adolescent girls with pituitary dwarfism. Author(s): Dacou-Voutetakis C, Kakourou T. Source: The Journal of Pediatrics. 1996 February; 128(2): 284-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8636832&dopt=Abstract

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Ultrasonographic prenatal diagnosis of microcephalic osteodysplastic primordial dwarfism types I/III. Author(s): Nadjari M, Fasouliotis SJ, Ariel I, Raas-Rothschild A, Bar-Ziv J, Elchalal U. Source: Prenatal Diagnosis. 2000 August; 20(8): 666-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10951479&dopt=Abstract

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CHAPTER 2. NUTRITION AND DWARFISM Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and dwarfism.

Finding Nutrition Studies on Dwarfism The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “dwarfism” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7

Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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The following information is typical of that found when using the “Full IBIDS Database” to search for “dwarfism” (or a synonym): •

Becker and limb-girdle muscular dystrophy associated with pituitary dwarfism. Author(s): Department of Neurology, University of Florence, Italy. Source: Marconi, G Taiuti, R Sbrilli, C Pizzi, A J-Neurol. 1987 August; 234(6): 430-2 03405354

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Gibberellic acid and dwarfism effects on the growth dynamics of B73 maize (Zea mays L.) leaf blades: a transient increase in apoplastic peroxidase activity precedes cessation of cell elongation. Author(s): Department of Plants, Soils, and Biometeorology, Utah State University, Logan, UT 84322-4820, USA. Source: de Souza, I R MacAdam, J W J-Exp-Bot. 2001 August; 52(361): 1673-82 0022-0957

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Paleodigms and paleodigmatics: a new theoretical construct applicable to Munchausen's syndrome by proxy, child-abuse dwarfism, paraphilias, anorexia nervosa, and other syndromes. Author(s): Johns Hopkins University and Hospital, Baltimore, MD. Source: Money, J Am-J-Psychother. 1989 January; 43(1): 15-24 0002-9564

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Possible association of human growth hormone treatment with an occurrence of acute myeloblastic leukemia with an inversion of chromosome 3 in a child of pituitary dwarfism. Author(s): Department of Pediatrics, Hakodate-Chuo Hospital, Japan. Source: Endo, M Kaneko, Y Shikano, T Minami, H Chino, J Med-Pediatr-Oncol. 1988; 16(1): 45-7 0098-1532

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Thyroid hormone-induced reduction of urinary 5-hydroxyindole acetic acid (5 HIAA) in obese children. Comparison with hypothyroid patients of similar age having either pituitary dwarfism or congenital myxedema. Author(s): C. I. Parhon Institute of Endocrinology, Bucharest, Romania. Source: Popa, M Stefanescu, A M Dumitriu, L Dimitriu, V Bartoc, R Endocrinologie. 1989 Jan-March; 27(1): 35-41 0253-1801

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Use of proligestone in the management of three German shepherd dogs with pituitary dwarfism. Author(s): Department of Veterinary Clinical Studies, University of Glasgow Veterinary School, Bearsden. Source: Knottenbelt, C M Herrtage, M E J-Small-Anim-Pract. 2002 April; 43(4): 164-70 0022-4510

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

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Google: http://directory.google.com/Top/Health/Nutrition/

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Healthnotes: http://www.healthnotes.com/

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Open Directory Project: http://dmoz.org/Health/Nutrition/

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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

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WebMDHealth: http://my.webmd.com/nutrition

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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CHAPTER 3. ALTERNATIVE MEDICINE AND DWARFISM Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to dwarfism. 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 dwarfism 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 “dwarfism” (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 dwarfism: •

A crucial role for the putative Arabidopsis topoisomerase VI in plant growth and development. Author(s): Yin Y, Cheong H, Friedrichsen D, Zhao Y, Hu J, Mora-Garcia S, Chory J. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 July 23; 99(15): 10191-6. Epub 2002 Jul 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12119417&dopt=Abstract

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A putative role for the tomato genes DUMPY and CURL-3 in brassinosteroid biosynthesis and response. Author(s): Koka CV, Cerny RE, Gardner RG, Noguchi T, Fujioka S, Takatsuto S, Yoshida S, Clouse SD. Source: Plant Physiology. 2000 January; 122(1): 85-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10631252&dopt=Abstract

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A specific brassinosteroid biosynthesis inhibitor, Brz2001: evaluation of its effects on Arabidopsis, cress, tobacco, and rice. Author(s): Sekimata K, Kimura T, Kaneko I, Nakano T, Yoneyama K, Takeuchi Y, Yoshida S, Asami T. Source: Planta. 2001 September; 213(5): 716-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11678275&dopt=Abstract

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Achondroplasia. Author(s): Castiglia PT. Source: Journal of Pediatric Health Care : Official Publication of National Association of Pediatric Nurse Associates & Practitioners. 1996 July-August; 10(4): 180-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8920380&dopt=Abstract

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ACTH, corticosteroids and the brain: clinical studies. Author(s): Cleghorn RA. Source: Prog Brain Res. 1970; 32: 343-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4321528&dopt=Abstract

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Assessment of the role of manganese in congenital joint laxity and dwarfism in calves. Author(s): Hidiroglou M, Ivan M, Bryan MK, Ribble CS, Janzen ED, Proulx JG, Elliot JI. Source: Ann Rech Vet. 1990; 21(4): 281-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2288454&dopt=Abstract

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Biocultural belief and iodine prophylaxis. Author(s): Lellep Fernandez R. Source: Social Science & Medicine (1982). 1988; 27(6): 587-96. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3067358&dopt=Abstract

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Chemotherapeutic treatment of extensive optic pathway tumors in infants. Author(s): Kretschmar CS, Linggood RM. Source: Journal of Neuro-Oncology. 1991 June; 10(3): 263-70. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1895167&dopt=Abstract

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Clinical contribution to dwarf symbolism. Author(s): Diamant L. Source: Psychoanalytic Review. 1977 Winter; 64(4): 611-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=74839&dopt=Abstract

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Constitutive expression of rice MADS box gene using seed explants in hot pepper (Capsicum annuum L.). Author(s): Kim S, Kim SR, An CS, Hong YN, Lee KW.

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Source: Molecules and Cells. 2001 October 31; 12(2): 221-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11710525&dopt=Abstract •

Controlled zinc supplementation for malnourished school boys: a pilot experiment. Author(s): Ronaghy H, Fox MR, Garnsm, Israel H, Harp A, Moe PG, Halsted JA. Source: The American Journal of Clinical Nutrition. 1969 October; 22(10): 1279-89. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4899224&dopt=Abstract

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Diastrophic dwarfism in early infancy. Author(s): LANGER LO Jr. Source: Am J Roentgenol Radium Ther Nucl Med. 1965 February; 93: 399-404. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14258290&dopt=Abstract

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Dwarfism and social identity: self-help group participation. Author(s): Ablon J. Source: Soc Sci Med [med Anthropol]. 1981 January; 15B(1): 25-30. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7209603&dopt=Abstract

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Dwarfism in the amish. ii. cartilage-hair hypoplasia. Author(s): MCKUSICK VA, ELDRIDGE R, HOSTETLER JA, RUANGWIT U, EGELAND JA. Source: Bull Johns Hopkins Hosp. 1965 May; 116: 285-326. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14284412&dopt=Abstract

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Effect of pituitary hollow fiber units and thyroid supplementation on growth in the little mouse. Author(s): Harkness JE, Hymer WC, Rosenberger JL, Grindeland RE. Source: Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.). 1984 November; 177(2): 312-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6483864&dopt=Abstract

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Effect of selenium supplementation in hypothyroid subjects of an iodine and selenium deficient area: the possible danger of indiscriminate supplementation of iodine-deficient subjects with selenium. Author(s): Contempre B, Dumont JE, Ngo B, Thilly CH, Diplock AT, Vanderpas J. Source: The Journal of Clinical Endocrinology and Metabolism. 1991 July; 73(1): 213-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2045471&dopt=Abstract

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Effect of triiodothyronine supplementation on thyrotropin-releasing hormoneinduced growth hormone secretion in sex-linked dwarf and normal chicks. Author(s): Tixier-Boichard M, Monvoisin JL, Decuypere E, Huybrechts LM, Kuhn ER.

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Source: General and Comparative Endocrinology. 1991 October; 84(1): 147-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1778404&dopt=Abstract •

Effects of insulin-like growth factor-I (IGF-I) infusion and dietary tri-iodothyronine (T3) supplementation on growth, body composition and plasma hormone levels in sex-linked dwarf mutant and normal chickens. Author(s): Tixier-Boichard M, Huybrechts LM, Decuypere E, Kuhn ER, Monvoisin JL, Coquerelle G, Charrier J, Simon J. Source: The Journal of Endocrinology. 1992 April; 133(1): 101-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1517699&dopt=Abstract

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Effects of topoisomerase II inhibition in lymphoblasts from patients with progeroid and “chromosome instability” syndromes. Author(s): Elli R, Chessa L, Antonelli A, Petrinelli P, Ambra R, Marcucci L. Source: Cancer Genetics and Cytogenetics. 1996 April; 87(2): 112-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8625255&dopt=Abstract

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Growth hormone and blood calcium homeostasis. Author(s): Gershberg H, Hecht A, Javier Z. Source: The Journal of Clinical Endocrinology and Metabolism. 1967 October; 27(10): 1492-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4963700&dopt=Abstract

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Growth-hormone deficiency in iatrogenic hypothyroidism. Author(s): Wilkinson R, Anderson M, Smart GA. Source: British Medical Journal. 1972 April 8; 2(805): 87-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5018314&dopt=Abstract

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Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse. Author(s): Marie PJ, Travers R, Glorieux FH. Source: The Journal of Clinical Investigation. 1981 March; 67(3): 911-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6259210&dopt=Abstract

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Hypersensitivity of Cockayne's syndrome cells to camptothecin is associated with the generation of abnormally high levels of double strand breaks in nascent DNA. Author(s): Squires S, Ryan AJ, Strutt HL, Johnson RT. Source: Cancer Research. 1993 May 1; 53(9): 2012-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7683249&dopt=Abstract

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Inadequate weight gain. Author(s): ILLINGWORTH RS.


Source: Clinical Pediatrics. 1964 March; 52: 125-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14127397&dopt=Abstract •

Influence of the sex-linked dwarfing gene (dw) on the contribution of dietary lipid to yolk lipid synthesis. Author(s): Burghelle-Mayeur C, Tixier-Boichard M, Merat P, Demarne Y. Source: British Poultry Science. 1990 March; 31(1): 197-206. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2354375&dopt=Abstract

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Intellectual assessment in primitive societies, with a preliminary report of a study of the effects of early iodine supplementation on intelligence. Author(s): Trowbridge FL. Source: Advances in Experimental Medicine and Biology. 1972; 30: 137-49. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4662265&dopt=Abstract

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Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Author(s): Andersen ED, Krasilnikoff PA, Overvad H. Source: Acta Paediatr Scand. 1971 September; 60(5): 559-64. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4106724&dopt=Abstract

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Iodine supplementation and the prevention of cretinism. Author(s): Dunn JT. Source: Annals of the New York Academy of Sciences. 1993 March 15; 678: 158-68. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8494259&dopt=Abstract

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Iodine-supplementation trials. Author(s): Pharoah PO. Source: The American Journal of Clinical Nutrition. 1993 February; 57(2 Suppl): 276S279S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8427204&dopt=Abstract

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Know your organizations: Association for Research into Restricted Growth. Author(s): Lindley M. Source: Health Visit. 1981 May; 54(5): 198. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6909173&dopt=Abstract

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Light and brassinosteroid signals are integrated via a dark-induced small G protein in etiolated seedling growth. Author(s): Kang JG, Yun J, Kim DH, Chung KS, Fujioka S, Kim JI, Dae HW, Yoshida S, Takatsuto S, Song PS, Park CM.

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Source: Cell. 2001 June 1; 105(5): 625-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11389832&dopt=Abstract •

Little People of America: position statement on genetic discoveries in dwarfism (1996). Author(s): Ricker R. Source: Genetic Resour. 1997; 11(1): 29. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12731507&dopt=Abstract

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Maternal iodine supplements in areas of deficiency. Author(s): Mahomed K, Gulmezoglu AM. Source: Cochrane Database Syst Rev. 2000; (2): Cd000135. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10796152&dopt=Abstract

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Neuroendocrine-thymus interactions: perspectives for intervention in aging. Author(s): Fabris N, Mocchegiani E, Muzzioli M, Provinciali M. Source: Annals of the New York Academy of Sciences. 1988; 521: 72-87. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3288046&dopt=Abstract

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Nonphysical causes of dwarfism. Author(s): Apley J, Davies J, Davis DR, Silk B. Source: Proc R Soc Med. 1971 February; 64(2): 135-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4323465&dopt=Abstract

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Nutritional dwarfing: growth, dieting, and fear of obesity. Author(s): Lifshitz F, Moses N. Source: Journal of the American College of Nutrition. 1988 October; 7(5): 367-76. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3053861&dopt=Abstract

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Pain agnosia and self-injury in the syndrome of reversible somatotropin deficiency (psychosocial dwarfism). Author(s): Money J, Wolff G, Annecillo C. Source: J Autism Child Schizophr. 1972 April-June; 2(2): 127-39. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5068666&dopt=Abstract

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Paleodigms and paleodigmatics: a new theoretical construct applicable to Munchausen's syndrome by proxy, child-abuse dwarfism, paraphilias, anorexia nervosa, and other syndromes. Author(s): Money J. Source: American Journal of Psychotherapy. 1989 January; 43(1): 15-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2929791&dopt=Abstract


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Pediatric neurology. Author(s): Baird HW. Source: Prog Neurol Psychiatry. 1968; 23: 242-52. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4977707&dopt=Abstract

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Persistence of iodine deficiency 25 years after initial correction efforts in the Khumbu region of Nepal. Author(s): Murdoch DR, Harding EG, Dunn JT. Source: N Z Med J. 1999 July 23; 112(1092): 266-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10472889&dopt=Abstract

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Pre-emptive renal transplantation in children. Author(s): Harada H, Seki T, Nonomura K, Chikaraishi T, Takeuchi I, Morita K, Usuki T, Watarai Y, Togashi M, Hirano T, Koyanagi T. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. 2001 May; 8(5): 205-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11328419&dopt=Abstract

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Primary central nervous system lymphoma in childhood presenting as progressive panhypopituitarism. Author(s): Silfen ME, Garvin JH Jr, Hays AP, Starkman HS, Aranoff GS, Levine LS, Feldstein NA, Wong B, Oberfield SE. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2001 February; 23(2): 130-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11216706&dopt=Abstract

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

•


•

Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

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Google: http://directory.google.com/Top/Health/Alternative/

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Healthnotes: http://www.healthnotes.com/

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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Open Directory Project: http://dmoz.org/Health/Alternative/

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HealthGate: http://www.tnp.com/

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WebMDHealth: http://my.webmd.com/drugs_and_herbs

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 4. DISSERTATIONS ON DWARFISM Overview In this chapter, we will give you a bibliography on recent dissertations relating to dwarfism. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “dwarfism” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on dwarfism, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Dwarfism ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to dwarfism. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

The Epidemiology of Psycho-Social Dwarfism: A Follow-up Study of Psycho-Social Dwarfs Presenting at the Children's Hospital of Pittsburgh during the Period, 19651974. by Diamond, Harvey, PhD from University of Pittsburgh, 1974, 288 pages http://wwwlib.umi.com/dissertations/fullcit/7519557

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 5. CLINICAL TRIALS AND DWARFISM Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning dwarfism.

Recent Trials on Dwarfism The following is a list of recent trials dedicated to dwarfism.8 Further information on a trial is available at the Web site indicated. •

Evaluation and Intervention for the Effects of Osteogenesis Imperfecta Condition(s): Dwarfism; Osteogenesis Imperfecta Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Child Health and Human Development (NICHD) Purpose - Excerpt: Osteogenesis Imperfecta is a genetic disorder occurring in children causing abnormally fragile bones. Patient's with osteogenesis imperfecta often suffer fractures from minimal trauma. These patient's can have deformities of long bones, blueness of the white portion of the eye (sclerae), weak ligaments, and deafness due to diseased bones in the inner ear (otosclerosis). Growth deficiency is a hallmark feature of Osteogenesis Imperfecta. Growth patterns have been defined for some of the different types of Osteogenesis Imperfecta. At about 1 year of age, children with Types III and IV Osteogenesis Imperfecta show a predictable leveling off (plateau) of their growth rate. Children with Type IV Osteogenesis Imperfecta begin to resume normal growth rate at about four to five years, but they will not "catch up" to a normal height. Children with Osteogenesis Imperfecta Type III will remain at a leveled off growth rate. The reason for the leveling off (plateau) of the growth rate is unknown. The purposes of this study will concentrate on four areas of research; genetics, rehabilitation, growth, and the natural history of the multiple secondary features of Osteogenesis Imperfecta. This study will be broken up into 2 steps or phases. Phase I will focus on children from birth to age 5, and Phase II will concentrate on children ages 5 - 18 years. One of the objectives in Phase I will be to determine the effects of long leg bracing in children with osteogenesis

8

These are listed at www.ClinicalTrials.gov.

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imperfecta. The study will observe the patient's ability to do activities while standing upright as well as the development of manual skills. In addition the study will observe the alignment of the patient's bones and the bone strength and density. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001594 •

Growth Hormone Therapy in Osteogenesis Imperfecta Condition(s): Dwarfism; Osteogenesis Imperfecta Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Child Health and Human Development (NICHD) Purpose - Excerpt: Growth deficiency is a key feature of severe Osteogenesis Imperfecta (OI) and a frequent feature of mild to moderate forms of the disease. The reason that children with OI are short is not fully understood. We do know that details such as the number of fractures suffered or the type of OI do not fully explain the short stature of OI. Growth patterns have been defined for children with OI Types I, III, and IV. At about 12 months of age, children with Types III and IV OI demonstrate a predictable plateau of their linear growth rate. Type IV OI children begin to resume a normal growth rate at about age four to five years, but they will not "catch up" to a normal height, as they have "lost" a significant period of growth. The plateau usually continues for children with Type III OI. The reason for this growth plateau is unknown. There have been no studies which evaluate the growth of OI children in this age range. Our previous studies of growth in OI children have begun at age 5 years. We have studied growth in OI children for the past 10 years. Different medications have been tried to both stimulate growth and improve bone density. Some children have responded to growth hormone (their growth rate increased by at least 50%) and some did not. The majority of children who did respond were Type IV. However, we need to carefully treat and study more children to try to determine which children will benefit from growth hormone medication. The Goals of this Study Are: 1. We want to try to find a cause for the growth plateau common in types III and IV OI. Long-term, our goal is to develop a treatment to eliminate this plateau. 2. We want to see how long and how well OI bone will respond to growth stimulation. 3. We hope to find a "predictor" for who will respond to growth hormone and who will not, by measuring your child's endocrine and growth hormone function before receiving any growth hormone treatment. 4. We want to measure the effects of growth stimulation on bone density, and the quality of OI bone. 5. We want to see if there are long term benefits resulting from this treatment in the form of final adult height, trunk height, and possibly improved function of the respiratory system. Median Subject Age (on p. 1 of webpage): 1-15 years (replaces 0-20) Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001305

•

The Effects of Hormones in Growth Hormone-Treated Girls with Turner Syndrome Condition(s): Dwarfism; Turner's Syndrome Study Status: This study is currently recruiting patients.

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Sponsor(s): National Institute of Child Health and Human Development (NICHD) Purpose - Excerpt: Turners Syndrome is a genetic condition in females that is a result of abnormal chromosomes. Patients with Turner syndrome are typically short, have abnormal physical features, and lack the physical changes normally associated with puberty. In addition, some patients with Turner syndrome have low bone density (osteoporosis) and differences in learning abilities. This study will research the effects of steroid hormones on patients with Turner syndrome. It will look closely at how taking steroid hormones effects the patient's rate of growth as well as the patient's ability to learn. In addition the study will investigate how different hormones (androgen and estrogen) work when given together as a combination. All patients asked to participate in this study will receive growth hormone injections. However, half of the patients will receive an additional sex steroid hormone (oxandrolone) in the form of a pill. The other half of the patients will receive a placebo or "sugar pill". This will allow the researchers to determine if the combination of the hormones produces different results than growth hormone alone. The study will last approximately 2 years. After 2 years of research the patients may qualify for an additional 2 years of treatment. Patients may benefit directly from this research with increased growth and improved ability to learn. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001343

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “dwarfism” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 6. PATENTS ON DWARFISM Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “dwarfism” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on dwarfism, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Dwarfism By performing a patent search focusing on dwarfism, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We

9Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on dwarfism: •

Method of constructing a replicable cloning vehicle having quasi-synthetic genes Inventor(s): Goeddel; David V. (Burlingame, CA), Heyneker; Herbert L. (Burlingame, CA) Assignee(s): Genentech, Inc. (South San Francisco, CA) Patent Number: 4,342,832 Date filed: July 5, 1979 Abstract: Described are methods and means for the construction and microbial expression of quasi-synthetic genes arising from the combination of organic synthesis and enzymatic reverse transcription from messenger RNA sequences incomplete from the standpoint of the desired protein product. Preferred products of expression lack bioinactivating leader sequences common in eukaryotic expression products but problematic with regard to microbial cleavage to yield bioactive material. Illustrative is a preferred embodiment in which a gene coding for human growth hormone (useful in, e.g., treatment of hypopituitary dwarfism) is constructed and expressed. Excerpt(s): 1. The enzyme RNA polymerase is activitated in the control region (hereafter the "promoter") and travels along the structural gene, transcribing its encoded information into messenger ribonucleic acid (mRNA) until transcription of translatable mRNA is ended at one or more "stop" codons. 2. The mRNA message is translated at the ribosomes into a protein for whose amino acid sequence the gene encodes, beginning at a translation "start" signal, most commonly ATG (which is transcribed "AUG" and translated "f-methionine"). In accordance with the genetic code, DNA specifies each amino acid by a triplet or "codon" of three adjacent nucleotides individually chosen from adenosine, thymidine, cytidine and guanine or, as used herein, A,T,C, or G. These appear in the coding strand or coding sequence of double-stranded ("duplex") DNA, whose remaining or "complementary" strand is formed of nucleotides ("bases") which hydrogen bond to their complements in the coding strand. A complements T, and C complements G. These and other subjects relating to the background of the invention are discussed at length in Benjamin Lewin, Gene Expression 1, 2 (1974) and 3 (1977), John Wiley and Sons, N.Y. This and the other publications alluded to herein are incorporated by reference. Web site: http://www.delphion.com/details?pn=US04342832__

Patent Applications on Dwarfism As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to dwarfism:

10

This has been a common practice outside the United States prior to December 2000.

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•

Compounds having growth hormone releasing activity Inventor(s): Bowers, Cyril Y.; (New Orleans, LA), Liang, Yongwu; (Sprin, TX), Momany, Frank; (Peoria, IL) Correspondence: Nixon Peabody Llp; Attention: David Resnick; 101 Federal Street; Boston; MA; 02110; US Patent Application Number: 20020151501 Date filed: March 29, 2002 Abstract: Compounds that promote growth hormone releasing activity are disclosed. These compounds have the formula:A.sub.1-A.sub.2-X; A.sub.1-X'; or A.sub.1.-YThese compounds can be present in a pharmaceutical composition. The compounds can be used with a second compound that acts as an agonist at the growth hormone releasing hormone receptor or which inhibits the effects of somatostatin. These compounds can be used for a variety of uses such as treating hypothalamic pituitary dwarfism, osteoporosis, burns, or promoting wound healing. Excerpt(s): This invention relates to novel compounds that promote the release of growth hormones when introduced to animals, preferably humans, and methods of use thereof. The elevation of growth hormone (GH) levels in animals, e.g., mammals including humans, upon administration of GH-releasing compounds can lead to enhanced body weight and to enhanced milk production if sufficiently elevated GH levels occur upon administration. Further, it is known that the elevation of growth hormone levels in mammals and humans can be accomplished by application of known growth hormone releasing agents, such as the naturally occurring growth hormone releasing hormones. The elevation of growth hormone levels in mammals can also be accomplished by application of growth hormone releasing peptides (GHRPs), some of which have been previously described, for example, in U.S. Pat. Nos. 4,223,019; 4,223,020; 4,223,021; 4,224,316; 4,226,857; 4,228,155; 4,228,156; 4,228,157; 4,228,158; 4,410,512; 4,410,513. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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New uses for corticotropin releasing factor antagonists Inventor(s): Chen, Yuhpyng L.; (Waterford, CT), Fossa, Anthony A.; (Mystic, CT) Correspondence: Paul H. Ginsburg; Pfizer Inc; 20th Floor; 235 East 42nd Street; New York; NY; 10017-5755; US Patent Application Number: 20010000340 Date filed: December 13, 2000 Abstract: A method of treating, preventing or inhibiting a disorder selected from the group consisting of cardiovascular or heart related diseases such as stroke, hypertension, tachycardia, and congestive heart failure, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus, and colonic hypersensitivity associated with psychopathological disturbance and stress, comprising administering to a mammal, including a human, in need of such treatment a therapeutically effective amount of a compound of the formula 1or pharmaceutically acceptable salt thereof, wherein A, B, D, E, Y, Z, R.sub.3, R.sub.4, and R.sub.5 are as defined herein.

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Excerpt(s): 1. The present invention relates to the treatment of certain conditions using a compound of formula I or II, or a pharmaceutically acceptable salt thereof, as defined below. Specifically, the compounds of formulas I and II, and their pharmaceutically acceptable salts, as defined below, exhibit corticotropin-releasing factor (CRF) antagonist activity and are useful in the treatment of cardiovascular or heart related diseases such as hypertension, tachycardia, and congestive heart failure, stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus, and colonic hypersensitivity associated with psychopathological disturbance and stress. 2. The compounds of formulas I and II, their pharmaceutically acceptable salts, and methods of preparing such compounds and salts are referred to in copending PCT international patent application numbers PCT/IB95/00373 (filed May 18, 1995) and PCT/IB95/00439 (filed Jun. 6, 1995), both of which designate the United States, and in copending U.S. patent applications Ser. Nos. 08/448,539 (filed Jun. 14, 1995) and 08/481,413 (filed Jun. 15, 1995). PCT international patent application numbers PCT/IB95/00373 and PCT/IB95/00439, and U.S. patent application Ser. Nos. 08/448,539 and 08/481,413, referred to above, are incorporated herein by reference in their entirety. 3. The foregoing PCT international patent applications and United States patent applications refer to the use of the compounds of formulas I and II in the treatment of illnesses induced or facilitated by corticotropin releasing factor and in the treatment of anxiety, depression, fatigue syndrome, gastrointestinal diseases, headache, pain, cancer, immune dysfunction, hemorrhagic stress, drug addiction, drug and alcohol withdrawal symptoms, fertility problems, stress-induced psychotic episodes, neurodegenerative diseases such as Alzheimer's disease; irritable bowel syndrome including Crohn's disease, spastic colon and irritable colon; eating disorders such as anorexia nervosa; and inflammatory disorders such as arthritis, asthma and allergies. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Therapeutic agents for achondroplasia Inventor(s): Nakao, Kazuwa; (Kyoto-shi, JP) Correspondence: Hunton & Williams; Intellectual Property Department; 1900 K Street, N.W.; Suite 1200; Washington; DC; 20006-1109; US Patent Application Number: 20030068313 Date filed: August 14, 2002 Abstract: The present invention aims to provide novel therapeutic agents for achondroplasia caused by mutations in FGFR3.Therapeutic agents for achondroplasia caused by the cartilage growth inhibition resulting from mutations in the gene for fibroblast growth factor receptor 3 (FGFR3), comprising a substance activating guanylyl cyclase B (GC-B) as an active ingredient are disclosed. Excerpt(s): The present invention relates to agents and methods for treating achondroplasia. Achondroplasia is one of the most common congenital diseases responsible for micromelic dwarfism characterized by short limbs relative to trunk. It is diagnosed by X-ray photographs in addition to growth failure in the major axes of the long bones of extremities and typical physical features such as a large frontally projecting cranium and a short nose. The disease is said to occur at an incidence of one to 10,000-25,000 people. This disease is an autosomal dominant hereditary disorder, but 80-90% of cases are found to be sporadic. Current therapies include orthopedic surgeries such as artificial hip joint replacement or leg lengthening and growth hormone therapy.

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Leg lengthening involves cutting bones at the age of 10 years or after and gradually increasing body height using a special device (leg lengthening device) over several courses of about six months. However, this procedure inflicts a great pain on patients. Growth hormone therapy increases body height by means of periodic growth hormone injections starting from childhood. However, growth ceases when injections are stopped. Neither therapy is curative, and neither are considered ideal from the viewpoint of patients' QOL (American Journal of Medical Genetics 72: 71-76, 1997; European Journal of Endocrinology 138: 275-280, 1998). Consequently, it is desirable to develop a achondroplasia therapy based on a new mechanism. Recent reports show that achondroplastic patients have mutations in fibroblast growth factor receptor 3 (FGFR3) located at chromosome 4p16.3, and two mutations are currently known. Of these mutations, 97% represents G1138A (change of 1138th G to A) and 2.5% represents G1138C (change of 1138th G to C), resulting in a change of the amino acid Gly at the 380position to Arg (G380R) (Nature 371: 252-254, 1994; Cell 78: 335-342, 1994). To examine the relation of this mutation to achondroplasia, G380R FGFR3 (sometimes hereinafter referred to as FGFR3.sup.ach) transgenic mice were bred to provide an animal model for human achondroplasia. The mice showed short limbs and craniofacial hypoplasia (Development. 125: 4977-4988, 1998). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with dwarfism, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “dwarfism” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on dwarfism. You can also use this procedure to view pending patent applications concerning dwarfism. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 7. BOOKS ON DWARFISM Overview This chapter provides bibliographic book references relating to dwarfism. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on dwarfism include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “dwarfism” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on dwarfism: •

How It Feels To Live with a Physical Disability Source: New York, NY: Simon and Schuster. 1992. 176 p. Contact: Available from Simon and Schuster. Order Department, 200 Old Tappan Road, Old Tappan, NJ 07675. (800) 223-2336. PRICE: $18.00. ISBN: 0671723715. Summary: This book portrays the lives of twelve children who live with physical disabilities, including blindness, dwarfism, paralysis, birth anomalies, spasticity, and cerebral palsy. Captured in text and photos, these children tell their own stories and speak with candor about their lives, their accomplishments and disappointments, and their hopes, fears, goals, and dreams. Topics addressed include physical limitations caused by their disabilities; surgeries, medications, and physical therapy; the pain and frustration they experience; and the mental strength that enables them to overcome obstacles. One of the young people featured has Treacher Collins syndrome.

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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 “dwarfism” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “dwarfism” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “dwarfism” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

Dwarfism: The Family & Professional Guide by Charles I. Scott, et al (1994); ISBN: 1884075002; http://www.amazon.com/exec/obidos/ASIN/1884075002/icongroupinterna

•

Little People in America: The Social Dimension of Dwarfism by Joan Ablon; ISBN: 0275915964; http://www.amazon.com/exec/obidos/ASIN/0275915964/icongroupinterna

•

The Kaspar Hauser Syndrome of "Psychosocial Dwarfism": Deficient Statural, Intellectual, and Social Growth Induced by Child Abuse by John Money (1992); ISBN: 087975754X; http://www.amazon.com/exec/obidos/ASIN/087975754X/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “dwarfism” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:11 •

Cystine storage disease with amino-aciduria and dwarfism: Lignac-Fanconi disease [by H. Bickel and others]. Author: Bickel, Horst,; Year: 1929; Birmingham [Eng., Juckes] 1952

•

Dwarfism; a clinical investigation, with special reference to the significance of endocrine factors. Author: Horstmann, Paul.; Year: 1971; Copenhagen, Munksgaard, 1949

•

Feebleness of growth and congenital dwarfism, with special reference to dysostosis cleido-cranialis; by Dr. Murk Jansen. Author: Jansen, Murk.; Year: 1952; London, H. Frowde; Hodder; Stoughton, 1921

11

In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

Books

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•

Investigations into the development of the pituitary at hereditary anterior pituitary dwarfism in mice with reference to the pathogenesis of the anterior pituitary dwarfism. Author: Francis, Torben Emil,; Year: 1949; Copenhagen, Munksgaard, 1944

•

Kaspar Hauser syndrome of “psychosocial dwarfism”: deficient statural, intellectual, and social growth induced by child abuse. Author: John Money; Year: 1992

Chapters on Dwarfism In order to find chapters that specifically relate to dwarfism, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and dwarfism using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “dwarfism” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on dwarfism: •

Achondroplasia: Achondroplastic Dwarfism, Short-Limbed Dwarfism Source: in Plumridge, D.; et al., eds. Student with a Genetic Disorder: Educational Implications for Special Education Teachers and for Physical Therapists, Occupational Therapists, and Speech Pathologists. Springfield, IL: Charles C Thomas Publisher. 1993. p. 53-59. Contact: Available from Charles C Thomas Publisher. 2600 South First Street, Springfield, IL 62794-9265. (212) 789-8980. Fax (217) 789-9130. PRICE: $75.95 plus shipping and handling (cloth); $39.95 plus shipping and handling (paper). ISBN: 0398058393. Summary: Achondroplasia is the most common of the many forms of short-limbed dwarfism. This chapter on achondroplasia is from a text for special education teachers, physical therapists, occupational therapists, and speech pathologists on the educational implications of genetic disorders. Topics covered include the characteristic features of the disorder, orthopedic and skeletal problems, neurological problems, cardiopulmonary complications, the genetics of the disorder, the cognitive and behavior profiles, the educational implications, physical therapy, occupational therapy, hearing and speech considerations, psychosocial issues, and prognosis. 1 figure. 9 references.

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CHAPTER 8. MULTIMEDIA ON DWARFISM Overview In this chapter, we show you how to keep current on multimedia sources of information on dwarfism. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Bibliography: Multimedia on Dwarfism The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in dwarfism (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on dwarfism: •

Diagnosis of lethal short-limbed dwarfism in utero [videorecording] Source: presented by the Department of Radiology, School of Medicine, University of California, San Diego, in cooperation with the Office of Learning Resources-Television, University of Califor; Year: 1987; Format: Videorecording; [San Diego, Calif.]: The Department, c1987

•

Thinking big [videorecording]: medical disorders and dwarfism Source: a presentation of Films for the Humanities & Sciences, ABC News Productions; Year: 2001; Format: Videorecording; Princeton, N.J.: Films for the Humanities & Sciences, c2001

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CHAPTER 9. PERIODICALS AND NEWS ON DWARFISM Overview In this chapter, we suggest a number of news sources and present various periodicals that cover dwarfism.

News Services and Press Releases One of the simplest ways of tracking press releases on dwarfism is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “dwarfism” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to dwarfism. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “dwarfism” (or synonyms). The following was recently listed in this archive for dwarfism: •

Genetic mutation for dwarfism found Source: Reuters Health eLine Date: January 19, 2001

•

Gene mutation linked to dwarfism in the Amish Source: Reuters Health eLine Date: March 03, 2000

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Gene mutation tied to treatable dwarfism Source: Reuters Health eLine Date: March 11, 1999

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Genetic Mechanism For Dwarfism Described Source: Reuters Medical News Date: June 03, 1996

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Gene That Causes Dwarfism Identified Source: Reuters Medical News Date: March 05, 1996 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “dwarfism” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “dwarfism” (or synonyms). If you know the name of a company that is relevant to dwarfism, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/.

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BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “dwarfism” (or synonyms).

Academic Periodicals covering Dwarfism Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to dwarfism. In addition to these sources, you can search for articles covering dwarfism that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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APPENDICES

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

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute12: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

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

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

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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

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

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

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

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

12

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

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

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

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

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

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

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

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

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

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

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

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

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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

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

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

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

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

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.13 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:14 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

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NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

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

13

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). 14 See http://www.nlm.nih.gov/databases/databases.html.

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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

The NLM Gateway15 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.16 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “dwarfism” (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 8935 51 29 5 1 9021

HSTAT17 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.18 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.19 Simply search by “dwarfism” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

15

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

16

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). 17 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 18 19

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.

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Coffee Break: Tutorials for Biologists20 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.21 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.22 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

The Genome Project and Dwarfism In the following section, we will discuss databases and references which relate to the Genome Project and dwarfism. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).23 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 20 Adapted 21

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 22 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. 23 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “dwarfism” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for dwarfism: •

Achondroplasia Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?100800

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Achondroplasia, So-called, and Swiss-type Agammaglobulinemia Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?200900

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Alaninuria with Microcephaly, Dwarfism, Enamel Hypoplasia, and Diabetes Mellitus Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?202900

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Alopecia-contractures-dwarfism Mental Retardation Syndrome Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?203550

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Aminoaciduria with Mental Deficiency, Dwarfism, Muscular Dystrophy, Osteoporosis, and Acidosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?204730

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Bird-headed Dwarfism with Progressive Ataxia, Insulin-resistant Diabetes, Goiter, and Primary Gonadal Insufficiency Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?210740

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Bird-headed Dwarfism, Montreal Type Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?210700

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Bowing of Legs, Anterior, with Dwarfism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?112350

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Deafness, Sensorineural, with Pituitary Dwarfism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?221750

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Dwarfism with Stiff Joints and Ocular Abnormalities Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?127200

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Dwarfism with Tall Vertebrae Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?126950

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Dwarfism, Familial, with Muscle Spasms Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600771

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Dwarfism, Levi Type Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?127100

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Dwarfism, Low-birth-weight Type, with Unresponsiveness to Growth Hormone Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?223500

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Dwarfism, Mental Retardation, and Eye Abnormality Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?223540

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Dwarfism, Proportionate, with Hip Dislocation Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?223550

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Dwarfism, Short-limb, with Absent Fibulas and Very Short Digits Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?223610

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Dyssegmental Dwarfism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?224400

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Ichthyosis, Mental Retardation, Dwarfism, and Renal Impairment Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?242530

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Keratosis Follicularis, Dwarfism, and Cerebral Atrophy Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?308830

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Lenz-majewski Hyperostotic Dwarfism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?151050

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Megaepiphyseal Dwarfism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?249230

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Mesomelic Dwarfism of Hypoplastic Tibia and Radius Type Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?156230

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Metatropic Dwarfism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?250600

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Microcephalic Osteodysplastic Primordial Dwarfism with Tooth Abnormalities Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?607561

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Microcephalic Osteodysplastic Primordial Dwarfism, Type I Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?210710

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Microcephalic Osteodysplastic Primordial Dwarfism, Type Ii Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?210720

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Microcephalic Osteodysplastic Primordial Dwarfism, Type Iii Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?210730

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Microcephalic Primordial Dwarfism, Toriello Type Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?251190

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Micromelic Dwarfism with Vertebral and Metaphyseal Abnormalities and Advanced Carpotarsal Ossification Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?251450

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Oculopalatocerebral Dwarfism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?257910

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Osteoglophonic Dwarfism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?166250

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Parastremmatic Dwarfism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?168400

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Pituitary Dwarfism due to Isolated Growth Hormone Deficiency, Autosomal Dominant Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?173100

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Pituitary Dwarfism I Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?262400

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Pituitary Dwarfism Ii Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?262500

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Pituitary Dwarfism Iii Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?262600

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Pituitary Dwarfism Iv Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?262650

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Pituitary Dwarfism with Large Sella Turcica Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?262710

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Pituitary Dwarfism with Small Sella Turcica Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?262700

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Syndesmodysplasic Dwarfism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?272450

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Synovial Chondromatosis, Familial, with Dwarfism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?186575

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Trichomegaly with Mental Retardation, Dwarfism, and Pigmentary Degeneration of Retina Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?275400

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Tryptophanuria with Dwarfism Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?276100 Genes and Disease (NCBI - Map)

The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •

Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html

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Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

•

Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

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Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html

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Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html

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Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

•

Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez

Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

•

Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

•

NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

•

Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

•

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

•

PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

•

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

•

PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

•

Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “dwarfism” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database24 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database25 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “dwarfism” (or synonyms) into the search box, and

24

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 25 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

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review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on dwarfism can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to dwarfism. 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 dwarfism. 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 “dwarfism”:

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•

Other guides Birth Defects http://www.nlm.nih.gov/medlineplus/birthdefects.html Dwarfism http://www.nlm.nih.gov/medlineplus/dwarfism.html Genetic Brain Disorders http://www.nlm.nih.gov/medlineplus/geneticbraindisorders.html Genetic Disorders http://www.nlm.nih.gov/medlineplus/geneticdisorders.html Genetic Testing/Counseling http://www.nlm.nih.gov/medlineplus/genetictestingcounseling.html Metabolic Disorders http://www.nlm.nih.gov/medlineplus/metabolicdisorders.html Osteogenesis Imperfecta http://www.nlm.nih.gov/medlineplus/osteogenesisimperfecta.html Thyroid Diseases http://www.nlm.nih.gov/medlineplus/thyroiddiseases.html Turner's Syndrome http://www.nlm.nih.gov/medlineplus/turnerssyndrome.html

Within the health topic page dedicated to dwarfism, the following was listed: •

General/Overviews Dwarfism Resources: Frequently Asked Questions Source: Little People of America http://www.lpaonline.org/resources_faq.html Dwarfism Types and Definitions Source: Little People of America http://www.lpaonline.org/resources_dwarftypes.html

•

Specific Conditions/Aspects Extended Limb-Lengthening: Introduction Source: Little People of America http://www.lpaonline.org/library_ellintro.html Genes and Disease: Cockayne Syndrome Source: National Center for Biotechnology Information http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowSection&rid=gnd. section.159 Genes and Disease: Diastrophic Dysplasia Source: National Center for Biotechnology Information http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowSection&rid=gnd. section.245

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Genes and Disease: Ellis-Van Creveld Syndrome Source: National Center for Biotechnology Information http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowSection&rid=gnd. section.162 •

Children Dwarfism Source: Nemours Foundation http://kidshealth.org/parent/medical/bones/dwarfism.html

•

Organizations Little People of America Online Source: Little People of America http://www.lpaonline.org/index.html National Institute of Child Health and Human Development http://www.nichd.nih.gov/

You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on dwarfism. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

Bridging the Gap: Share and Care Cockayne Syndrome Network Source: Stanleytown, VA: Share and Care Cockayne Syndrome Network. 199x. 4 p. Contact: Share and Care Cockayne Syndrome Network. P.O. Box 552, Stanleytown, VA 24168. (703) 629-2369. PRICE: Single copy free. Summary: This brochure, from a support organization, describes Cockayne syndrome (CS), a rare form of dwarfism. After a brief description of CS, the brochure lists the characteristic features of the condition, including oral manifestations, and describes the genetics of CS. The brochure features black-and-white photographs of numerous children and adults with CS. The brochure concludes with a description of the activities of Share and Care, the CS Network. A form with which readers can join Share and Care is included.

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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: •

Achondroplasia Source: March of Dimes Birth Defects Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=2578 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 dwarfism. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •


•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMDHealth: http://my.webmd.com/health_topics

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to dwarfism. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with dwarfism.

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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 dwarfism. 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://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “dwarfism” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “dwarfism”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “dwarfism” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “dwarfism” (or a synonym) into the search box, and click “Submit Query.”

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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.26

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

26

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)27: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

27

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

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•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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•

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

110 Dwarfism

•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on dwarfism: •

Basic Guidelines for Dwarfism Achondroplasia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001577.htm

•

Signs & Symptoms for Dwarfism Frontal bossing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003301.htm Hypotonia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003298.htm Lordosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003278.htm Polyhydramnios Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003267.htm

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Short stature Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003271.htm Skeletal (limb) abnormalities Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003170.htm Waddling gait Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003199.htm •

Diagnostics and Tests for Dwarfism Bone X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003808.htm

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Background Topics for Dwarfism Autosomal dominant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002049.htm Gene Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002371.htm Genetic counseling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002053.htm Homozygous Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002048.htm Long bones Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002249.htm Occipital-frontal circumference Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002379.htm Proximal Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002287.htm

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

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MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

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Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

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Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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DWARFISM DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 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] Abdominal fat: Fat (adipose tissue) that is centrally distributed between the thorax and pelvis and that induces greater health risk. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Acrodermatitis: Inflammation involving the skin of the extremities, especially the hands and feet. Several forms are known, some idiopathic and some hereditary. The infantile form is called Gianotti-Crosti syndrome. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adolescent Nutrition: Nutrition of children aged 13-18 years. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal insufficiency: The reduced secretion of adrenal glands. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agnosia: Loss of the ability to comprehend the meaning or recognize the importance of various forms of stimulation that cannot be attributed to impairment of a primary sensory modality. Tactile agnosia is characterized by an inability to perceive the shape and nature of an object by touch alone, despite unimpaired sensation to light touch, position, and other

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primary sensory modalities. [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] Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1. [NIH] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Alpha-helix: One of the secondary element of protein. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alveolar Process: The thickest and spongiest part of the maxilla and mandible hollowed out into deep cavities for the teeth. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amelogenesis Imperfecta: Either hereditary enamel hypoplasia or hypocalcification. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Anabolic: Relating to, characterized by, or promoting anabolism. [EU] Anaemia: A reduction below normal in the number of erythrocytes per cu. mm., in the quantity of haemoglobin, or in the volume of packed red cells per 100 ml. of blood which occurs when the equilibrium between blood loss (through bleeding or destruction) and blood production is disturbed. [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] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH]

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Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgenic: Producing masculine characteristics. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anorexia Nervosa: The chief symptoms are inability to eat, weight loss, and amenorrhea. [NIH]

Anterograde: Moving or extending forward; called also antegrade. [EU] 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-infective: An agent that so acts. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Aperture: A natural hole of perforation, especially one in a bone. [NIH] Aplastic anaemia: A form of anaemia generally unresponsive to specific antianaemia therapy, often accompanied by granulocytopenia and thrombocytopenia, in which the bone marrow may not necessarily be acellular or hypoplastic but fails to produce adequate

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numbers of peripheral blood elements. The term actually is all-inclusive and most probably encompasses several clinical syndromes. [EU] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Approximate: Approximal [EU] Aqueous: Having to do with water. [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] Arthroplasty: Surgical reconstruction of a joint to relieve pain or restore motion. [NIH] Articular: Of or pertaining to a joint. [EU] Aseptic: Free from infection or septic material; sterile. [EU] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] 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] Atrial: Pertaining to an atrium. [EU] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH] Axonal: Condition associated with metabolic derangement of the entire neuron and is manifest by degeneration of the distal portion of the nerve fiber. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or

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bacillary, and spiral or spirochetal. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

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] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological 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] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH]

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Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bladder: The organ that stores urine. [NIH] Blast phase: The phase of chronic myelogenous leukemia in which the number of immature, abnormal white blood cells in the bone marrow and blood is extremely high. Also called blast crisis. [NIH] Blepharophimosis: A condition in which the palpebral aperture is abnormally small. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Bone Density: The amount of mineral per square centimeter of bone. This is the definition used in clinical practice. Actual bone density would be expressed in grams per milliliter. It is most frequently measured by photon absorptiometry or x-ray computed tomography. [NIH] Bone Development: Gross development of bones from fetus to adult. It includes osteogenesis, which is restricted to formation and development of bone from the undifferentiated cells of the germ layers of the embryo. It does not include osseointegration. [NIH]

Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brain Neoplasms: Neoplasms of the intracranial components of the central nervous system, including the cerebral hemispheres, basal ganglia, hypothalamus, thalamus, brain stem, and cerebellum. Brain neoplasms are subdivided into primary (originating from brain tissue) and secondary (i.e., metastatic) forms. Primary neoplasms are subdivided into benign and malignant forms. In general, brain tumors may also be classified by age of onset, histologic type, or presenting location in the brain. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

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Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Brown Fat: A thermogenic form of adipose tissue found in newborns of many species, including humans, and in hibernating mammals. The tissue is capable of rapid liberation of energy and seems to be important in the maintenance of body temperature immediately after birth and upon waking from hibernation. [NIH] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge of electricity. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Camptothecin: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA topoisomerase. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [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]

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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] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [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] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [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] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called

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the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [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] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Chondrogenesis: The formation of cartilage. This process is directed by chondrocytes which continually divide and lay down matrix during development. It is sometimes a precursor to osteogenesis. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic lymphocytic leukemia: A slowly progressing disease in which too many white blood cells (called lymphocytes) are found in the body. [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] Chronic phase: Refers to the early stages of chronic myelogenous leukemia or chronic lymphocytic leukemia. The number of mature and immature abnormal white blood cells in the bone marrow and blood is higher than normal, but lower than in the accelerated or blast phase. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Cleft Palate: Congenital fissure of the soft and/or hard palate, due to faulty fusion. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic

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engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Cochlea: The part of the internal ear that is concerned with hearing. It forms the anterior part of the labyrinth, is conical, and is placed almost horizontally anterior to the vestibule. [NIH]

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] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collagen disease: A term previously used to describe chronic diseases of the connective tissue (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] 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

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are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] 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] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Cone: One of the special retinal receptor elements which are presumed to be primarily concerned with perception of light and color stimuli when the eye is adapted to light. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [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] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum

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and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Corpus Callosum: Broad plate of dense myelinated fibers that reciprocally interconnect regions of the cortex in all lobes with corresponding regions of the opposite hemisphere. The corpus callosum is located deep in the longitudinal fissure. [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] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

Cytidine: A pyrimidine nucleoside that is composed of the base cytosine linked to the fivecarbon sugar D-ribose. [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

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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] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Materials: Materials used in the production of dental bases, restorations, impressions, prostheses, etc. [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] 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] Dermal: Pertaining to or coming from the skin. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Diabetes Insipidus: A metabolic disorder due to disorders in the production or release of vasopressin. It is characterized by the chronic excretion of large amounts of low specific gravity urine and great thirst. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH]

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Diastolic: Of or pertaining to the diastole. [EU] Diastolic blood pressure: The minimum pressure that remains within the artery when the heart is at rest. [NIH] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilatation: The act of dilating. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dreams: A series of thoughts, images, or emotions occurring during sleep which are dissociated from the usual stream of consciousness of the waking state. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Dwarfism: The condition of being undersized as a result of premature arrest of skeletal growth. It may be caused by insufficient secretion of growth hormone (pituitary dwarfism). [NIH]

Dysostosis: Defective bone formation. [NIH]

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Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eating Disorders: A group of disorders characterized by physiological and psychological disturbances in appetite or food intake. [NIH] Ectopic: Pertaining to or characterized by ectopia. [EU] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastin: The protein that gives flexibility to tissues. [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] 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] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [NIH] Encephalocele: Cerebral tissue herniation through a congenital or acquired defect in the skull. The majority of congenital encephaloceles occur in the occipital or frontal regions. Clinical features include a protuberant mass that may be pulsatile. The quantity and location of protruding neural tissue determines the type and degree of neurologic deficit. Visual defects, psychomotor developmental delay, and persistent motor deficits frequently occur. [NIH]

Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocrine Glands: Ductless glands that secrete substances which are released directly into the circulation and which influence metabolism and other body functions. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing

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radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Epicanthus: Fold of the skin partially covering the inner canthus, the caruncle, and the plica semilunaris. [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] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epiphyseal: Pertaining to or of the nature of an epiphysis. [EU] Epiphyses: The head of a long bone that is separated from the shaft by the epiphyseal plate until bone growth stops. At that time, the plate disappears and the head and shaft are united. [NIH] Epithalamus: The dorsal posterior subdivision of the diencephalon. The epithalamus is generally considered to include the habenular nuclei (habenula) and associated fiber bundles, the pineal body, and the epithelial roof of the third ventricle. The anterior and posterior paraventricular nuclei of the thalamus are included with the thalamic nuclei although they develop from the same pronuclear mass as the epithalamic nuclei and are sometimes considered part of the epithalamus. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estrogen: One of the two female sex hormones. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Excisional: The surgical procedure of removing a tumor by cutting it out. The biopsy is then examined under a microscope. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU]

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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 Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Facial: Of or pertaining to the face. [EU] Failure to Thrive: A condition in which an infant or child's weight gain and growth are far below usual levels for age. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Femoral: Pertaining to the femur, or to the thigh. [EU] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fetal Development: Morphologic and physiologic growth and development of the mammalian embryo or fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] 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] Flexor: Muscles which flex a joint. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has

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calories. [NIH] Gait: Manner or style of walking. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [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] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germ Layers: The three layers of cells comprising the early embryo. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gibberellin: One of a class of plant hormones that promote elongation. Synthesis occurs mainly in leaves and roots. They function by stimulating cell division and the hydrolisis of sugars to glucose and fructose, and stimulate extensive growth, especially of internodes. [NIH]

Gigantism: The condition of abnormal overgrowth or excessive size of the whole body or any of its parts. [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] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally

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occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

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] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadorelin: A decapeptide hormone released by the hypothalamus. It stimulates the synthesis and secretion of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. [NIH] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [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] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Granulocytopenia: A deficiency in the number of granulocytes, a type of white blood cell. [NIH]

Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth Disorders: Deviations from the average values for a specific age and sex in any or all of the following: height, weight, skeletal proportions, osseous development, or maturation of features. Included here are both acceleration and retardation of growth. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Growth Plate: The area between the epiphysis and the diaphysis within which bone growth

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occurs. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] 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] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hepatic: Refers to the liver. [NIH] Hepatocyte: A liver cell. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] Hibernation: The dormant state in which some animal species pass the winter. It is characterized by narcosis and by sharp reduction in body temperature and metabolic activity and by a depression of vital signs. It is a natural physiological process in many warm-blooded animals. [NIH] Histology: The study of tissues and cells under a microscope. [NIH]

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Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homeotic: Characterizes genes the mutations of which lead to inappropriate expressions of characteristics normally associated with another part of the organism (homeotic mutants). [NIH]

Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Human Development: Continuous sequential changes which occur in the physiological and psychological functions during the individual's life. [NIH] Human growth hormone: A protein hormone, secreted by the anterior lobe of the pituitary, which promotes growth of the whole body by stimulating protein synthesis. The human gene has already been cloned and successfully expressed in bacteria. [NIH] Humeri: A condition similar to tennis elbow involving the flexor origin at the medial epicondyle of the humerus, characterized by pain in or near the medial epicondyle of the humerus as a result of unusual strain. [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] Hydrocephalus: Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial hypertension; headache; lethargy; urinary incontinence; and ataxia (and in infants macrocephaly). This condition may be caused by obstruction of cerebrospinal fluid pathways due to neurologic abnormalities, intracranial hemorrhages; central nervous system infections; brain neoplasms; craniocerebral trauma; and other conditions. Impaired resorption of cerebrospinal fluid from the arachnoid villi results in a communicating form of hydrocephalus. Hydrocephalus ex-vacuo refers to ventricular dilation that occurs as a result of brain substance loss from cerebral infarction and other conditions. [NIH] Hydrocortisone: The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive

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isotope tritium. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophic cardiomyopathy: Heart muscle disease that leads to thickening of the heart walls, interfering with the heart's ability to fill with and pump blood. [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] Hypophyseal: Hypophysial. [EU] Hypophysis: A remnant of the entodermal pouch of Rathke beneath the mucous membrane of the pharynx, which shows pituitary tissue. [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypothyroidism: Deficiency of thyroid activity. In adults, it is most common in women and is characterized by decrease in basal metabolic rate, tiredness and lethargy, sensitivity to cold, and menstrual disturbances. If untreated, it progresses to full-blown myxoedema. In infants, severe hypothyroidism leads to cretinism. In juveniles, the manifestations are intermediate, with less severe mental and developmental retardation and only mild symptoms of the adult form. When due to pituitary deficiency of thyrotropin secretion it is called secondary hypothyroidism. [EU] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Ileus: Obstruction of the intestines. [EU]

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Immortal: Stage when the mother cell and its descendants will multiply indefinitely. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [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] Immunology: The study of the body's immune system. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] 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]

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Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Insertional: A technique in which foreign DNA is cloned into a restriction site which occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [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] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Intervertebral: Situated between two contiguous vertebrae. [EU] Intestinal: Having to do with the intestines. [NIH] Intestines: The section of the alimentary canal from the stomach to the anus. It includes the large intestine and small intestine. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracranial Hemorrhages: Bleeding within the intracranial cavity, including hemorrhages in the brain and within the cranial epidural, subdural, and subarachnoid spaces. [NIH] Intracranial Hypertension: Increased pressure within the cranial vault. This may result from several conditions, including hydrocephalus; brain edema; intracranial masses; severe systemic hypertension; pseudotumor cerebri; and other disorders. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH] 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

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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] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [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] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Lactation: The period of the secretion of milk. [EU] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] 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] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Lethargy: Abnormal drowsiness or stupor; a condition of indifference. [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.

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[NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leuprolide: A potent and long acting analog of naturally occurring gonadotropin-releasing hormone (gonadorelin). Its action is similar to gonadorelin, which regulates the synthesis and release of pituitary gonadotropins. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Lichen Planus: An inflammatory, pruritic disease of the skin and mucous membranes, which can be either generalized or localized. It is characterized by distinctive purplish, flattopped papules having a predilection for the trunk and flexor surfaces. The lesions may be discrete or coalesce to form plaques. Histologically, there is a "saw-tooth" pattern of epidermal hyperplasia and vacuolar alteration of the basal layer of the epidermis along with an intense upper dermal inflammatory infiltrate composed predominantly of T-cells. Etiology is unknown. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] 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] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] 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] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [NIH] Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph

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nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] 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] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malformation: A morphologic developmental process. [EU]

defect

resulting

from

an

intrinsically

abnormal

Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

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] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Median Eminence: Raised area on the infundibular hypothalamus at the floor of the third ventricle of the brain which contains the primary capillary network of the hypophyseal portal system. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] 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

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color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental 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] Meristem: A tissue capable of active cell division and therefore of adding new cells to the plant body. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metatarsal Bones: The five long bones of the metatarsus articulating with the tarsal bones proximally and the toes (phalanges) distally. [NIH] Metatarsus: The part of the foot between the tarsa and the toes. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] 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] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller

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than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] 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] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]

Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH]

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Myxedema: A condition characterized by a dry, waxy type of swelling with abnormal deposits of mucin in the skin and other tissues. It is produced by a functional insufficiency of the thyroid gland, resulting in deficiency of thyroid hormone. The skin becomes puffy around the eyes and on the cheeks and the face is dull and expressionless with thickened nose and lips. The congenital form of the disease is cretinism. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] 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] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatal period: The first 4 weeks after birth. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural tube defects: These defects include problems stemming from fetal development of the spinal cord, spine, brain, and skull, and include birth defects such as spina bifida, anencephaly, and encephalocele. Neural tube defects occur early in pregnancy at about 4 to 6 weeks, usually before a woman knows she is pregnant. Many babies with neural tube defects have difficulty walking and with bladder and bowel control. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU]

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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] 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 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] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [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] Occupational Therapy: The field concerned with utilizing craft or work activities in the rehabilitation of patients. Occupational therapy can also refer to the activities themselves. [NIH]

Odontoid Process: The toothlike process on the upper surface of the axis, which articulates with the atlas above. [NIH] Oligo: Chemical and mineral elements that exist in minimal (oligo) quantities in the body, in foods, in the air, in soil; name applied to any element observed as a microconstituent of plant or animal tissue and of beneficial, harmful, or even doubtful significance. [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] Oncology: The study of cancer. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Optic disc: The circular area (disc) where the optic nerve connects to the retina. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the

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suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Oral Manifestations: Disorders of the mouth attendant upon non-oral disease or injury. [NIH]

Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Osseointegration: The growth action of bone tissue, as it assimilates surgically implanted devices or prostheses to be used as either replacement parts (e.g., hip) or as anchors (e.g., endosseous dental implants). [NIH] Ossicles: The hammer, anvil and stirrup, the small bones of the middle ear, which transmit the vibrations from the tympanic membrane to the oval window. [NIH] Ossification: The formation of bone or of a bony substance; the conversion of fibrous tissue or of cartilage into bone or a bony substance. [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteoblasts: Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. [NIH] Osteocalcin: Vitamin K-dependent calcium-binding protein synthesized by osteoblasts and found primarily in bone. Serum osteocalcin measurements provide a noninvasive specific marker of bone metabolism. The protein contains three residues of the amino acid gammacarboxyglutamic acid (GLA), which, in the presence of calcium, promotes binding to hydroxyapatite and subsequent accumulation in bone matrix. [NIH] Osteochondrodysplasias: Abnormal development of cartilage and bone. [NIH] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Osteogenesis: The histogenesis of bone including ossification. It occurs continuously but particularly in the embryo and child and during fracture repair. [NIH] Osteogenesis Imperfecta: A collagen disorder resulting from defective biosynthesis of type I collagen and characterized by brittle, osteoporotic, and easily fractured bones. It may also present with blue sclerae, loose joints, and imperfect dentin formation. There are four major types, I-IV. [NIH] Osteopetrosis: Excessive formation of dense trabecular bone leading to pathological fractures, osteitis, splenomegaly with infarct, anemia, and extramedullary hemopoiesis. [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] Otosclerosis: The formation of spongy bone in the labyrinth capsule. The ossicles can become fixed and unable to transmit sound vibrations, thereby causing deafness. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH]

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Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxandrolone: A synthetic hormone with anabolic and androgenic properties. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Paralysis: Loss of ability to move all or part of the body. [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] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Parturition: The act or process of given birth to a child. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pediatric Endocrinologist: A doctor who sees and treats children with problems of the endocrine glands; diabetes is an endocrine disorder. [NIH] Pelvic: Pertaining to the pelvis. [EU] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH]

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Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Personnel Management: Planning, organizing, and administering all activities related to personnel. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photoperiod: The time period of daily exposure that an organism receives from daylight or

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artificial light. It is believed that photoperiodic responses may affect the control of energy balance and thermoregulation. [NIH] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] Physical Therapy: The restoration of function and the prevention of disability following disease or injury with the use of light, heat, cold, water, electricity, ultrasound, and exercise. [NIH]

Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Pituitary Hormones: Hormones secreted by the anterior and posterior lobes of the pituitary gland and the pars intermedia, an ill-defined region between the two. Their secretion is regulated by the hypothalamus. [NIH] Plague: An acute infectious disease caused by Yersinia pestis that affects humans, wild rodents, and their ectoparasites. This condition persists due to its firm entrenchment in sylvatic rodent-flea ecosystems throughout the world. Bubonic plague is the most common form. [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] 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] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]

Pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Pollen: The male fertilizing element of flowering plants analogous to sperm in animals. It is released from the anthers as yellow dust, to be carried by insect or other vectors, including wind, to the ovary (stigma) of other flowers to produce the embryo enclosed by the seed. The pollens of many plants are allergenic. [NIH]

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Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Portal System: A system of vessels in which blood, after passing through one capillary bed, is conveyed through a second set of capillaries before it returns to the systemic circulation. It pertains especially to the hepatic portal system. [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] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-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] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] 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] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prenatal Diagnosis: Determination of the nature of a pathological condition or disease in the postimplantation embryo, fetus, or pregnant female before birth. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare

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the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prosencephalon: The part of the brain developed from the most rostral of the three primary vesicles of the embryonic neural tube and consisting of the diencephalon and telencephalon. [NIH]

Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein 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] 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]

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

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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] Proxy: A person authorized to decide or act for another person, for example, a person having durable power of attorney. [NIH] Pruritic: Pertaining to or characterized by pruritus. [EU] Ptosis: 1. Prolapse of an organ or part. 2. Drooping of the upper eyelid from paralysis of the third nerve or from sympathetic innervation. [EU] Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [EU] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulmonary Ventilation: The total volume of gas per minute inspired or expired measured in liters per minute. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

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] Radioactive: Giving off radiation. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of

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an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Rape: Unlawful sexual intercourse without consent of the victim. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] 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] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflux: The term used when liquid backs up into the esophagus from the stomach. [NIH] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Replicon: In order to be replicated, DNA molecules must contain an origin of duplication and in bacteria and viruses there is usually only one per genome. Such molecules are called replicons. [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] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH]

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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] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] 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] Rickets: A condition caused by deficiency of vitamin D, especially in infancy and childhood, with disturbance of normal ossification. The disease is marked by bending and distortion of the bones under muscular action, by the formation of nodular enlargements on the ends and sides of the bones, by delayed closure of the fontanelles, pain in the muscles, and sweating of the head. Vitamin D and sunlight together with an adequate diet are curative, provided that the parathyroid glands are functioning properly. [EU] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Saline: A solution of salt and water. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] 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] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH]

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Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerae: A circular furrow between the sclerocorneal junction and the iris. [NIH] Scleroproteins: Simple proteins characterized by their insolubility and fibrous structure. Within the body, they perform a supportive or protective function. [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] Sebaceous: Gland that secretes sebum. [NIH] Sebaceous gland: Gland that secretes sebum. [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] 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] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semicircular canal: Three long canals of the bony labyrinth of the ear, forming loops and opening into the vestibule by five openings. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Sequester: A portion of dead bone which has become detached from the healthy bone tissue, as occurs in necrosis. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH]

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Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the 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] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [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] 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] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a

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neurotransmitter in the central and peripheral nervous systems. [NIH] Somatotropin: A small peptide hormone released by the anterior pituitary under hypothalamic control. Somatotropin, or growth hormone, stimulates mitosis, cell growth, and, for some cell types, differentiation in many tissues of the body. It has profound effects on many aspects of gene expression and metabolism. [NIH] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Spasticity: A state of hypertonicity, or increase over the normal tone of a muscle, with heightened deep tendon reflexes. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrophotometry: The art or process of comparing photometrically the relative intensities of the light in different parts of the spectrum. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Speech pathologist: A specialist who evaluates and treats people with communication and swallowing problems. Also called a speech therapist. [NIH] 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] Spina bifida: A defect in development of the vertebral column in which there is a central deficiency of the vertebral lamina. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones,

158 Dwarfism

bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] 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] Streptomycin: O-2-Deoxy-2-(methylamino)-alpha-L-glucopyranosyl-(1-2)-O-5- deoxy-3-Cformyl-alpha-L-lyxofuranosyl-(1-4)-N,N'-bis(aminoiminomethyl)-D-streptamine. Antibiotic substance produced by the soil actinomycete Streptomyces griseus. It acts by inhibiting the initiation and elongation processes during protein synthesis. [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] 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] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Subthalamus: A transition zone in the anterior part of the diencephalon interposed between the thalamus, hypothalamus, and tegmentum of the mesencephalon. Components of the subthalamus include the subthalamic nucleus, zona incerta, nucleus of field H, and the nucleus of ansa lenticularis. The latter contains the entopeduncular nucleus. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Symphysis: A secondary cartilaginous joint. [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] Synovial: Of pertaining to, or secreting synovia. [EU] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above

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100 beats per minute. [NIH] Tarsal Bones: The seven bones which form the tarsus - namely, calcaneus, talus, cuboid, navicular, and first, second and third cuneiforms. The tarsus is a skeletal part of the foot. [NIH]

Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Tennis Elbow: A condition characterized by pain in or near the lateral humeral epicondyle or in the forearm extensor muscle mass as a result of unusual strain. It occurs in tennis players as well as housewives, artisans, and violinists. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Thalamus: Paired bodies containing mostly gray substance and forming part of the lateral wall of the third ventricle of the brain. The thalamus represents the major portion of the diencephalon and is commonly divided into cellular aggregates known as nuclear groups. [NIH]

Thanatophoric Dysplasia: A severe form of neonatal dwarfism with very short limbs. All cases have died at birth or in the neonatal period. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermoregulation: Heat regulation. [EU] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Thoracic: Having to do with the chest. [NIH] Thorax: A part of the trunk between the neck and the abdomen; 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] Thrombocytopenia: A decrease in the number of blood platelets. [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]

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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]

Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] 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] Thyrotropin: A peptide hormone secreted by the anterior pituitary. It promotes the growth of the thyroid gland and stimulates the synthesis of thyroid hormones and the release of thyroxine by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [NIH] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH]

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Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] 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] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]

Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [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 marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH]

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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] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasopressor: 1. Stimulating contraction of the muscular tissue of the capillaries and arteries. 2. An agent that stimulates contraction of the muscular tissue of the capillaries and arteries. [EU]

Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vegetative: 1. Concerned with growth and with nutrition. 2. Functioning involuntarily or unconsciously, as the vegetative nervous system. 3. Resting; denoting the portion of a cell cycle during which the cell is not involved in replication. 4. Of, pertaining to, or characteristic of plants. [EU] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villi: The tiny, fingerlike projections on the surface of the small intestine. Villi help absorb nutrients. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virilization: The induction or development of male secondary sec characters, especially the induction of such changes in the female, including enlargement of the clitoris, growth of facial and body hair, development of a hairline typical of the male forehead, stimulation of secretion and proliferation of the sebaceous glands (often with acne), and deepening of the voice. Called also masculinization) [EU] 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] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] 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]

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War: Hostile conflict between organized groups of people. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] Weight-Bearing: The physical state of supporting an applied load. This often refers to the weight-bearing bones or joints that support the body's weight, especially those in the spine, hip, knee, and foot. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] Xeroderma Pigmentosum: A rare, pigmentary, and atrophic autosomal recessive disease affecting all races. It is manifested as an extreme photosensitivity to ultraviolet light as the result of a deficiency in the enzyme that permits excisional repair of ultraviolet-damaged DNA. [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] 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]

165

INDEX A Abdominal, 7, 115, 139, 147 Abdominal fat, 7, 115 Abdominal Pain, 115, 139 Acne, 115, 162 Acrodermatitis, 21, 115 Adaptability, 115, 122 Adenine, 115 Adenosine, 70, 115, 148 Adipose Tissue, 10, 115, 121 Adolescent Nutrition, 21, 115 Adrenal Cortex, 115, 126, 135, 150 Adrenal Glands, 115 Adrenal insufficiency, 17, 115 Adverse Effect, 115, 156 Affinity, 13, 115, 116 Agnosia, 60, 115 Agonist, 71, 116 Algorithms, 116, 119 Alkaline, 6, 116, 121 Alkaline Phosphatase, 6, 116 Alkaloid, 116, 121 Alleles, 5, 14, 16, 25, 116, 134 Alpha-helix, 116, 139 Alternative medicine, 82, 116 Alveolar Process, 116, 153 Ameliorating, 25, 116 Amelogenesis Imperfecta, 4, 116 Amenorrhea, 49, 116, 117 Amino Acid Sequence, 70, 116, 117, 131, 132 Amino Acids, 116, 124, 132, 147, 150, 151, 154, 158, 161 Ampulla, 116, 123 Anabolic, 7, 116, 128, 147 Anaemia, 116, 117 Anaesthesia, 116, 137 Analog, 116, 140 Analogous, 7, 117, 149, 161 Anatomical, 9, 117, 118, 129, 137, 155 Androgenic, 117, 147 Anemia, 95, 117, 146 Angiogenesis, 24, 26, 117 Animal model, 8, 18, 28, 73, 117 Anomalies, 35, 59, 75, 117 Anorexia, 52, 60, 72, 117 Anorexia Nervosa, 52, 60, 72, 117 Anterograde, 17, 117

Antibodies, 117, 134, 141 Antibody, 115, 117, 124, 134, 135, 137, 141, 157 Anticoagulant, 117, 151 Antigen, 115, 117, 124, 135, 136, 137, 141 Anti-infective, 117, 138 Antioxidant, 21, 117 Anxiety, 18, 72, 117 Aperture, 117, 120 Aplastic anaemia, 48, 117 Apolipoproteins, 118, 140 Apoptosis, 26, 27, 118 Approximate, 32, 118 Aqueous, 118, 119, 127 Arterial, 118, 122, 123, 125, 136, 151, 158 Arteries, 118, 120, 126, 140, 142, 152, 162 Arterioles, 118, 120, 121 Arthroplasty, 50, 118 Articular, 11, 28, 32, 118, 146 Aseptic, 118, 146, 157 Assay, 29, 118 Ataxia, 92, 95, 118, 135, 159 Atrial, 118, 125, 161 Atrioventricular, 118, 125 Atrium, 118, 125, 161, 162 Atrophy, 93, 94, 95, 118, 144 Autosuggestion, 118, 136 Axonal, 17, 118 Axons, 17, 118, 145 B Bacteria, 117, 118, 135, 142, 153, 157, 161, 162 Basal Ganglia, 118, 119, 120 Basal Ganglia Diseases, 118, 119 Base, 10, 24, 31, 115, 119, 126, 127, 131, 132, 139, 149 Base Sequence, 119, 131, 132 Basement Membrane, 119, 131 Benign, 119, 120, 134, 144 Bilateral, 34, 119 Bile, 119, 132, 140, 158 Biliary, 119, 123 Binding Sites, 16, 119 Bioavailability, 24, 119 Biochemical, 14, 16, 24, 25, 27, 116, 119, 146 Biological therapy, 119, 133 Biomarkers, 21, 29, 119

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Biosynthesis, 13, 33, 42, 55, 56, 119, 146 Biotechnology, 32, 34, 76, 82, 89, 91, 94, 95, 96, 100, 101, 119 Biotransformation, 120 Bladder, 120, 137, 144, 151, 161 Blast phase, 120, 123 Blepharophimosis, 49, 120 Bloating, 120, 139 Blood Coagulation, 120, 121, 159 Blood pressure, 18, 120, 136, 143, 152 Blood vessel, 29, 117, 120, 121, 125, 126, 129, 139, 141, 142, 148, 156, 158, 159, 160, 162 Body Composition, 7, 11, 58, 120 Body Fluids, 119, 120, 161 Bone Density, 66, 67, 120 Bone Development, 30, 120 Bone Marrow, 117, 120, 123, 140, 141, 156 Bowel, 120, 128, 144, 158 Bowel Movement, 120, 128, 158 Brain Neoplasms, 120, 135, 159 Branch, 109, 120, 127, 141, 147, 157, 159 Breakdown, 6, 121, 128, 132 Breeding, 8, 121 Bronchi, 121, 130, 160 Brown Fat, 10, 121 Burns, 71, 121 Burns, Electric, 121 C Calcium, 6, 11, 58, 121, 124, 136, 146, 147, 156 Callus, 121, 129 Camptothecin, 25, 58, 121 Capillary, 121, 141, 150, 162 Carbohydrate, 121, 133, 150 Carcinogenesis, 27, 121 Carcinogenic, 121, 138, 145, 151, 158 Carcinogens, 121, 145 Cardiac, 25, 121, 126, 130, 143, 157 Cardiomyopathy, 121 Cardiopulmonary, 77, 121 Cardiovascular, 8, 71, 72, 121 Case report, 4, 17, 37, 39, 44, 47, 121, 122, 123 Case series, 122, 123 Caudal, 122, 128, 136, 150 Cell Cycle, 12, 26, 27, 35, 122, 126, 162 Cell Death, 17, 26, 118, 122, 144 Cell Differentiation, 12, 122, 156 Cell Division, 23, 27, 94, 118, 122, 127, 132, 133, 141, 142, 143, 149, 155 Cell proliferation, 12, 122, 156

Cell Survival, 122, 133 Cellulose, 122, 149 Central Nervous System, 43, 46, 61, 120, 122, 133, 134, 135, 146 Central Nervous System Infections, 122, 134, 135 Cerebellar, 118, 122, 153 Cerebral, 75, 93, 118, 119, 120, 122, 123, 129, 130, 131, 135, 157, 159 Cerebral Infarction, 122, 135 Cerebral Palsy, 75, 122, 157 Cerebrospinal, 122, 135 Cerebrospinal fluid, 122, 135 Cerebrum, 122, 161 Cholestasis, 45, 123 Cholesterol, 119, 123, 140, 158 Cholesterol Esters, 123, 140 Chondrogenesis, 29, 123 Chromatin, 10, 118, 123 Chromosomal, 25, 123, 154 Chromosome, 19, 43, 52, 58, 73, 123, 134, 140, 154, 155 Chronic, 6, 7, 14, 17, 28, 94, 120, 123, 124, 127, 129, 137, 139, 150 Chronic lymphocytic leukemia, 123 Chronic myelogenous leukemia, 120, 123 Chronic phase, 17, 123 Chronic renal, 14, 123, 150 Chylomicrons, 123, 140 Cleft Palate, 35, 123 Clinical Medicine, 123, 150 Clinical study, 15, 123 Clinical trial, 4, 25, 65, 67, 89, 123, 125, 151, 153 Clone, 5, 9, 123 Cloning, 7, 25, 33, 47, 70, 119, 123, 138 Cochlea, 124, 138 Codon, 49, 70, 124, 132 Cofactor, 124, 151, 159 Colitis, 124, 139 Collagen, 7, 20, 24, 28, 31, 119, 124, 135, 146, 151 Collagen disease, 124, 135 Collapse, 121, 124 Complement, 124, 125, 132 Complementary and alternative medicine, 55, 62, 124 Complementary medicine, 55, 125 Complementation, 20, 125 Computational Biology, 89, 91, 125 Conception, 125, 131, 157 Concomitant, 17, 125

Index 167

Cone, 43, 44, 125 Congestive heart failure, 71, 72, 125 Conjugated, 125, 127, 145 Connective Tissue, 120, 124, 125, 131, 142, 151 Consciousness, 125, 128 Constipation, 125, 139 Constriction, 125, 139, 154 Continuous infusion, 7, 125 Contraindications, ii, 125 Control group, 15, 125, 152 Controlled study, 6, 125 Cor, 71, 72, 125 Coronary, 126, 142 Coronary Thrombosis, 126, 142 Corpus, 39, 126, 140, 150, 159 Corpus Callosum, 39, 126, 159 Cortex, 118, 126, 131, 153 Cortical, 7, 43, 126, 155, 159 Corticosteroids, 56, 126, 132 Cortisol, 7, 18, 22, 126 Cranial, 126, 134, 138, 145, 148, 157 Craniocerebral Trauma, 119, 126, 134, 135, 159 Creatinine, 6, 126 Crossing-over, 126, 153 Curative, 73, 126, 154, 159 Cyclin, 23, 27, 126 Cysteine, 44, 126, 158 Cystine, 76, 126 Cytidine, 70, 126 Cytochrome, 126 Cytogenetics, 58, 127, 154 Cytoplasm, 118, 127, 133, 154 Cytosine, 126, 127 Cytotoxic, 25, 127, 156 D Databases, Bibliographic, 89, 127 Degenerative, 127, 146 Deletion, 9, 18, 23, 29, 31, 118, 127 Dendrites, 127, 145 Density, 5, 6, 15, 66, 120, 127, 140, 145 Dental Materials, 4, 127 Deoxyribonucleic, 127, 154 Deoxyribonucleic acid, 127, 154 Depolarization, 127, 156 Dermal, 127, 140 Deuterium, 127, 135 Diabetes Insipidus, 49, 127 Diagnostic procedure, 69, 82, 127 Diarrhea, 71, 72, 127, 139 Diastole, 127, 128

Diastolic, 7, 128, 136 Diastolic blood pressure, 7, 128 Diencephalon, 16, 128, 130, 136, 151, 158, 159 Digestion, 119, 120, 128, 140, 158 Digestive system, 68, 128, 143 Dihydrotestosterone, 128, 153 Dilatation, 128, 150 Dilation, 128, 135 Dimerization, 128 Diploid, 125, 128, 149 Direct, iii, 12, 19, 22, 27, 123, 128, 153 Discrimination, 128 Dissociation, 115, 128 Distal, 118, 128 Dominance, 128 Dorsal, 128, 130, 150 Dreams, 75, 128 Drug Interactions, 128 Dysostosis, 76, 128 Dysplasia, 11, 26, 36, 37, 39, 43, 44, 45, 50, 95, 100, 129 Dystrophy, 52, 92, 94, 129 E Eating Disorders, 72, 129 Ectopic, 31, 129 Efficacy, 5, 11, 129, 161 Elastin, 124, 129 Electrons, 117, 119, 129, 138, 147, 152 Embryo, 120, 122, 129, 131, 132, 137, 142, 146, 149, 150 Embryogenesis, 29, 129 Enamel, 4, 92, 116, 129, 139 Encephalocele, 129, 144 Endemic, 129, 157 Endocrine Glands, 129, 147 Endocrine System, 129, 144 Endothelial cell, 129, 131, 159 End-stage renal, 14, 123, 129, 150 Energy balance, 129, 149 Enhancer, 16, 31, 129 Environmental Exposure, 129, 145 Environmental Health, 88, 90, 130 Enzymatic, 70, 121, 124, 130, 154 Enzyme, 70, 116, 121, 130, 133, 142, 148, 150, 151, 153, 156, 159, 162, 163 Epicanthus, 49, 130 Epidemic, 130, 157 Epidermal, 130, 140, 141 Epidermis, 130, 139, 140 Epigastric, 130, 147 Epinephrine, 130, 161

168 Dwarfism

Epiphyseal, 11, 12, 15, 29, 50, 130 Epiphyses, 43, 44, 130 Epithalamus, 128, 130 Erythrocytes, 116, 117, 120, 130 Esophagus, 128, 130, 153, 158 Essential Tremor, 95, 130 Estrogen, 67, 130, 151 Eukaryotic Cells, 9, 130, 137 Excisional, 130, 163 Exocrine, 130, 147 Exogenous, 120, 130, 151 Exon, 5, 27, 131 Extracellular, 11, 24, 33, 125, 131, 146 Extracellular Matrix, 11, 24, 125, 131, 146 Extracellular Space, 131 F Facial, 3, 131, 162 Failure to Thrive, 41, 131 Family Planning, 89, 131 Fat, 7, 11, 115, 120, 125, 131, 140, 156 Fatigue, 18, 72, 131, 134 Femoral, 6, 131 Femur, 44, 131 Fetal Development, 131, 144 Fetus, 26, 120, 131, 150, 161 Fibroblast Growth Factor, 26, 30, 33, 35, 49, 72, 73, 131 Fibrosis, 95, 131, 155 Fissure, 4, 123, 126, 131 Flexor, 131, 135, 140 Fold, 130, 131 Forearm, 120, 131, 159 Frameshift, 22, 131 Frameshift Mutation, 22, 131 Fructose, 131, 132 G Gait, 112, 132 Gallbladder, 115, 119, 128, 132 Gas, 132, 135, 139, 152, 153 Gas exchange, 132, 153 Gastrin, 132, 135 Gastrointestinal, 72, 130, 132, 156, 158, 161 Gastrointestinal tract, 132, 156, 161 Gene Expression, 5, 8, 18, 21, 29, 32, 70, 95, 132, 157 Genetic Code, 70, 132, 145 Genetic Engineering, 119, 124, 132 Genotype, 25, 132, 148 Germ Cells, 132, 141, 146 Germ Layers, 120, 132 Gestation, 132, 148 Gibberellin, 132

Gigantism, 38, 132 Gland, 17, 115, 132, 147, 149, 151, 155, 160 Glucocorticoid, 132, 135 Glucose, 7, 21, 23, 94, 122, 132, 133, 134, 138, 154 Glucose tolerance, 7, 133 Glucose Tolerance Test, 7, 133 Glutamic Acid, 133, 151 Glutathione Peroxidase, 133, 155 Glycosaminoglycans, 133, 151 Gonad, 133 Gonadal, 5, 92, 133, 157 Gonadorelin, 133, 140 Gonadotropin, 133, 140 Governing Board, 133, 150 Graft, 133, 135 Granulocytes, 133, 139, 156, 163 Granulocytopenia, 117, 133 Growth Disorders, 27, 133 Growth factors, 15, 133 Growth Plate, 7, 12, 29, 66, 133 H Haploid, 134, 149 Haptens, 115, 134 Headache, 72, 134, 135 Headache Disorders, 134 Heart failure, 134 Heme, 126, 134 Hemoglobin, 117, 130, 134 Hemoglobinuria, 94, 134 Hemorrhage, 126, 134, 158 Hepatic, 21, 133, 134, 150 Hepatocyte, 123, 134 Hereditary, 9, 28, 72, 77, 115, 116, 134, 144, 148, 154 Heredity, 132, 134 Heterogeneity, 115, 134 Heterozygote, 33, 134 Hibernation, 121, 134 Histology, 32, 134 Homeostasis, 7, 8, 21, 58, 135 Homeotic, 135 Homologous, 24, 116, 126, 134, 135, 155, 158 Homozygotes, 128, 135 Hormonal, 20, 118, 135 Hormone Replacement Therapy, 23, 135 Hormone therapy, 20, 24, 72, 135 Host, 25, 135 Human Development, 19, 65, 66, 67, 88, 101, 135

Index 169

Human growth hormone, 11, 14, 32, 34, 38, 52, 70, 135, 156 Humeri, 9, 135 Hybrid, 22, 123, 135 Hybridization, 19, 135 Hydrocephalus, 43, 135, 138 Hydrocortisone, 18, 135 Hydrogen, 70, 119, 121, 127, 133, 135, 143, 145, 147, 148, 152 Hydrolysis, 120, 136, 148, 150 Hydrophobic, 136, 140 Hydroxylysine, 124, 136 Hydroxyproline, 124, 136 Hypercalcemia, 7, 136 Hyperplasia, 22, 136, 140 Hypersensitivity, 58, 71, 72, 136 Hypertension, 71, 72, 136, 138 Hypertrophic cardiomyopathy, 48, 136 Hypertrophy, 25, 126, 136, 161 Hypophyseal, 136, 141 Hypophysis, 136, 155 Hypoplasia, 35, 57, 73, 92, 116, 136 Hypothalamic, 16, 17, 38, 71, 136, 157 Hypothalamus, 120, 128, 133, 136, 141, 149, 156, 158, 159 Hypothyroidism, 5, 58, 136 I Iatrogenic, 58, 136 Id, 53, 61, 102, 108, 110, 136 Idiopathic, 18, 28, 115, 136 Ileus, 71, 72, 136 Immortal, 20, 137 Immune function, 21, 137 Immune response, 117, 134, 137, 158, 162 Immune system, 21, 119, 137, 141, 144, 162, 163 Immunodeficiency, 94, 137 Immunofluorescence, 32, 137 Immunology, 115, 137 Impairment, 18, 93, 115, 118, 123, 137, 142 In situ, 5, 17, 137 In Situ Hybridization, 5, 17, 137 In vitro, 9, 16, 20, 24, 26, 29, 137, 160 In vivo, 10, 16, 24, 26, 30, 137 Incontinence, 135, 137 Indicative, 76, 137, 147, 162 Induction, 25, 26, 27, 137, 151, 162 Infancy, 57, 137, 154 Infantile, 115, 137 Infarction, 122, 126, 137, 142 Infection, 118, 119, 137, 141, 163 Infertility, 5, 33, 137

Inflammation, 115, 124, 131, 135, 137 Infusion, 7, 58, 138 Ingestion, 133, 138 Initiation, 13, 23, 29, 138, 158, 160 Inner ear, 65, 138 Innervation, 138, 152 Insertional, 23, 138 Insight, 19, 28, 138 Insulin, 7, 15, 19, 21, 24, 33, 58, 92, 133, 138 Insulin-dependent diabetes mellitus, 138 Insulin-like, 15, 24, 58, 138 Intervertebral, 32, 138 Intestinal, 133, 138, 141 Intestines, 115, 132, 136, 138, 155 Intoxication, 138, 163 Intracellular, 137, 138, 155, 156 Intracranial Hemorrhages, 135, 138, 159 Intracranial Hypertension, 134, 135, 138 Intravenous, 138 Intrinsic, 115, 119, 138 Invasive, 138, 141 Involuntary, 119, 130, 138, 143 Iodine, 56, 57, 59, 60, 61, 138 Ions, 119, 128, 135, 138 Iris, 139, 155 Irritable Bowel Syndrome, 72, 139 Ischemia, 118, 139 J Joint, 11, 28, 31, 39, 42, 56, 72, 118, 131, 139, 146, 158 K Kb, 5, 88, 139 Keratin, 139 Kidney Disease, 68, 88, 95, 139 Kidney Failure, 129, 139 Kinetic, 139 L Labyrinth, 124, 138, 139, 146, 155, 162 Lactation, 139, 151 Large Intestine, 128, 138, 139, 153, 156 Larynx, 139, 160 Lesion, 139, 140, 161 Lethal, 31, 35, 42, 45, 49, 79, 139 Lethargy, 135, 136, 139 Leucocyte, 139, 141 Leukemia, 22, 52, 94, 123, 140 Leukocytes, 120, 133, 140, 148 Leuprolide, 5, 140 Library Services, 8, 108, 140 Lichen Planus, 38, 140 Ligament, 140, 151 Linkage, 27, 140

170 Dwarfism

Lipid, 59, 118, 138, 140 Lipoprotein, 7, 140 Liposarcoma, 22, 140 Liver, 10, 21, 115, 119, 128, 132, 133, 134, 140 Lobe, 38, 122, 135, 140 Localization, 23, 43, 140 Localized, 137, 140, 149, 161 Locomotion, 140, 149 Loop, 22, 140 Low-density lipoprotein, 140 Lutein Cells, 140, 151 Lymphatic, 137, 140, 141, 142, 156, 160 Lymphatic system, 141, 156, 160 Lymphoblasts, 58, 141 Lymphocyte, 20, 117, 141 Lymphoid, 117, 126, 139, 141 Lymphoma, 61, 94, 141 M Magnetic Resonance Imaging, 10, 141 Malabsorption, 94, 141 Malformation, 43, 141 Malignant, 27, 94, 120, 141, 144 Malnutrition, 118, 141, 143 Mandible, 116, 141, 153 Manifest, 118, 141 Medial, 135, 141, 157 Median Eminence, 17, 141 Mediate, 16, 141 Mediator, 12, 141 MEDLINE, 89, 91, 95, 141 Medullary, 45, 141 Meiosis, 13, 141, 158 Melanin, 139, 141, 148, 161 Melanocytes, 141, 142 Melanoma, 94, 142 Membrane, 13, 24, 124, 127, 130, 136, 139, 142, 143, 146, 148, 154, 156 Memory, 16, 18, 117, 142 Meninges, 122, 126, 142 Menopause, 142, 150 Menstruation, 116, 142 Mental Disorders, 68, 142 Mental Retardation, 19, 24, 92, 93, 94, 96, 142 Mentors, 18, 142 Meristem, 142 Mesenchymal, 30, 142 Mesoderm, 25, 142 Metabolic disorder, 127, 142 Metatarsal Bones, 30, 142 Metatarsus, 142

Methionine, 70, 142, 158 MI, 112, 142 Microorganism, 124, 142, 162 Microscopy, 17, 21, 29, 32, 119, 142 Migration, 26, 142 Milliliter, 120, 142 Mitochondrial Swelling, 143, 144 Mitosis, 118, 143, 157 Mitotic, 13, 143 Mobility, 9, 143 Modification, 4, 132, 143, 152 Molecule, 117, 119, 124, 126, 128, 136, 138, 143, 145, 147, 149, 151, 153, 156, 162 Monitor, 8, 126, 143, 145 Morphogenesis, 9, 30, 143 Morphology, 13, 34, 143 Mucosa, 143, 151 Mucositis, 143, 160 Muscle Fibers, 143 Muscular Atrophy, 94, 143 Muscular Dystrophies, 129, 143 Mutagenesis, 23, 143 Mutagenic, 22, 143 Mutagens, 131, 143 Myocardium, 142, 143 Myotonic Dystrophy, 94, 143 Myxedema, 52, 144 N Naive, 17, 144 NCI, 1, 67, 87, 144 Necrosis, 17, 118, 122, 137, 142, 144, 155 Need, 3, 22, 66, 71, 75, 77, 103, 123, 144, 160 Neonatal, 31, 35, 37, 45, 144, 159 Neonatal period, 144, 159 Neoplasia, 94, 144 Neoplasm, 144 Neoplastic, 23, 135, 141, 144 Nephropathy, 40, 139, 144 Nerve, 118, 127, 138, 141, 144, 145, 150, 152, 155, 161 Nervous System, 95, 122, 141, 144, 145, 148, 162 Neural, 23, 129, 144, 151 Neural tube defects, 23, 144 Neurodegenerative Diseases, 72, 119, 144 Neuroendocrine, 18, 33, 60, 144 Neurologic, 129, 135, 144 Neurology, 52, 61, 144 Neuronal, 17, 144 Neurons, 16, 38, 127, 144, 145, 158

Index 171

Nuclear, 13, 23, 119, 121, 129, 130, 144, 145, 159 Nuclear Pore, 23, 145 Nuclear Proteins, 145 Nuclei, 129, 130, 132, 141, 143, 145, 152 Nucleic acid, 119, 127, 132, 135, 137, 143, 145, 154 Nucleic Acid Hybridization, 135, 145 Nucleus, 26, 118, 119, 123, 127, 130, 141, 145, 152, 158, 159 O Occupational Therapy, 77, 145 Odontoid Process, 36, 145 Oligo, 145 Oncogene, 27, 94, 145 Oncogenic, 27, 145 Oncology, 28, 56, 61, 145 Opacity, 127, 145 Operon, 145, 153 Optic disc, 45, 145 Optic Nerve, 145, 154 Oral Manifestations, 101, 146 Organ Culture, 30, 146, 160 Osseointegration, 120, 146 Ossicles, 146 Ossification, 11, 24, 29, 93, 146, 154 Osteoarthritis, 28, 31, 146 Osteoblasts, 29, 30, 146 Osteocalcin, 7, 146 Osteochondrodysplasias, 9, 146 Osteoclasts, 29, 146 Osteogenesis, 65, 66, 100, 120, 123, 146 Osteogenesis Imperfecta, 65, 66, 100, 146 Osteopetrosis, 29, 146 Osteoporosis, 3, 32, 67, 71, 72, 92, 146 Otosclerosis, 65, 146 Ovary, 133, 146, 147, 149 Ovulation, 146, 147 Ovum, 39, 132, 147, 151 Oxandrolone, 67, 147 Oxidation, 117, 120, 126, 133, 147 P Palate, 123, 147 Palliative, 147, 159 Pancreas, 39, 115, 119, 128, 138, 147, 156, 161 Pancreatic, 94, 147 Pancreatic cancer, 94, 147 Paralysis, 75, 147, 152, 157 Parathyroid, 147, 154 Parathyroid Glands, 147, 154 Paroxysmal, 94, 134, 147

Parturition, 147, 151 Pathogenesis, 25, 28, 30, 77, 147 Pathologic, 118, 126, 136, 147, 153 Pathologic Processes, 118, 147 Pathophysiology, 6, 147 Patient Education, 101, 106, 108, 112, 147 Pediatric Endocrinologist, 18, 147 Pelvic, 147, 151 Peptide, 14, 33, 131, 139, 147, 150, 151, 157, 160 Perception, 125, 147, 155 Perfusion, 148, 160 Perinatal, 9, 148 Periodontal disease, 4, 148 Peripheral blood, 118, 148 Peripheral Nervous System, 144, 148, 157, 158 Peroxidase, 52, 148 Peroxide, 133, 148 Personnel Management, 8, 148 PH, 7, 120, 148 Pharmacokinetic, 148 Pharmacologic, 148, 160 Phenotype, 5, 9, 14, 19, 20, 24, 25, 32, 46, 125, 148 Phenylalanine, 148, 161 Phospholipases, 148, 156 Phospholipids, 131, 140, 148 Phosphorus, 121, 147, 148 Phosphorylation, 23, 148 Photoperiod, 148 Photosensitivity, 149, 163 Physical Therapy, 75, 77, 149 Physiologic, 23, 116, 119, 131, 142, 149, 153 Physiology, 10, 20, 28, 55, 149 Pigment, 141, 142, 149 Pituitary Gland, 16, 17, 18, 131, 133, 149 Pituitary Hormones, 16, 149 Plague, 17, 149 Plants, 13, 52, 116, 121, 133, 143, 149, 154, 162 Plasma, 13, 21, 58, 117, 123, 133, 134, 139, 149, 155, 160 Platelet Activation, 149, 156 Platinum, 140, 149 Pleated, 139, 149 Point Mutation, 11, 18, 149 Pollen, 149 Polycystic, 39, 95, 150 Polymerase, 9, 70, 150, 153 Polymorphism, 150

172 Dwarfism

Polypeptide, 116, 124, 135, 150, 151, 156, 163 Polysaccharide, 117, 122, 150, 151 Portal System, 141, 150 Posterior, 35, 118, 128, 130, 139, 147, 149, 150, 157 Postmenopausal, 146, 150 Postnatal, 41, 150, 157 Postsynaptic, 150, 156 Post-traumatic, 17, 134, 150 Potentiation, 150, 156 Practicability, 150, 161 Practice Guidelines, 90, 150 Precursor, 5, 123, 130, 148, 150, 161 Premenopausal, 7, 150 Prenatal, 34, 39, 42, 47, 50, 129, 150 Prenatal Diagnosis, 39, 42, 47, 50, 150 Probe, 5, 150 Progesterone, 150, 151, 157 Progression, 25, 29, 117, 151 Progressive, 3, 27, 34, 40, 61, 92, 122, 123, 133, 143, 144, 146, 149, 151 Prolactin, 5, 17, 18, 151 Proline, 124, 136, 151 Promoter, 7, 70, 151 Prone, 9, 151 Prophylaxis, 56, 151 Proportional, 5, 151 Prosencephalon, 128, 151 Prostate, 94, 119, 151, 161 Protease, 24, 151 Protein Binding, 151, 160 Protein C, 9, 13, 34, 116, 118, 124, 139, 140, 146, 151 Protein Conformation, 116, 139, 151 Protein S, 76, 95, 119, 132, 135, 146, 151, 154, 158 Proteoglycan, 29, 151 Protocol, 18, 20, 27, 28, 151 Protons, 135, 152 Proxy, 52, 60, 152 Pruritic, 140, 152 Ptosis, 49, 152 Puberty, 5, 67, 152 Public Policy, 89, 152 Publishing, 32, 152 Pulmonary, 120, 126, 139, 152, 153, 162 Pulmonary Artery, 120, 152, 162 Pulmonary hypertension, 126, 152 Pulmonary Ventilation, 152, 153 Pulse, 143, 152

Q Quality of Life, 6, 9, 15, 17, 152 R Race, 142, 152 Radiation, 130, 152, 163 Radioactive, 135, 145, 152 Radiological, 7, 152 Radiology, 25, 36, 37, 45, 46, 47, 79, 152 Random Allocation, 152 Randomization, 14, 152 Randomized, 6, 15, 18, 129, 153 Rape, 153 Reactive Oxygen Species, 22, 153 Recombinant, 7, 11, 14, 32, 47, 153, 162 Recombination, 13, 24, 153 Rectum, 120, 128, 132, 137, 139, 151, 153 Red Nucleus, 118, 153 Reductase, 42, 153 Refer, 1, 72, 124, 140, 144, 145, 153 Reflux, 40, 153 Regeneration, 12, 131, 153 Regimen, 11, 129, 153 Replicon, 25, 153 Repressor, 16, 145, 153 Resorption, 24, 135, 146, 153 Respiration, 143, 153 Respiratory System, 66, 153 Restoration, 149, 153, 163 Retina, 94, 145, 154 Retinal, 125, 145, 154 Retinoblastoma, 22, 94, 154 Retrograde, 17, 154 Ribonucleic acid, 70, 154 Ribose, 115, 126, 154 Ribosome, 154, 161 Rickets, 58, 154 Rigidity, 149, 154 S Saline, 8, 154 Salivary, 128, 147, 154 Salivary glands, 128, 154 Saponins, 154, 158 Satellite, 8, 154 Schizoid, 154, 163 Schizophrenia, 154, 155, 163 Schizotypal Personality Disorder, 155, 163 Sclerae, 65, 146, 155 Scleroproteins, 139, 155 Sclerosis, 95, 124, 155 Scoliosis, 19, 36, 155 Screening, 27, 123, 155 Sebaceous, 155, 162

Index 173

Sebaceous gland, 155, 162 Secretion, 7, 18, 28, 48, 57, 115, 128, 133, 136, 138, 139, 149, 155, 162 Segmentation, 43, 44, 155 Segregation, 153, 155 Seizures, 147, 155 Selenium, 57, 155 Sella, 17, 94, 149, 155 Semen, 151, 155 Semicircular canal, 138, 155 Semisynthetic, 121, 155 Senescence, 12, 20, 155 Senile, 146, 155 Sequencing, 27, 155 Sequester, 27, 155 Serum, 6, 7, 124, 133, 140, 146, 155 Sex Characteristics, 152, 156, 159 Sex Determination, 95, 156 Shock, 135, 156, 161 Side effect, 115, 119, 156, 160 Signal Transduction, 25, 26, 30, 156 Skeletal, 3, 7, 9, 10, 12, 19, 24, 26, 28, 29, 30, 32, 45, 77, 112, 128, 133, 143, 156, 159 Skeleton, 9, 29, 131, 139, 156 Skull, 45, 126, 129, 144, 156 Small intestine, 123, 135, 138, 156, 162 Social Environment, 152, 156 Soft tissue, 120, 156 Solid tumor, 117, 156 Somatic, 129, 141, 143, 148, 156 Somatic cells, 141, 143, 156 Somatostatin, 17, 71, 156 Somatotropin, 6, 60, 157 Spastic, 72, 139, 157 Spasticity, 75, 157 Specialist, 103, 128, 157 Species, 19, 121, 130, 134, 135, 141, 142, 143, 152, 153, 157, 158, 161, 163 Specificity, 115, 157, 160 Spectrophotometry, 43, 157 Spectrum, 157 Speech pathologist, 77, 157 Sperm, 13, 123, 149, 157 Sphenoid, 155, 157 Spina bifida, 144, 157 Spinal cord, 122, 123, 142, 144, 148, 157 Splenomegaly, 146, 157 Sporadic, 25, 72, 144, 154, 157 Stem Cells, 24, 30, 157 Sterile, 118, 147, 157 Sterility, 13, 137, 157 Steroid, 7, 67, 126, 154, 157

Stomach, 115, 128, 130, 132, 133, 135, 138, 153, 156, 158 Stool, 137, 139, 158 Strand, 22, 25, 27, 58, 70, 150, 158 Streptomycin, 158 Stress, 22, 71, 72, 126, 139, 158 Stroke, 68, 71, 72, 88, 158 Subarachnoid, 134, 138, 158 Subspecies, 157, 158 Substance P, 155, 158 Subthalamus, 128, 158 Sulfur, 142, 158 Supplementation, 14, 57, 58, 59, 158 Suppression, 19, 23, 34, 158 Symphysis, 151, 158 Synaptic, 156, 158 Synergistic, 151, 158 Synovial, 28, 94, 158 Systemic, 4, 21, 120, 124, 130, 137, 138, 150, 158, 161 Systolic, 136, 158 T Tachycardia, 71, 72, 158 Tarsal Bones, 142, 159 Telangiectasia, 95, 159 Tennis Elbow, 135, 159 Terminator, 124, 159 Testosterone, 153, 159 Thalamic, 118, 130, 159 Thalamic Diseases, 118, 159 Thalamus, 120, 128, 130, 158, 159 Thanatophoric Dysplasia, 36, 159 Therapeutics, 159 Thermoregulation, 149, 159 Thigh, 131, 159 Third Ventricle, 130, 136, 141, 159 Thoracic, 9, 159, 163 Thorax, 19, 39, 115, 159 Threshold, 136, 159 Thrombin, 151, 159 Thrombocytopenia, 117, 159 Thrombomodulin, 151, 159 Thrombosis, 151, 158, 160 Thymidine, 70, 160 Thymus, 140, 141, 160 Thyroid, 5, 7, 21, 33, 52, 57, 100, 136, 138, 144, 147, 160, 161 Thyroid Gland, 144, 147, 160 Thyroid Hormones, 160, 161 Thyrotropin, 57, 136, 160 Thyroxine, 148, 160 Tissue Culture, 26, 27, 160

174 Dwarfism

Tissue Distribution, 5, 11, 160 Tolerance, 115, 133, 160 Tomography, 10, 120, 160 Topical, 4, 160 Toxic, iv, 130, 155, 160 Toxicity, 128, 160 Toxicokinetics, 160 Toxicology, 90, 160 Trachea, 25, 121, 139, 160 Transcription Factors, 9, 16, 18, 29, 41, 160 Transduction, 156, 161 Transfection, 119, 161 Translation, 23, 70, 161 Translocation, 26, 37, 161 Transmitter, 141, 161 Transplantation, 61, 123, 161 Trauma, 50, 65, 144, 161 Treatment Outcome, 5, 161 Tricuspid Atresia, 126, 161 Tryptophan, 124, 161 Tuberous Sclerosis, 95, 161 Tumor marker, 119, 161 Tyrosine, 24, 26, 161 U Ulcer, 71, 72, 161 Unconscious, 136, 161 Urethra, 151, 161 Urinary, 6, 52, 135, 137, 161 Urine, 120, 126, 127, 134, 137, 161 Uterus, 126, 142, 151, 161 V Vaccine, 151, 162 Vascular, 17, 134, 137, 160, 162 Vasopressor, 18, 162 Vector, 32, 138, 161, 162 Vegetative, 162

Vein, 138, 145, 154, 162 Venous, 122, 151, 161, 162 Ventral, 16, 136, 162 Ventricle, 118, 125, 152, 158, 159, 161, 162 Ventricular, 125, 135, 161, 162 Venules, 120, 121, 162 Vertebrae, 92, 138, 157, 162 Vertebral, 35, 43, 44, 50, 93, 157, 162 Vestibule, 124, 138, 155, 162 Veterinary Medicine, 89, 162 Villi, 135, 162 Viral, 145, 161, 162 Virilization, 22, 162 Virus, 20, 25, 122, 129, 132, 161, 162 Visceral, 7, 162 Vitro, 10, 16, 24, 162 Vivo, 26, 162 W War, 33, 38, 57, 76, 93, 94, 100, 163 Weight Gain, 58, 131, 163 Weight-Bearing, 29, 163 White blood cell, 117, 120, 123, 133, 140, 141, 163 Windpipe, 160, 163 Withdrawal, 72, 163 Wound Healing, 71, 131, 163 X Xenograft, 117, 163 Xeroderma Pigmentosum, 9, 163 X-ray, 6, 7, 11, 15, 72, 112, 120, 145, 152, 163 Y Yeasts, 148, 163 Z Zymogen, 151, 163

Index 175

176 Dwarfism

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