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

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

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

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Retinol: 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: 0-597-84607-3 1. Retinol-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 retinol. 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 RETINOL .................................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Retinol........................................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 59 The National Library of Medicine: PubMed ................................................................................ 61 CHAPTER 2. NUTRITION AND RETINOL ........................................................................................ 109 Overview.................................................................................................................................... 109 Finding Nutrition Studies on Retinol........................................................................................ 109 Federal Resources on Nutrition ................................................................................................. 115 Additional Web Resources ......................................................................................................... 115 CHAPTER 3. CLINICAL TRIALS AND RETINOL .............................................................................. 119 Overview.................................................................................................................................... 119 Recent Trials on Retinol............................................................................................................. 119 Keeping Current on Clinical Trials ........................................................................................... 120 CHAPTER 4. PATENTS ON RETINOL .............................................................................................. 123 Overview.................................................................................................................................... 123 Patents on Retinol...................................................................................................................... 123 Patent Applications on Retinol .................................................................................................. 144 Keeping Current ........................................................................................................................ 162 CHAPTER 5. BOOKS ON RETINOL .................................................................................................. 163 Overview.................................................................................................................................... 163 Chapters on Retinol.................................................................................................................... 163 CHAPTER 6. PERIODICALS AND NEWS ON RETINOL .................................................................... 165 Overview.................................................................................................................................... 165 News Services and Press Releases.............................................................................................. 165 Newsletter Articles .................................................................................................................... 166 Academic Periodicals covering Retinol ...................................................................................... 167 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 171 Overview.................................................................................................................................... 171 NIH Guidelines.......................................................................................................................... 171 NIH Databases........................................................................................................................... 173 Other Commercial Databases..................................................................................................... 175 The Genome Project and Retinol................................................................................................ 175 APPENDIX B. PATIENT RESOURCES ............................................................................................... 181 Overview.................................................................................................................................... 181 Patient Guideline Sources.......................................................................................................... 181 Finding Associations.................................................................................................................. 183 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 185 Overview.................................................................................................................................... 185 Preparation................................................................................................................................. 185 Finding a Local Medical Library................................................................................................ 185 Medical Libraries in the U.S. and Canada ................................................................................. 185 ONLINE GLOSSARIES................................................................................................................ 191 Online Dictionary Directories ................................................................................................... 191 RETINOL DICTIONARY............................................................................................................. 193 INDEX .............................................................................................................................................. 273

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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 retinol is indexed in search engines, such as www.google.com or others, a nonsystematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about retinol, 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 retinol, 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 retinol. 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 retinol, 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 retinol. 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 RETINOL Overview In this chapter, we will show you how to locate peer-reviewed references and studies on retinol.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and retinol, 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 “retinol” (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: •

Vitamins and Trace Metals Status in Non Insulin Dependent Diabetes Mellitus Source: International Journal of Vitamin and Nutrition Research. 61(4): 328-333. 1991. Summary: This article reports on a study in which the status of various vitamins and trace metals in plasma of 100 persons with noninsulin dependent diabetes mellitus (NIDDM) was compared to those of 112 age-and sex-matched individuals without diabetes. The plasma concentration of riboflavin, pyridoxine, and folic acid were found to be decreased in the people with diabetes, while retinol and ascorbic acid were relatively increased, in comparison to the control groups. However, in those with NIDDM, the mean plasma concentration of all the trace metals and vitamins, except for riboflavin, were within the range of normal values. In spite of these findings, the percent of patients with diabetes with various vitamin or metal deficiencies was significantly

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higher than in the healthy population. The authors conclude that vitamin and metal deficiency is common in people with NIDDM. 5 tables. 34 references. (AA-M). •

Psychological and Nutritional Effects of Redecorating the Physical Environment in Nursing Homes Source: Interdisciplinary Topics in Gerontology. Volume 26: 28-32. 1989. Summary: This journal article describes a study to evaluate the psychological and nutritional effects of a redecorated interior environment in a geriatric hospital in Sweden. The aim was to create a dining room environment in a style common to Swedish homes in the 1930s or early 1940s. For most patients, this environment would represent an active period in their lives. Sixteen patients, including five with dementia of the Alzheimer's type, participated. Data were collected during an 8 week preexperimental period, a 16 week experimental period, and an 8 week postexperimental period with the original environment. During the experimental period, a clear improvement was observed in the behavioral dimensions of facial expression, social interest, and conversation. The changed meal environment also resulted in increased intakes of energy and nutrients from originally low levels. Among the blood chemistry variables, blood folate, serum creatinine, and serum retinol showed significant increases during the experimental period. 4 references.

Federally Funded Research on Retinol The U.S. Government supports a variety of research studies relating to retinol. 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 retinol. 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 retinol. The following is typical of the type of information found when searching the CRISP database for retinol: •

Project Title: PHYSIOLOGY

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RETINOL

DEHYDROGENASE--PROPERTIES

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Principal Investigator & Institution: Blaner, William S.; Professor; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 15-MAY-1997; Project End 30-NOV-2004 Summary: The 9-cis-isomer of retinoic acid is proposed to be the retinoid ligand for the ligand-dependent transcription factors, the retinoid X receptors (RXRs). There is very 2

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

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little information available regarding how 9-cis-retinoic acid is synthesized within cells or tissues. Three pathways for 9-cis-retinoic acid formation have been proposed in the literature; through isomerization from all-trans-retinoic acid, through cleavage of 9-ciscarotene, and through two sequential enzyme catalyzed oxidations starting from 9-cisretinol. Studies proposed in this application will characterize fundamental upstream aspects of this later pathway. Specifically, in the first Aim of the application, we will investigate the biochemical factors and processes involved in the formation and metabolism of 9-cis-retinol. Our preliminary studies demonstrate that 9-cis-retinol is present at low levels in mouse liver, can be formed in a cellular milieu through isomerization from all-transretinol and can be processed and metabolized to 9-cis-retinyl esters by liver cells. Thus, the studies proposed in Aim I of the application will investigate the biochemistry of 9-cis-retinol formation and its metabolism. We have identified a previously unknown member of the fatty acid-binding protein (FABP) family of proteins. This 16 kDa protein binds 9-cis-, 13-cis- and all-trans-retinol but not other retinoids or long chain fatty acids, short chain fatty acids or fatty alcohols. For the mouse, this protein is 54 percent identical at the amino acid level to cellular retinolbinding protein, type I (CRBP I). In the second Aim of the application, we propose to investigate the biochemical properties of the human and mouse forms of this protein. We also propose to characterize the structures of the genes encoding these proteins and to investigate the physiological actions of the protein in the mouse. Thus, we are proposing to characterize the biochemical properties, genes and physiological function(s) of this protein in Aim 2. Based on our preliminary data, we also believe that this novel member of the FABP family of proteins may be involved in 9-cis-retinol formation and/or metabolism and as part of the studies proposed in Aims I and 2 we will investigate this hypothesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ABERRANT RETINOID SIGNALING IN BREAST CANCER Principal Investigator & Institution: Mira-Y-Lopez, Rafael; Associate Professor; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-APR-1991; Project End 31-AUG-2005 Summary: (Applicant's Abstract) The applicant's long term goal is to understand the role of the vitamin A signaling pathway in normal breast development and the role of inactivation of this pathway in breast cancer development. Vitamin A is essential in mammalian embryogenesis and the maintenance of tissue differentiation. Cellular response to vitamin A, or retinol, is mediated by a family of nuclear receptors for retinoic acid, i.e., cells must import, store and oxidize retinol, forming retinoic acid (RA) or other RAR ligands in order to evoke a response. The cellular retinol binding protein I (CRBP) was recently shown to be essential for vitamin A homeostasis due to its role in retinol storage. Once formed, RA binds to nuclear RA receptors (RAR-alpha, -beta, gamma), which act as ligand dependent transcription factors to regulate target gene transcription. RAR-beta2 is a growth suppressor that is inactivated in human breast cancer. The applicant has shown that CRBP expression is also inactivated in human breast cancer and that CRBP suppresses the malignant transformation of SV40 large Timmortalized human breast epithelial cells. These and other observations provide a strong rationale for the thus far untested hypothesis that underexpression of these and other retinoid signaling genes promote mammary carcinogenesis. He will now address this hypothesis using two animal models: CRBP and RAR knockout mice (Aim 1) and MMTV-dominant negative RAR (DNRAR) transgenic mice (Aim 2). The susceptibility of

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these animals to DMBA-induced carcinogenesis and the ability of functional RAR inactivation to synergize with the neu oncogene (bitransgenic animals) will be studied. Biomarker assays will identify the cellular process accounting for observed changes in tumor incidence. In Aim 3 the applicant will define the mechanism of tumor suppression by CRBP, focusing on the hypothesis, based on preliminary data, that CRBP increases retinol storage and RA availability and downregulates the expression of invasion and metastasis genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALCOHOL INTAKE AND RETINOID METABOLISM AND SIGNALING Principal Investigator & Institution: Wang, Xiang-Dong; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 28-FEB-2005 Summary: (provided by applicant): Our long-term objective is to study the +___________________________________ chemopreventive effect of retinoids on chronic and excessive alcohol related carcinogenesis in the liver and peripheral organs. The present grant proposal focuses on cell proliferation, which plays a central role in hepatic carcinogenesis in both the initiation and promotion stages, particularly when chemical carcinogens are involved. Retinoic acid plays an important role in controlling carcinogenic progression in a variety of cancers, including liver cancer. One of the chemopreventive effects of retinoids is thought to be mediated through control of proliferation via delaying progression of damaged cells into S phase, which allows for DNA repair and induction of apoptosis, thereby reducing the risk of carcinogenic initiation. However, long term and excessive ethanol intake reduces hepatic retinoid levels. The observation that retinoid concentrations are decreased in both plasma and cancerous liver tissues of hepatocarcinoma patients, suggests a role for retinoid depletion in hepatocarcinogenesis. However, it is not known 1) whether chronic ethanol-induced hepatocellular proliferation (which could convert hepatocytes from a state of resistance to a carcinogen to a state of susceptibility) is due to alcohol-impaired retinoid metabolism and signaling, and if so, 2) whether restoration of retinoid status by either inhibiting ethanol-induced retinoid catabolism or supplementing retinoic acid can suppress both ethanol-induced cell hyperproliferation as well as ethanol-promoted (diethylnitrosamine induced) hepatocellular carcinogenesis. We will investigate the possible role of diminished retinoid signaling and/or the up-regulation of the Jun Nterminal kinases-dependent (JNK) signaling pathway by chronic ethanol treatment on alcohol induced hepatocellular cell proliferation as well as alcohol-promoted hepatocellular carcinogenesis (induced by diethylnitrosamine). Simultaneously, we will test whether treatment with either chlormethiazole (an inhibitor of retinoic acid catabolism) and all-trans retinoic acid in ethanol-fed rats can inhibit alcohol-induced hepatocellular cell proliferation as well as alcohol-promoted hepatocellular carcinogenesis via either restoring normal retinoid signaling and/or inhibiting the JNK dependent signaling pathway. This study will be the first to link the regulation of retinoid signaling with Jun N-terminal kinases-dependent pathway, cell proliferation and apoptosis in an alcohol-treated, chemically induced carcinogenesis animal model, which would have implications for the prevention and treatment of alcohol related human cancers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANALOG STUDIES OF 4-HPR AND ITS GLUCURONIDE Principal Investigator & Institution: Curley, Robert W.; Professor; None; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 01-JAN-1991; Project End 31-DEC-2007 Summary: (provided by applicant): Retinoic acid (RA) and its analogs have emerged as dermatological agents and as potential cancer chemopreventive/chemotherapeutic agents. As a class, these compounds tend to share teratogenic potential and the ability to show vitamin A toxicity. However, the O-acyl glucuronide metabolite of RA has been suggested to be a less toxic, active product. The synthetic retinoid 4hydroxyphenylretinamide (4-HPR) shows some uniquely desirable features as a breast cancer chemopreventive agent with reduced toxicity and teratogenicity. Our own studies with 4-HPR-O-glucuronide show it to be even less toxic and more active than 4HPR as a breast cancer chemopreventive. However, these glucuronides are unstable toward hydrolysis. We have been synthesizing stable C-linked analogs of 4-HPR-Oglucuronide for evaluation of breast cancer chemopreventive/chemotherapeutic activity (CA49837). A number of these analogs show great promise despite the fact that they do not bind well to any of the known nuclear receptors. The specific aims of our proposed research program are: 1) synthesis of the C-linked glucuronide analog of 4-HBR (4HBRCG) and evaluation of its efficacy in chemotherapy of DMBA-induced mammary tumors relative to 4-HPRCG, the latter of which represents our most effective analog in chemoprevention. If 4-HBRCG proves to be the most active compound in chemotherapy, and if like its parent drug, 4-HBR, it shows reduced liability in reducing blood retinol, then MTD and chemoprevention studies will be performed with 4HBRCG. If however, 4- HPRCG proves superior, we will focus our attention on studies of this analog, including MTD evaluation; 2) Evaluation of the chemopreventive/chemotherapeutic activity of our most potent analog; 3) evaluate the necessity for RAR activation in the initiation of apoptosis by 4-HPR and its analogs; 4) synthesis of [3H]HPR and its use to determine whether metabolism of 4-HPR is needed for it to act; and identification of the primary target of 4-HPR action in cells and/or in vivo; 5) evaluation of our most potent analog (4-HPRCG or 4- HBRCG) with regard to tissue distribution and teratogenic potential. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANGIOGENESIS AND ALVEOLIZATION Principal Investigator & Institution: Savani, Rashmin C.; Associate Professor; Pediatrics; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 16-AUG-1999; Project End 30-JUN-2004 Summary: Normal lung function requires appropriate alveolization during development, and lung injury results in alveolar septal destruction. Repair of damaged lung injury results in alveolar septal destruction. Repair of damaged lung likely involves a recapitulation of normal development to restore alveolar integrity. Alveolar septation involves the interaction of epithelial, endothelial and stromal components under the control of soluble factors, adhesion molecules and micro-environmental signals, through paracrine and autocrine communication, to convert terminal saccules into alveoli. Rat alveolization occurs postnatually and is used as a model to examine factors that regulate this process. Steroid administration during this critical period results in retarded septation, while treatment with trans-retinol rescues both steroid- and injury-induced hypo-alveolization. These findings offer the potential of therapy for clinical diseases such as diffuse alveolar damage and bronchopulmonary dysplasia. While endothelial

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cells are clearly involved, no information is currently available on the contribution of or factors regulating angiogenesis during alveolization. In order to determine the role of angiogenesis during repair, the angiogenic process during normal development must first be examined. We propose to test the hypothesis that: Normal alveolar formation is dependent on the appropriate tempero-spatial expression on the soluble factor, VEGF, the endothelial cell:cell adhesion molecule, PECAM-1, and the cell:matrix pro-migratory molecule RHAMM, that together promote angiogenesis. To test this hypothesis, we will first: 1. Examine the expression of VEGF & its receptors (VEGFR-1 & -2), PECAM-1 and hyaluronan (HA) and one of its receptors, RHAMM, during normal rat alveolization. We will use northern blot, in situ hybridization, western blot, immunohistochemistry, confocal microscopy and immunogold-labeled electron microscopy for these studies. The second aim of this proposal will: 2. Determine the effect of steroid and/or retinoid treatment on the expression of these molecules during alveolization. In the third aim, using specific blocking antibodies, we will: 3. Determine the role of VEGF, PECAM-1 and RHAMM in angiogenesis and alveolization during development. Collectively these studies will begin to define the molecular regulation of angiogenesis during alveolar formation in normal and steroid-treatment lungs, as well as provide insight into the effects of retinoid treatment on angiogenesis during this critical period of development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOCHEMISTRY OF THE RETINA AND PIGMENT EPITHELIUM Principal Investigator & Institution: Saari, John C.; Professor; Ophthalmology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-APR-1977; Project End 31-DEC-2003 Summary: (Verbatim from applicant's abstract): Light activates the visual pigments in photoreceptor cells by converting the chromophore, 11-cis-retinal, to all-trans-retinal (bleaching). The visual pigment is regenerated in adjacent retinal pigment epithelial (RPE) cells where all-trans-retinal is converted to 11-cis-retinal in a series of chemical reactions. The reactions in the two cells are coupled into the visual cycle by intercellular diffusion of the retinoids. At any given physiologic level of illumination, a steady state is established in which the bleach rate is equal to the regeneration rate. The reactions, enzymes and processes of the visual cycle are as important to vision as those of phototransduction; however, they remain poorly characterized and present models of the cycle do not even include several important components. The long-range goal of this research is to use techniques of biochemistry, molecular biology and cell biology to provide new molecular information about the visual cycle. During the proposed project period, we shall: (1) Examine visual cycle function in mice with a targeted disruption of the CRALBP gene. Preliminary results suggest that these animals regenerate 11-cisretinal very slowly, relative to a control. Thus, the phenotype of the CRALBP-/-mouse appears to resemble that of humans with a form of congenital stationary night blindness. (2) Explore mechanisms that could account for the apparent modulation of the rate of all-trans-retinal reduction, the rate-limiting step of the mouse visual cycle. One likely possibility, which will be tested, is that production of NADPH determined the rate of reduction of all-trans-retinal. (3) Employ HPLC retinoid analysis to determine whether the rate-determining step of the mouse visual cycle changes as the fractional bleach increases. In addition, the phenotype of mice bearing a targeted disruption of the gene encoding cellular retinal-binding protein (CRBP) will be examined. (4) Determine the subcellular localization in RPE of enzymes and proteins associated with visual cycle activity and examine the mechanism of retinoid secretion from cultured RPE cells. The proposed studies will provide information necessary for an understanding of visual

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cycle function and will provide a new animal model for human retinal disease (the CRALBLP-/- mouse). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOSYNTHESIS OF 9-CIS-RETINOIC ACID Principal Investigator & Institution: Napoli, Joseph L.; Professor; Nutritional Scis & Toxicology; University of California Berkeley Berkeley, Ca 94720 Timing: Fiscal Year 2002; Project Start 01-JUN-1994; Project End 30-JUN-2004 Summary: The long-term goals of this project are to provide detailed insight into the biosynthesis of 9-cis--retinoic acid (9cRA) at the nutritional, biochemical and molecular levels. The endogenous retinoid 9cRA serves as an activator of the ligand-dependent transcription facts RXRs. The three RXRs (Alpha, Beta, gamma) comprise a sub family of the steroid/thyroid/retinoid/vitamin D superfamily of hormone receptors. RXRs regulate development and growth by modulating expression of genes with TXT response elements and by heterodimerizing with and regulating the effects of several other receptors in the superfamily, such as the peroxisome proliferator activated receptors and the retinoic acid receptors, RARs. Yet little is understood concerning the biosynthesis of 9cRA. Thus, the immediate goals of the work proposed here are to expand our initial insight into the generation 9cRA. We hypothesize: 1) that a quantitatively important route physiologically of 9cRA biosynthesis involves conversion of 9-cis-retinol into 9-cis-retinal catalyzed by a short chain dehydrogenases, followed by conversion of 9-cis-retinal into 9cRA; and 2) therefore 9cRA biosynthesis may be regulated independently of all-trans-retinoic acid biosynthesis, i.e. all- trans-retinoic acid would not serve as an obligatory precursor of 9cRA. The specific aims are to: 1) determine whether the mitochondria and lamda subcellular fractions produce 9cRA from 9-cis- retinol, all-trans-retinol or all-trans retinoic acid; 2) clone the cDNA encoding a putative soluble 9-cis-retinol dehydrogenase kinetically and biochemically, including establishing the effects of vitamin A status on their expression and activities; and 4) determine which cells express 9-cis-retinol dehydrogenase(s) in embryos and adults by in situ hybridization. The cumulative data anticipated will contribute to establishing the pathways of 9cRA biosynthesis and provide insight into their regulation. These results also will contribute into regulation of RXT function and will provide reagents for future examination of pathology possibly associated with impaired 9cRA biosynthesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CADMIUM & PANCREATIC CANCER: A PILOT CASE-CONTROL STUDY Principal Investigator & Institution: Schwartz, Gary G.; Associate; Cancer Biology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Little is known about the etiology of pancreatic cancer, which causes more than 29,000 deaths per year in the U.S. The P.I. recently proposed that cadmium is a cause of pancreatic cancer (Cancer Epidemiology, Biomarkers &Prevention, 9:139-145, 2000). Cadmium is a non-essential metal that accumulates in the human pancreas. Cadmium is known to cause pancreatic cancer in animals and is a plausible cause of pancreatic cancer in humans. We will conduct a pilot, hospital-based case-control study to determine whether exposure to cadmium, as measured by questionnaire data on dietary, occupational and recreational exposure to cadmium, and by measurements of cadmium in urine, predicts risk for pancreatic

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cancer. We hypothesize that, controlling for age and smoking history, reported exposure to cadmium and cadmium levels in urine will be higher from persons with pancreatic cancer than from persons without pancreatic cancer. Our Specific Aims are to: 1. Recruit 50 patients with incident cancer of the exocrine pancreas (cases) seen at Wake Forest University Baptist Medical Center (WFUBMC). 2. Recruit two sets of control patients: a. 50 patients matched on race, gender, smoking history, and age (4- 5 years) without cancer seen inthe Department of Gastroenterology (G.I.) at WFUBMC (the clinic referral population) b. 50 patients matched on race, gender, smoking history, and age (4-5 years) without cancer seen at General Internal Medicine clinics at WFUBMC (the hospital referral population). 3. Obtain informed consent, urine samples, and questionnaire data for cases and controls. 4. Analyze these data to determine risk of pancreatic cancer from: cadmium in urine, corrected for creatinine levels (a biomarker of exposure to cadmium), reported exposure to cadmium, and retinol binding protein in urine (a measure of biological effect of exposure to cadmium). 5. Secondarily, analyze urine specimens for zinc and copper and compare tile patient groups with respect to the zinc:cadmium ratio, and to the concentrations of copper. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR RETINOL BINDING PROTEIN, TYPE I--LINKING RETINOID METABOLISM/ACTION Principal Investigator & Institution: Talmage, David; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002 Summary: The ability of tissues to respond to vitamin A is affected by three factors: delivery of vitamin A, predominantly as retinol, to the tissues from the circulation; uptake of vitamin A from circulating pools and subsequent metabolism into biologically active forms within the tissue; and the presence of functional retinoic acid and retinoid receptors that mediate the genomic response, or the other response to vitamin A metabolites. In this project I am proposing a genetic approach to determine the importance of cyclical CRBP expression and of retinoid status in sustaining normal cervical squamous metaplasia. These experiments will utilize mice in which either the CRBP or RARalpha genes have been disrupted by homologous recombination, and mice in which CRBP is constitutively expressed in basal and suprabasal keratinocytes. The proposed experiments are divided into two complimentary parts. In Aim 1 studies are proposed to establish the effects of dysregulated CRBP expression and of vitamin A insufficiency on the differentiation of the cervical epithelium. In Aim 2 experiments are proposed that will use cultured cervical epithelial cells isolated from CRBP+/+ and CRBP-/- mice to establish the effect of CRBP expression on differentiation of cultured CECs, on retinol uptake and metabolism in CECs, and on RAR function. The Aims of this Project are: Aim 1. Determine if CRBP modulates in vivo retinoid status in the rodent cervix. Aim 2. Determine if CRBP alters retinol uptake and metabolism, or retinol regulation of cultured cervical epithelial cell differentiation. Although these experiments focus on the role of RBP in the biology of the cervical epithelium, the insights gained should be applicable to other tissues in which vitamin A status must be dynamically regulated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CONTROL OF RETINOID BIOSYNTHESIS BY APC AND CDX2 Principal Investigator & Institution: Jones, David A.; University of Utah Salt Lake City, Ut 84102

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Timing: Fiscal Year 2003; Project Start 12-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Retinoids are attracting interest as potential chemopreventive and chemotherapeutic agents for a variety of human cancers. Although the molecular responses elicited by retinoids are poorly understood, these responses appear to cause cellular differentiation. The differentiating effects of retinoids fit a parallel model for tumor development that may account for their success in the clinic. This model suggests that certain tumors arise due to improper differentiation of specific precursor cells. Tumors of the colon represent one type of neoplastic disease that fits this.lack of differentiation. model. Development of normal colon epithelial cells proceeds through a systematic differentiation of cells that emerge from stem cells within the base of colon crypts. Genetic mutations in the adenomatous polyposis coli (APC) gene are thought to create stem cells that fail to differentiate and, therefore, produce colon polyps and colon tumors. Using microarray expression profiling, we have found molecular evidence supporting lack of differentiation as the mechanism for development of colon polyps and tumors. Our preliminary data revealed a surprising prevalence of down-regulated genes in sporadic colon polyp and colon tumor colonocytes as compared to normal colonocytes. Among the genes absent were a number of retinoic acid response genes. The absence of these response genes was paralleled by the lack of expression of retinol dehydrogenase 5 and a novel, colon specific retinol dehydrogenase termed RDHL. The RDHL promoter is induced by APC and the colon specific transciption factor Cdx2. Based on these observations, we hypothesize that APC and Cdx2 control colonocyte differentiation, in part, by regulating retinoid responsiveness within the colon crypt. Mutations in APC or Cdx2 lead to a failure to produce retinoic acid by colon epithelial cells. This failure to synthesize retinoic acid impairs colonocyte differentiation and contributes to colon polyp and colon tumor development. In this proposal, we will examine the specific hypothesis that APC and cdx2 control retinoid biosynthesis and responsiveness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--ANALYTICAL FACILITY /LIPIDS Principal Investigator & Institution: Swift, Larry L.; Professor of Pathology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002 Summary: (adapted from the application): When the Clinical Nutrition Research Unit (CNRU) was first funded in 1979, the only core facility other than the Administrative/Clinical Core was the Analytical Core. The primary function of this core was to develop and validate vitamin-trace mineral assays for the CNRU investigators. With the continuation of the grant in 1984, the Analytical Core was expanded to include amino acid analyses as well as assays for several blood proteins, including retinol binding protein, transferrin, prealbumin, and albumin. In addition, during this period the laboratory developed more sensitive HPLC assays for vitamins, including assays for vitamins A and E, as well as for the vitamers of vitamins B2 and B6. New instrumentation was also added for quantitative amino acid determinations. In addition, because of an increased interest in research involving lipids and lipid peroxidation, we began the process of expanding the laboratory to include quantitative measurements of the lipid components of tissue, cells, and blood. New methods for studying lipid peroxidative injury were also added to the services provided by the core. A growing need for investigations involving amino acid metabolism prompted a stronger collaboration of the Core Laboratory with the Departments of Surgery, Molecular Physiology and Biophysics, and Medicine, in particular the Diabetes Research and

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Training Center (DRTC). To accommodate all of the needs, the Analytical Core was reorganized once again, and Dr. Larry L. Swift, Department of Pathology, was appointed the Director. The core was subdivided into three areas of specialization: Amino Acid Section, The Lipids/Lipid Peroxidation Section, and the Vitamin/Trace Element Section, with each section directly independently. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--ANIMAL Principal Investigator & Institution: Wright, William W.; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002 Summary: The major function of the animal core is to provide vitamin a depleted (VAD) synchronized testes for Projects 2-4. The core will be responsible for vitamin depletion, retinol replacement, and staging of rats. The core will perform assessment and verification of synchronized testes, and maintain records of rat experiments. The rats will be housed and cared for by the Hopkins animal facility and a significant portion of the budget reflects the per diem care costs for the rats. The animal core directory estimates that only 70% of the VAD rats will become synchronized. Project 1 will utilize 70 rats, and projects 2 and 3 will share animals and utilize a total of 24 rats per year. The number of rats required for isolation of Sertoli cells is estimated to be 148 rats per year. Considering a 30 percent failure rate in VAD synchronization, the estimated number of rats required per year will be 352. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORRECTION OF DENDRITIC CELLS DEFECTS IN CANCER Principal Investigator & Institution: Gabrilovich, Dmitry I.; Associate Professor; H. Lee Moffitt Cancer Ctr & Research Ins and Research Institute, Inc. Tampa, Fl 336129497 Timing: Fiscal Year 2003; Project Start 21-APR-1999; Project End 31-DEC-2007 Summary: (provided by applicant): Inability of host immune system to develop and maintain antitumor immune response is one of the mechanisms of tumor progression. We have previously described a new mechanism of immune deficiency in cancer associated with defective differentiation of dendritic cells (DC). These findings were confirmed in many laboratories. Defective DC differentiation is mediated by tumorderived factors and manifests in decreased production of the mature DCs. Decreased presence of functionally competent DCs substantially altered the ability of immune system to react to tumor associated antigens. Recently we have found that decreased DC production in cancer patients and tumor-bearing mice is associated with striking accumulation of immature myeloid cells (ImC). This effect is not restricted to a certain type of cancer. To date studies from different laboratories demonstrated increased production of these cells in patients with all tested types of cancer and in all tested tumor animal models. ImC actively suppress antigen-specific immune response in tumor-bearing hosts. These cells may play a critical role in tumor non-responsiveness. They may compromise attempts to immunotherapy of cancer, since administration of tumor-specific antigens to the patients will make these antigens available for ImC. ImC would inhibit the very same immune response that immunization is trying to generate. It appears, that elimination of ImC by therapeutic intervention may be one of the possible ways to improve the immune response in cancer and the efficiency of cancer immunotherapy. Our preliminary data have demonstrated that differentiation of ImC could be the most effective way to eliminate these cells and all-trans-retinoic acid

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(ATRA) could be one of the most attractive candidates. The mechanisms of ImC inhibition of T-cell responses remain unclear. Elucidation of these mechanisms can be important for our better understanding of tumor immunology as well as for development of new therapeutics. In this application we tried to achieve two major goals: 1) to understand the mechanisms of ImC function and 2) to identify the effective methods of elimination of ImC in tumor-bearing hosts. To achieve these goals I propose the following specific aims: Specific Aim 1. Identify the mechanisms of antigen presentation and T-cell inhibition by immature myeloid cells generated in tumorbearing hosts. Specific Aim 2. Determine mechanisms of ImC development in tumorbearing hosts. Specific Aim 3. Identify the effect of ATRA on the development of antitumor immune response in tumor-bearing mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORRELATIVE GLIOBLASTOMAS

TRIAL

OF

FENRETINIDE

AGAINST

Principal Investigator & Institution: Puduvalli, Vinay K.; Neuro-Oncology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Malignant gliomas, the most common of which in adults is glioblastoma multiforme, carry a grave prognosis with high morbidity and mortality. Surgery, radiotherapy and chemotherapy are only of modest value in the management of these tumors. Among novel compounds being tested against gliomas, 13 cis-retinoic acid, as single agent or in combination, has shown activity against recurrent gliomas in clinical trials. Fenretinide, a related synthetic retinoid, induces apoptosis & decreases proliferation in a variety of malignancies in vitro and is well tolerated on oral administration in humans. Fenretinide inhibits proliferation of glioma cells by induction of apoptosis at 3 - 5 muM concentration (Puduvalli et al 1999). Data from Phase I trials indicate that fenretinide is well tolerated and concentrations of approximately10?M are achievable at a dose of 1200 mg/m2 twice daily. Based on these data, we hypothesize that fenretinide administered at this dose will result in glioma tissue concentrations sufficient to induce apoptosis and result in clinical efficacy in this tumor type. We also hypothesize that fenretinide can induce molecular & radiological changes that can serve as surrogate markers for the effect of this agent against gliomas. To test these hypotheses, we propose a Phase II trial (placebo-controlled) with clinical & correlative endpoints. Clinical Trial Design: 40 patients with recurrent glioblastoma due to undergo surgery will be randomized in a blinded manner to receive fenretinide or placebo orally (20 patients each group) for 7 days prior to surgery with serum samples being collected for pharmacokinetic studies. At surgery, resected tissue will be collected with concurrent serum samples for correlative studies. All 40 patients will then continue on open label fenrentinide therapy until tumor progression. Specific Aims: Aim 1) To determine the efficacy of fenretinide against recurrent glioblastomas as measured by 6month progression free survival (clinical endpoint) Aim 2) To determine the levels of fenretinide in glioma tissue and correlate it with serum concentrations. Aim 3) To determine whether fenretinide induces apoptosis in tumor tissue and correlate the degree of apoptosis with serum and tissue concentrations of 4-HPR and with clinical efficacy. Aim 4) To identify radiological and molecular surrogate markers of fenretinide effects on glioma tissue by utilizing - a) serum & tissue markers related to retinoid signaling such as retinol, retinol binding protein, retinoid receptors (RARgamma, RARbeta & RXR alpha) and IGF-1; b) Multivoxel MR Spectroscopy (MRS) of the tumor (before and after 7 day presurgery treatment with fenretinide) to detect changes

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indicative of apoptosis and correlate this with apoptosis seen in MRS-targeted tissue samples; c) Oligonucleotide microarrays to determine transcriptionally altered molecules relevant to gliomas including those that mediate invasion, angiogenesis and apoptosis. Data from this study about the tissue effects of fenretinide could hence provide new insights into the mechanism of action of fenretinide at the target tissue level. Such data could be relevant not only to future trials of retinoids in gliomas but also for ongoing trials of fenretinide in other malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TECHNIQUES

DEVELOPMENT

OF

13C-RETINOL

ISOTOPE

DILUTION

Principal Investigator & Institution: Tanumihardjo, Sherry A.; Nutritional Sciences; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Improved, simplified methods to determine vitamin A status are needed to accurately assess both individuals and populations at risk of either vitamin A deficiency or toxicity. The vitamin A statuses of women and children in lower socioeconomic groups in both the underdeveloped world and the United States are compromised. Multiple reasons for this compromised status include low dietary intakes, increased demands during pregnancy and lactation and recurrent infections. The 13C-retinol isotope dilution (13C-RID) test, first developed in the rodent model using 13C4-retinyl acetate and gas chromatography-combustion-isotope ratio mass spectrometry (GCCIRMS), is sensitive and accurate. The major goals of this project are to validate the 13C-RID test for use in human population groups to assess total body reserves of vitamin A and determine vitamin A requirements of young adults. The success of this project will provide a sensitive tool for investigators to evaluate the vitamin A status of individuals and population groups using minimal sample sizes. The test has direct application to determining the outcome of intervention strategies aimed at improving vitamin A status and in determining vitamin A needs of humans and animals throughout their life cycles. The proposed studies will for the first time: (1) validate the 13C-RID test to assess a sub-toxic vitamin A status in non-human primates; (2) validate the 13C-RID test to assess sub-clinical vitamin A deficiency in the weanling pig; (3) refine the 13C-RID test for use in humans by looking at different dose levels and blood sampling times; and (4) investigate the use of the 13C-RID test in a human intervention study designed to look at vitamin A requirements in young adults. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIET AND GENETIC RISKS FOR LUNG CANCER Principal Investigator & Institution: Patterson, Ruth E.; Associate Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 05-MAR-2001; Project End 31-DEC-2002 Summary: (Applicant's Description) This proposal is for an investigation into the associations of diet, and interactions of diet and genetic polymorphisms, with the risk of lung cancer. Data are from 18,314 men and women enrolled in a chemoprevention trial of beta-carotene and retinol (CARET). After a mean of 7.4 years of follow up, CARET has endpoint data on almost 800 cases of lung cancer. Dietary intake was measured with a food frequency questionnaire. Serum micronutrient and genetic polymorphisms have been analyzed for 388 lung cancer cases and 753 controls. Our specific aims are: 1. To better understand the association of fruit and vegetable intake with the reduced risk of

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lung cancer. Fruit and vegetable intake will be measured as: (i) servings per day (total and grouped by phytochemical content), (ii) micronutrient associated with fruits and vegetables, including vitamins C and E, folate, and carotenoids, and (iii) serum carotenoids and vitamin E. 2. To examine whether the associations of fruit and vegetable intake with lung cancer risk are modified by genotypes of carcinogen metabolizing enzymes (i.e., CYP2D6, CYP2El, CYP1Al, GSTM1, GSTT1, and EH). We will conduct cohort analyses for dietary intake data and case control analyses for laboratory based studies. Although the baseline dietary data have been collected and the laboratory analyses (for serum micronutrients and genotypes) have been completed, there are no CARET investigators with expertise in nutrition science who are funded to conduct these analyses and write the associated manuscripts. Therefore, to meet the specific aims proposed above, we request support for nutritional epidemiologists, a statistician, molecular biologist, and the staff support needed to publish the findings. This work addresses important questions about the etiology and prevention of lung cancer, and can be completed with a modest amount of funding in addition to what has already been invested in this large chemoprevention trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIET AND GENETIC RISKS FOR PROSTATE CANCER Principal Investigator & Institution: Neuhouser, Marian L.; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2003; Project Start 23-JUN-2003; Project End 30-APR-2006 Summary: (provided by applicant): Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths among American men. Prostate cancer etiology remains elusive but there is growing evidence that dietary patterns are associated with prostate carcinogenesis. The most consistent dietary finding is that diets high in fat or high-fat foods increase risk and there is increasing evidence that compounds found in vegetables (e.g., lycopene, glucosinolates) decrease risk. However, results are not consistent across studies and there is no scientific consensus for specific dietary recommendations to reduce prostate cancer risk. Non-dietary factors associated with risk include age, race and family history. These and other risk factors may interact with dietary components and alter the prooxidant-antioxidant balance in the prostate. This proposal is for a comprehensive investigation into the associations of dietary fat, fruit and vegetable intakes and polymorphisms in genes that encode oxidative stress regulatory enzymes with the risk of prostate cancer. Our hypothesis is that dietary and other factors that increase oxidative stress (e.g., dietary fat, smoking) are associated with increased risk of prostate cancer; dietary factors that decrease oxidative stress are associated with decreased risk of prostate cancer; and the magnitude of these risks will vary by cancer susceptibility genetic profile. We will test whether polymorphisms in genes whose products affect tissue responses to oxidative stress influence prostate cancer risk, and whether there are interactions of these polymorphisms with dietary factors related to oxidative stress. Our study sample is the 12,025 male participants in CARET (The Beta-Carotene and Retinol Efficacy Trial). To date, there are 718 confirmed cases of primary prostatic carcinoma. This proposed study will provide important information about prostate cancer etiology and suggest new strategies for prevention and control. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIETARY FACTORS IN THE ETIOLOGY OF CANCER IN SHANGHAI Principal Investigator & Institution: Ross, Ronald K.; Professor; Preventive Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-APR-1987; Project End 30-JUN-2007 Summary: (provided by applicant): This is a revised grant application requesting continued funding of a residential cohort of 18,244 men in Shanghai, China, assembled during 1986-89 when subjects were between the ages of 45 and 64 years. At recruitment, all cohort members provided detailed dietary and medical histories as well as blood and urine specimens. The cohort has been followed for the occurrence of cancer and death through routine ascertainment of new cases from the population-based Shanghai Cancer Registry and Shanghai Vital Statistics Units, and annual visits to all known surviving cohort members. To date, the cohort has accumulated 204,010 person-years of observation. Only 231 subjects have been lost to follow-up. There have been 1,463 incident cancer cases and 2,599 cohort members have died. The leading cancer sites are lung, liver, stomach, and colorectum. Stroke accounts for 23% of all deaths. Active follow-up of this cohort will continue for another 5 years. During the annual personal visit to each surviving cohort member, buccal cells will be collected to facilitate future etiologic studies involving DNA analysis. Although study investigators have been successful in harvesting DNA from serum samples collected at baseline, cost-based analysis revealed that it is more cost-effective for future gene-based studies to rely on this new source of DNA. It is estimated that buccal cells will be collected from about 11,000 cohort subjects. During the next 5 years, a series of nested case-control studies will be conducted to further elucidate the interplay of genetic and dietary factors in influencing cancer risk. Specifically, study investigators will assess the roles of dietary aflatoxin and antioxidants (selenium, retinol, carotenoids, tea polyphenols) in cancers of the lung and liver; the role of dietary isothiocyanates in cancers of the stomach, esophagus, and colorectum; and the role of tea polyphenols in cancers of the stomach and esophagus. In all instances of diet-cancer investigations, relevant genes with potential modifying effects on the respective diet-cancer associations will be included in the investigations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ELIMINATION OF CHEMOTHERAPY IN NEWLY-DIAGNOSED APL Principal Investigator & Institution: Estey, Elihu; Leukemia; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Administration of all-transretinoic acid (ATRA) + myelotoxic chemotherapy results in long-term remission in 70% of patients with newly diagnosed acute promyelocytic leukemia (APL). It is becoming clear however that this approach is associated with development, several years later, of myelodysplastic syndromes and AML. The demonstration of the effectiveness of arsenic trioxide (ATO) in APL makes it feasible to assess, in newly diagnosed APL, whether the combination of ATO + ATRA will enable elimination of myelotoxic therapy. To test this hypothesis (SA#1) we will conduct a trial of ATO + ATRA, with myelotoxic therapy added only if minimal residual disease (MRD), as judged by the standard manual PCR assay, persists or recurs. For safety monitoring we will use a published Bayesian "multiple outcome" design that allows early termination if the rates of either CR, or PCR negativity at 6 months from CR date, are too low. More effective means of measuring MRD would

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obviously make similar trials more feasible in the future, and SA#2 tests the hypothesis that use of high sensitivity quantitative real-time PCR, rather than the standard assay, and blood rather than marrow will increase the accuracy of current methods. Similarly, understanding of mechanisms underlying resistance to ATRA would increase the possibility of eliminating myelotoxic therapy, and SA#3 tests the hypothesis that addition of ATO to ATRA, while decreasing the overall relapse rate, increases the frequency of missense mutations in the PML-RAR( gene among patients who do relapse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULES

ENZYMATIC

ACTIVATION

OF

LIPOPHILIC

SIGNALING

Principal Investigator & Institution: Newcomer, Marcia E.; Professor; Biological Sciences; Louisiana State Univ A&M Col Baton Rouge Office of Sponsored Programs Baton Rouge, La 70803 Timing: Fiscal Year 2002; Project Start 15-MAY-1991; Project End 30-NOV-2004 Summary: (Applicant's abstract) Retinoids and eicosanoids are mediators of numerous biological processes and as such are compounds of enormous pharmacological potential. Structural studies on proteins which catalyze the activation of these compounds, which readily partition into the cell membrane, to their potent biological forms will add to our understanding of substrate recognition and acquisition, two themes directly addressed by experiments in this proposal. Two contrasting mechanisms of substrate acquisition are represented herein: one which utilizes a freely soluble carrier protein for delivery of the substrate to an activating enzyme (intermolecular) and one in which two sequential catalytic activities are expressed on a single polypeptide and consequently co-localized (intramolecular). The following proposed aims involve x-ray crystallographic studies on three enzymes: retinol dehydrogenase, retinol dehydratase, and allene oxide synthase. The specific questions to be addressed are: (1) Does substrate binding order the substrate access channel and catalytic machinery of retinaldehyde dehydrogenase? Both crystallographic and kinetic experiments are proposed to elucidate the mechanism of substrate recognition by this enzyme. (2) Is protein:protein recognition involved in substrate recognition by retinal dehydrogenase? In vivo retinol and retina1 are protein bound. Both crystallographic and solution studies are proposed to determine how RalDH2 interacts with the carrier protein for retinol. (3) Determination of the structure and mechanism of retinol dehydratase, a sulfotransferase which catalyzes the dehydration of retinol. (4) Determination of the three dimensional structural of the allene oxide synthase domain, a unique member of a catalase super-family of heme enzymes. A naturally occurring fusion protein which contains a lipoxygenase domain and an allene oxide synthase domain has been identified. The lipoxygenase domain catalyzes the production of 8hydroperoxyeicsoatetraenoic acid (8-HPETE) from arachidonic acid and the allene oxide synthase domain catalyzes the transformation of the hydroperoxide to an allene oxide. The expression of this activity as a fusion protein with lipoxygenase is predicted to facilitate the transfer of the reaction intermediate between catalytic sites. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ETHANOL, MALFORMATIONS

RETINOIDS,

AND

CONGENITAL

HEART

Principal Investigator & Institution: Gelineau-Van Waes, Janee; Munroe-Meyer Institute; University of Nebraska Medical Center Omaha, Ne 681987835

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Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2004 Summary: (provided by applicant): Congenital malformations of the heart have been reported following maternal exposure to various environmental toxins, but the precise mechanism(s) by which these teratogenic exposures disrupt normal morphogenesis remains unknown. Prenatal exposure to ethanol (Fetal Alcohol Syndrome) or maternal vitamin A (retinoic acid) deficiency or excess during gestation have been shown to cause conotruncal heart defects. In the proposed research program, the complex processes underlying embryological development of the mammalian heart and the impact of prenatal exposure to ethanol and perturbed retinoic acid levels leading to cardiac dysmorphogenesis will be studied using molecular-genetic approaches. The proposed studies will focus on a critical gestational timepoint during murine heart development when the cardiac neural crest cells are migrating from the dorsal neural tube to the heart. Alterations in the network of developmentally regulated genes in this cell population will be analyzed following teratogen exposure through the use of genetic microarrays. Potential mechanisms suggested by altered gene expression profiles will be further evaluated relative to the observed cellular dysmorphology by examining protein expression of critical candidate genes identified in the cDNA arrays, as well as proteins associated with changes in cell proliferation and apoptosis. The goal will be to identify significant gene/protein interactions that take place during normal heart development, and the mechanism(s) by which in utero ethanol exposure disrupts this process. We will also further investigate the possibility that malformations of the heart subsequent to prenatal alcohol exposure are a result of decreased endogenous retinoic acid synthesis due to competition between alcohol and retinol for alcohol dehydrogenase enzymatic pathways. The proposed research program will therefore test the hypothesis that prenatal ethanol exposure leads to congenital heart malformations by disrupting normal retinoid signaling pathways critical for cell fate determination in the migrating cardiac neural crest cells/conotruncus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ETHANOL-RETINOID MALFORMATIONS

INTERACTION

IN

INNER

EAR

Principal Investigator & Institution: Van Waes, Janee; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: Using a molecular genetic approach, this project will focus mechanistically on alterations in developmental events that result in congenital malformations of the inner ear following prenatal alcohol exposure (Fetal Alcohol Syndrome). The ovedying hypothesis is that malformations of the inner ear subsequent to prenatal alcohol exposure are a result of decreased endogenous retinoic acid synthesis due to competition between alcohol and retinol for alcohol dehydrogenase enzyme pathways. Specific Aim 1 will examine the severity and range of malformations in the inner ear subsequent to prenatal ethanol exposure, or as a result of maternal vitamin A deficiency or excess. Additionally, alterations in gene pathways likely to result in dysmorphogenesis and/or cellular dysfunction will be analyzed using cDNA microarrays. The analysis will focus primarily on those genes known to be relevant for inner ear morphogenesis (e.g. FGF, EYA, GATA, BMP) and cell fate determination (e.g. Ngn1, Math1, Hes1, Hes5). Alternations in the spatio-temporal pattern of these genes will be analyzed using such methods as hierarchical and k-means clustering, selforganizing maps, and principal components analysis. Results will be verified using quantitative PCR (Q-PCR). Specific Aim 2 will confirm and extend the data from

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Specific Aim 1 by localizing expression of "critical genes" during inner ear development through the use of in situ hybridization and immunohistochemical techniques. Specific Aim 3 will directly test the suggested molecular interaction of ethanol and retinoic acid competition for common enzymatic pathways by using two different techniques (HPLC and a bioassay using retinoic acid responsive reporter cell lines). In a future RO1 submission, the identified candidate genes will be further analyzed in the teratogenic context using existing mutant and transgenic mouse strains (e.g. FGF10 null, ngn1 BAC) to probe for enhanced susceptibility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTION OF PDGFS AND FGFS IN THE RETINA AND RPE Principal Investigator & Institution: Campochiaro, Peter A.; Professor; Ophthalmology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-1985; Project End 30-NOV-2004 Summary: Growth factors have been implicated in many important functions in the retina, including development and differentiation, cell survival, and wound repair. They have also been implicated in the pathogenesis of several disease processes including exaggerated wound repair leading to scarring and retinal detachment, ocular neovascularization, and retinal degenerations. In order to modulate the normal and pathologic roles of growth factors, it is important to have a detailed understanding of how alterations in their expression in the retina affect retinal structure and function. In past grant periods, we have demonstrated that the expression of platelet-derived growth factor (PDGF)-A and PDGF-B, and their receptors are increased in vitro and in vivo in models of retinal and retinal pigmented epithelial (RPE) cell wound repair and proliferative retinopathies, while fibroblast growth factor (FGF) signaling is necessary for photoreceptor cell survival. In this grant period, we plan to use tissue- specific promoters in transgenic mice to study the effects of altered expression of each of these factors in the retina. Using photoreceptor- specific promoters (rhodopsin or inter photoreceptor retinol binding protein) or the neuron-specific enolase promoter, which drives expression in the inner retina, we will control the location of expression in the retina. In addition, we will use the tetracycline-induced promoter system to control the timing and duration of expression. We will determine the effect of altered expression of these factors in the retina at various stages of development and in several models of proliferative retinopathies or retinal degenerations. This will provide important new information that is needed for the development of new treatments for these disease processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC DISSECTION OF ALCOHOL/RETINOL METABOLIC PATHWAYS Principal Investigator & Institution: Duester, Gregg L.; Burnham Institute 10901 N Torrey Pines Rd La Jolla, Ca 920371005 Timing: Fiscal Year 2002; Project Start 01-APR-1995; Project End 31-MAR-2003 Summary: (Adapted from the Investigator's Abstract) Vitamin A (retinol) must be metabolized to an active retinoid ligand in order to fulfill all of its roles in vertebrate development. During retinoid signaling retinol is first converted to retinal followed by conversion of retinal to the active ligand retinoic acid which modulates nuclear retinoic acid receptors. The alcohol dehydrogenase (ADH) enzyme family may function in the metabolism of retinol, the alcohol form of vitamin A, as well as ethanol metabolism.

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Some members of the ADH family prefer retinol as a substrate over ethanol, and the ability to oxidize retinol is competitively inhibited by intoxicating levels of ethanol. Likewise, there exists an aldehyde dehydrogenase (ALDH) family containing members preferring retinal, the aldehyde form of vitamin A, as a substrate over acetaldehyde. The spatiotemporal expression patterns of mouse ADHs and ALDHs overlap, suggesting that these enzymes may cooperate to upregulate retinoic acid synthesis during development. Retinoic acid synthesis may be decreased by excess ethanol consumption due to the ability of ethanol to act as a competitive inhibitor of ADH-catalyzed retinol oxidation. This suggests a mechanism whereby ethanol damage may occur during alcohol abuse. Treatment of mouse embryos at the neurulation stage with an intoxicating amount of ethanol leads to a reduction in retinoic acid levels, thus suggesting ADH participates in the retinoic acid synthetic pathway. This may be a contributing factor in fetal alcohol syndrome, characterized by malformations of neural and craniofacial tissues known to require retinoic acid for proper development. The in vitro properties and gene expression profiles of the ADH and ALDH enzyme families suggest a role in both alcohol and retinol metabolism, but there is a need for genetic loss-of-function studies in mice to address their true physiological roles. The mouse ADH gene family consists of three classes (ADH-I, ADH-III, and ADH-IV), with only ADH-I and ADH-IV known to oxidize retinol in vitro. The extent of the mouse ALDH gene family is unknown, but ALDH-I has been shown to oxidize retinal in vitro and has an expression pattern overlapping that of ADH-I and ADH-IV. Mutational analysis of all three mouse ADHs and ALDH-I is proposed here. Goals: (1) Complete the genetic analysis of ADH now in progress by preparing mice carrying knockout mutations of ADH-I, ADH-III, and ADH-IV, as well as mice carrying mutations of multiple ADHs since redundancy of function is suspected. (2) Analyze the phenotype of mice carrying mutations in single or multiple ADH genes for morphological defects during development and adulthood, for the ability to metabolize ethanol and retinol, and for the ability to survive and reproduce during vitamin A deficiency. (3) Prepare and ALDH-I knockout mouse plus mice mutated for one or more ADHs and ALDH-I, then analyze their phenotype as above. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYDROLYSIS OF VITAMIN A ESTERS IN LIVER Principal Investigator & Institution: Harrison, Earl H.; Research Leader; U.S. Department of Agriculture 14Th St and Independence Ave Sw Washington, Dc 20250 Timing: Fiscal Year 2003; Project Start 30-SEP-1992; Project End 30-JUN-2008 Summary: (provided by applicant): Hydrolysis of retinyl esters (RE) in the liver plays a key role in the body's metabolism of vitamin A. Dietary vitamin A enters the liver as RE in chylomicron remnants, which undergo hydrolysis and reesterification for storage. Prior to mobilization, RE are hydrolyzed and free retinol binds to retinol-binding protein for secretion into the plasma. Neutral and acid retinyl ester hydrolases (REHs) have been purified from rat liver and shown by sequence analysis to be carboxylesterases, ES-2 and ES-10. The goal of this project is to define the role of ES-2, ES-10, and the related ES-3 and ES-4, in the metabolism of vitamin A. Carboxylesterases have been studied with other substrates, but it is not known if they are important in vitamin A metabolism. Their efficiencies in catalyzing the hydrolysis of RE compared with other esters are also unknown. These gaps in knowledge will be explored with the following specific aims: AIM 1: Enzymoloqy of REHs. Enzyme kinetics will be used to study the substrate specificity of the carboxylesterases and to test the hypothesis that these enzymes differ in their intrinsic ability to catalyze the hydrolysis of RE and other

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lipid esters. AIM 2: Tissue distribution of carboxylesterases. Real-time PCR (for mRNA), immunodetection (for protein) and enzyme assay will be used to define the levels and distributions of enzymes in various tissues and to test the hypothesis that the carboxylesterases are present in peripheral tissues as well as in liver. AIM 3: Cell type distribution in liver. Laser Capture Microdissection and cell separations coupled with real-time PCR, immunodetection, and enzyme assays will be used to define the distribution of carboxylesterases between stellate cells & hepatocytes and to test the hypotheses that carboxylesterase ES-2 is localized exclusively in hepatocytes and that carboxylesterase ES-10 is localized in hepatocytes and stellate cells. AIM 4: Physiologic roles of the carboxylesterases in the metabolism of RE in cultured cells, cDNA transfection and RNA interference will be used to modulate carboxylesterase enzyme levels to test the hypothesis that the various carboxylesterases play a metabolic role in the hepatic uptake and/or metabolism of chylomicron RE, and to test the hypothesis that the carboxylesterases play a metabolic role in the turnover of intracellular RE and cholesteryl esters in cells that store them. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IGFBP 6--A TARGET IN LUNG CANCER PREVENTION Principal Investigator & Institution: Kurie, Jonathan M.; Associate Professor; Thoracic Head/Neck Med Oncol; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: (provided by applicant): Despite three decades of advancement in cancer treatment modalities, non-small cell lung cancer (NSCLC) remains a devastating disease with a 5-yearsurvival rate of 10 percent at best. This statistic points out the need for a radical change in our approach to treating NSCLC. Initial clinical studies indicated that retinoids decrease the incidence of second primary tumors in patients who have previously undergone resection for NSCLC or head and neck cancer. However, subsequent large-scale chemoprevention trials demonstrated that retinoids induce substantial toxicity and are of minimal benefit to individuals at high-risk for lung cancer, illustrating the need for more effective lung cancer chemoprevention strategies. Efforts to improve the chemopreventive effect of retinoids will require that we elucidate intracellular signals that are growth inhibitory in premalignant and fully transformed bronchial epithelial cells. Studies using retinoids have elucidated many potent growth inhibitory signals in human bronchial epithelial (HBE) cells. We have shown, in tissue culture, that retinoids inhibit the growth of HBE cells, which accumulate in the G0 phase of the cell cycle. We recently observed that all-trans retinoic acid (t-RA) increases the expression of insulin-like growth factor binding protein (IGFBP)-6 in primary cultures of HBE cells and in the epithelial layer of bronchial mucosal specimens established in organ culture. IGFBP-6 is secreted into the extracellular space and binds predominantly to IGF-II, inhibiting IGF-II bioavailability. HBE cells and NSCLC cell lines express IGF-I and II, and the growth of HBE cells and some NSCLC cell lines is stimulated by treatment with IGFs. Consistent with these observations, we have shown that adenoviral vectors that constitutively express IGFBP-6 (Ad5CMV-BP6) inhibit the growth of A549 and H226B NSCLC cell lines and primary cultures of HBE cells, and intratumoral injection of Ad5CMVBP6 reduces the size of H226B NSCLC cell xenografts in athymic nude mice. These findings demonstrate that IGFBP-6 has an anti-proliferative effect in HBE cells that range from phenotypically normal to fully transformed cells. Importantly, the growth suppressive effects of IGFBP-6 differed in HBE cells and NSCLC cells; HBE cells underwent a proliferative arrest in G0, while NSCLC cell lines

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Retinol

underwent apoptosis. Based on these findings, we hypothesize that IGFBP-6 is an important target in both the prevention and treatment of lung cancer. To test this hypothesis, we propose the following Specific Aims: Aim 1) To investigate the role of IGFBP-6 in the proliferative arrest induced by t-RA in HBE cells. Aim 2) To investigate the role of IGF-dependent pathways in IGFBP-6 actions. Aim 3) To investigate whether loss of IGFBP-6 abrogates the chemopreventive effects of 13-cis retinoic acid in SV40 T antigen transgenic mice, which develop lung cancer. Aim 4) To investigate whether IGFBP-6 expression increases in the bronchial epithelium of patients treated with retinoids. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPACT OF VITAMIN A AND ZINC ON DIARRHEAL DISEASE Principal Investigator & Institution: Long, Kurt Z.; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 30-APR-2005 Summary: (provided by applicant) Vitamin A and zinc supplementation have contrasting or inconsistent effects on diarrheal disease morbidity. These two micronutrients also have contrasting effects on the T helper type 1 (Th1) and type 2 (Th2) responses: vitamin A supplementation up-regulates a Th2 response while zinc supplementation upregulates a Th1 response. This differential impact may be responsible for the contrasting efficacies of vitamin A and zinc since a protective immune response against specific diarrheal disease pathogens can involve distinct combinations of the Th1-Th2 response. The goal of our proposal is to characterize the differential impact of vitamin A and zinc on health outcomes associated with specific pathogen infections and determine if the regulation of the Th1-Th2 response is the biological mechanism mediating this impact. This study is a double blind, randomized, placebo-controlled trial in which children between the ages of 6-15 months are assigned to one of four groups: a group receiving 200,000 IU of retinol every two months (100,000 IU for children aged less than one year), a group receiving a daily doses 20 mg of zinc methionin, a group receiving a combined vitamin A-zinc supplement and a placebo group. The 788 children enrolled in the study are being followed for up to 15 months with project personnel visiting household twice a week to monitor morbidity episodes in the child. Stool samples, collected once a month and following a diarrheal disease episode, are being screened for the presence of enteric pathogens. Basal and final blood samples are being collected to determine levels of retinol and zinc and the production of Th1 and Th2 cytokines by T lymphocytes. The evaluation of the impact of the vitamin A and zinc supplements on infections by diarrheal disease pathogens will be carried out through the use of multi-state, competing risks hazards models. The same analytical method will be used to validate each of the Th1-Th2 cytokines for use in predicting the impact of supplementation on infections. A meta-analysis of the pooled effect of vitamin A and zinc on growth will also be carried out to confirm the findings from the community micronutrient trial regarding the efficacy of supplementation in improving growth. Information generated from this research project will significantly enhance the current understanding of the role of the Th1-Th2 response in mediating the differential impact of vitamin A and zinc on health outcomes. In the Iong term, this work will allow the development of new micronutrient supplementation strategies that more effectively reduce childhood mortality and morbidity in developing countries. These studies will provide the necessary training in epidemiology and immunology that will further prepare the applicant for a career as an independent investigator in the biomedical sciences.

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

Project Title: IN VIVO DYNAMIC OF BETA-CAROTENE METABOLISM IN HUMANS Principal Investigator & Institution: Clifford, Andrew J.; Professor; Nutrition; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 01-MAR-1996; Project End 30-JUN-2003 Summary: Beta-carotene is found in the diets of virtually all humans around the world. Its best known functions are to provide vitamin A and to treat erythropoietic protoporphria. While a large body of evidence indicates that dietary beta-carotene reduces the risk of cancer an chronic disease, several large chernoprevention trials found that pharmacologic supplements of beta-carotene may cause cancer in certain high-risk subpopulations. Despite its clinical significance the metabolism of beta-carotene and its ability to deliver bioactive retinoids to tissues and organs is poorly understood. The long-range goal is to define the behavior of human beta-carotene metabolism in terms of hereditary and environmental factors that can affect it. The immediate objective is to determine the bioavailability and vitamin A value of ingested beta-carotene using Accelerator Mass Spectrometry detection in 15 male and 15 female subjects. The experimental design is longitudinal test-retest format that will establish the prevalence and stability of metabolic phenotypes to beta-carotene. The central hypothesis is that a discrete and significant percentage of the population utilizes beta-carotene very inefficiently. These individual are identified by a low plasma response to ingested betacarotene that can result from low intestinal absorption and bioconversion of betacarotene to vitamin A following a beta-carotene oral dose. Identification of the phenomenon as stable characteristic (metabolic phenotype would suggest a genetic basis of it. The proposal is unique in that these investigators can determine mass balance as well as follow major and minor vitamin A metabolites of radiolabeled beta-carotene at attomole levels of sensitivity with excellent measurement precision. There are four specific aims. (1) Determine the bioavailability of a 1 mg oral dose of beta-[14C]carotene (100 nanoCi) in 15 male and 15 female subjects. Bioavailability is determined by mass balance for 10 days. Urinary loss is determined from complete 10-d urine collections. (2) Determine the vitamin A value of beta-carotene by quantitative analysis of postprandial retinyl esters, retinoic acids, and retinol in blood. (3) Assess the long-term kinetics of beta-carotene, retinol, retinoic acids and novel metabolites by HPLC fractionation of plasma with AMS analysis of label out to 40 days. (4) Repeat aims 1,2,and 3 on day 75 (retest) to assess stability of metabolic phenotype and variance of the individual response. The expectations are that, at the conclusion of the proposed period of support, we will have determined important parameters of beta-carotene metabolism that include its vitamin A value, bioavailability, and established or rejected the concept of the discrete metabolic phenotype. These studies can serve as a basis for future investigations into the influence of environmental, genetic, and drug/nutrient interactions on the behavior of beta-carotene metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IRBP: STRUCTURE AND FUNCTION Principal Investigator & Institution: Gonzalez-Fernandez, Federico; Associate Professor; Ophthalmology; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2003; Project Start 01-JUL-1993; Project End 31-JUL-2007

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Summary: (provided by applicant): Interphotoreceptor retinoid-binding protein (IRBP), which is secreted by photoreceptors into the interphotoreceptor matrix, is a candidate for retinal degenerations. In the matrix, IRBP has access to Muller cell villi, outer segments, and apical RPE. Mata et al. proposed that IRBP carries 11-cis and all-trans retinol between the Muller cells and cone outer segments. However, this role, or another function is poorly understood because little is known about the structure of IRBP. Our long term goal is to define the relationship between the structure and function of IRBP. IRBP consists of homologous "modules" (4 in tetrapods and 2 in teleost fish). Each module is about 300 residues in length, and binds 1 to 2 molecules of retinoid or fatty acid. The X-ray crystal structure of an individual module shows: 1) a hydrophobic betabetaalpha-spiral fold, and 2) a solvent exposed surface domain containing highly conserved basic residues. Our Hypothesis is: the betabetaalpha fold forms the retinoidbinding site, and the surface domain allows IRBP to interact with the matrix and or outer segment. This will be evaluated through the following complementary Specific Aims. Aim #1: To determine if the betabetaalpha-spiral fold is IRBP's hydrophobic ligand-binding domain, and whether it can discriminate between 11-cis and all-trans retinol. Aim #2: To determine whether the conserved surface domain: 1) binds glycosaminoglycans particularly hyaluronan, and/or 2) facilitates the release or delivery of retinoids at the outer segment. Aim #3: To determine the X-ray crystal structure of the IRBP-ligand complex, and the full-length native bovine IRBP and zebrafish IRBP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: KINETIC HYPORETINEMIA

STUDY

OF

INFLAMMATION-INDUCED

Principal Investigator & Institution: Rosales, Francisco J.; Nutritional Sciences; Pennsylvania State University-Univ Park 110 Technology Center University Park, Pa 16802 Timing: Fiscal Year 2003; Project Start 04-AUG-2003; Project End 31-MAY-2006 Summary: (provided by applicant): The long-term objective of this proposal is to examine the consequences of inflammation-induced hyporetinemia on hepatic vitamin A (VA) stores and retinal function. Previously, it has been demonstrated that the synthesis of hepatic retinol-binding protein (RBP) and transthyretin (TTR) are reduced during acute inflammation causing a reduction of plasma retinol concentrations (hyporetinemia). The premise of the current study is that hyporetinemia, if prolonged, will impair the distribution of VA between hepatic and non-hepatic tissues. Two studies are proposed. In the first, the distribution and kinetic behavior of plasma retinol will be evaluated using kinetic data and model-based compartmental analysis during acute inflammation. Plasma containing labeled retinol {[3H]retinoI-RBP-TTR} will be injected iv to marginally-VA deficient rats and circulating tracer concentrations will be allowed to reach a terminal slope; then, the system will be perturbed by inducing acute inflammation with lipopolysaccharide from P. aeruginosa, and circulating tracer concentrations will be allowed to reach a new terminal slope. Tracer and tracee data will be collected from plasma, liver, kidneys, eyeballs and remaining carcass. Model-based compartmental analysis using the Simulation, Analysis and Modeling (SAAM) computer program will be used to adjust model parameters to best fit the data. Based on this analysis, hypotheses will be generated to explain the dynamics of pools of retinol among plasma, liver and kidneys, and how alterations in these pools may contribute to decrease retinal VA. in the second study, an animal model of chronic inflammation will be developed with continuous administration of recombinant human intedeukin-6 (rhlL6) to assess the effect of hyporetinemia on retinal function. Marginally-VA deficient

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rats will receive rhlL6 or saline by means of osmotic pumps for 7 to 14 d. VA concentrations in hepatic and non-hepatic tissues will be determined by HPLC at various times. Retinal function will be examined by means of electroretinography during the first and second weeks of experimentation. This information will help in redefining VA status in the presence of low circulating retinol concentrations during inflammation. In addition, the application of these methods and the development of a model of chronic inflammation will foster research on other micronutrients like iron and zinc that are similarly affected by inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIPID GROWTH FACTOR FOR NORMAL AND MALIGNANT B CELLS Principal Investigator & Institution: Hammerling, Ulrich G.; Member; Sloan-Kettering Institute for Cancer Res New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 24-JUL-1989; Project End 31-MAR-2005 Summary: The pleotropic symptoms of Vitamin A deficiency include a marked immune deficiency. During the past decade our group has defined a tissue culture model, has shown that cell survival/death decisions are regulated by retinol, has identified several novel retinol metabolites important for lymphocyte survival, and has solved their structure. 14-hydroxy retro- retinol (HRR) is the prototype of agonistically acting retinoids, supporting lymphocyte survival, whereas anhydroretinol (AR) most often induces apoptosis. Both retro-retinoids can be traced fa br back in evolution to invertebrates, implying a very basic biological role. By contrast, retinoic acid is an invention of vertebrates. During the last grant period we have identified serine/threonine kinases, cRaf and PKC, as the principal receptors of retro-retinoids. Binding occurs at high affinity at the cysteine-rich domain that these kinases share in common, and bound retinol and HRR enhance the activation of phosphotransferase activity by oxidizing agents. We have formulated the working hypothesis that the cys domain functions as a retinoid-regulated redox switch. Retinoids act as catalysts to target special cysteines for selective oxidation. The proposed work will seek to identify the crucial step in the cRaf activation cycle where redox activation occurs (AIM number 1), to define the chemical changes in the oxidized cys domain, and the possible changes in redox potential created by bound retinoids (AIM number 2), and to identify the precise cysteine residues undergoing oxidation. If substantiated the new paradigm will lead to an understanding of how redox activation can be targeted effectively to signaling molecules. Redox regulation is increasingly accepted as controlling factor of immune cells in innate and adaptive immune reactions. The significance of retinoids lies in their capacity to fine-tune this redox signaling network. The marked differences in redox regulation among different retinoids, especially the capacity in AR to block redox signaling that we have demonstrated, may also allow translation into cancer therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISM AND REGULATION OF RETINOL BINDING PROTEIN SECRETION Principal Investigator & Institution: Golttesman, Maxwell; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002 Summary: The synthesis and secretion of the serum retinol binding protein (RBP) is subject to regulation. In the liver, the major site of RBP synthesis, vitA influences

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transcription of the RBP gene and i required for its secretion. It is found in the liver in association with transthyretin (TTR) two which it also binds in the serum. TTR-deficient mutant mice show elevated translation rates of hepatic RBP and accumulate the protein, possibly in the ER. This project is designed to study RBP synthesis and secretion in TTRmutant mice, as well as in mice deficient in the cellular retinal binding protein, CRBP-1. These biochemical studies will focus will focus on the liver and on Sertoli cells, which synthesize and secrete RBP but not TTR. To facilitate the analysis of RBP metabolism, the mutant mice will be crossed with the SV40 temperature-sensitive T antigen transgenic mouse, the "immortomouse", and permanent hepatocyte and Sertoli cell lines will be established. The TTR-deficient mice have the unusual phenotype of enhanced resistance to hypervitaminosis A. The likely possibility that this is related to changes in hepatic RBP and retinol metabolism will be explored. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM OF AMYLOID FORMATION BY TRANSTHYRETIN Principal Investigator & Institution: Hurshman, Amy R.; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2003; Project Start 19-MAR-2003 Summary: (provided by applicant): Transthyretin (TTR) is a carrier protein that is involved in the binding and transport of thyroid hormone and the retinol binding protein/vitamin A complex. TTR is normally present in human plasma and cerobrospinal fluid as a soluble, tetrameric protein, but in several disease conditions can be converted into insoluble amyloid. More than 80 point mutations in TTR have been described and implicated in a group of diseases known collectively as familial amyloid polyneuropathy (FAP). Previous studies have shown that dissociation of the tetramer is rate-limiting for fibril formation in vitro; furthermore, the severity of FAP disease is correlated with the thermodynamic and kinetic stability of the variant tetramers. This study will focus on the mechanism of fibril formation by wild-type and variant TTR using engineered monomeric forms of TTR. The kinetics of the reaction will be examined, and intermediates in the pathway from amyloidogenic monomers to mature fibrils will be characterized using turbidity and dye-binding assays, electron microscopy, analytical ultracentrifugation, and time-lapse atomic force microscopy. These studies will address whether fibrillization is a nucleation dependent polymerization that can be seeded in vivo and whether FAP-variants differ from wildtype TTR in the fibril formation pathway. The results will enhance our understanding of TTR amyloid disease and may shed light on the nature of the intermediates responsible for cellular toxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF OCULAR DEVELOPMENT Principal Investigator & Institution: Norton, Thomas T.; Professor; Physiological Optics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-APR-1986; Project End 31-MAR-2007 Summary: (Provided by applicant): The goal of this project is to understand the "emmetropization" mechanism that uses visual signals to match the axial length of juvenile eyes to their optical power. Normally this mechanism produces eyes with little refractive error. However, a significant proportion of the population develops refractive errors, particularly myopia, in which the eye is too long for its own optical power. In high myopia, the axial elongation (which is not corrected by optical treatments,

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including refractive surgery) is a risk factor for glaucoma and retinal detachment, making myopia the 7th leading cause of blindness in the U.S. The emmetropization mechanism has at least three key components: 1) the retina, which detects the amount of defocus, 2) a signaling cascade from the retina, through the choroid to the sclera (the fibrous outer coat of the eye), and 3) fibroblasts in the sclera which respond to retinal signals by regulating the axial length. Our hypothesis is that remodeling of the scleral extracellular matrix controls scleral extensibility, axial elongation and refractive state. In the previous project period, a pattern of changes in mRNA levels was found for specific proteins in tree shrew sclera during the development of myopia induced with monocular form deprivation (MD) and during recovery from induced myopia. In the proposed project period we will expand on this discovery. Specific Aim I will examine whether myopia induced with a minus-power lens produces the same pattern of changes in scleral mRNA levels (with a different time-course) as when form deprivation is used. Specific Aim 2 will examine the role played by specific proteins in regulating scleral remodeling. We will measure changes in mRNA and protein levels of a membrane-bound matrix metalloproteinase (MTIMMP), of MMP-3 and mRNA levels of proteoglycan core proteins (biglycan, aggrecan, lumican and fibromodulin) during the development of minus-lens induced myopia and recovery. Specific Aim 3 will examine the potential role of all-trans-retinoic acid (at-RA) in the signaling cascade to the sclera. We will measure changes in specific mRNAs and changes in scleral extensibility (creep rate) induced in organ culture by physiological levels of at-RA. These experiments will expand our understanding of the visual regulation of axial length and refractive state by describing the molecular events that occur in the sclera of eyes developing myopia. Understanding the mechanisms regulating scleral remodeling may point the way toward targets for drug intervention to one-day control myopia progression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODULATION OF RETINOIC ACID ACTION IN RENAL CANCER Principal Investigator & Institution: Nanus, David M.; Associate Professor; Medicine; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 03-AUG-2001; Project End 31-JUL-2006 Summary: (Provided by applicant) Renal cell carcinoma is the most common primary cancer arising from the kidney in adults, and is a frequent cause of cancer morbidity and mortality in the U.S., with over 12,000 deaths per year. Currently, there are no consistently effective chemotherapeutic or biologic treatment modalities for patients with advanced disease. Recent results of clinical trials in patients with advanced renal cancer (RC), and of pre-clinical studies using cell culture and human RC tissue specimens, suggest that natural and synthetic derivatives of vitamin A (retinol), a group of compounds called retinoids, play a role in the therapy of RC. We have preliminary data that intracellular levels of retinoic acid (RA) are significantly diminished in human RC cells and that retinol metabolism is aberrant in RC cells as compared to normal human kidney proximal tubule cells. Furthermore, our data indicate that combining retinoids with agents which augment retinoid actions, such as IFN (IFN) or histone deacetylase (HDAC) inhibitors, significantly increases the anti-tumor effect of RA. In this grant application, we propose to study the effects of modulating retinoid anti-tumor action by combining RA with other therapies. The specific aims are: 1) to perform a series of Phase I-II clinical trials designed to evaluate the safety and efficacy of combining liposomal all trans RA (ATRA) with modulators of RA such as interferon and HDAC inhibitors in patients with metastatic RC; 2) to collect peripheral blood samples and tumor tissues to allow laboratory analysis in order to monitor the presence and

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magnitude of specific therapies on retinoid metabolites and retinoid related genes; and 3) to analyze modulators of RA such as interferon and HDAC inhibitors at a molecular level in RC cell lines and xenograft models to delineate mechanisms of action, and to use this information to design strategies to test specific drugs in combination with RA in preparation for future clinical trials. These aims will allow us to perform clinical trials and laboratory studies aimed at gaining a better understanding of the involvement of retinoids in the development, progression and therapy of RC. Moreover, the experiments proposed in this application will help to clarify the potential use of retinoids as a therapeutic strategy to treat patients with RC, and may lead to the identification of new therapeutic agents which result in increased retinol actions for the treatment of various stages of renal cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECUL TRANSPORT/METABOLISM

BIOLOGY

OF

INTESTINAL

LIPID

Principal Investigator & Institution: Davidson, Nicholas O.; Professor & Chief, G.I. Division; Federation of Amer Soc for Exper Biology Bethesda, Md 208143998 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2004 Summary: (provided by applicant): The FASEB Summer Conference on the Molecular Biology of Intestinal Lipid Transport and Metabolism will bring together scientists in a variety of related fields with the purpose of defining, describing and analyzing critical scientific problems and recent advances in an intimate and interactive environment. A key feature of this meeting is the opportunity to facilitate the interactions of students and postdoctoral fellows with senior established figures in the field. Such interactions have historically been successful in defining new research agendas and fostering scientific discourse and collaborations. This application requests partial funding for a Conference to be held August 3-7, 2003 at Snowmass Village in Snowmass, Colorado. This will be the fifth such conference on this theme; the last one was held in the summer of 2000. This conference is unique in both its highly multidisciplinary approach and in its focus on an understudied topic. Thus, we will bring together a diverse group of senior and junior investigators with expertise in the areas of nutrition, physiology, biochemistry, protein chemistry, cell and molecular biology, and developmental biology, to address recent advances in lipid metabolism as they relate to the intestine. The format will consist of seven major oral sessions scheduled over four days (four AM and three PM), an evening Keynote Address and two poster sessions. To date 26 invited speakers have confirmed their desire to participate. The seven formal sessions focus on active research areas: 1) Sterol absorption and transport; 2) Intestinal bile acid and retinol transport; 3) Fatty acid transporters; 4) Enzymes associated with intracellular lipid assembly; 5) Transcriptional control of lipid metabolism; 6) Molecular genetics of lipoprotein assembly and metabolism; and 7) Integrated regulation of hepatic lipid metabolism and secretion. All participants will be invited to submit an abstract to one of two poster sessions that will be held during the conference in order to allow all attendees, especially students and junior investigators to present data and participate in discussions. Additional speakers will be chosen from the abstract submissions, and all participants will be encouraged to submit particularly novel late-breaking developments for brief oral presentation in the form of "hot topics". These hot topics sessions will be targeted specifically to accommodate junior scientists. In the past this conference has promoted interactions and scientific discussions among basic and clinical investigators from academia and industry. The limited attendance, state of the art scientific sessions, "hot topics" additions, and novel poster presentations combine to provide an essential

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forum that will further scientific advances in a field that is largely underserved by other conferences and national venues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR BIOLOGY OF 11CIS RETNYL ESTER HYDROLASE Principal Investigator & Institution: Tsin, Andrew T C.; Professor; Biology; University of Texas San Antonio San Antonio, Tx 78249 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: Current concept of the visual pathway involves the formation of 11-cis retinol from all-trans retinyl esters by an isomerohydrolase. Both 11- cis retinal and 11cis retinyl esters are derived from this 11-cis retinol and this branch point of the visual pathway is known. Although the fate of 11-cis retinal to serve as visual chromophore has been well studied, exactly how 11-cis retinyl esters are used to supply retinal chromophores for pigment regeneration is not known. Previous studies conducted in our laboratory established the presence of an 11-cis retinyl ester hydrolase activity in the bovine retinal pigment epithelium (RPE) microsomes. Our current research focused on the purification and biochemical characterization of this 11-cis retinyl ester hydrolase enzyme. In this faculty development project, we propose to expand the focus of our current biochemistry research to cover molecular biology. The applicant will work fulltime for five consecutive summers in the laboratory of Dr. John Lee at the Department of Biochemistry at the University of Texas Health Science Center in San Antonio to clone and to sequence the gene encoding this protein. Expression of the gene encoding this enzyme will also be studied in bovine retinal pigment epithelial primary cell cultures. This research is important because an understanding of the details of this branch of the visual pathway is lacking. In addition, this faculty development program will also expand the applicant's current teaching and research focus from biochemistry to molecular biology. This is supportive of his department's new focus in the area of cellular and molecular neurobiology. This expansion of the applicant's teaching and research programs will also bring modern biology concepts and techniques to minority and non-minority students at The University of Texas at San Antonio. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR REGULATION OF LRAT AND CYP26 IN LIVER Principal Investigator & Institution: Ross, a C.; Professor; Nutritional Sciences; Pennsylvania State University-Univ Park 110 Technology Center University Park, Pa 16802 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: Retinoic acid and related retinoids are potent hormone-like ligand for two families of ligand-activated nuclear receptors, RAR and RXR. Retinoic acid is synthesized from vitamin A precursors in a variety of cells where it potentially acts in situ to induce gene expression, control growth, and promote normal cellular differentness. These actions make retinoids a great interest in situ chemoprevention of cancer. Despite many advances in retinoid receptor biology, our understanding of the factors that regulate endogenous retinoid concentrations has lagged behind. Understanding the production and catabolism of retinoids is critical to understanding their receptor-mediated actions. The central hypothesis to be tested is that two liver microsomal enzymes - lecithin: retinol acyltransferase, LRAT, and cytochrome P450RA1, or CYP26- serve as key regulators of Retinoic acid biosynthesis and catabolism, respectively. Recently we have cloned LRAT cDNA from rat and mouse

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liver. Preliminary studies are presented in which LRAT and CYP26 gene expression was strongly regulated in liver, both actually by exogenous retinoids and chronically by dietary vitamin A. To critically test our hypothesis we will conduct 4 specific aims. In aim 1 we will examine retinoid- and diet- induced differences in LRAT and CYP26 gene expression and retinoid metabolism in intact rats. In aim 2 we will investigate which liver cell types express LRAT and CYP26 and further test our model of retinoid metabolism in hepatocytes and stellate cells. In aim 3, we will sequence the homologous cDNA for human liver LRAT and conduct molecular studies of LRAT and CYP26 expression in normal and diseased liver specimens available from the Liver Tissue Procurement and Distribution System (LTPADS). In aim 4, we will study the 5' regulatory regions of the LRAT and CYP26 genes to determine the molecular basis for their responsiveness to Retinoic acid in liver. By investigating both LRAT and CYP26 simultaneously we expect to obtain novel insights into the molecular and cell-type specific regulation of Retinoic acid biosynthesis and degradation. This information could shed new light on the endogenous factors that control the availability of Retinoic acid in tissues and plasma which, in turn, are likely to affect Retinoic acid's anticarcinogenic potential. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NUTRITION SUPPLEMENTATION STUDIES IN SICKLE CELL DISEASE Principal Investigator & Institution: Stallings, Virginia A.; Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2003; Project Start 22-JUL-2003; Project End 31-MAR-2008 Summary: For several decades it has been recognized that children with sickle cell disease(SCD), especially those with HbSS genotype SCD (SCD-SS), have poor growth and delayed maturation. In addition, children with SCD experience frequent SCDrelated pain and fever episodes and also infection. Increased nutrient requirements and/or poor nutritional status have been documented in children with SCD suggesting that chronic undernutrition may contribute to poor health outcome, growth failure and delayed development. Low serum levels of vitamin A and vitamin B6 have been documented in children with SCD suggesting that dietary intake of these micronutrients may not be adequate to meet the increased nutrient needs of children with SCD. The proposed study consists of two projects to determine whether supplementation of vitamin A or vitamin B6, can improve health outcomes, nutritional status, growth and hematologic status in children with SCD-SS. Our preliminary data from prepubertal children with SCD show that 66% have suboptimal vitamin A status (serum retinol< 30 mu g/dL), and that those children with suboptimal status have more frequent hospitalizations, have reduced body mass index, and poorer hematologic status than those with normal vitamin A status. Furthermore, preliminary studies in children and adolescents with SCD show that suboptimal vitamin B6 status (serum pyridoxal 5'phosphate [PLP]< 20 nmol/L) is also prevalent (77%), and that low serum B6 concentration is associated with poor nutritional status as indicated by reduced body mass index, weight and mid-arm circumference and also with poorer hematologic status. The first study is a randomized placebo-control clinical trial to determine the effect of vitamin A supplementation at the current Recommended Dietary Allowance (RDA) on number of hospitalizations, the number and length of both SCD-related and nonSCD-related disease events, on growth, body composition, hematologic status, rod cell integrity,and immune status in prepubertal children (ages 2.0 to 9.9 years) with SCD. Seventy-five children with SCD will be screened for vitamin A status and 44

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subjects with serum retinol levels< 30 mu g/dL at screening will be randomized to receive either the RDA for vitamin A daily or placebo for 12 months. The second study will explore the effect of vitamin B6, supplementation at two doses on growth and nutritional status and hematological indices of SCD disease severity in children and adolescents (ages 6.0 to 17.9 years) with SCD. A total of 100 children and adolescents with SCD and 100 healthy controls, similar in age, gender and ethnic background, will be screened to document the prevalence of vitamin B6 deficiency in children with SCD. Forty children with serum PLP levels < 20 nmol/L will be identified and randomized to receive either 5 mg/day or 25 mg/day vitamin B6 for 12 months. For both supplementation studies, assessments will be made at baseline, 3, 6, 9 and 12 months. These two projects will provide systematic investigations of the roles of both vitamin A and vitamin B6 in improving health outcomes, growth and nutritional status in children with SCD and will potentially result in cost-effective nutritional interventions that can be quickly implemented into the standard of care for these children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NUTRITIONAL INFLUENCES ON ARSENIC TOXICITY Principal Investigator & Institution: Gamble, Mary V.; Assistant Professor; Biochem & Molecular Biophysics; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 17-MAR-2003; Project End 28-FEB-2007 Summary: (provided by applicant): The largest known mass exposure to arsenic is presently occurring due to ground water contamination of well water throughout the Ganges-Brahmaputra Delta There is significant inter-individual variability in susceptibility to progression from arsenic exposure to clinical manifestations of arsenic toxicity (e g skin, lung, liver and bladder cancers) Several observational as well as biochemical studies have led to a prevalent hypothesis that nutritional status may account for a substantial portion of this variability, though no controlled clinical studies have addressed this important hypothesis. Methylation of inorganic arsenic (InAs) is generally considered to be a detoxification pathway InAs and DNA are both methylated via one-carbon metabolism, a biochemical pathway which is dependent on folate for de novo generation of one-carbon groups, and also uses vitamins B12 and B6 as cofactors The primary hypothesis of this proposal is that nutritional regulation of one-carbon metabolism, specifically folate availability, contributes substantially to the large interindividual variability observed in InAs and DNA methylation, and thus progression from arsenic exposure to toxicity This hypothesis will first be tested in cross-sectional studies of adults and children chronically exposed to arsenic-contaminated drinking water in Bangladesh Other nutritional deficiencies, including those of retinol, carotenoids and protein, have also been implicated as possibly influencing progression from arsenic exposure to toxicity, although the mechanistic bases for these interactions are somewhat less clear Exploratory studies will address these possibilities as secondary objectives in children, who are more likely to be deficient in these nutrients A third objective will test whether, in adults or children, arsenic exposure is correlated with lymphocyte DNA hypomethylation, an early event in some cancers. Finally, a 12-week double blind placebo controlled folate supplementation trial of adults with elevated plasma homocysteine concentrations and low plasma folate concentrations will be conducted to determine if folate supplementation results in improved arsenic and/or lymphocyte DNA methylation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OPSINS, G PROTEIN PATHWAYS AND REGULATION IN RPE CELLS Principal Investigator & Institution: Fong, Henry K.; Doheny Eye Institute 1450 San Pablo St Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-AUG-1990; Project End 31-JUL-2007 Summary: (provided by applicant): Vertebrate opsins in photoreceptors and the retinal pigment epithelium (RPE) have fundamental roles in the visual process. The visual pigments in photoreceptors are bound to 11 -cis-retinal and are responsible for the initiation of visual excitation. Retinochrome-like opsins in the RPE are bound to alltrans-retinal and may play an important role in chromophore metabolism. The retinal G protein-coupled receptor (RGR) in the RPE and Muller cells is an opsin that is necessary for normal synthesis of 11 -cis-retinal and regeneration of rhodopsin during light adaptation. It is hypothesized that RGR has a central role in light-dependent synthesis of 11-cis-retinal and the regeneration of rhodopsin, hence RGR is involved in the visual cycle. The objective of this grant application is to prove this hypothesis by demonstration of a detailed mechanistic model for the function of RGR at the molecular and physiological levels. The study of RGR opsin is impeded by limitations in accessibility, low abundance, biochemical properties, and the lack of an appropriate cell culture model. To be able to study the RGR opsin, three experimental approaches to this research problem have been created. A functional RGR opsin from bovine RPE has been isolated. Second, a cell culture model of RPE cells that stably express RGR and remain able to process retinoids has been established. Third, the RGR opsin knockout mouse with an informative phenotype has been produced. These experimental approaches will be used in this grant proposal to further investigate the function of RGR and its role in retinoid metabolism and regulation in the RPE. By preserving rhodopsin levels and retinal sensitivity, the RGR opsin gene helps to prevent night blindness and provides a selective advantage for species subject to wide variation in environmental luminance. Further understanding of RGR at the biochemical level will be important in learning how RPE cells work, and characterization of defects in RGR function may show how human RPE cells undergo dysfunction and deteriorate leading to disease. Since RGR is involved in a fundamental visual process, defects in RGR are likely to impair the health of the RPE and retina. The importance of RGR opsin to the health and viability of the neuroretina is shown by mutations in the human RGR gene that segregate with retinitis pigmentosa (RP) in patients with autosomal dominant or recessive RP. Errors in retinoid metabolism in either the photoreceptors or RPE cells may lead to abnormal levels of A2E, a major compound of lipofuscin that accumulates in the RPE during aging and age-related macular degeneration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDF AND PHOTORECEPTOR PROTECTION: A NAKED DNA APPROACH Principal Investigator & Institution: Cao, Wei; Ophthalmology; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2005 Summary: (provided by applicant): PEDF and photoreceotor protection: a naked DNA approach. Photoreceptor cell death is an irreversible event in many blinding diseases including retinitis pigmentosa, age-related macular degeneration and retinal detachment. Pigment epithelium derived factor (PEDF), a secreted protein with both neurotrophic and anti-angiogenic properties, is made in vivo by a variety of cells in both

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fetal and adult animals. Within the retina, it is secreted by retinal pigment epithelial (RPE) cells into the interphotoreceptor matrix, placing it in a prime physical location to affect the underlying photoreceptor cells. We recently reported that the intravitreal injection of PEDF protected photoreceptor cells against constant light induced damage in a rat model. An alternative method for delivering a protein factor to cells and tissues is to use only the DNA which codes for the protein. Our preliminary data show that primary cell cultures of rat retinal neurons can be transfected with a naked DNA coding for enhanced green fluorescent protein under the control of the photoreceptor cellspecific promoter, mouse interphotoreceptor retinol binding protein. We have performed similar experiments expressing other reporter genes under control of other photoreceptor cell specific promoters. These experiments suggest that we are able to transfect PEDF cDNA into retinal neurons which will then express the PEDF protein. I am seeking three years of funding in this proposal to develop a novel approach using plasmid DNA cassettes expressing PEDF and apply it to the retina to prolong useful vision by delaying or preventing retinal degeneration. This novel method is actually being employed in phase I clinical trials with the injection of a naked DNA encoding the angiogenesis factor, VEGF, into the hearts of cardiac patients. In several phase II trials, direct injection of DNA has also demonstrated significant therapeutic effects in cancer patients. The specific aims of this proposal are: I) To demonstrate the expression and protection efficiency of transfected naked plasmid DNA, encoding PEDF, in cultured rodent retinal cells. 2) To maximize the in vivo expression of naked plasmid PEDF in the eye, through the optimization of the route of administration, such as topical application, anterior chamber/intravitreal/subretinal injection. 3) To evaluate the protective efficacy of this protocol to prevent the retinal degeneration induced by light or by heredity. The proposed studies are innovative and could have a significant clinical impact as a novel therapeutic approach to delay or prevent retinal degeneration and to prolong useful vision. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE I STUDIES OF ANTICANCER AGENTS Principal Investigator & Institution: Spriggs, David R.; Chief/Associate Attending Physican; Sloan-Kettering Institute for Cancer Res New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 16-MAY-1995; Project End 28-FEB-2003 Summary: (Applicant's Description) This research proposes to develop new knowledge relevant to the treatment of cancer by conducting phase I studies of new anticancer drugs and pharmacologic modulatory regimens which attempt to enhance the therapeutic efficacy of new drugs. Concurrent with the clinical studies, the research will evaluate the distribution and metabolism of the study drugs and examine their biological effects at the clinical biochemical and molecular level. The Specific Aims of this proposal will be: 1)Putative Cytodifferentiation Agents: The institution has a longstanding interest in differentiation agents including studies of HMBA, all trans-retinoic acid, 9-cis retinoic acid, RXR specific ligands and phenylbutyrate (supported under other mechanisms). Studies under this agreement are planned for new bryostatin analogs (UCN-01) and other differentiation inducing agents currently under development at CTEP. 2)Signal Transduction Targets: MSKCC laboratories have national leadership roles in the evaluation of ras inhibitors, ceramide mediated signaling and the interaction between factors and cytotoxic chemotherapy. Inhibition of protein kinase C will be a target of particular interest. Trials of these agents, alone and in combination with cisplatin, paclitaxel and mitomycin C are planned. 3)Reversal of Drug Resistance: The mechanisms of drug resistance continue to be a major area of interest for

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the pharmacology group at MSKCC. Combination studies of established agents and agents with novel mechanisms which appears to interfere with the acquisition and maintenance of drug resistance are planned. One such combination would be cisplatin and flavopiridol. 4)Phase I Testing of Disease Specific Therapies: One of the strengths of MSKCC is its large patient population. Through this cooperative agreement, we will look for particularly interesting agents which require early targeting to specific cancer types. Our high patient volume will allow us to rapidly complete such studies. A good example of one such trial is the proposed study of vaccine therapy for prostate cancer. T h e studies to be performed during the funding period will include pharmacokinetric studies, studies of adaptive dosing and pharmacodynamic studies of new agents or combinations. Laboratory correlates, based on tumor biopsies or surrogate tissues will also be performed as appropriate. Quality of life and cost of therapy vs alternative therapy will be prospectively collected for all studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHYSICIANS HEALTH STUDY--CONTINUED FOLLOW UP Principal Investigator & Institution: Buring, Julie E.; Professor of Ambulatory Care and Prevent; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-FEB-1991; Project End 31-MAY-2003 Summary: (Applicant's Description) In the May 2, 1996 issue of The New England Journal of Medicine, the results of two large-scale randomized trials which included beta carotene were published: the Physicians' Health Study (PHS) and the Beta Carotene and Retinol Efficacy Trial (CARET). In the PHS, conducted among 22,071 US male physicians, after an average of 12 years of supplementation with beta carotene or placebo, there were no differences between the groups in the rates of malignant neoplasms, cancer mortality, cardiovascular mortality, or mortality from all causes. In the CARET study, 18,314 men and women at high risk of lung cancer, due to smoking or asbestos exposure, were assigned to a combination of beta carotene and retinol. This trial was terminated early by its Data Monitoring Board primarily because of an inability to demonstrate a benefit, but also because of observed possible increased risks of lung cancer, cardiovascular mortality, and total mortality consistent with the results of the Alpha-Tocopherol/Beta Carotene Cancer Prevention Study (ATBC). In a press conference convened by the National Cancer Institute (NCI) on January 17, 1996, NCI Director Dr. Richard Klausner emphasized the critical importance of continued followup of the trial cohorts. Given the unexpected results of ATBC and CARET, and the finding of no effect of beta carotene in the PHS, continued surveillance of all these trial cohorts is crucial to ensure complete documentation of the long-term health effects of beta carotene supplementation. To help achieve this goal, we have established the Antioxidant Trialists' Collaborative Group which will conduct a systematic metaanalysis of the post-publication results of continued follow-up in all completed trials, to fully assess the effects of beta carotene supplementation among smokers and nonsmokers. Post-trial follow-up has already been funded by NCI for CARET, ATBC, the Chinese Cancer Prevention Study, and the two Dartmouth trials of skin cancer and colon polyps. This application proposes to continue by mail the post-trial follow-up of the PHS cohort for 5 years. Continued follow-up of the PHS cohort is particularly important given the unique aspects of the trial, including its large populations of never and ex-smokers which are more representative of the general population of healthconscious individuals who take vitamin supplements, its highly compliant population and record of extremely complete follow-up, its long duration of randomized beta

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carotene supplementation, and its extremely cost-efficient design for follow-up of a chemoprevention trial cohort. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PLACENTAL CAROTENOIDS: METABOLISM AND DEVELOPMENT Principal Investigator & Institution: Rubin, Lewis P.; Professor; Women and Infants Hospital-Rhode Island 101 Dudley St Providence, Ri 02905 Timing: Fiscal Year 2002; Project Start 27-JUN-2002; Project End 31-MAY-2007 Summary: (Provided By Applicant) Vitamin A (retinol) supplied by the mother to her fetus is essential for normal embryogenesis, fetal development, and neonatal survival. The major source of vitamin A in mammals is oxidative cleavage of the principal dietary provitamin A carotenoid, beta-carotene (betaC). Epidemiologic and animal investigations indicate betaC and other carotenoids have pregnancy-promoting actions. An intriguing finding is that several of these properties apparently are independent of provitamin A activity. In Preliminary Studies, we have shown that placental trophoblast metabolizes betaC to retinol via the principal betaC cleavage enzyme, betaC-15,15'dioxygenase (betaCDO). In addition, we have shown specific provitamin A and non-pro vitamin A carotenoids modulate placental growth and differentiation by actions on trophoblast gene expression. These observations have prompted the following experimental questions: (a) Does placental regulation of BetaC to retinoid metabolism serve a physiologic role akin to the placental enzymatic barrier functions which maintain intrauterine glucocorticoid and vitamin D homeostasis?; and (b) Do specific dietary carotenoids promote normal pregnancy by a combination of genomic and nongenomic events in uteroplacental target cells? This proposal addresses deficiencies of current understanding about nutritional regulation of intrauterine physiology. In order to characterize the cellular changes induced by carotenoids and to determine relevant molecular mechanisms, we will combine: well-characterized trophoblast cell culture models, systems for uniform delivery of bioavailable carotenoids over a wide concentration range, and biochemical and molecular biological analysis of carotenoid metabolism in intact cells and placental tissue. We will test the hypotheses: (a) Placental betaC-1 5,1 5'-dioxygenase (betaCDO) activity is the major (or sole) enzymatic route for fetal biotransformation to retinal, the precursor of retinoic acids. (b) Nutrient and hormonal regulation of placental betaCDO gene expression and enzyme activity modulate fetal exposure to potentially deleterious fluctuations of maternal vitamin A. We also will determine which specific carotenoids are important gestational agedependent regulators of placental gene expression and trophoblast proliferation, migration/invasiveness and survival. Finally, we will establish whether these biological activities require carotenoid conversion to retinoids or carotenoid antioxidant activities. These studies will provide new information about potentially critical aspects of intrauterine homeostasis. Consequently, this research will increase understanding and suggest interventional strategies for vitamin A deficiency in pregnancy, a major global public health problem. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PPAR-GAMMA NUCLEAR TRANSCRIPTION FACTOR: A NOVEL TARGET FOR LEUKEMIA THERAPY Principal Investigator & Institution: Andreeff, Michael W.; Stringer Professor for Cancer Treatment; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 05-AUG-2003; Project End 30-APR-2008

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Summary: New approaches are needed to improve cure rates in adult hematological malignancies. PPARgamma (Peroxisome Proliferator-Activated Receptor Gamma) is a member of the nuclear transcription factor family involved in signaling of differentiation. We have demonstrated that PPARgamma is expressed in the majority of primary human leukemias but not in normal hematopoietic progenitors, and that ligation of PPARgamma induces differentiation, growth arrest and apoptosis in leukemias. We propose to extend our initial studies on the mechanisms and efficacy of PPARgamma signaling in acute myeloid leukemia to acute and chronic (CLL) leukemia, with the goal of developing PPARgamma as a novel target for the treatment of hematological malignancies. We are encouraged to pursue this goal by the seminal impact on leukemia therapy that was affected by targeting RARalpha in acute promyelocytic leukemia (APL) with ATRA. First, we will investigate the expression of PPARgamma, in acute and chronic myeloid and lymphoid human leukemias and leukemic stem cells and study the effects of PPARgamma ligands on apoptosis and differentiation. We will determine the effects of combined targeting of PPARgamma and RXR in leukemias, as PPARgamma, and RXR heterodimerization is required to maximize transcriptional activation. In the second aim, we will further elucidate the specific mechanisms of apoptotic cell death and growth arrest that are triggered by PPARgamma, ligation. Preliminary data demonstrate that PPARgamma ligands induce loss of mitochondrial membrane potential and activation of effector caspases. Finally, we propose to initiate Phase I studies using PPARgamma ligands, in combination with rexinoids. These studies will utilize FDA approved PPARgamma and RXR ligands and the new potent triterpenoid CDDO, a novel PPARgamma, ligand that is presently being developed by us with assistance from CTEP/RAID at the National Cancer Institute. The long-term goal of the proposed studies is to determine the molecular, biological and clinical effects of PPARgamma/RXR ligation in human leukemia and to develop the PPARgamma/RXR nuclear receptor system as a novel target for leukemia therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PRECLIN. MODEL FOR PREVENTION OF NSCLC IN FORMER SMOKERS Principal Investigator & Institution: Schuller, Hildegard M.; Distinguished Professor; Pathobiology; University of Tennessee Knoxville Knoxville, Tn 37996 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2006 Summary: (provided by applicant) The central hypothesis of this application is that growth regulating pathways expressed in human and mouse alveolar type II cell pulmonary adenocarcinomas (PAC type II) and in human and hamster pulmonary squamous cell carcinomas (SQCs) are antagonistic to those expressed in human and hamster Clara cell type pulmonary adenocarcinomas (PACCs). Chemoprevention studies applicable to former smokers therefore need to use models representing these differently regulated cancer types. Non-invasive methods need to be developed that allow to monitor the expression levels of these pathways in former smokers to asses response to treatment and to ensure assignment of individuals to effective chemopreventive treatments while avoiding potentially cancer promoting agents. To achieve these goals in a preclinical setup, our specific aims are as follows: 1) We will characterize the effects of green tea, theophylline, beta-carotene, retinol, glucocorticoid beta- blockers, cAMP antaogonists, and inhibitors of cyclooxygenase-2 (COX-2) or 51ipooxygenase (5-.LOX) in human lung cancer cell lines derived from PAC type II, PACC or QSQC and in non-tumorigenic and tumorigenic mouse PAC type II cell lines. 2) We will synthesize iodine-125 and -123-labeled analogues of inhibitors of COX-2,

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cAMP-dependent PKA and 5-LOX for use in micro-photon emisssion tomography (micro-SPECT). We will verify the binding of these analogues to their cellular targets by in vitro binding assays, using human lung cancer cell lines characterized under aim 1 and by in vivo bio-distribution studies, using mice carrying xenographs of these human lung cancer cell lines. 3) We will study the chemopreventive effects of selected agents from aim 1 in bioassay experiments, using the A/J/mouse PAC type II model, the hamster PACC model and the hamster SQC model. The experimental designs will simulate chemoprevention in former smokers by starting the chemopreventive treatments at the time when tumor induction treatment has been discontinued and precancerous lesions are present in the animals. Evaluation of data will include histopathology, including immunostains for COX-2, PKA and 5-LOX as well as analysis of protein expression of these enzymes by Western blots in normal cells of origin of the induced tumors, premalignant lesions, and in lung cancers harvested by laser capture microscopy. 4) Using the iodine-125-1abeled analogues from aim 2, we will conduct micro-SPECT analysis of five randomly chosen animals per treatment group of aim 3 before, during and after completion of chemopreventive treatments and we will attempt to quantitate levels of COX-2, PKA, and 5-LOX in lung tissues and lung tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTEASE INHIBITOR-INDUCED HYPERLIPIDEMIA IN AIDS Principal Investigator & Institution: Brown, Virgil W.; Professor of Medicine; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 28-SEP-2000; Project End 31-JUL-2005 Summary: (Adapted from the applicant's abstract) HIV-protease inhibitors (PI) prevent the maturation of nascent virions and are thus very effective in blocking further infection in HIV-positive patients. Significant reductions in mortality from AIDS have been achieved with the use of PI. Cross-sectional studies, however, have suggested accelerated atherosclerosis in HIV-positive patients receiving PI therapy and this may be associated with high prevalence of several risk factors for atherosclerosis: hyperlipidemia, hyperglycemia, insulin resistance and fat redistribution. The exact mechanisms underlying these metabolic changes are not known. Based on homology studies, HIV-protease inhibitors may interfere with the function of the low density lipoprotein receptor-related protein (LRP) and the cytoplasmic retinol binding protein (CRBP). LRP is responsible for the hepatic uptake of intestinal lipoproteins transporting dietary fats and fat- soluble vitamins such as vitamin A. Inside the cell, the transport of retinoic acid by CRBP may interact with peroxisome proliferator activator receptor (PPAR) and thus affect the production of apoC-III and the differ- entiation of adipocytes. Using non-radioactive tracers, we propose to examine the changes in lipoprotein metabolism associated with HIV infection and the therapeutic use of PI. The metabolism of oral retinol will be examined with respect to the effect of PI on LRP. The production of apoC-III, a PPAR- regulated apolipoprotein linked to hypertriglyceridemia and diabetes, will be examined with respect to its association in PI-induced hypertriglyceridemia. While hyperlipidemia may be associated with atherosclerosis, it cannot explain the accelerated progression of the disease. Changes in physiological and biochemical responses with oxidative stress associated with postprandial lipemia will be examined as a possible mechanism for accelerated disease progression. A comprehensive longitudinal study with new markers for CAD will also be conducted to characterize the progression of the risk factors with PI. In a subset of patients with hyperlipidemia, the efficacy of combined therapy with vitamin A, fibrates,

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and thiazoladinediones will be evaluated. These are specific agents that are effective in reducing triglyceride as well as improving insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGENERATION OF 11-CIS-RETINAL IN THE RETINA Principal Investigator & Institution: Rando, Robert R.; Gustavus Adolphus Pfeiffer Professor; Biological Chem & Molecular Pharm; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-APR-1982; Project End 31-AUG-2005 Summary: (Adapted from applicant's abstract): The vertebrate visual cycle is comprised of biochemical reactions involved in processing all-trans retinal produced by the photoisomerisation of 11-cis retinal in rhodopsin. The visual cycle is essential for vision and visual adaptation. The goal of this project is to characterize on a molecular level essential components of the visual cycle and to learn how the cycle is regulated. Two of the key reactions in the visual cycle are catalyzed by the retinal pigment epithelium membrane bound enzymes, lecithin retinol acyl transferase (LRAT)and the isomerohydrolase. LRAT transfers an acyl group from lecithin to vitamin A to generate all-trans retinyl esters and the omerohydrolase processes the esters to produce 11-cis retinol. Both enzymes are essential for vision. An understanding of LRAT at the molecular level is of major interest in this grant proposal. LRAT has a unique sequence which does not reveal the mechanistic class to which it belongs. Biochemical studies including chemical mapping studies using the novel technique of biotin affinity labeling and site-specific mutagenic studies are proposed to both map elements of the active-site structure of LRAT and define its molecular mechanism of action. Chemical mapping studies are also proposed to begin to elucidate the structure of LRAT in the membrane and to reveal nearest neighbor proteins in RPE membranes. One of the LRAT associated proteins may be the isomerohydrolase. Identification and characterization of isomerohydrolase is another important aspect of this proposal. Approaches to the identification of this enzyme system will involve both exploiting interactions with LRAT to either affinity purify or cross-link isomerohydrolase and photoaffinity labeling approaches to label the enzyme. When isomerohydrolase is identified it will be coned sequenced and expressed in LRAT transfected HEK cells. The structure, mechanism of action and regulation of the isomerohydrolase will be explored as will possible relationships to diseases of vision caused by mutations in the enzyme. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGENERATION OF CONE PIGMENTS & TREATMENT OF STARGARDT'S Principal Investigator & Institution: Travis, Gabriel H.; Assistant Professor; Jules Stein Eye Institute; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-MAR-1997; Project End 28-FEB-2007 Summary: (provided by applicant): Vision in civilized man is mediated largely by cone photoreceptors. Despite the importance of cones, much more is known about the biology of rods. The first step in visual perception is absorption of a photon by a visual pigment molecule, which induces 11-cis to all-trans isomerization of the retinaldehyde chromophore. Before light-sensitivity can be restored, all-trans-retinaldehyde must be re-isomerized to 11-cis-retinaldehyde. This involves a multi-step process called the visual cycle, which has been worked out mainly in rod-dominant species. Several lines

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of published evidence suggest that cone photoreceptors regenerate visual pigment by an alternate pathway. Nothing is known, however, about the biochemistry of this alternate pathway. We have recently identified three new catalytic activities in cone-dominant ground squirrel and chicken retinas that mediate regeneration of 11-cis-retinaldehyde from all-trans-retinol. The first aim of this application will be to purify and clone the mRNA for: (1) a new 11-cis-retinol dehydrogenase distinct from the 11-cis-retinol dehydrogenase type-5 in retinal pigment epithelial cells; (2) an all-trans-retinol isomerase that catalyzes the direct conversion of all-trans-retinol to 11-cis-retinol utilizing fatty-acyl-CoAs as an energy source; and (3) an 11-cis-retinyl-ester synthase that acts by a mechanism clearly distinct from that of lecithin-retinol acyl transferase (LRAT). We plan to characterize these proteins functionally, using in vitro biochemical, cell culture expression, and mouse transgenic/knockout systems. Recessive Stargardt's disease is an inherited form of macular degeneration caused by mutations in the ABCR gene. During the previous funding period, we generated mice with a knockout mutation in abcr. The phenotype in these animals is strikingly similar to the clinical phenotype in patients with recessive Stargardt's disease, including accumulation of lipofuscin in the retinal pigment epithelium. Lipofuscin accumulation appears to be a critical event in the development of retinal pathology. The second aim of this application is to test a promising strategy for inhibiting lipofuscin deposition and photoreceptor degeneration in abcr-/- mice. If successful, this strategy should lead to the initiation of clinical trials on patients with active Stargardt's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF THE SODIUM/IODIDE SYMPORTER IN BREAST Principal Investigator & Institution: Brent, Gregory A.; Professor; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 12-JAN-2001; Project End 31-DEC-2004 Summary: (Adapted from the applicant's abstract) In the lactating mammary gland, iodide is concentrated up to 36-fold in milk compared with the plasma iodide concentration, due to stimulation of the sodium/iodide symporter (NIS). Some hormone-dependent breast cancers also concentrate iodide, up to 7-fold, but iodide uptake in breast cancer must be enhanced to make radioiodine treatment possible, analagous to the TSH stimulation required for uptake of radioiodine into thyroid cancer. All-trans retinoic acid (RA) treatment stimulates iodide uptake, MS mRNA, and MS protein in MCF-7 cells, an estrogen receptor (ER) positive human breast cancer cell line, in a time and dose dependent fashion. No RA-induction of iodide uptake is seen in an ER-negative breast cancer cell line, MDA-MB 231, or a normal breast-derived cell line, MCF-12A. An in vitro clonogenic assay demonstrated selective toxicity of radioiodine following RA stimulation of MCF-7 cells. MCF-12A cells have abundant MS protein, but no functional iodide uptake. MS regulation differs significantly in the breast compared to the thyroid, and differs in normal breast and breast cancer cell lines. We propose to study the regulation of iodide transport in breast cancer cell lines compared to normal breast and thyroid cell lines, with the goals of optimzing iodide uptake and selectively targeting breast cancer cells. Specific aims include: 1. Determine the mechanism of RAmediated transcriptional regulation of the NIS gene in breast-derived cells utilizing selective retinoid agonists and cell lines with a range of endogenous RAR and RXR expression. 2. To determine the characteristics of NIS protein expression, subcellular localization, and kinetics that are associated with maximal function of NIS in breastderived cell lines and those features that distinguish functional iodide uptake among cell lines that express NIS protein. 3. Utilize an in vitro model to optimize RA-stimulated

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radiation-mediated cell killing in breast cancer cells. 4. Develop in vivo models to determine the efficacy and specificity of RA-stimulated iodide uptake into breast cancer and determine the influence of enhancers and radiation sensitizers. RA raioiodide uptake may be useful for diagnosis and treatment of some differentiated breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETINOIC ACID RESPONSE IN HUMAN LUNG CANCER Principal Investigator & Institution: Zhang, Xiao-Kun; Associate Professor; Burnham Institute 10901 N Torrey Pines Rd La Jolla, Ca 920371005 Timing: Fiscal Year 2002; Project Start 01-AUG-1993; Project End 31-JUL-2004 Summary: Lung cancer is the leading cause of cancer death in the United States. Therefore, more effective methods to prevent and treat lung cancer are urgently needed. Epidemiological and animal studies have demonstrated that vitamin A and its natural and synthetic derivatives, retinoids, are promising agents in preventing the development of lung cancer. However, clinical trials have found no preventative effects of vitamin A against lung cancer development, suggesting that retinoid responses may be impaired in lung cancer cells. The effects of retinoids are mainly mediated by two classes of nuclear receptors, the retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both of which are encoded by three distinct genes, alpha, beta, and gamma. In our previous study, we found that retinoid responses are impaired in a majority of lung cancer cells and that loss of RARbeta is primarily responsible for the defect. In addition, we observed that loss of RARbeta can be attributed to abnormal regulation of a RA responsive element (beta RARE) in the RARbeta promoter, due to low levels of COUPTF that is required to maintain retinoid sensitivity and/or elevated levels of orphan receptor nur77 which inhibits RXR and COUP-TF activities through heterodimers. The loss of RARbeta could also be attributed to low binding activity of a pEA3 binding site in the RARbeta promoter. Furthermore, we demonstrated that nur77 can induce lung cancer cell apoptosis depending on its stimulus. In the proposed study, we will first study the anti-cancer effects of RARbeta by identifying its specific DNA binding sequences and interacting proteins as well as genes mediating its growth inhibition and apoptosis inducing effects. We will then analyze and clone protein that actively binds to pEA3 site and regulates RARbeta promoter activity. In addition, we will study the mechanism by which COUP-TF sensitizes RAREs and their responsiveness to trans-RA. Finally, we will investigate how phosphorylation of nur77 regulates its DNA binding and heterodimerization specificity and their involvement in determining the effects of nur77 on trans-RA resistance and induction of apoptosis, and identify genes responsible for its apoptosis inducing effects. Results from these studies will contribute to our understanding of the mechanism by which RARbeta exerts its anti-cancer activities and how the activities are lost in lung cancer cells, and may provide means to increase retinoid sensitivity in lung cancer cells, thereby enhancing the anti-cancer efficacy and spectrum of retinoids against this diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RETINOID CANCER PREVENTION MECHANISMS Principal Investigator & Institution: Dmitrovsky, Ethan; Andrew G. Wallace Professor of Pharmacol; Pharmacology and Toxicology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 30-JUN-2005

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Summary: There is rapidly evolving evidence for beneficial retinoid actions in preventing or treating clinical tumors. This application explores a novel all-transretinoic acid (RA)- dependent G1 cell cycle arrest mechanism active in preventing carcinogenic transformation of human bronchial epithelial cells. Preliminary findings indicate that using cultured human bronchial epithelial cells that RA-treatment engages the G1 cell cycle machinery to trigger growth arrest and antagonize carcinogenic transformation. Interest in studying this further is propelled by our unexpected finding that retinoids signal G1 arrest through a pharmacological mechanism: proteolysis of G1 cyclins via ubiquitin-dependent degradation of G1 cyclins. This RA-triggered G1 arrest is hypothesized to permit repair of genomic damage by carcinogens. This proposal explores whether retinoid-dependent degradation of G1 cyclins is a cancer chemoprevention mechanism through these specific aims: (1) To define precisely the retinoid chemoprevention mechanism inducing ubiquitin-dependent proteolysis of G1 cyclins in human bronchial epithelial cells through these questions: (a) Does RA affect stability of wild- type versus ubiquitin-degradation resistant cyclin D1 and E proteins? (b) Does RA affect directly ubiquitination of these G1 cyclins? (c) Does RA signal phosphorylation of these G1 cyclins at sites involved in ubiquitination: and (d) Does RA regulate in these cells ubiquitin-ligase components induced by RA in other cell contexts? (2) To determine whether this ubiquitin-dependent proteolysis of G1 cyclins is required for retinoid suppression of bronchial epithelial cell transformation by: (a) assaying transformation of human bronchial epithelial cells engineered to over-express wild-type and/or degradation resistant G1 cyclins; (b) exploring whether RA or other prevention agents overcome this G1 cyclin-dependent transformation through a ubiquitindegradation mechanism; and (c) transfecting antisense constructs for these G1 cyclins into human bronchial epithelial cells to establish whether this mimics RA effects. (3) To establish the in vivo relevancy of these findings using bronchial tissues derived during a clinical chemoprevention trial to determine that basal G1 cyclin expression in neoplastic lung tissues is repressed by retinoid treatment. In this proposal, cellular, biochemical, and molecular genetic techniques are used to investigate in unique preclinical experimental models how retinoids act in lung cancer prevention. Successful completion of these aims should lead to an improved understanding of how RA exerts its anticarcinogenic actions in cancer prevention models. Studies of retinoid signaled cell cycle control mechanisms are relevant to learning how retinoids act in cancer therapy or prevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETINOID METABOLISM IN HEPATITIC STELLATE CELLS Principal Investigator & Institution: Bosron, William F.; Professor; Biochem and Molecular Biology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-JUL-2006 Summary: (provided by applicant): The overall goal of this proposal is to understand the role of specific rat retinoid metabolizing enzymes (especially retinyl ester hydrolases) in the regulation of retinoid metabolism in hepatic stellate cells. Hepatic stellate cells are the main reservoir of Vitamin A in the liver where it is stored mainly as retinyl palmitate in highly visible intracellular lipid droplets. When animals are exposed to hepatotoxins or humans chronically abuse alcohol, the stellate cells become activated and transform into myofibroblast-like cells. These transformed cells are the sites of collagen and extracellular matrix protein formation in alcohol-induced hepatic fibrosis. One of the earliest events in stellate cell activation is the hydrolysis of retinyl esters and

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the depletion of the intracellular lipid droplets. The most likely retinyl ester hydrolase candidates are the members of the families of broad substrate specificity lipases and carboxylesterases. The specific retinyl ester hydrolases expressed in hepatic stellate cells and the mechanisms for regulation of their activity during stellate cell activation is not known. In preliminary data, we show that the five most common rat liver carboxylesterases with retinyl palmitate activity are not highly expressed in stellate cells. However, the hormone-sensitive lipase gene is expressed in rat hepatic stellate cells and it has retinyl palmitate hydrolase activity in vitro. The goals of the grant are to identify the specific retinyl ester hydrolases (lipases and carboxylesterases) that are expressed in isolated rat liver cells (stellate cells, Kupffer cells, hepatocytes) by real-time, quantitative PCR of RNA and immunofluorescence microscopy of stellate cells with enzyme-specific antibodies. The expression of retinyl ester hydrolases and retinol dehydrogenases will be correlated with retinoid autofluorescence in lipid droplets and expression of cellspecific markers in cultured rat stellate cells as they undergo activation to myofibroblast-like cells. When feasible, we will measure retinyl palmitate hydrolase activity and perform protein gel electrophoresis of cellular extracts with esterase activity staining. We will examine the kinetics of purified rat stellate cell retinyl ester hydrolases and examine the effects of enzyme activators and inhibitors. Inhibitors of retinyl ester hydrolysis in stellate cells may be an effective therapeutic strategy for arresting stellate cell activation early in hepatic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETINOID SIGNALING IN THE MAMMARY GLAND Principal Investigator & Institution: Peacocke, Monica; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002 Summary: Micronutrients are known to play a central role in regulating a variety of biological processes, like cell proliferation. Vitamin A and its derivatives (retinoids) regulate gene expression by acting as ligands that modulate transcription by binding to specific nuclear receptors. These ligand-receptors complexes then bind to cognitive response elements and modulate gene transcription. Our group has a long-standing interest in nuclear receptors for retinoic acid, and how these receptors function to inhibit cell growth. In this proposal, we hope to extend these studies to identify how the micronutrient, all-trans retinoic acid functions to inhibit cell growth in the mammary gland, first in vitro and then, in vivo. Initial studies will test the hypothesis that the ligand, retinoic acid, plays a central role in the ability of one nuclear receptor, RARbeta2, to inhibit cell growth, using ligand binding mutants of this receptor. We will then extend these studies to identify what specific cells in the mammary gland in vivo express RARbeta2, and how hormones effect the expression of this gene. Finally, using differential display, we hope to identify genes, both known and novel, regulated by retinoic acid, which may function to inhibit cell proliferation in the mammary gland. In this way, we hope to generate a framework to better understand how this micronutrient regulates the structure and the function of the normal mammary gland. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RETINOIDS AND SUBSTANCES OF ABUSE IN HIV-1 INFECTION Principal Investigator & Institution: Royal, Walter I.; Associate Professor; Medicine; Morehouse School of Medicine Atlanta, Ga 30310 Timing: Fiscal Year 2002; Project Start 15-MAY-2002; Project End 30-APR-2007

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Summary: (provided by applicant) Neurologic disease in HIV infection has been associated with damage to nervous system tissue induced by pro-inflammatory cytokines and other soluble factors that are released by activated mononuclear phagocytes (MP). In this proposal, we will examine mechanisms by which retinoids suppress pro-inflammatory activity in immune cells from individuals with HIV infection and in immune cell lines. Retinoids, which are vitamin A-related compounds, have been demonstrated to suppress such immune activity, and, in studies of m -1 infection, can suppress replication of virus in infected mononuclear cell lines. Among individuals with HIV-1 (HIV) infection, vitamin A deficiency has been associated with an increased risk of developing HIV-related complications. However, in most cases, the administration of vitamin A in clinical trials has not been associated with improvement in HIV-related clinical parameters. Our prior studies demonstrate that 1) parameters of vitamin A metabolism in plasma are lower among HIV-infected individuals than among non-infected subjects and suggest that such abnormalities can be observed in CSF; 2) plasma retinol levels are lower in seronegative patients with chronic inflammatory neurologic disease than in control subjects with non-inflammatory neurologic disease and treatment of these individuals with an immunomodulatory agent is associated with specific effects on retinoid receptor subtype expression patterns; 3) retinoid compounds suppress pro-inflammatory cytokine production by peripheral blood immune cells and cell lines and that, in the cell lines, retinoid-induced suppressive activity can be inhibited by simultaneous exposure of the cells to morphine or cocaine. Therefore, we propose the following aims for this proposal: 1) to examine the expression of proinflammatory cytokine (TNF-a) by mononuclear cells from opiate users and non-drug users with or without a history of HIV infection; 2) to examine the effects of specific retinoid receptor activation on the immune effects elicited in retinoid-exposed mononuclear cell lines; 3) to examine the effects of substances of abuse (morphine and cocaine) on specific immune responses induced by retinoid receptor agonists and receptor antagonists in mononuclear cell lines; and 4) and to assess the role of inhibition of nuclear NF-KB binding in the effects of retinoids and substances of abuse on proinflammatory cytokine production by the patient cells and by the mononuclear cell lines. These studies will broaden our understanding of the immune effects of retinoid compounds in individuals with HIV infection, and may lead to effective approaches to the treatment of the infection and its complications with vitamin A. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETINOIDS IN VISION Principal Investigator & Institution: Palczewski, Krzysztof; Professor; Ophthalmology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-AUG-1992; Project End 31-DEC-2006 Summary: (provided by applicant): The long-term objective of the proposed studies is to understand the regeneration of 11-cis-retinal, the universal chromophore of the vertebrate retina. 11-cis-Retinal is coupled to the protein opsin in both rod and cone photoreceptor cells and is photoisomerized to all-trans-retinal by light. The importance of inactivation and regeneration of photoactivated rhodopsin has become apparent recently, as malfunctions in the processing of this chromophore and the inhibition of rhodopsin regeneration lead to impairment of vision and the degeneration of photoreceptors. Elucidation of the molecular steps involved in the retinoid cycle would greatly contribute to our understanding of the basis of these disease states and provide a foundation for rational approaches to treatments. We propose to examine four fundamental steps of the visual cycle and how each step is involved in the quenching of

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phototransduction and the regeneration of rhodopsin. We would like to understand (1) the release of the photoisomerized chromophore from the binding pocket of opsin (the first step of the visual cycle), the role of all-trans-retinol dehydrogenase, and the role of all-trans-retinal during dark adaptation; (2) the chemistry and enzymology of the isomerization process that occurs in retinal pigment epithelial cells (RPE); (3) the contribution of reverse photoisomerization in the production of 11-cis-retinal in mouse RPE; and (4) the oxidation of 11-cis-retinol by RDH5 dehydrogenase (the final step of the visual cycle), the detoxification of RPE from non-functional 13-cis-retinoids, and the role of additional, novel dehydrogenase(s) involved in the cycle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETINOL BINDING PROTEIN AND HEART DEVELOPMENT Principal Investigator & Institution: Lough, John W.; Professor; Cell Biol, Neurobiol/Anatomy; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: (the applicant's description verbatim): This laboratory's objective is to identify support and specification factors that are secreted by early embryonic endoderm cells, which regulate heart development. We have recently determined that endoderm strongly expresses the vitamin A transport proteins transthyretin (TTR) and retinol binding protein (RBP). Mapping sites of TTR and RBP protein and mRNA expression in the embryo has revealed that these factors are associated with the heart forming region in general and with definitive myocardial structures in particular. Because the developing heart is highly sensitive metabolic products of retinol, particularly retinoic acid (RA), it is hypothesized that RBP derived from both endoderm and definitive myocardial cells is necessary to regulate retinol delivery to myocardial structures during their development. Deletion of the RBP gene via homologous recombination will be used to test this hypothesis in a variety of murine embryonic models. (1) The first aim will use targeted ES cells to examine the effect of the RBP-/mutation during cardiogenesis in embryoid bodies. (2) The second aim will utilize chimeric embryos prepared by combining homozygous-deficient RBP-/- ES cells with morula-stage Rosa26 wild-type embryos that constitutively express b-galactosidase. The exclusion of RBP-/- mutant cells from the heart of embryos whose organs are otherwise chimeric would indicate an autonomous requirement for the RBP gene in heart development. (3) The third aim will directly establish the necessity of the RBP gene for heart development by producing RBP-/- embryos from RBP-/- ES cells using the technique of tetraploid aggregation. Finally, (4) a line of RBP-null mice will be prepared to extend these studies. Results from these experiments will elucidate the dependence of the developing myocardium on carefully regulated levels of vitamin A and its product, retinoic acid (RA). These findings will further contribute to an elucidation of the mechanisms which underlie congenital heart defects as well as the reasons why the adult myocardium is incapable of repair. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHILDREN

RETINOL

EQUIVALENCE

OF

PLANT

CAROTENOIDS

IN

Principal Investigator & Institution: Tang, Guangwen; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2003; Project Start 20-MAY-2003; Project End 28-FEB-2007

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Summary: (provided by applicant): This project is to determine the vitamin A value (equivalence) of dietary provitamin A carotenes from spinach, Golden Rice, and pure Beta-carotene (B-C) in oil. These experiments will be conducted in children (ages 6-8) with/without adequate vitamin A nutrition. As plant provitamin A carotenoids are a major and safe vitamin A source for a vast population in the world, it is essential to determine the efficiency of provitamin A carotenoid (mainly B-C) conversion to vitamin A. By introducing B-C into rice endosperm, Golden Rice may directly benefit consumers by providing vitamin A nutrition. Our investigation uses hydroponically grown, decadeuterium labeled spinach and Golden Rice, synthetic Beta-C-d10 and a vitamin A isotope reference, decadeuterated retinyl acetate (RAc-d10), to evaluate the bioavailability and the bioconversion of plant provitamin A carotenes to retinol as compared with B-C in oil capsules in vivo. Our objectives will be to test the following hypotheses and to make the following determinations: (1) The absorption and bioconversion of provitamin A carotenes taken by children are different between spinach, Golden Rice, and B-C in oil capsules. (2) The absorption of provitamin A carotenes and their bioconversion to vitamin A are different in children with or without adequate vitamin A nutrition. (3) To define the vitamin A equivalence(s) of dietary spinach, Golden Rice, and a B-C in oil dose by using an isotope reference method in children with or without adequate vitamin A nutrition and to compare those values with values derived from model based compartmental analysis. (4) To determine the number and time of blood samples needed for future studies in various field settings on the retinol equivalence of a large number of plant sources. Seventy-two children each will take two meals, lunch and supper, containing equal amounts of B-C in labeled spinach (along with white rice), or Golden Rice (along with light colored vegetables), or B-C oil capsules (along with white rice and light colored vegetables), every day for 7 days. Before the two meals, the volunteers will take a breakfast with a RAc-d10 dose as a reference for 7 days. The enrichment of labeled B-C and labeled retinol in human circulation will be determined using advanced liquid chromatography / mass spectrometry and gas chromatography / mass spectrometry. Through the applications of these novel technologies, we will be able to determine the relative biological activities of endogenous carotenoids; that is, the vitamin A value of spinach, Golden Rice, and BC in oil capsules for children with/without vitamin A malnutrition. This study will be of importance in planning vitamin A deficiency prevention strategies and also will provide useful information regarding the potential efficacy of a bioengineered crop to provide vitamin A nutrition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF RETINOL BINDING PROTEIN DURING HEART DEVELOPMENT Principal Investigator & Institution: Wendler, Christopher C.; Cell Biol, Neurobiol/Anatomy; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-JUL-2002 Summary: (the applicant?s description verbatim): Vitamin A (retinol) has long been known to be essential for normal development, and vitamin A deficiency (VAD) can result in developmental malformations of many different tissues including limb, palate, skull, kidney and heart. The long term objective of the proposal is an increased understanding of the role retinol binding protein (RBP) plays in the delivery of Vitamin A to embryonic tissues. The role of RBP in the delivery of vitamin A in the adult circulation is well documented, but its function in the early embryo is poorly

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understood. The specific aims of this proposal are to examine embryogenesis in RBP knockout mice, and specifically study the effect of RBP deletion on cardiogenesis. This will be achieved by examining embryogenesis in mice with a targeted knockout of the RBP gene. In addition, the creloxP system will be used to produce a conditional knockout of RBP, which will delete RBP from the heart only. The final aim will be to use knockout mice and wild type mice to study VAD over specific time windows, in order to determine the stage of heart development at which delivery of vitamin A is critical. Overall this project will provide a better understanding of the role and delivery of vitamin A during early cardiogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SAME, RXRALPHA-MEDIATED PATHWAYS AND ALD Principal Investigator & Institution: Wan, Yu-Jui Y.; Professor; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 905022052 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The goal of this project is to study the mechanism underlying nuclear receptor retinoid x receptor et (RXR-alpha)-mediated pathways on regulating S-adenosyl-L-methionine (SAMe) homeostasis. The main hypothesis is that RXR-alpha-mediated pathways either directly or indirectly control SAMe synthesis and alter the levels of glutathione and phosphatidylcholine in the liver, which consequently play a crucial role in the development of alcoholic liver disease (ALD). Most of the retinol and alcohol studies rely on either feeding animals with excess amount of retinoids or introducing animals with retinol deficient diet. Feeding animals with retinoids can be toxic. Retinol deficiency can also cause many unwanted effects. Knockout technology avoids these potential problems. Tissue specific knockout further allows studying the function of the gene in a cell type specific manner without affecting the gene function systemically. We have established an animal model in that the RXRalpha gene is knocked out only in the hepatocyte. RXR-alpha is highly expressed in the liver and is required for almost all the nuclear receptor-mediated pathways. Therefore, hepatocyte RXR-alpha deficient mouse serves as an excellent model for studying retinoid signaling in alcoholic liver disease. When hepatocyte RXR-alpha is deficient, liver retinoic acid is elevated, alcohol elimination rate is increased and alcohol-induced liver damage becomes more severe. In addition, the expression of more than ten genes encoding enzymes involved in the SAMe pathway is altered. Those data indicate that RXR-alpha, SAMe and ALD are intricately interlinked. Two specific aims are proposed to study the direct and indirect effect of RXR-alpha on SAMe homeostasis. First is to examine how RXR-alpha-mediated pathways regulate alcohol metabolism, which may indirectly control SAMe synthesis and affect the development of ALD. Second is to characterize how RXR-alpha-mediated pathways regulate genes encoding enzymes in the SAMe pathway and directly control SAMe homeostasis. RXR-alpha-mediated pathways including PPARcz and 3' and RXR-alpha homodimer and others will be studied. The effect of those nuclear receptor ligands on regulating SAMe synthesis will be analyzed. The proposed study not only allows us to understand how nuclear receptors regulate SAMe homeostasis, it also provides an opportunity to identify potential therapeutical targets and treatment agents for ALD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SHORT CHAIN DEHYDROGENASES IN RETINOL/STEROL METABOLISM Principal Investigator & Institution: Kedishvili, Natalia Y.; Molecular Biology and Biochem; University of Missouri Kansas City Kansas City, Mo 64110 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: Retinoid and steroid hormones regulate a variety of physiological processes from morphogenesis to reproduction. Biosynthesis of both types of hormones involves oxidation and reduction of their corresponding precursors to the biologically active forms. Recent data from this and other laboratories suggest that mammalian tissues contain a group of elated enzymes capable of utilizing in vitro both retinoid and steroid alcohols and aldehydes as substrates. These enzymes share more than 40 percent sequence identity and belong to the superfamily of short-chain dehydrogenases/reductases. The main hypotheses of this proposal are that: (1) this group of structurally related enzymes is involved in biosynthesis of both retinoid and steroid hormones in vivo; (2) individual retinol/sterol dehydrogenases exhibit different tissue-specific expression patterns in human tissues, which determines their contribution to each metabolic pathway; and (3) the active site of these microsomal dehydrogenases faces the cytosol, where the NAD+-dependent enzymes function in the oxidative direction, and the NADP+-dependent enzymes function in the reductive direction. The existence of common enzymes should provide the means for joint regulation of retinoid and steroid signaling pathways. This hypothesis is consistent with the observations that retinoic acid significantly decreases serum levels of dihydrotestosterone and that the levels of retinoic acid are decreased in prostate carcinoma tissue. The overall objective of this proposal is to determine the role of the human microsomal retinol/sterol dehydrogenases, recently identified by this laboratory, in retinoid and steroid metabolism in the cells. The specific aims of this proposal are to: (1) develop a procedure for preparation of catalytically active purified recombinant retinol/sterol dehydrogenases; (2) characterize the substrate specificity and catalytic properties of the human retinol/sterol dehydrogenases; (3) determine the expression patterns of retinol/sterol dehydrogenases in human tissues; and 4) determine the topology of transmembrane insertion of human dehydrogenases in the microsomal membrane. Accomplishment of these objectives will allow us to gain understanding of the role of this new group of short-chain dehydrogenases in retinoid and steroid metabolism in health and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SPECTRAL AND METABOLIC BASIS OF VISUAL RESPONSES Principal Investigator & Institution: Cornwall, Carter M.; Professor; Physiology and Biophysics; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 01-APR-1977; Project End 31-MAR-2007 Summary: We will investigate the mechanisms that regulate the sensitivity of vertebrate retinal rods and cones during and following bright light. To do this, we will make electrophysiological recordings of membrane current microspectrophotometric measurements of visual pigment, and microfluorometric measurements of retinal and retinol in solitary rods and cones in darkness before and following bleaching and following exogenous incorporation of retinal and its analogs. The following hypotheses will be tested: (1) The reduction of all-trans retinal to all- trans retinol plays an important rote in regulation of response kinetics and sensitivity in vertebrate photoreceptors. We will perform microfluorometric experiments on solitary salamander

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rods and cones as well as mouse rods to determine and compare the kinetics, spatial distribution and metabolic dependence of reduction of retinal to retinol following bleaching and treatment with retinal analogs. We shall determine the kinetics of removal of retinal from bleached cells by extracellular agents (e.g. IRBP). We will make simultaneous determinations of the physiological state of cells under these same conditions using extracellular current recordings to determine the effect that reduction of bleached photopigment has on sensitivity recovery. Finally, we shall make simultaneous fluorometric and electrophysiological measurements to determine if retinal reduction occurs before, at the same time as, or after retinal is released from the opsin binding site. (1) The state of occupation of the non-covalent binding site in opsin plays a crucial role in determining the adaptational state of photoreceptors. We shall measure PDE and guanylyl cyclase velocities in salamander photoreceptors that have been bleached and treated with analogs of retinal to determine the essential structural features of the opsin/retinal interaction required for pigment regeneration and recovery of sensitivity during dark-adaptation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SQUAMOUS CELL CARCINOMAS--EFFECT OF RETINOIDS Principal Investigator & Institution: Gudas, Lorraine J.; Professor and Chair; Pharmacology; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 01-JUN-1992; Project End 30-APR-2004 Summary: The fact that high levels of retinyl esters have been measured in normal epithelia throughout the body suggests that these retinyl esters play some role in the function, growth, or differentiation of these normal epithelial cells. Furthermore, retinoids are known to control normal differentiation and can convert preneoplastic epithelial cells to a more normal phenotype. Nevertheless, the functions of these retinyl esters are not well understood. We have recently shown that whereas cultured normal human epithelial cell strains from the oral cavity and skin rapidly esterify retinol, human squamous cell carcinoma cell lines from the oral cavity and skin exhibit almost no retinol esterification. Therefore, we plan to analyze the molecular actions of these retinyl esters and to determine how the synthesis of these retinyl esters is regulated. To accomplish this, we propose to clone and biochemically characterize the enzyme(s), ARAT (acyl-CoA: retinol acyltransferase) and LRAT (lecithin:retinol acyltransferase), involved in the synthesis of retinyl esters from retinol in normal epithelial cells. We will determine why ARAT levels are low in the squamous cell carcinomas (SCCs) as compared to the normal epithelial cells. We also propose to establish to what extent this defect in retinol esterification is associated with aspects of the tumorgenic phenotype. This will be accomplished first by stably transfecting the ARAT sense cDNA, under the control of a tetracycline regulated promoter, into the human SCC lines and measuring cell growth, invasiveness, and differentiation associated gene expression in cells cultured tet, or by blocking the expression of ARAT in normal cells. We also propose to test whether this defect in the conversion of retinol to retinyl esters is observed in an animal model of carcinogenesis which recapitulates most of the development of human SCC of the oral cavity. In addition, we will generate mice in which the ARAT gene is ectopically expressed in the oral cavity of transgenic animals to determine whether this ectopic expression will reduce tumor development after treatment of the oral cavities of the mice with 4-nitroquinoline-1-oxide. These proposed studies should determine the importance of retinyl esters in normal epithelial cells of the oral cavity and skin and the relevance of the loss of these retinyl esters in establishing the transformed state. Moreover, if a high level of retinol esterification is shown to be critical for normal cell

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functioning, then it may be possible to develop drugs which stimulate retinol esterification in tumor cells as a therapy for human squamous cell carcinomas of the oral cavity and skin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURE DEHYDROGENASE GENES

&

EXPRESSION

OF

MAMMAL

ALC

Principal Investigator & Institution: Edenberg, Howard J.; Professor; Biochem and Molecular Biology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-JUL-1989; Project End 30-APR-2007 Summary: (provided by applicant): The long-term goals of this research are to understand the mechanisms that regulate human alcohol dehydrogenase (ADH) gene expression, and the physiological and pathological consequences of alterations in ADH expression. We hypothesize that differences in the expression of the ADH genes affect the metabolism of alcohol, the risk for alcoholism and the physiological and pathological consequences of alcohol consumption. To begin testing this hypothesis we will identify the regions that control ADH expression, identify polymorphisms in these regions, and then analyze whether these polymorphisms affect gene expression.We will identify cisacting elements important in the regulation of the human ADH genes, with primary focus on the class I genes and ADH7. These have different patterns of expression, and produce enzymes that influence important metabolic processes including metabolism of ethanol and retinol. Cis-acting elements will be identified by a combination of functional studies (transfections) and protein-binding analyses (DNaseI footprinting and gel retardation). We will identify transcription factors that bind to these sequences. The ADH genes are clustered on chromosome 4, and we hypothesize that distant flanking sequences are important in regulating this group of genes. We will test this hypothesis by studying more distant sequences, extending at least 10 kb from the coding regions. We will also analyze the regulation of large chromosomal segments (BACs) carrying groups of ADH genes to detect potential interactions in a chromosomal context. We hypothesize that inter-individual differences in regulatory sequences cause differences in ADH gene expression. We will identify and characterize polymorphisms in the regulatory regions and test their effects on gene expression in vitro. These two aims will be closely coupled, with the localization of cis-acting elements directing our search for polymorphisms, and our detection of functional polymorphisms helping to prioritize further study of the cis-acting elements.These studies will contribute to our understanding of the genetic factors underlying differences among individuals in the metabolic, pharmacological and pathological effects of alcohol consumption. They will also increase our basic understanding of gene regulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYNTHETIC RETINAL PIGMENTS AND BINDING PROTEINS Principal Investigator & Institution: Crouch, Rosalie K.; Professor; Ophthalmology; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-AUG-1983; Project End 31-MAR-2006 Summary: (provided by applicant): The aldehyde form of vitamin A, retinal, is the ligand of the visual pigments in both rod and cone photoreceptors. This ligand can either act as an inverse agonist, placing the protein into its inactive conformation, or an agonist, moving the protein into an active conformation and activating the visual

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transduction process. This small molecule is thus critical to the visual process. Our research is focused on the study of the interaction of this ligand with the various rod and cone opsins and the role of one protein, RPE65, which is critical for the generation of the form of retinal that binds to those opsins, the 11-cis isomer. Analogues of retinal will bind to the opsins and can be used to manipulate these G-protein receptors. Using a variety of physiological techniques, we propose to use retinal analogues to address a number of hypotheses particularly focused on studies of the green rod and three cone opsins of the salamander. With these structurally modified forms of retinal, the protein conformation can be altered such that particular steps in the ligand binding or the protein activation can be examined. Through these studies, we are addressing hypotheses that the rod and cone opsins have very different interactions with 11-cisretinal and that their mechanisms for the release of the end product, all-trans-retinol, also differs. The protein RPE65 is critical for the generation of 11-cis-retinal, although the exact function of this protein is still unknown. We are testing the hypothesis that the protein is a scaffolding protein, involved in a complex that brings about the isomerization/oxidation of all-trans-retinol to 11-cis-retinal. Using a cell line HEK296, which itself contains RPE65, and an opsin expression system which then provides a "trap" for the 11-cis-retinal, we propose to determine which other retinoidbinding/metabolizing proteins are critical for this process. Secondly, using animal models, which have had one or more of the retinoid-binding proteins knocked out, we will examine the levels of RPE65 and the ability of the animal to produce 11-cis-retinal. It is now being clearly shown that many retinal disorders are due to errors in retinoid metabolism or binding of the ligand with the visual pigments. Examples are various: Stargardt's disease, autosomal recessive retinitis pigmentosa, and Leber's congenital amaurosis. This project is focused on determining the mechanisms of retinoid metabolism and retinal-opsin protein interactions so that a rational design of prevention or therapies for these blinding disorders can be undertaken. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEUKEMIA

TARGETED

LIPOSOMAL

DOXORUBICIN

DELIVERY

TO

Principal Investigator & Institution: Lee, Robert J.; Associate Professor; None; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Targeted drug delivery has the potential to improve the efficacy of a therapeutic agent while reducing its side effects. Folate receptor typebeta (FRB) is a cell surface marker selectively expressed by approximately70 percent of acute myeloid leukemias (AMLs). Increased FR-beta expression can be specifically induced by all trans retinoic acid (ATRA) in FR-beta-positive KG-1 and primary AML cells, without inducing cellular differentiation or growth inhibition. Folic acid is a high affinity ligand for FR-beta (Kd approximately 1 nM). Importantly, FR-beta expressed by normal hematopoietic cells has been found to be non-functional, whereas the receptor expressed by KG-1 AML cells and FR-beta-transfected CHO cells mediates selective uptake and cytotoxicity of folate-coated liposomes. Both uptake and cytotoxicity of folate coated liposome doxorubicin (f-L-Dox) in KG-1 cells were further increased by ATRA, which induced FR-beta upregulation. Moreover, f-L-DOX exhibited greater therapeutic efficacy than non-targeted liposomal DOX (LDox) in FR positive murine L1210JF and human KG-1 AML ascitic tumor models. Increased survival due to treatment with f-L-Dox was further enhanced by ATRA in the KG-1 engrafted mice. FRtargeted liposomal Dox delivery has also been shown to bypass the P-glycoprotein-

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mediated drug efflux in FR positive tumor cells exhibiting resistance to free Dox. The objective of this project is to evaluate f-L-Dox, combined with ATRA-induction of FRbeta upregulation, for the treatment of AML, a concept based on the selective targeting of the FR positive tumor cells. The specific aims are: 1. To evaluate the effect of ATRA on FR-beta expression by AML cells in vivo. 2. To evaluate liposome formulation and FRbeta level as factors in the binding and in vitro cytotoxicity of f-L-Dox to AML cells, as well as the pharmacokinetic properties of the liposomes; the effect of dietary folate will also be studied. 3. To evaluate the selective cytotoxicity of f-L-Dox, alone or combined with ATRA, against AML blast cells, clonogenic progenitor cells (CFUs), and primitive AML stem cells (SL-Ics); and 4. To evaluate the in vivo therapeutic efficacy of f-L-Dox alone or combined with ATRA in murine leukemia models. This project should lead to the development of a novel therapeutic strategy based on the combination of targeted drug delivery to tumor cells and upregulation of the cellular target for the treatment of chemotherapy refractory AMLs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE CAROTENE AND RETINOL EFFICACY TRIAL (CARET) Principal Investigator & Institution: Goodman, Gary E.; Associate Professor; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 01-JUL-1994; Project End 31-MAY-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE ROLE OF RETINOIDS IN LACRIMAL GLAND FUNCTION Principal Investigator & Institution: Ubels, John L.; Professor; Biology; Calvin College Grand Rapids, Mi 49506 Timing: Fiscal Year 2002; Project Start 01-JUL-1991; Project End 31-AUG-2003 Summary: The lacrimal glands play an essential role in maintenance of the health of the ocular surface. The lacrimal gland fluid provides the ocular surface with lubrication, anti-bacterial proteins, electrolytes and nutrients. Deficits in lacrimal gland function set the stage for diseases, such as keratoconjunctivitis sicca, a disease that occurs more often in women than in men. The development of rational therapy for dry eye diseases requires a thorough understanding of normal lacrimal gland function. The proposed work will test the hypotheses that the lacrimal gland transports, metabolizes and secretes vitamin A which is required by the ocular surface epithelium and that retinoids (vitamin A derivatives) are required for maintenance of lacrimal gland structure and function. The specific aims of the proposed research are to: l) characterize the enzymes that synthesize and hydrolyse retinyl esters in the lacrimal gland with emphasis of the control of these enzymes by cellular retinol binding protein. This will be accomplished by measuring the activity of lecithin: retinol acyltransferase and retinyl ester hydrolase in lacrimal glands of rabbits and rats and determining the effects of cellular retinol binding protein on the activity of these enzymes. 2) Determine whether nuclear retinoic acid receptors are present in the lacrimal gland and cornea and to study the effect of retinoids on the expression these receptors. This will be accomplished by probing tissues and cultured cells of rats and rabbits for the messenger RNA for these receptors, and detection of the receptors by binding assays and antibodies. 3) Characterize the function of lacrimal gland cells with emphasis on the role of retinoids by studying the effects of retinoic acid on the growth, differentiation, and metabolism of these cells in culture. These cells will also be probed for the mRNA for retinoid binding protein. 4)

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Characterize retinoid metabolism in human lacrimal gland. This will be accomplished by measurement of the activity of enzymes of retinyl ester metabolism and by probing the human lacrimal gland for mRNA for retinoid binding proteins and nuclear receptors. These experiments will affirm the relevance of the animal data to human lacrimal function. The proposed research will help to elucidate the role of retinoids in lacrimal gland and ocular surface function and thereby will contribute to the overall understanding of the role of nutrition in maintaining normal vision. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TOLERANCE AND AUTOIMMUNITY IN THE EYE Principal Investigator & Institution: Woodward, Jerold G.; Professor; Microbiology Immunology, and Molecular Genetics; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006 Summary: (provided by applicant): Autoimmune uveitis is a sight threatening autoimmune disease affecting some 20/100,000 people per year. Like other autoimmune diseases, uveitis appears to result form the aberrant activation of T cells toward self antigen present within the eye. How the T cells become activated, and the mechanism of autoimmune tissue destruction is poorly understood. In mice, experimental autoimmune uveitis (EAU) can be induced by immunization with the retinal antigen, interphotoreceptor retinol binding protein (IRBP). This laboratory has optimized the production of human recombinant IRBP, and will use this to probe the nature of the IRBP specific T cells which mediate EAU. One of the fundamental processes in T cell activation is the interaction of the T cell with the antigen presenting cell, yet nothing is known about how this interaction affects EAU in vivo. In the first aim, the role of the antigen presenting cell in the priming and effector function of the IRBP specific T cell will be studied. This will be accomplished through in vivo modulation of APC function and adoptive transfer studies. These experiments will answer important questions regarding how the autoreactive T cell becomes activated, and the nature of the antigen presenting cell within the eye itself which is responsible for T cell effector function. While the transfer of EAU into na ve mice with IRBP specific T cells has been demonstrated, the nature of the T cell that is capable of inducing disease is not known. In the second aim, a panel of IRBP specific T cell clones will be characterized for a variety of functional properties, as well as their ability to transfer EAU to normal mice. In the third aim, T cell receptor genes from select clones will be isolated and used to produce transgenic mice. These mice will provide a valuable new model system in which to further study the mechanism of EAU. Toward this aim, we will also further develop a transgenic model system in which ovalbumin is expressed in the retina. This will involve the production of new transgenic mice which express a form of ovalbumin which will be retained within the retina, rather than being secreted. Together, these studies will provide important new information as well as produce a new model system resulting in much greater understanding of the mechanisms of autoimmune uveitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TOPICAL RETINOIDS FOR DIABETIC FOOT ULCERS Principal Investigator & Institution: Varani, James J.; Professor; Pathology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004

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Summary: (adapted from the application) Diabetes remains one of the leading causes of lower limb amputation and is a contributing factor in up to 70 percent of the greater than 55,000 amputations annually. In the majority of diabetic subjects, the underlying factor which contributes to eventual amputation is the diabetic foot ulcer. The overall goal of this application is to determine the capacity of topical retinoid treatment to induce changes in the skin of diabetic patients that would reduce the incidence of ulcer formation and improve healing of wounds when they did occur. We know from recent studies that topical retinoid treatment improves histological structure and biochemical function of skin damaged by age and/or excessive exposure to solar radiation. Since diabetic skin demonstrates the same atrophic changes seen in aged human skin, it might be possible to improve structure and function in diabetic skin with the same approach. If one can improve the structure and function of diabetic skin in a similar fashion, such skin would be (in theory) more resistant to ulcer formation, and would heal better if wounding did occur. A three-part approach is proposed to achieve the overall goal of this application. We will in Specific Aim I assess fibroblast growth, connective tissue synthesis, matrix metalloproteinase (MMP) elaboration, vascular development and reactivity and indices of oxidative stress in hip skin from diabetic patients, including those with microangiopathic complications, and evaluate the effects of topical retinol treatment on these parameters. In Specific Aim 2, the goal will be to assess fibroblast growth, connective tissue synthesis, MMP elaboration, vascular development and reactivity and indices of oxidative stress in diabetic skin predisposed to the development of ulceration utilizing organ culture techniques. The effects of retinol treatment on these parameters will be assessed. Specific Aim 3 will make use of a rodent model of diabetes. Here we will determine the effects of topical retinol treatment on dermal structure/function in streptozotocin diabetic (STZ-D) rats and compare abrasion wound formation and healing in control rats, STZ-D rats and STZ-D rats that have been pretreated with topical retinol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSLATIONAL STUDY OF RETINOID REVERSAL OR ORAL CARCINOGENESIS Principal Investigator & Institution: Lippman, Scott M.; Professor and Chair; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002 Summary: This is a proposal for a randomized trial designed to study the long- term chemopreventive effects of low-dose 13-cis retinoic acid (13-cRA) and of the relatively non-toxic micronutrients beta-carotene and retinol in suppressing premalignant oral lesions (oral leukoplakia). The study's primary hypothesis--i.e., that daily supplementation with oral beta-carotene and retinol will be as effective or more effective than low-dose 13-cRA in producing and maintaining remission in oral leukoplakia--will be tested through assessment of response in the two groups using standard clinical and histologic criteria and measurement of micronuclei frequency. The expression and modulation of a series of biologic biomarkers will be tested through careful correlations between marker expression and modulation and outcome in the two treatment groups. We also plan to prospectively assess and biochemically validate (by assaying for cotinine, retinyl palmitate, and beta-carotene serum levels) the roles of tobacco cessation and dietary intake in the natural history or oral leukoplakia. Preclinical, epidemiologic and early clinical data support the role of retinoids and carotenoids in suppressing upper aerodigestive tract (UADT) and lung carcinogenesis. This proposed long-term, phase III trial has evolved directly from our other two studies

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Retinol

of 13-cRA in oral leukoplakia. The first study, now concluded, was in the form of a prospective, randomized trial and established the significant activity of 13-cRA. Preliminary data from the second study indicate the efficacy of low-dose 13-cRA (0.5 mg/kg/d) as short-term (9 month) maintenance therapy and the feasibility of analyzing a limited panel of biomarkers from small tissue samples, which is critical in chemoprevention trials. The proposed study will be significant even if it establishes only that the relatively nontoxic natural agents being tested are effective chemopreventive drugs against oral leukoplakia, as this would imply that they have high potential for chemoprevention of other UADT and lung epithelial cancers. Equally significant, however, will be progress in the laboratory toward the identification of biologic markers as indicators of intermediate endpoints within the multistep carcinogenic process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VISUAL CYCLE PROTEINS Principal Investigator & Institution: Crabb, John W.; Professor and Staff Manager; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 01-JUL-1986; Project End 28-FEB-2004 Summary: The hypothesis of this proposal is that CRALBP plays a fundamental role in vitamin A metabolism in the retina and retinal pigment epithelium (RPE). The unifying long range goals of the proposal are to establish a molecular basis for understanding the normal structure, function and regulation of CRALBP in order that questions concerning CRALBP-related visual disorders can be answered. Specific aims focus on both the CRALBP protein and gene and include: Mapping the retinoid-binding pocket of rCRALBP by measuring retinoid binding properties and ligand associated conformational changes in mutant and wildtype proteins; Seeking direct protein-protein interaction between CRALBP and RPE 11- cis-retinol dehydrogenase; Developing an in vivo system for characterizing tissue-specific CRALBP gene expression; and characterize CRALBP knockout mice with regard to retinal vitamin A metabolism, electrophysiology and morphology. Methods will include recombinant protein production using bacterial and baculovirus expression systems, retinoid-binding analysis by UV-visible absorbance, fluorescence titrations and 13C and 19F NMR. Protein -protein interactions will be sought by chromatographic, electrophoretic and immunological methods and characterized by electrospray mass spectrometry, sequence analysis and by enzyme/substrate carrier activity. Standard molecular biology methods will be used to prepare and test mouse wildtype and PCE-1 mutant CRALBP reporter gene constructs in transgenic mice. Retinoid HPLC, Western analysis, ERG and ultra structural methods will be used to characterize CRALBP knockout mice. Mutations in human CRALBP that destroy retinoid binding have been linked to autosomal recessive retinitis pigmentosa. The proposed studies will lead to a better understanding of the structure, function and regulation of CRALBP and the visual disorders with which at may be associated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VISUAL PIGMENT AND PHOTORECEPTOR ADAPTATION Principal Investigator & Institution: Pepperberg, David R.; Professor; Ophthalmology and Visual Scis; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-DEC-1983; Project End 31-AUG-2007 Summary: (provided by applicant): Exposure of rod photoreceptors to bright (rhodopsin bleaching) light triggers operation of the retinoid visual cycle and markedly desensitizes the rod flash response. Subsequent dark adaptation of the rods requires, in addition to

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excitation decay (shut-off of activated transduction intermediates and cGMP replenishment), recovery from "silent" desensitization processes that depress transduction signaling even after the near-complete recovery of circulating current. In vitro studies show that the magnitude of silent desensitization far exceeds that attributable to bleach-induced reduction in quantum catch, and have identified numerous likely contributing reactions. However, the lack of information on the operation of silent desensitization in the living eye is a major current obstacle to ultimately understanding in vivo mechanisms and relative roles of the contributing reactions. A main focus of the project is to determine the in vivo bleaching-dependence of the silent desensitizations's magnitude and timing in mouse and in human rods using paired-flash electroretinographic (ERG) recording, a recently developed technique that permits noninvasive determination of the full time course of the rod weak-flash response. In normally functioning rods of mice and of human subjects, and in abcr-/mice that exhibit sluggish excitation decay due to lack of the ABCA4 transporter of alltrans retinal bleaching product, we will test the specific hypothesis that excitation decay rate-limits the duration of silent desensitization. The accuracy of the paired-flash method in quantitatively determining the rod flash response -- specifically, the possibility that ERG b-wave intrusion skews derivation of the rod response amplitude -will be tested in experiments on the nob mouse, a b-wave deficient model. A further focus of the project is to test a recently raised hypothesis concerning retinoid metabolism in the retinal pigment epithelium (RPE), a process directly linked with the RPE's role in supporting rhodopsin regeneration in dark adapting rods. The hypothesis -- that 11-cis retinoid in the RPE regulates the efflux of all-trans retinol at the RPE basolateral membrane -- will be tested in radiolabeling experiments on mice that exhibit normal or impaired visual cycle operation. Results of the project will advance fundamental knowledge of rod dark adaptation and provide foundation for further studies of photoreceptor disease in human subjects and experimental animals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VITAMIN A AND REPRODUCTION Principal Investigator & Institution: Ong, David E.; Professor; Biochemistry; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 30-SEP-1989; Project End 31-MAR-2005 Summary: Vitamin A, retinol, is an essential nutrient that serves as precursor to the important hormone, retinoic acid (RA). Relatively little is known of the control of synthesis of RA from retinol in the normal, fully-developed animal and sites of action of RA are inferred, rather than demonstrated. Previous work has identified estrogen as a physiological signal which induces the synthesis of RA in the rat uterus and that coordinately directs cell-specific expression of the three cellular retinoid-binding proteins present in the uterus during the estrous cycle. Proposed studies will: l) Identify uterine genes that are under estrogen control indirectly, via RA stimulation. The techniques of differential display or subtractive hybridization followed by library screening or will be used to identify these genes. Candidate genes will be followed during the estrous cycle to confirm their physiological significance. 2) Demonstrate the site(s) of expression of the estrogen-stimulated RA responsive genes by in situ hybridization and immunolocalization during the estrous cycle. Demonstration of expression/non-expression of candidate genes in cells expressing cellular retinoic acidbinding protein will test the competing hypotheses that this protein either blocks or enhances the RA responsiveness of cells. 3) Establish the mechanism by which estrogen directly regulates cellular retinoic-acid binding protein (II) expression in the uterus. The

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promoter region of the rat gene will be cloned, dissected and tested using CAT reporter constructs in an estrogen responsive cell line. 4) Demonstrate the mechanism by which estrogen induces RA synthesis in the uterus. Specifically, is this induction a direct effect of estrogen on pre-existing enzymes, does it require transcription, or is it indirect? A novel radioreceptor assay capable of detecting small amounts of RA has been developed for this aim. In summary, the work to be accomplished here will allow dissection of the effects of the demonstrated estrogen-stimulated synthesis of RA signal that is part of a normal physiological process. This will provide important information on retinoic acid action in the unmanipulated, intact animal. Regulation of retinoic acid production by estrogen has direct importance for understanding/treating conditions such as endometriosis, breast cancer, and cancers of the female reproductive system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VITAMIN A DEFICIENCY MUTATIONS IN SPERMATOGENESIS

AND

RETINOID

RECEPTOR

Principal Investigator & Institution: Wolgemuth, Debra J.; Professor; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002 Summary: The importance of dietary retinol (vitamin A) for normal spermatogenesis and other aspects of male fertility has been recognized for many years. Animals deprived of vitamin A in their diet exhibit a variety of abnormalities, including male sterility. The requirement for dietary retinol raise interesting question concerning the function of retinoids in the testis, with regard to both their targets which are required for spermatogenesis to occur as well as to their metabolism with various testicular compartments. The ability to mutate endogenous genes involved in the pathways by which vitamin A elicits its effects in the mouse model system has enhanced our understanding of the diverse functions of the retinoids and has opened the opportunity for understanding the molecular basis of their functions. Studies generating mutations in specific receptors for vitamin A metabolites have clearly shown a role for the retinoid receptor RAR-alpha and RXR-beta genes in spermatogenesis. To further our understanding of the role of vitamin A in controlling spermatogenesis, this project will 1) Characterize the phenotypic abnormalities resulting in male sterility in the recently generated strains of mice mutated in RAR-alpha and RXR-beta, with particular emphasis on the developmental etiology of the abnormalities in the testis; 2) Test the hypothesis that the effects of the RAR-alpha and RXR-beta mutations on spermatogenesis are essentially phenocopied by vitamin A- deficiency in mice by comparing the spermatogenic abnormalities in the mutant strain mice with mice which have been vitamin A-deficient from birth, and 3) Explore the role of the RAR-alpha gene in the progression of spermatogenesis, specifically in germ cells. The hypothesis to be tested is that RAR-alpha has distinct functions in the germ line versus somatic cells. Furthermore, it is hypothesized that within the germ line lineage, RAR-alpha may have different functions at different stages of the developmental pathway. To distinguish these functions, it will be necessary to interfere with the function of the RAR-alpha gene selectively in one or the other cell types. To mutate its function in the germ line, conditional knockout mutations will be generated in RAR-alpha uniquely in germ cells at specific stages of development. This will be accomplished by mating mice carrying RAR-alpha flanked by loxP sites with mice carrying a transgene with Cre recombinase driven by regulatory elements driving expression specifically in spermatogonia, early pachytene spermatocytes, and early spermatids, respectively. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VITAMIN A EFFECTS ON ALVEOLAR FORMATION Principal Investigator & Institution: Albertine, Kurt H.; Professor of Pediatrics; Pediatrics; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-JUL-2003 Summary: Impaired alveolar formation is associated with chronic lung disease (CLD) of prematurity (bronchopulmonary dysplasia or BPD) or prolonged drainage of amniotic liquid (oligohydramnios). The mechanisms by which alveolar formation is inhibited with both diseases remain unclear, and treatment strategies to reduce their incidence or severity have achieved modest success at best. We have developed a model of BPD in lambs that reproduces the pathophysiology and pathology of this disease, including impairment of alveolar formation. The lambs are delivered prematurely and mechanically ventilated for 3-4 wks. Their lungs have impaired growth of alveolar secondary crests (septa), resulting in reduced numbers of alveoli. Alveolar capillaries do not grow into the abnormal secondary crests. These pathological changes are associated with respiratory insufficiency. Our immunohistochemical, biochemical, and molecular analysis suggest that extracellular matrix components and growth factor expression are adversely affected (elastin gene expression is upregulated; elastic fiber and proteoglycan accumulation are excessive; vascular endothelial growth factor protein expression is reduced). Preliminary studies suggest that these changes can be reversed by daily parenteral administration of vitamin A (retinol). How these changes occur is not known and is the basis of our grant application. We propose to study the regulation of alveolar formation, including the role of retinoids, in our lamb model of BPD, and in a fetal lamb model of oligohydramnios that will allow us to investigate the regulation of alveolar formation in utero. Paired preterm and fetal lambs, respectively, will be treated with or without retinoids daily to test 3 hypotheses: (1) retinoids will reverse the impaired alveolar formation by regulating the expression of growth factors that promote mesenchymal, endothelial, and epithelial development such that more normal alveolar septation occurs; (2) retinoids will have an early effect (postnatal days 3-4) on extracellular matrix components and growth factors that are likely to be involved with development of distal airspace mesenchyme, endothelium, and epithelium; and (3) retinoids will reverse arrest of alveolar formation and lung hypoplasia during fetal development in utero by augmenting the expression of growth factors that promote mesenchymal, endothelial, and epithelial development. This work should provide important insights into the molecular mechanisms that contribute to impairment of alveolar formation in 2 large-animal, chronic models of 2 important pediatric diseases. The experiments also should help establish the molecular basis for the potentially therapeutic benefit of retinoids. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VITAMIN A SUPPLEMENTATION FOR HIV INFECTED CHILDREN Principal Investigator & Institution: Semba, Richard D.; Ophthalmology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 15-FEB-1995; Project End 31-JUL-2003 Summary: Vitamin A is essential for normal immune function and has shown promise for treatment of different infectious diseases in children. The purpose of the project is to determine whether periodic, oral vitamin A supplementation reduces morbidity and mortality for HIV-infected children in sub-Saharan Africa. The goals of the project are being met through a randomized, double-masked, controlled clinical trial of oral vitamin A supplementation, 60 mg retinol equivalent, every three months for HIV-

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infected children from 12 to 36 months of age. The project is collaboration between Makerere University and the Johns Hopkins University at the Mulago Hospitals in Kampala, Uganda. The project has involved HIV screening of 23,439 women, identification of 3,751 HIV-infected women, and HIV screening of 1241 infants. The project has enrolled 300 HIV-infected children and is in-progress, and children are scheduled to reach 36 months of age by January 2002. Interim analysis shows that groups appear to be similar at baseline (with different characteristics measured at different ages). The application notes a trend in possible mortality benefit to the children receiving vitamin A. The study is being reviewed annually by a data and safety monitoring committee. In this competing continuation application, it is proposed to complete the clinical trial, laboratory studies, and data analysis over the next 3 years. If vitamin A supplementation is shown to reduce morbidity and mortality for HIVinfected children, this would be an appropriate, low-cost (8 cents for capsules per year), safe, and widely applicable intervention to increase survival for HIV-infected children in developing countries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VITAMIN A THERAPY IN PRETERM INFANTS: VACCINE RESPONSE Principal Investigator & Institution: Ballow, Mark; Professor of Pediatrics; Pediatrics; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2002; Project Start 15-SEP-1999; Project End 31-AUG-2003 Summary: The role of vitamin A as an immune modulatory factor has been the focus of many studies both in animals and man. Epidemiologic studies emphasize that vitamin A is essential for supporting the immune system against infection. Despite many therapeutic improvements in recent years, infection still remains a major problem in very low birth weight (VLBW) pre-term infants. Pre-term infants have lower plasma vitamin A (retinol) levels and limited hepatic reserves compared to full term infants. Vitamin A deficiency may lead to increased susceptibility to infection in pre-term infants. Hepatitis B immunization in the neonatal period offers an excellent opportunity to determine what effects vitamin A supplementation has in pre-term infants on their antibody immune response to this vaccine. VLBW pre-term infants less than 1500g (less than 32 weeks gestation) will be randomized into two treatment groups: vitamin A supplemented and placebo (saline). The vitamin A treatment group will receive 2000 IU of retinyl palmitate by intramuscular injection starting on postnatal day 2 and thereafter on alternate days for 28 days. Plasma vitamin A levels will be closely monitored for toxicity. Plasma immunoglobulins and antibodies to HbsAg and tetanus toxoid will be quantified by ELISA after the second and third doses of hepatitis B vaccine. These results will be correlated with changes in CD4+ T-cell subsets as defined by their cytokine secretion profile and the proportion of naive (CD45RA) to memory (CD45R0) T-cells as analyzed by flow cytometry. Acceleration in the maturation of T-cells (naive to memory), and augmentation in the proportion of intracellular cytokine producing Tcells will provide a mechanism for the enhancement in the humoral immune responses to hepatitis B vaccine by vitamin A supplementation. Finally, the type and number of infections in the NICU and to 9 months of age will be recorded to determine if vitamin A supplementation affects the incidence and severity of infection in early infancy. Vitamin A supplementation may be useful in pre-term infants in augmenting B-cell immune responses to infectious agents and in their response to vaccines. These factors could lead to decreased morbidity and mortality of pre-term infants during early postnatal life.

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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 “retinol” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for retinol in the PubMed Central database: •

4-Oxoretinol, a New Natural Ligand and Transactivator of the Retinoic Acid Receptors. by Achkar CC, Derguini F, Blumberg B, Langston A, Levin AA, Speck J, Evans RM, Bolado J, Nakanishi K, Buck J, Gudas LJ.; 1996 May 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39373

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All-Trans-Retinol is a Ligand for the Retinoic Acid Receptors. by Repa JJ, Hanson KK, Clagett-Dame M.; 1993 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47123

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Cloning and sequencing of a full length cDNA coding for human retinol-binding protein. by Colantuoni V, Romano V, Bensi G, Santoro C, Costanzo F, Raugei G, Cortese R.; 1983 Nov 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=326530

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Comparative Analysis of Glycosylated and Nonglycosylated Filarial Homologues of the 20-Kilodalton Retinol Binding Protein from Onchocerca volvulus (Ov20). by Nirmalan N, Cordeiro NJ, Klager SL, Bradley JE, Allen JE.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97037

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Developmental Abnormalities in Cultured Mouse Embryos Deprived of Retinoic Acid by Inhibition of Yolk-sac Retinol Binding Protein Synthesis. by Bavik C, Ward SJ, Chambon P.; 1996 Apr 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39770

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Disruption of the 11-cis-Retinol Dehydrogenase Gene Leads to Accumulation of cisRetinols and cis-Retinyl Esters. by Driessen CA, Winkens HJ, Hoffmann K, Kuhlmann LD, Janssen BP, Van Vugt AH, Van Hooser JP, Wieringa BE, Deutman AF, Palczewski K, Ruether K, Janssen JJ.; 2000 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85795

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

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

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Disruption of the Transthyretin Gene Results in Mice with Depressed Levels of Plasma Retinol and Thyroid Hormone. by Episkopou V, Maeda S, Nishiguchi S, Shimada K, Gaitanaris GA, Gottesman ME, Robertson EJ.; 1993 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46089

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Extinction of retinol-binding protein gene expression in somatic cell-hybrids: identification of the target sequences. by Faraonio R, Musy M, Colantuoni V.; 1990 Dec 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=332858

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Gecko [iota]-crystallin: How cellular retinol-binding protein became an eye lens ultraviolet filter. by Werten PJ, Roll B, van Aalten DM, de Jong WW.; 2000 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16230

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Identification, retinoid binding, and x-ray analysis of a human retinol-binding protein. by Folli C, Calderone V, Ottonello S, Bolchi A, Zanotti G, Stoppini M, Berni R.; 2001 Mar 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31117

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In vivo uptake of chylomicron [3H]retinyl ester by rat liver: evidence for retinol transfer from parenchymal to nonparenchymal cells. by Blomhoff R, Helgerud P, Rasmussen M, Berg T, Norum KR.; 1982 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=347332

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Localization of Cellular Retinol-Binding Protein and Retinol-Binding Protein in Cells Comprising the Blood-Brain Barrier of Rat and Human. by MacDonald PN, Bok D, Ong DE.; 1990 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54089

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Rat cellular retinol-binding protein: cDNA sequence and rapid retinol-dependent accumulation of mRNA. by Sherman DR, Lloyd RS, Chytil F.; 1987 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=304838

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Removal of LIF (leukemia inhibitory factor) results in increased vitamin A (retinol) metabolism to 4-oxoretinol in embryonic stem cells. by Lane MA, Chen AC, Roman SD, Derguini F, Gudas LJ.; 1999 Nov 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23981

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Retinoic Acid Affects the Expression of Nuclear Retinoic Acid Receptors in Tissues of Retinol-Deficient Rats. by Riaz-ul-Haq, Pfahl M, Chytil F.; 1991 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52489

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Spatial and temporal pattern of expression of the cellular retinoic acid-binding protein and the cellular retinol-binding protein during mouse embryogenesis. by Perez-Castro AV, Toth-Rogler LE, Wei LN, Nguyen-Huu MC.; 1989 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=298380

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Support for the multigenic hypothesis of amyloidosis: The binding stoichiometry of retinol-binding protein, vitamin A, and thyroid hormone influences transthyretin amyloidogenicity in vitro. by White JT, Kelly JW.; 2001 Nov 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60817

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Taq I RFLP in the human cellular retinol-binding protein (CRBP) gene. by Pellegrino A, Garofalo S, Cocozza S, Monticelli A, Faraonio R, Varrone S, Colantuoni V.; 1988 Aug 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=338480

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The identification of a 9-cis retinol dehydrogenase in the mouse embryo reveals a pathway for synthesis of 9-cis retinoic acid. by Romert A, Tuvendal P, Simon A, Dencker L, Eriksson U.; 1998 Apr 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22501

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Transfer of retinol from parenchymal to stellate cells in liver is mediated by retinolbinding protein. by Blomhoff R, Berg T, Norum KR.; 1988 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=280230

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Transfer of Retinol-Binding Protein from HepG2 Human Hepatoma Cells to Cocultured Rat Stellate Cells. by Senoo H, Smeland S, Malaba L, Bjerknes T, Stang E, Roos N, Berg T, Norum KR, Blomhoff R.; 1993 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46352

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

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A case of human vitamin A deficiency caused by an inherited defect in retinolbinding protein without clinical symptoms except night blindness. Author(s): Wolf G. Source: Nutrition Reviews. 1999 August; 57(8): 258-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10518414

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 double-blind evaluation of the activity of an anti-cellulite product containing retinol, caffeine, and ruscogenine by a combination of several non-invasive methods. Author(s): Bertin C, Zunino H, Pittet JC, Beau P, Pineau P, Massonneau M, Robert C, Hopkins J. Source: J Cosmet Sci. 2001 July-August; 52(4): 199-210. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11479653

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A liquid chromatography-mass spectrometry method for the quantification of bioavailability and bioconversion of beta-carotene to retinol in humans. Author(s): Wang Y, Xu X, van Lieshout M, West CE, Lugtenburg J, Verhoeven MA, Creemers AF, Muhilal, van Breemen RB. Source: Analytical Chemistry. 2000 October 15; 72(20): 4999-5003. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11055721

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A novel compound heterozygote (FAP ATTR Arg104His/ATTR Val30Met) with high serum transthyretin (TTR) and retinol binding protein (RBP) levels. Author(s): Terazaki H, Ando Y, Misumi S, Nakamura M, Ando E, Matsunaga N, Shoji S, Okuyama M, Ideta H, Nakagawa K, Ishizaki T, Ando M, Saraiva MJ. Source: Biochemical and Biophysical Research Communications. 1999 October 22; 264(2): 365-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10529370

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A prospective cohort study on intake of retinol, vitamins C and E, and carotenoids and prostate cancer risk (Netherlands). Author(s): Schuurman AG, Goldbohm RA, Brants HA, van den Brandt PA. Source: Cancer Causes & Control : Ccc. 2002 August; 13(6): 573-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12195647

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A randomized, placebo-controlled trial of topical retinol in the treatment of cellulite. Author(s): Pierard-Franchimont C, Pierard GE, Henry F, Vroome V, Cauwenbergh G. Source: American Journal of Clinical Dermatology. 2000 November-December; 1(6): 36974. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11702613

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Activity of human 11-cis-retinol dehydrogenase (Rdh5) with steroids and retinoids and expression of its mRNA in extra-ocular human tissue. Author(s): Wang J, Chai X, Eriksson U, Napoli JL. Source: The Biochemical Journal. 1999 February 15; 338 ( Pt 1): 23-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9931293

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Acute effect of dietary stanyl ester dose on post-absorptive alpha-tocopherol, betacarotene, retinol and retinyl palmitate concentrations. Author(s): Relas H, Gylling H, Miettinen TA. Source: The British Journal of Nutrition. 2001 February; 85(2): 141-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11242481

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Age and sex are important factors in determining normal retinol levels. Author(s): Lindblad BS, Patel M, Hamadeh M, Helmy N, Ahmad I, Dawodu A, Zaman S. Source: Journal of Tropical Pediatrics. 1998 April; 44(2): 96-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9604598

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Albumin, IgG, retinol-binding protein, and alpha1-microglobulin excretion in childhood. Author(s): Lehrnbecher T, Greissinger S, Navid F, Pfuller H, Jeschke R. Source: Pediatric Nephrology (Berlin, Germany). 1998 May; 12(4): 290-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9655359

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Alterations in cellular retinol metabolism contribute to differential retinoid responsiveness in normal human mammary epithelial cells versus breast cancer cells. Author(s): Hayden LJ, Satre MA. Source: Breast Cancer Research and Treatment. 2002 March; 72(2): 95-105. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12038710

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An isocratic liquid chromatographic method with diode-array detection for the simultaneous determination of alpha-tocopherol, retinol, and five carotenoids in human serum. Author(s): Gueguen S, Herbeth B, Siest G, Leroy P. Source: Journal of Chromatographic Science. 2002 February; 40(2): 69-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11881707

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Analysis of human cellular retinol-binding protein II promoter during enterocyte differentiation. Author(s): Zhang L, E X, Luker KE, Shao JS, Levin MS, Suh E, Li E. Source: American Journal of Physiology. Gastrointestinal and Liver Physiology. 2002 June; 282(6): G1079-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12016134

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Analysis of rat cytosolic 9-cis-retinol dehydrogenase activity and enzymatic characterization of rat ADHII. Author(s): Popescu G, Napoli JL. Source: Biochimica Et Biophysica Acta. 2000 January 3; 1476(1): 43-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10606766

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Are lifestyle factors good predictors of retinol and vitamin C deficiency in apparently healthy adults? Author(s): Chiplonkar SA, Agte VV, Mengale SS, Tarwadi KV. Source: European Journal of Clinical Nutrition. 2002 February; 56(2): 96-104. Erratum In: Eur J Clin Nutr. 2003 April; 57(4): 628. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11857042

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Are retinol, vitamin C, vitamin E, folate and carotenoids intake associated with bladder cancer risk? Results from the Netherlands Cohort Study. Author(s): Zeegers MP, Goldbohm RA, van den Brandt PA. Source: British Journal of Cancer. 2001 September 28; 85(7): 977-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11592769

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Assessment of total body stores of vitamin A in Guatemalan elderly by the deuterated-retinol-dilution method. Author(s): Ribaya-Mercado JD, Mazariegos M, Tang G, Romero-Abal ME, Mena I, Solomons NW, Russell RM. Source: The American Journal of Clinical Nutrition. 1999 February; 69(2): 278-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9989693

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Assessment of vitamin A status of preschool children in Indonesia using plasma retinol-binding protein. Author(s): Semba RD, Yuniar Y, Gamble MV, Natadisastra G, Muhilal. Source: Journal of Tropical Pediatrics. 2002 April; 48(2): 84-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12022434

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Assignment of the cellular retinol-binding protein 2 gene (RBP2) to human chromosome band 3q23 by in situ hybridization. Author(s): De Baere E, Speleman F, Van Roy N, Mortier K, De Paepe A, Messiaen L. Source: Cytogenetics and Cell Genetics. 1998; 83(3-4): 240-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10072590

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Association between increased levels of TNF-alpha, decreased levels of prealbumin and retinol-binding protein, and disease outcome. Author(s): Kuvibidila S, Yu L, Gardner R, Velez M, Ode D, Warrier RP. Source: Journal of the National Medical Association. 2000 October; 92(10): 485-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11105729

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Beta-carotene modulates human prostate cancer cell growth and may undergo intracellular metabolism to retinol. Author(s): Williams AW, Boileau TW, Zhou JR, Clinton SK, Erdman JW Jr. Source: The Journal of Nutrition. 2000 April; 130(4): 728-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10736321

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Beta-carotene uptake and bioconversion to retinol differ between human melanocytes and keratinocytes. Author(s): Andersson E, Vahlquist A, Rosdahl I. Source: Nutrition and Cancer. 2001; 39(2): 300-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11759295

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beta-Carotene uptake and effects on intracellular levels of retinol in vitro. Author(s): Wei RR, Wamer WG, Lambert LA, Kornhauser A. Source: Nutrition and Cancer. 1998; 30(1): 53-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9507513

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Bias and random error in retinol measurements of laboratories in countries with populations with mild to severe vitamin A deficiency. Author(s): Hulshof PJ, Brouwer JT, Burema J, West CE. Source: Clinical Chemistry. 2002 November; 48(11): 2061-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12406999

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Bile salt-stimulated lipase in human milk: evidence of activity in vivo and of a role in the digestion of milk retinol esters. Author(s): Fredrikzon B, Hernell O, Blackberg L, Olivecrona T. Source: Pediatric Research. 1978 November; 12(11): 1048-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=31590

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Binding affinities of retinol and related compounds to retinol binding proteins. Author(s): Cogan U, Kopelman M, Mokady S, Shinitzky M. Source: European Journal of Biochemistry / Febs. 1976 May 17; 65(1): 71-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=945163

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Binding of retinol to isolated retinal pigment epithelium in the presence and absence of retinol-binding protein. Author(s): Maraini G, Gozzoli F. Source: Invest Ophthalmol. 1975 October; 14(10): 785-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1237477

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Binding of retinol-binding protein obtained from human urine with vitamin A derivatives and terpenoids. Author(s): Hase J, Kobashi K, Nakai N, Onosaka S. Source: Journal of Biochemistry. 1976 February; 79(2): 373-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1270409

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Binding proteins for retinol in retina and pigment epithelium. Author(s): Maraini G. Source: Curr Top Eye Res. 1979; 1: 143-74. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=400679

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Biochemical basis for depressed serum retinol levels in transthyretin-deficient mice. Author(s): van Bennekum AM, Wei S, Gamble MV, Vogel S, Piantedosi R, Gottesman M, Episkopou V, Blaner WS. Source: The Journal of Biological Chemistry. 2001 January 12; 276(2): 1107-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11036082

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Biochemical but not clinical vitamin A deficiency results from mutations in the gene for retinol binding protein. Author(s): Biesalski HK, Frank J, Beck SC, Heinrich F, Illek B, Reifen R, Gollnick H, Seeliger MW, Wissinger B, Zrenner E. Source: The American Journal of Clinical Nutrition. 1999 May; 69(5): 931-6. Erratum In: Am J Clin Nutr 2000 April; 71(4): 1010. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10232633

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Biochemical defects in 11-cis-retinol dehydrogenase mutants associated with fundus albipunctatus. Author(s): Liden M, Romert A, Tryggvason K, Persson B, Eriksson U. Source: The Journal of Biological Chemistry. 2001 December 28; 276(52): 49251-7. Epub 2001 October 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11675386

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Biochemical indicators of vitamin A deficiency: serum retinol and serum retinol binding protein. Author(s): de Pee S, Dary O. Source: The Journal of Nutrition. 2002 September; 132(9 Suppl): 2895S-2901S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12221267

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Biochemical properties, tissue expression, and gene structure of a short chain dehydrogenase/ reductase able to catalyze cis-retinol oxidation. Author(s): Gamble MV, Shang E, Zott RP, Mertz JR, Wolgemuth DJ, Blaner WS. Source: Journal of Lipid Research. 1999 December; 40(12): 2279-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10588954

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Biological activity of all-trans retinol requires metabolic conversion to all-trans retinoic acid and is mediated through activation of nuclear retinoid receptors in human keratinocytes. Author(s): Kurlandsky SB, Xiao JH, Duell EA, Voorhees JJ, Fisher GJ. Source: The Journal of Biological Chemistry. 1994 December 30; 269(52): 32821-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7806506

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Biosynthesis of 9-cis-retinoic acid in vivo. The roles of different retinol dehydrogenases and a structure-activity analysis of microsomal retinol dehydrogenases. Author(s): Tryggvason K, Romert A, Eriksson U. Source: The Journal of Biological Chemistry. 2001 June 1; 276(22): 19253-8. Epub 2001 March 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11279029

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Biosynthesis of all-trans-retinoic acid from all-trans-retinol: catalysis of all-transretinol oxidation by human P-450 cytochromes. Author(s): Chen H, Howald WN, Juchau MR. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2000 March; 28(3): 315-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10681376

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Blood retinol and beta-carotene levels in rural Guatemalan preschool children. Author(s): Romero-Abal ME, Mendoza I, Bulux J, Solomons NW. Source: European Journal of Epidemiology. 1995 April; 11(2): 133-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7672065

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Breast milk immune factors in Bangladeshi women supplemented postpartum with retinol or beta-carotene. Author(s): Filteau SM, Rice AL, Ball JJ, Chakraborty J, Stoltzfus R, de Francisco A, Willumsen JF. Source: The American Journal of Clinical Nutrition. 1999 May; 69(5): 953-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10232636

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By the way, doctor. You've written about the dangers of getting too much vitamin A from retinol. Do you know of any multivitamin brands that tell you how much retinol you're getting? Author(s): Robb-Nicholson C. Source: Harvard Women's Health Watch. 2003 July; 10(11): 8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12888459

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Carotenoids, alpha-tocopherols, and retinol in plasma and breast cancer risk in northern Sweden. Author(s): Hulten K, Van Kappel AL, Winkvist A, Kaaks R, Hallmans G, Lenner P, Riboli E. Source: Cancer Causes & Control : Ccc. 2001 August; 12(6): 529-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11519761

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cDNA cloning, tissue distribution, and substrate characteristics of a cisRetinol/3alpha-hydroxysterol short-chain dehydrogenase isozyme. Author(s): Su J, Chai X, Kahn B, Napoli JL. Source: The Journal of Biological Chemistry. 1998 July 10; 273(28): 17910-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9651397

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Cellular Retinol Binding Protein 1 (RBP1): a frequent polymorphism, refined map position and exclusion as the Blepharophimosis Ptosis Epicanthus inversus Syndrome gene. Author(s): Bisceglia L, d'Ambrosio L, Piemontese MR, Carella M, Amati P, Bonneau D, Pilia G, Gasparini P, Zelante L. Source: Molecular and Cellular Probes. 1998 August; 12(4): 255-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9727204

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Cellular retinol-binding protein expression and breast cancer. Author(s): Kuppumbatti YS, Bleiweiss IJ, Mandeli JP, Waxman S, Mira-Y-Lopez R. Source: Journal of the National Cancer Institute. 2000 March 15; 92(6): 475-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10716965

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Cellular retinol-binding protein type II (CRBPII) in adult zebrafish (Danio rerio). cDNA sequence, tissue-specific expression and gene linkage analysis. Author(s): Cameron MC, Denovan-Wright EM, Sharma MK, Wright JM. Source: European Journal of Biochemistry / Febs. 2002 September; 269(18): 4685-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12230582

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Cellular retinol-binding protein-1 in hepatocellular carcinoma correlates with betacatenin, Ki-67 index, and patient survival. Author(s): Schmitt-Graff A, Ertelt V, Allgaier HP, Koelble K, Olschewski M, Nitschke R, Bochaton-Piallat ML, Gabbiani G, Blum HE. Source: Hepatology (Baltimore, Md.). 2003 August; 38(2): 470-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883492

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Changes in serum retinol, alpha-tocopherol, vitamin C, carotenoids, xinc and selenium after micronutrient supplementation during alcohol rehabilitation. Author(s): Gueguen S, Pirollet P, Leroy P, Guilland JC, Arnaud J, Paille F, Siest G, Visvikis S, Hercberg S, Herbeth B. Source: Journal of the American College of Nutrition. 2003 August; 22(4): 303-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12897045

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Characterization of a novel airway epithelial cell-specific short chain alcohol dehydrogenase/reductase gene whose expression is up-regulated by retinoids and is involved in the metabolism of retinol. Author(s): Soref CM, Di YP, Hayden L, Zhao YH, Satre MA, Wu R. Source: The Journal of Biological Chemistry. 2001 June 29; 276(26): 24194-202. Epub 2001 April 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11304534

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Characterization of the oxidative 3alpha-hydroxysteroid dehydrogenase activity of human recombinant 11-cis-retinol dehydrogenase. Author(s): Huang XF, Luu-The V. Source: Biochimica Et Biophysica Acta. 2001 June 11; 1547(2): 351-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11410291

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Circulating levels of retinol, tocopherol and carotenoid in Nepali pregnant and postpartum women following long-term beta-carotene and vitamin A supplementation. Author(s): Yamini S, West KP Jr, Wu L, Dreyfuss ML, Yang DX, Khatry SK. Source: European Journal of Clinical Nutrition. 2001 April; 55(4): 252-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11360129

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Clinical and analytical evaluation of the simultaneous HPLC assay of retinol and alpha-tocopherol. Author(s): Ihara H, Ishigaki H, Shino YHashizume N, Takase M, Nagao J, Sumiyama Y. Source: J Nutr Sci Vitaminol (Tokyo). 2000 October; 46(5): 257-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11234920

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Clinical trial of bleaching treatment with 10% all-trans retinol gel. Author(s): Yoshimura K, Momosawa A, Aiba E, Sato K, Matsumoto D, Mitoma Y, Harii K, Aoyama T, Iga T. Source: Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [et Al.]. 2003 February; 29(2): 155-60; Discussion 160. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12562345

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Cloning and characterization of a novel all-trans retinol short-chain dehydrogenase/reductase from the RPE. Author(s): Wu BX, Chen Y, Chen Y, Fan J, Rohrer B, Crouch RK, Ma JX. Source: Investigative Ophthalmology & Visual Science. 2002 November; 43(11): 3365-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12407145

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Cloning and molecular expression analysis of large and small lecithin:retinol acyltransferase mRNAs in the liver and other tissues of adult rats. Author(s): Zolfaghari R, Wang Y, Chen Q, Sancher A, Ross AC. Source: The Biochemical Journal. 2002 December 1; 368(Pt 2): 621-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12201819

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Comparative analysis of glycosylated and nonglycosylated filarial homologues of the 20-kilodalton retinol binding protein from Onchocerca volvulus (Ov20). Author(s): Nirmalan N, Cordeiro NJ, Klager SL, Bradley JE, Allen JE. Source: Infection and Immunity. 1999 December; 67(12): 6329-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10569745

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Comparative phenotypic analyses of human plasma and urinary retinol binding protein using mass spectrometric immunoassay. Author(s): Kiernan UA, Tubbs KA, Nedelkov D, Niederkofler EE, Nelson RW. Source: Biochemical and Biophysical Research Communications. 2002 September 20; 297(2): 401-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12237133

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Concentrations of carotenoids, retinol and alpha-tocopherol in plasma and follicular fluid of women undergoing IVF. Author(s): Schweigert FJ, Steinhagen B, Raila J, Siemann A, Peet D, Buscher U. Source: Human Reproduction (Oxford, England). 2003 June; 18(6): 1259-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12773456

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Contribution to first-pass metabolism of ethanol and inhibition by ethanol for retinol oxidation in human alcohol dehydrogenase family--implications for etiology of fetal alcohol syndrome and alcohol-related diseases. Author(s): Han CL, Liao CS, Wu CW, Hwong CL, Lee AR, Yin SJ. Source: European Journal of Biochemistry / Febs. 1998 May 15; 254(1): 25-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9652389

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Crystallization and preliminary X-ray data for the human transthyretin-retinolbinding protein (RBP) complex bound to an anti-RBP Fab. Author(s): Malpeli G, Zanotti G, Gliubich F, Rizzotto A, Nishida SK, Folli C, Berni R. Source: Acta Crystallographica. Section D, Biological Crystallography. 1999 January; 55 ( Pt 1): 276-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10089423

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Cystatin C, beta 2-microglobulin, and retinol-binding protein as indicators of glomerular filtration rate: comparison with plasma creatinine. Author(s): Donadio C, Lucchesi A, Ardini M, Giordani R. Source: Journal of Pharmaceutical and Biomedical Analysis. 2001 March; 24(5-6): 835-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11248475

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Decline in plasma retinol in unconjugated hyperbilirubinemia treated with bilirubin adsorption using an anion-exchange resin. Author(s): Ihara H, Shino Y, Hashizume N, Aoki T, Suzuki Y, Igarasi Y, Naito C. Source: J Nutr Sci Vitaminol (Tokyo). 1998 April; 44(2): 329-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9675713

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Decreased expression of retinol-binding proteins is associated with malignant transformation of the ovarian surface epithelium. Author(s): Roberts D, Williams SJ, Cvetkovic D, Weinstein JK, Godwin AK, Johnson SW, Hamilton TC. Source: Dna and Cell Biology. 2002 January; 21(1): 11-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11879576

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Decreasing serum concentrations of all-trans, 13-cis retinoic acids and retinol during fasting and caloric restriction. Author(s): Berggren Soderlund M, Fex G, Nilsson-Ehle P. Source: Journal of Internal Medicine. 2003 March; 253(3): 375-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12603506

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Dermal fibroblasts actively metabolize retinoic acid but not retinol. Author(s): Randolph RK, Simon M. Source: The Journal of Investigative Dermatology. 1998 September; 111(3): 478-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9740244

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Determinants of plasma retinol concentrations of middle-aged women in rural China. Author(s): Root MM, Hu J, Stephenson LS, Parker RS, Campbell TC. Source: Nutrition (Burbank, Los Angeles County, Calif.). 1999 February; 15(2): 101-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9990573

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Determination of a cut-off value for the molar ratio of retinol-binding protein to transthyretin (RBP:TTR) in Bangladeshi patients with low hepatic vitamin A stores. Author(s): Rosales FJ, Chau KK, Haskell MH, Shankar AH. Source: The Journal of Nutrition. 2002 December; 132(12): 3687-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12468608

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Determination of retinol, alpha-tocopherol, alpha- and beta-carotene by direct extraction of human serum using high performance liquid chromatography. Author(s): Abahusain MA, Wright J, Dickerson JW, el-Hazmi MA, Aboul Enein HY. Source: Biomedical Chromatography : Bmc. 1998 March-April; 12(2): 89-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9568277

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Determination of retinol, antioxidant vitamins and homocysteine in skin puncture blood. Author(s): Erhardt JG, Heinrich F, Biesalski HK. Source: Int J Vitam Nutr Res. 1999 September; 69(5): 309-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10526774

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Development and validation of a fast and sensitive chromatographic assay for alltrans-retinol and tocopherols in human serum and plasma using liquid-liquid extraction. Author(s): Taibi G, Nicotra CM. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2002 November 25; 780(2): 261-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12401351

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Development of a rapid enzyme immunoassay for the detection of retinol-binding protein. Author(s): Hix J, Martinez C, Buchanan I, Morgan J, Tam M, Shankar A. Source: The American Journal of Clinical Nutrition. 2004 January; 79(1): 93-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684403

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Diagnostic value of urinary retinol-binding protein in childhood nephrotic syndrome. Author(s): Dillon SC, Taylor GM, Shah V. Source: Pediatric Nephrology (Berlin, Germany). 1998 October; 12(8): 643-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9811386

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Dietary and serum alpha-tocopherol, beta-carotene and retinol, and risk for colorectal cancer in male smokers. Author(s): Malila N, Virtamo J, Virtanen M, Pietinen P, Albanes D, Teppo L. Source: European Journal of Clinical Nutrition. 2002 July; 56(7): 615-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12080400

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Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish women. Author(s): Michels KB, Holmberg L, Bergkvist L, Ljung H, Bruce A, Wolk A. Source: International Journal of Cancer. Journal International Du Cancer. 2001 February 15; 91(4): 563-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11251982

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Dietary carotenoids, serum beta-carotene, and retinol and risk of lung cancer in the alpha-tocopherol, beta-carotene cohort study. Author(s): Holick CN, Michaud DS, Stolzenberg-Solomon R, Mayne ST, Pietinen P, Taylor PR, Virtamo J, Albanes D. Source: American Journal of Epidemiology. 2002 September 15; 156(6): 536-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12226001

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Dietary retinol--a double-edged sword. Author(s): Denke MA. Source: Jama : the Journal of the American Medical Association. 2002 January 2; 287(1): 102-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11754715

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Differential binding to soluble nuclear receptors and effects on cell viability of retinol and retinoic acid in cultured retinoblastoma cells. Author(s): Wiggert B, Russell P, Lewis M, Chader G. Source: Biochemical and Biophysical Research Communications. 1977 November 7; 79(1): 218-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=921797

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Differential recognition of the free versus bound retinol by human microsomal retinol/sterol dehydrogenases: characterization of the holo-CRBP dehydrogenase activity of RoDH-4. Author(s): Lapshina EA, Belyaeva OV, Chumakova OV, Kedishvili NY. Source: Biochemistry. 2003 January 28; 42(3): 776-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12534290

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Disruption of the 11-cis-retinol dehydrogenase gene leads to accumulation of cisretinols and cis-retinyl esters. Author(s): Driessen CA, Winkens HJ, Hoffmann K, Kuhlmann LD, Janssen BP, Van Vugt AH, Van Hooser JP, Wieringa BE, Deutman AF, Palczewski K, Ruether K, Janssen JJ. Source: Molecular and Cellular Biology. 2000 June; 20(12): 4275-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10825191

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Dissection of multi-protein complexes using mass spectrometry: subunit interactions in transthyretin and retinol-binding protein complexes. Author(s): Rostom AA, Sunde M, Richardson SJ, Schreiber G, Jarvis S, Bateman R, Dobson CM, Robinson CV. Source: Proteins. 1998; Suppl 2: 3-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9849905

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Dual-substrate specificity short chain retinol dehydrogenases from the vertebrate retina. Author(s): Haeseleer F, Jang GF, Imanishi Y, Driessen CA, Matsumura M, Nelson PS, Palczewski K. Source: The Journal of Biological Chemistry. 2002 November 22; 277(47): 45537-46. Epub 2002 September 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12226107

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Effect of long-term beta-carotene and vitamin A on serum cholesterol and triglyceride levels among participants in the Carotene and Retinol Efficacy Trial (CARET) Author(s): Redlich CA, Chung JS, Cullen MR, Blaner WS, Van Bennekum AM, Berglund L. Source: Atherosclerosis. 1999 August; 145(2): 425-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10488974

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Effect of long-term beta-carotene and vitamin A on serum cholesterol and triglyceride levels among participants in the Carotene and Retinol Efficacy Trial (CARET) Author(s): Redlich CA, Chung JS, Cullen MR, Blaner WS, Van Bennekum AM, Berglund L. Source: Atherosclerosis. 1999 April; 143(2): 427-34. Corrected and Republished In: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10217373

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Effect of supplementation on haemoglobin and serum retinol levels and nutritional status of school children of northern India. Author(s): Jood S, Gupta M, Yadav SK, Khetarpaul N. Source: Nutr Health. 2001; 15(2): 97-111. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11694072

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Effect of vitamin A status at the end of term pregnancy on the saturation of retinol binding protein with retinol. Author(s): Sapin V, Alexandre MC, Chaib S, Bournazeau JA, Sauvant P, Borel P, Jacquetin B, Grolier P, Lemery D, Dastugue B, Azais-Braesco V. Source: The American Journal of Clinical Nutrition. 2000 February; 71(2): 537-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10648269

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Effects of arachidonic acid, prostaglandins, retinol, retinoic acid and cholecalciferol on xenobiotic oxidations catalysed by human cytochrome P450 enzymes. Author(s): Yamazaki H, Shimada T. Source: Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 1999 March; 29(3): 231-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10219964

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Effects of long-term intake of retinol on selected clinical and laboratory indexes. Author(s): Cartmel B, Moon TE, Levine N. Source: The American Journal of Clinical Nutrition. 1999 May; 69(5): 937-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10232634

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Effects of subclinical infection on plasma retinol concentrations and assessment of prevalence of vitamin A deficiency: meta-analysis. Author(s): Thurnham DI, McCabe GP, Northrop-Clewes CA, Nestel P. Source: Lancet. 2003 December 20; 362(9401): 2052-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14697804

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Effects of topical vitamin K and retinol on laser-induced purpura on nonlesional skin. Author(s): Lou WW, Quintana AT, Geronemus RG, Grossman MC. Source: Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [et Al.]. 1999 December; 25(12): 942-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10594627

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Effects on serum retinol of multi-micronutrient supplementation and multi-helminth chemotherapy: a randomised, controlled trial in Kenyan school children. Author(s): Mwaniki D, Omondi B, Muniu E, Thiong'o F, Ouma J, Magnussen P, Geissler PW, Michaelsen KF, Friis H. Source: European Journal of Clinical Nutrition. 2002 July; 56(7): 666-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12080408

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Efficacy validation of synthesized retinol derivatives In vitro: stability, toxicity, and activity. Author(s): Han HS, Kwon YJ, Park MS, Park SH, Cho SM, Rho YS, Kim JW, Sin HS, Um SJ. Source: Bioorganic & Medicinal Chemistry. 2003 August 15; 11(17): 3839-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12901928

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Endogenous sex hormones and prostate cancer risk: a case-control study nested within the Carotene and Retinol Efficacy Trial. Author(s): Chen C, Weiss NS, Stanczyk FZ, Lewis SK, DiTommaso D, Etzioni R, Barnett MJ, Goodman GE. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 December; 12(12): 1410-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14693730

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Esterification of all-trans-retinol in normal human epithelial cell strains and carcinoma lines from oral cavity, skin and breast: reduced expression of lecithin:retinol acyltransferase in carcinoma lines. Author(s): Guo X, Ruiz A, Rando RR, Bok D, Gudas LJ. Source: Carcinogenesis. 2000 November; 21(11): 1925-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11062150

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Evaluation of plasma retinol-binding protein as a surrogate measure for plasma retinol concentrations. Author(s): Almekinder J, Manda W, Soko D, Lan Y, Hoover DR, Semba RD. Source: Scandinavian Journal of Clinical and Laboratory Investigation. 2000 May; 60(3): 199-203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10885491

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Evaluation of serum retinol, the modified-relative-dose-response ratio, and breastmilk vitamin A as indicators of response to postpartum maternal vitamin A supplementation. Author(s): Rice AL, Stoltzfus RJ, de Francisco A, Kjolhede CL. Source: The American Journal of Clinical Nutrition. 2000 March; 71(3): 799-806. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10702176

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Expression and mutagenesis of retinol-binding protein. Author(s): Sundaram M, Sivaprasadarao A, Findlay JB. Source: Methods in Molecular Biology (Clifton, N.J.). 1998; 89: 141-53. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9664325

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Expression of a retinol dehydrogenase (hRoDH-4), a member of the retinol/steroid dehydrogenase family implicated in retinoic acid biosynthesis, in normal and neoplastic endometria. Author(s): Cain JM, Zaino R, Shearer D, Bennett RA, Olt G, Weisz J. Source: American Journal of Obstetrics and Gynecology. 2002 April; 186(4): 675-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11967490

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Expression of a smaller lecithin:retinol acyl transferase transcript and reduced retinol esterification in MCF-7 cells. Author(s): Andreola F, Giandomenico V, Spero R, De Luca LM. Source: Biochemical and Biophysical Research Communications. 2000 December 29; 279(3): 920-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11162450

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Expression of cellular retinol- and retinoic acid-binding proteins in normal and pathologic human parathyroid glands. Author(s): Melhus H, Li Q, Nordlinder H, Farnebo LO, Grimelius L. Source: Endocrine Pathology. 2001 Winter; 12(4): 423-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11914476

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Expression of retinol binding protein and transthyretin during early embryogenesis. Author(s): Barron M, McAllister D, Smith SM, Lough J. Source: Developmental Dynamics : an Official Publication of the American Association of Anatomists. 1998 July; 212(3): 413-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9671945

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Expression pattern and biochemical characteristics of a major epidermal retinol dehydrogenase. Author(s): Markova NG, Pinkas-Sarafova A, Karaman-Jurukovska N, Jurukovski V, Simon M. Source: Molecular Genetics and Metabolism. 2003 February; 78(2): 119-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12618084

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Factors affecting plasma retinol decline during long-term administration of the synthetic retinoid fenretinide in breast cancer patients. Author(s): Torrisi R, Parodi S, Fontana V, Rondanina G, Formelli F, Costa A, Boccardo F, Decensi A. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 1994 September; 3(6): 507-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8000302

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Factors affecting the binding of retinol to serum and its components. Author(s): Moffa DJ, Krause RF. Source: Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.). 1970 June; 134(2): 406-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4192542

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Factors associated with low serum retinol levels in children aged 6-24 months in a rural South African community. Author(s): Faber M, Spinnler Benade AJ. Source: Public Health Nutrition. 2000 December; 3(4): 395-402. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11135793

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Factors influencing the conversion of carotenoids to retinol: bioavailability to bioconversion to bioefficacy. Author(s): Tanumihardjo SA. Source: Int J Vitam Nutr Res. 2002 January; 72(1): 40-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11887751

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Fast determination of retinol and alpha-tocopherol in plasma by LC. Author(s): Rodriguez-Delgado MA, Diaz-Flores Estevez JF, Diaz-Flores Estevez F, Hernandez Calzadilla C, Diaz Romero C. Source: Journal of Pharmaceutical and Biomedical Analysis. 2002 June 1; 28(5): 991-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12039642

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Fatal self-medication with retinol and carrot juice. Author(s): Leitner ZA, Moore T, Sharman IM. Source: The Proceedings of the Nutrition Society. 1975 September; 34(2): 44A-45A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1187615

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Fenretinide breast cancer prevention trial: drug and retinol plasma levels in relation to age and disease outcome. Author(s): Formelli F, Camerini T, Cavadini E, Appierto V, Villani MG, Costa A, De Palo G, Di Mauro MG, Veronesi U. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 January; 12(1): 34-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12540501

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Fluorescence assay of retinol-binding holoprotein. Author(s): Glover J. Source: Methods Enzymol. 1980; 67: 282-7. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7189235

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Fluorescence studies of human plasma retinol-binding protein and of the retinolbinding protein-prealbumin complex. Author(s): Goodman DS, Leslie RB. Source: Biochimica Et Biophysica Acta. 1972 April 18; 260(4): 670-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5063712

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Fractional synthesis rates of retinol-binding protein, transthyretin, and a new peptide measured by stable isotope techniques in neonatal pigs. Author(s): Sivakumar B, Jahoor F, Burrin DG, Frazer EM, Reeds PJ. Source: The Journal of Biological Chemistry. 1994 October 21; 269(42): 26196-200. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7929333

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Frozen storage of urine samples before ELISA measurement of retinol-binding protein. Author(s): Mao J, Chen S, Na Z, Xhang Y, Huang Y, Li Y. Source: Clinical Chemistry. 1996 March; 42(3): 466-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8598116

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Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the beta-carotene and retinol efficacy trial (CARET). Author(s): Neuhouser ML, Patterson RE, Thornquist MD, Omenn GS, King IB, Goodman GE. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 April; 12(4): 350-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692110

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Functional aspects of the plasma retinol-binding protein. Author(s): Rask L, Forsum U. Source: World Review of Nutrition and Dietetics. 1978; 31: 71-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=104443

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Gecko iota-crystallin: how cellular retinol-binding protein became an eye lens ultraviolet filter. Author(s): Werten PJ, Roll B, van Aalten DM, de Jong WW. Source: Proceedings of the National Academy of Sciences of the United States of America. 2000 March 28; 97(7): 3282-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10725366

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Gene structure and promoter for Adh3 encoding mouse class IV alcohol dehydrogenase (retinol dehydrogenase). Author(s): Zgombic-Knight M, Deltour L, Haselbeck RJ, Foglio MH, Duester G. Source: Genomics. 1997 April 1; 41(1): 105-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9126489

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Genomic organization and mutation analysis of the gene encoding lecithin retinol acyltransferase in human retinal pigment epithelium. Author(s): Ruiz A, Kuehn MH, Andorf JL, Stone E, Hageman GS, Bok D. Source: Investigative Ophthalmology & Visual Science. 2001 January; 42(1): 31-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11133845

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Genomic organization and transcription of the human retinol dehydrogenase 10 (RDH10) gene. Author(s): Picozzi P, Marozzi A, Fornasari D, Benfante R, Barisani D, Meneveri R, Ginelli E. Source: Febs Letters. 2003 November 6; 554(1-2): 59-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14596915

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Genomic structure and expression of the ADH7 gene encoding human class IV alcohol dehydrogenase, the form most efficient for retinol metabolism in vitro. Author(s): Zgombic-Knight M, Foglio MH, Duester G. Source: The Journal of Biological Chemistry. 1995 March 3; 270(9): 4305-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7876191

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Grafting of a high-affinity Zn(II)-binding site on the beta-barrel of retinol-binding protein results in enhanced folding stability and enables simplified purification. Author(s): Muller HN, Skerra A. Source: Biochemistry. 1994 November 29; 33(47): 14126-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7947824

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Growth modification of normal and tumor cell lines with retinol. Author(s): Audette M, Page M. Source: Cancer Detection and Prevention. 1983; 6(6): 497-505. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6661740

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Growth, fatty acid composition of plasma lipid classes, and plasma retinol and alphatocopherol concentrations in full-term infants fed formula enriched with omega-6 and omega-3 long-chain polyunsaturated fatty acids. Author(s): Decsi T, Koletzko B. Source: Acta Paediatrica (Oslo, Norway : 1992). 1995 July; 84(7): 725-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7549287

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Hepatic synthesis, maturation and complex formation between retinol-binding protein and transthyretin. Author(s): Gaetani S, Bellovino D, Apreda M, Devirgiliis C. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 December; 40(12): 1211-20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12553421

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Heterogeneous activity in vitro of vitamin A (retinol) in combination with novel and established antimalarial drugs. Author(s): Skinner-Adams T, Barrett H, Davis TM. Source: Transactions of the Royal Society of Tropical Medicine and Hygiene. 1999 September-October; 93(5): 550-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10696420

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High levels of cellular retinol binding protein-1 expression in leiomyosarcoma: possible implications for diagnostic evaluation. Author(s): Orlandi A, Francesconi A, Clement S, Ropraz P, Spagnoli LG, Gabbiani G. Source: Virchows Archiv : an International Journal of Pathology. 2002 July; 441(1): 31-40. Epub 2002 January 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12111198

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High levels of retinol intake during the first trimester of pregnancy result from use of over-the-counter vitamin/mineral supplements. Author(s): Voyles LM, Turner RE, Lukowski MJ, Langkamp-Henken B. Source: Journal of the American Dietetic Association. 2000 September; 100(9): 1068-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11019357

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High retinol/retinol-binding protein ratio in noninsulin-dependent diabetes mellitus. Author(s): Sasaki H, Iwasaki T, Kato S, Tada N. Source: The American Journal of the Medical Sciences. 1995 November; 310(5): 177-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7485220

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High-performance liquid chromatography of 13-cis-retinoic acid and of endogenous retinol in human plasma. Author(s): Besner JG, Leclaire R. Source: Journal of Chromatography. 1980 September 12; 183(3): 346-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7419652

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HINT predictive analysis of binding between retinol binding protein and hydrophobic ligands. Author(s): Marabotti A, Balestreri L, Cozzini P, Mozzarelli A, Kellogg GE, Abraham DJ. Source: Bioorganic & Medicinal Chemistry Letters. 2000 September 18; 10(18): 2129-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10999486

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HIV and other predictors of serum beta-carotene and retinol in pregnancy: a crosssectional study in Zimbabwe. Author(s): Friis H, Gomo E, Koestel P, Ndhlovu P, Nyazema N, Krarup H, Michaelsen KF. Source: The American Journal of Clinical Nutrition. 2001 June; 73(6): 1058-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11382660

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Home gardens focusing on the production of yellow and dark-green leafy vegetables increase the serum retinol concentrations of 2-5-y-old children in South Africa. Author(s): Faber M, Phungula MA, Venter SL, Dhansay MA, Benade AJ. Source: The American Journal of Clinical Nutrition. 2002 November; 76(5): 1048-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12399277

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Human alcohol dehydrogenase family. Functional classification, ethanol/retinol metabolism, and medical implications. Author(s): Yin SJ, Han CL, Lee AI, Wu CW. Source: Advances in Experimental Medicine and Biology. 1999; 463: 265-74. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10352695

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Human breast cancer cells and normal mammary epithelial cells: retinol metabolism and growth inhibition by the retinol metabolite 4-oxoretinol. Author(s): Chen AC, Guo X, Derguini F, Gudas LJ. Source: Cancer Research. 1997 October 15; 57(20): 4642-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9377581

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Human choriocarcinoma cell line JEG-3 produces and secretes active retinoids from retinol. Author(s): Blanchon L, Sauvant P, Bavik C, Gallot D, Charbonne F, Alexandre-Gouabau MC, Lemery D, Jacquetin B, Dastugue B, Ward S, Sapin V. Source: Molecular Human Reproduction. 2002 May; 8(5): 485-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11994546

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Human interphotoreceptor matrix contains serum albumin and retinol-binding protein. Author(s): Adler AJ, Edwards RB. Source: Experimental Eye Research. 2000 February; 70(2): 227-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10655149

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Human leukemic K562 cells treated with cytosine arabinoside: enhancement of erythroid differentiation by retinoic acid and retinol. Author(s): Cortesi R, Gui V, Osti F, Nastruzzi C, Gambari R. Source: European Journal of Haematology. 1998 November; 61(5): 295-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9855243

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Human serum retinol transport in malabsorption. Author(s): Smith FR, Lindenbaum J. Source: The American Journal of Clinical Nutrition. 1974 July; 27(7): 700-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4422240

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Hurler's syndrome. Effect of retinol (vitamin A alcohol) on cellular mucopolysaccharides in cultured human skin fibroblasts. Author(s): Danes BS, Bearn AG. Source: The Journal of Experimental Medicine. 1966 December 1; 124(6): 1181-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4224371

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Hypermethylation-associated Inactivation of the Cellular Retinol-Binding-Protein 1 Gene in Human Cancer. Author(s): Esteller M, Guo M, Moreno V, Peinado MA, Capella G, Galm O, Baylin SB, Herman JG. Source: Cancer Research. 2002 October 15; 62(20): 5902-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12384555

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Hypersensitivity to retinol palmitate injection. Author(s): Shelley WB, Shelley ED, Talanin NY. Source: Bmj (Clinical Research Ed.). 1995 July 22; 311(6999): 232. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7627039

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Hypovitaminemia A in idiopathic hemochromatosis and hepatic cirrhosis. Role of retinol-binding protein and zinc. Author(s): Brissot P, Le Treut A, Dien G, Cottencin M, Simon M, Bourel M. Source: Digestion. 1978; 17(6): 469-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=568576

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Identification and characterization of all-trans-retinol dehydrogenase from photoreceptor outer segments, the visual cycle enzyme that reduces all-trans-retinal to all-trans-retinol. Author(s): Rattner A, Smallwood PM, Nathans J. Source: The Journal of Biological Chemistry. 2000 April 14; 275(15): 11034-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10753906

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Identification and structural analysis of a zebrafish apo and holo cellular retinolbinding protein. Author(s): Calderone V, Folli C, Marchesani A, Berni R, Zanotti G. Source: Journal of Molecular Biology. 2002 August 16; 321(3): 527-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12162964

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Identification of the oxidative 3alpha-hydroxysteroid dehydrogenase activity of rat Leydig cells as type II retinol dehydrogenase. Author(s): Hardy DO, Ge RS, Catterall JF, Hou YT, Penning TM, Hardy MP. Source: Endocrinology. 2000 May; 141(5): 1608-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10803568

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Identification, retinoid binding, and x-ray analysis of a human retinol-binding protein. Author(s): Folli C, Calderone V, Ottonello S, Bolchi A, Zanotti G, Stoppini M, Berni R. Source: Proceedings of the National Academy of Sciences of the United States of America. 2001 March 27; 98(7): 3710-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11274389

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Immune response to influenza vaccine in healthy elderly: lack of association with plasma beta-carotene, retinol, alpha-tocopherol, or zinc. Author(s): Gardner EM, Bernstein ED, Popoff KA, Abrutyn E, Gross P, Murasko DM. Source: Mechanisms of Ageing and Development. 2000 August 15; 117(1-3): 29-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10958921

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Impact of vitamin A supplementation through different dosages of red palm oil and retinol palmitate on preschool children. Author(s): Sivan YS, Alwin Jayakumar Y, Arumughan C, Sundaresan A, Jayalekshmy A, Suja KP, Soban Kumar DR, Deepa SS, Damodaran M, Soman CR, Raman Kutty V, Sankara Sarma P. Source: Journal of Tropical Pediatrics. 2002 February; 48(1): 24-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11871368

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Impaired alveolar development and abnormal lung elastin in preterm lambs with chronic lung injury: potential benefits of retinol treatment. Author(s): Bland RD, Albertine KH, Pierce RA, Starcher BC, Carlton DP. Source: Biology of the Neonate. 2003; 84(1): 101-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12890945

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Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein. Author(s): Quadro L, Blaner WS, Salchow DJ, Vogel S, Piantedosi R, Gouras P, Freeman S, Cosma MP, Colantuoni V, Gottesman ME. Source: The Embo Journal. 1999 September 1; 18(17): 4633-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10469643

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Improved method for measurement of retinol and didehydroretinol in the modified relative dose response test to detect vitamin A deficiency. Author(s): Erhardt JG, Biesalski HK, Malaba LC, Craft NE. Source: Clinical Chemistry. 2003 February; 49(2): 338-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12560370

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Improved simultaneous determination method of beta-carotene and retinol with saponification in human serum and rat liver. Author(s): Hosotani K, Kitagawa M. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 July 5; 791(1-2): 305-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798190

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In vitro growth inhibition of Plasmodium falciparum by retinol at concentrations present in normal human serum. Author(s): Davis TM, Skinner-Adams TS, Beilby J. Source: Acta Tropica. 1998 May; 69(2): 111-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9588231

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In vitro metabolism by human skin and fibroblasts of retinol, retinal and retinoic acid. Author(s): Bailly J, Crettaz M, Schifflers MH, Marty JP. Source: Experimental Dermatology. 1998 February; 7(1): 27-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9517919

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Increased retinol binding protein in the sera of patients with severe ischemic damage of the liver after transplantation. Author(s): Mastroianni A, Regalia E, Facchetti G, Longoni PD, Formelli F, Pulvirenti A, Mazzaferro V. Source: Clinical Biochemistry. 1998 March; 31(2): 113-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9622775

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Increased urinary retinol loss in children with severe infections. Author(s): Mitra AK, Alvarez JO, Stephensen CB. Source: Lancet. 1998 April 4; 351(9108): 1033-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9546517

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Infant hypervitaminosis A causes severe anemia and thrombocytopenia: evidence of a retinol-dependent bone marrow cell growth inhibition. Author(s): Perrotta S, Nobili B, Rossi F, Criscuolo M, Iolascon A, Di Pinto D, Passaro I, Cennamo L, Oliva A, Della Ragione F. Source: Blood. 2002 March 15; 99(6): 2017-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11877274

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Infection-induced depression of serum retinol--a component of the acute phase response or a consequence? Author(s): Beisel WR. Source: The American Journal of Clinical Nutrition. 1998 November; 68(5): 993-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9808211

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Inflammation-induced changes in the nutritional biomarkers serum retinol and carotenoids. Author(s): Schweigert FJ. Source: Current Opinion in Clinical Nutrition and Metabolic Care. 2001 November; 4(6): 477-81. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11706279

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Interaction of ethanol with retinol and retinoic acid in RAR beta and GAP-43 expression. Author(s): Grummer MA, Zachman RD. Source: Neurotoxicology and Teratology. 2000 November-December; 22(6): 829-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11120388

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Interactions of retinol-binding protein with transthyretin and its receptor. Author(s): Sivaprasadarao A, Sundaram M, Findlay JB. Source: Methods in Molecular Biology (Clifton, N.J.). 1998; 89: 155-63. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9664326

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Isomerization of all-trans-retinol to cis-retinols in bovine retinal pigment epithelial cells: dependence on the specificity of retinoid-binding proteins. Author(s): McBee JK, Kuksa V, Alvarez R, de Lera AR, Prezhdo O, Haeseleer F, Sokal I, Palczewski K. Source: Biochemistry. 2000 September 19; 39(37): 11370-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10985782

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Kinetic mechanism of human class IV alcohol dehydrogenase functioning as retinol dehydrogenase. Author(s): Chou CF, Lai CL, Chang YC, Duester G, Yin SJ. Source: The Journal of Biological Chemistry. 2002 July 12; 277(28): 25209-16. Epub 2002 May 07. Erratum In: J Biol Chem 2002 October 25; 277(43): 41294. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11997393

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Latex immunoassay of retinol-binding protein. Author(s): Bernard AM, Moreau D, Lauwerys RR. Source: Clinical Chemistry. 1982 May; 28(5): 1167-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6176366

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Lecithin retinol acyltransferase contains cysteine residues essential for catalysis. Author(s): Mondal MS, Ruiz A, Bok D, Rando RR. Source: Biochemistry. 2000 May 2; 39(17): 5215-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10819989

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Lecithin retinol acyltransferase is a founder member of a novel family of enzymes. Author(s): Jahng WJ, Xue L, Rando RR. Source: Biochemistry. 2003 November 11; 42(44): 12805-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14596594

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Lecithin:retinol acyltransferase from mouse and rat liver. CDNA cloning and liverspecific regulation by dietary vitamin a and retinoic acid. Author(s): Zolfaghari R, Ross AC. Source: Journal of Lipid Research. 2000 December; 41(12): 2024-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11108736

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Liarozole inhibits human epidermal retinoic acid 4-hydroxylase activity and differentially augments human skin responses to retinoic acid and retinol in vivo. Author(s): Kang S, Duell EA, Kim KJ, Voorhees JJ. Source: The Journal of Investigative Dermatology. 1996 August; 107(2): 183-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8757760

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Ligand binding and structural analysis of a human putative cellular retinol-binding protein. Author(s): Folli C, Calderone V, Ramazzina I, Zanotti G, Berni R. Source: The Journal of Biological Chemistry. 2002 November 1; 277(44): 41970-7. Epub 2002 August 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12177003

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Linkage mapping of the retinol-binding protein 4 (RBP4) gene to porcine chromosome 14. Author(s): Messer LA, Wang L, Yelich J, Pomp D, Geisert RD, Rothschild MF. Source: Mammalian Genome : Official Journal of the International Mammalian Genome Society. 1996 May; 7(5): 396. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8661737

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Lipases and carboxylesterases: possible roles in the hepatic metabolism of retinol. Author(s): Harrison EH. Source: Annual Review of Nutrition. 1998; 18: 259-76. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9706226

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Liquid-chromatographic assay for retinol (vitamin A) and retinol analogs in therapeutic trials. Author(s): McClean SW, Ruddel ME, Gross EG, DeGiovanna JJ, Peck GL. Source: Clinical Chemistry. 1982 April; 28(4 Pt 1): 693-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6804118

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Lobe of origin and histologic type of lung cancer associated with asbestos exposure in the Carotene and Retinol Efficacy Trial (CARET). Author(s): Brodkin CA, McCullough J, Stover B, Balmes J, Hammar S, Omenn GS, Checkoway H, Barnhart S. Source: American Journal of Industrial Medicine. 1997 December; 32(6): 582-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9358913

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Long-term vitamin A does not produce clinically significant hypertriglyceridemia: results from CARET, the beta-carotene and retinol efficacy trial. Author(s): Omenn GS, Goodman GE, Thornquist M, Brunzell JD. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 1994 December; 3(8): 711-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7881345

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Loss of cellular retinol-binding protein 1 gene expression in microdissected human ovarian cancer. Author(s): Cvetkovic D, Williams SJ, Hamilton TC. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 March; 9(3): 1013-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12631600

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Low molecular weight urinary proteins. I. Partial amino acid sequences of the retinolbinding proteins of man and dog. Author(s): Poulik MD, Farrah D, Malek GH, Shinnick CJ, Smithies O. Source: Biochimica Et Biophysica Acta. 1975 December 15; 412(2): 326-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1103975

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Low plasma concentrations of retinol and alpha-tocopherol in hematopoietic stem cell transplant recipients: the effect of mucositis and the risk of infection. Author(s): High KP, Legault C, Sinclair JA, Cruz J, Hill K, Hurd DD. Source: The American Journal of Clinical Nutrition. 2002 December; 76(6): 1358-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12450904

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Low plasma concentrations of retinol-binding protein in individuals with mutations affecting position 84 of the transthyretin molecule. Author(s): Waits RP, Yamada T, Uemichi T, Benson MD. Source: Clinical Chemistry. 1995 September; 41(9): 1288-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7656439

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Low serum retinol levels are associated with hepatocellular carcinoma in patients with chronic liver disease. Author(s): Newsome PN, Beldon I, Moussa Y, Delahooke TE, Poulopoulos G, Hayes PC, Plevris JN. Source: Alimentary Pharmacology & Therapeutics. 2000 October; 14(10): 1295-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11012474

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Malaria is associated with reduced serum retinol levels in rural Zambian children. Author(s): Hautvast JL, Tolboom JJ, West CE, Kafwembe EM, Sauerwein RW, van Staveren WA. Source: Int J Vitam Nutr Res. 1998; 68(6): 384-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9857266

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Measurement of microalbumin and retinol binding protein in cardiac and lung transplant recipients. Author(s): el-Gamel A, Yonan N, Keevil B, Nicholls S, Smith KJ, Campbell C, Rahman A, Deiraniya AK. Source: Transplantation Proceedings. 1995 June; 27(3): 1969-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7792854

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Measurement of urinary retinol binding protein by immunonephelometry. Author(s): Twyman SJ, Overton J, Rowe DJ. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2000 July; 297(1-2): 155-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10841917

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Megalin and the neurodevelopmental biology of sonic hedgehog and retinol. Author(s): McCarthy RA, Argraves WS. Source: Journal of Cell Science. 2003 March 15; 116(Pt 6): 955-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12584240

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Membrane-bound lecithin-retinol acyltransferase. Author(s): Rando RR. Source: Biochemical and Biophysical Research Communications. 2002 April 19; 292(5): 1243-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11969222

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Metabolic conversion of retinol to retinoic acid mediates the biological responsiveness of human mammary epithelial cells to retinol. Author(s): Hayden LJ, Hawk SN, Sih TR, Satre MA. Source: Journal of Cellular Physiology. 2001 March; 186(3): 437-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11169983

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Metabolism of all-trans-retinol in normal human cell strains and squamous cell carcinoma (SCC) lines from the oral cavity and skin: reduced esterification of retinol in SCC lines. Author(s): Guo X, Gudas LJ. Source: Cancer Research. 1998 January 1; 58(1): 166-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9426073

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Metabolites of retinol in cultured human dermal fibroblasts. Author(s): Gindhart TD, Bhat PV, Silverman-Jones C. Source: Annals of the New York Academy of Sciences. 1981 February 27; 359: 393. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6942687

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Method for the simultaneous determination of retinol and beta-carotene concentrations in human tissues and plasma. Author(s): Lunetta JM, Zulim RA, Dueker SR, Lin Y, Flaig V, Schneider PD, Wolfe BM, Clifford AJ. Source: Analytical Biochemistry. 2002 May 1; 304(1): 100-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11969193

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MMH cells: An in vitro model for the study of retinol-binding protein secretion regulated by retinol. Author(s): Bellovino D, Lanyau Y, Garaguso I, Amicone L, Cavallari C, Tripodi M, Gaetani S. Source: Journal of Cellular Physiology. 1999 October; 181(1): 24-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10457350

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Modification of tryptophan residues in retinol-binding protein and prealbumin with 2-hydroxy-5-nitrobenzyl bromide. Effects of the modification of the protein-retinol and protein-protein interaction. Author(s): Horwitz J, Heller J. Source: The Journal of Biological Chemistry. 1974 November 25; 249(22): 7181-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4436304

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Modulation of the androgenic response by recombinant human 11-cis retinol dehydrogenase. Author(s): Huang XF, Luu-The V. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2001 May; 77(2-3): 129-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11377978

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Molecular and biochemical characterization of lecithin retinol acyltransferase. Author(s): Ruiz A, Winston A, Lim YH, Gilbert BA, Rando RR, Bok D. Source: The Journal of Biological Chemistry. 1999 February 5; 274(6): 3834-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9920938

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Molecular characterization of lecithin-retinol acyltransferase. Author(s): Ruiz A, Bok D. Source: Methods Enzymol. 2000; 316: 400-13. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10800690

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Molecular docking studies on interaction of diverse retinol structures with human alcohol dehydrogenases predict a broad role in retinoid ligand synthesis. Author(s): Foglio MH, Duester G. Source: Biochimica Et Biophysica Acta. 1999 July 13; 1432(2): 239-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10407146

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Muscle expression of human retinol-binding protein (RBP). Suppression of the visual defect of RBP knockout mice. Author(s): Quadro L, Blaner WS, Hamberger L, Van Gelder RN, Vogel S, Piantedosi R, Gouras P, Colantuoni V, Gottesman ME. Source: The Journal of Biological Chemistry. 2002 August 16; 277(33): 30191-7. Epub 2002 June 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12048218

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Mutations in the 11-cis retinol dehydrogenase gene in Japanese patients with Fundus albipunctatus. Author(s): Hirose E, Inoue Y, Morimura H, Okamoto N, Fukuda M, Yamamoto S, Fujikado T, Tano Y. Source: Investigative Ophthalmology & Visual Science. 2000 November; 41(12): 3933-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11053296

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Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus. Author(s): Yamamoto H, Simon A, Eriksson U, Harris E, Berson EL, Dryja TP. Source: Nature Genetics. 1999 June; 22(2): 188-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10369264

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Mutations in the gene encoding lecithin retinol acyltransferase are associated with early-onset severe retinal dystrophy. Author(s): Thompson DA, Li Y, McHenry CL, Carlson TJ, Ding X, Sieving PA, Apfelstedt-Sylla E, Gal A. Source: Nature Genetics. 2001 June; 28(2): 123-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11381255

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Mutations in the gene encoding retinol binding protein and retinol deficiency: is there compensation by retinyl esters and retinoic acid? Author(s): Ross AC. Source: The American Journal of Clinical Nutrition. 1999 May; 69(5): 829-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10232619

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Nanosecond spectroscopy of retinol. Author(s): Georghiou S, Churchich JE. Source: The Journal of Biological Chemistry. 1975 February 10; 250(3): 1149-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=235512

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Nature and properties of retinol-binding proteins. Author(s): Kirby W, White G, Glover J. Source: The Biochemical Journal. 1971 July; 123(4): 31P. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4108340

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Netilmicin effect on urinary retinol binding protein (RBP) and N-acetyl-beta-Dglucosaminidase (NAG) in preterm newborns with and without anoxia. Author(s): Cataldi L, Mussap M, Verlato G, Plebani M, Fanos V; Neonatal Nephrology Study Group of the Italian Society of Neonatology. Source: J Chemother. 2002 February; 14(1): 76-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11892904

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New aspects of the tolerance of retinol in humans. Author(s): Korner WF, Vollm J. Source: Int J Vitam Nutr Res. 1975; 45(4): 363-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1213862

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Nicotinamide adenine dinucleotide-dependent retinoic acid formation from retinol in the human gastric mucosa: inhibition by ethanol, acetaldehyde, and H2 blockers. Author(s): Yokoyama H, Matsumoto M, Shiraishi H, Miyagi M, Kato And S, Ishii H. Source: Alcoholism, Clinical and Experimental Research. 2001 June; 25(6 Suppl): 24S-8S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11410737

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Normal interaction of plasma retinol-binding protein from retinitis pigmentosa with bovine pigment epithelium. Author(s): Maraini G, Gozzoli F. Source: Invest Ophthalmol. 1976 December; 15(12): 1020-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1033169

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Null mutation in the human 11-cis retinol dehydrogenase gene associated with fundus albipunctatus. Author(s): Driessen CA, Janssen BP, Winkens HJ, Kuhlmann LD, Van Vugt AH, Pinckers AJ, Deutman AF, Janssen JJ. Source: Ophthalmology. 2001 August; 108(8): 1479-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11470705

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Nutritional state of beta-carotene and retinol in institutionalized elderly individuals of Mexico City. Author(s): Lares-Asseff I, Lopez Hernandez Mdel C, Santiago Porras P, Ramirez Lopez E, Perez Guille G, Cravioto J. Source: Int J Vitam Nutr Res. 1995; 65(4): 236-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8789619

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Nutritional status of beta-carotene, alpha-tocopherol and retinol in obese children. Author(s): Morinobu T, Murata T, Takaya R, Tamai H. Source: Int J Vitam Nutr Res. 2002 May; 72(3): 119-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12098878

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On the sources of retinoic acid in the lung: understanding the local conversion of retinol to retinoic acid. Author(s): Ross AC. Source: American Journal of Physiology. Lung Cellular and Molecular Physiology. 2004 February; 286(2): L247-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14711799

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On the stoichiometry of the interaction between prealbumin and retinol-binding protein. Author(s): Tragardh L, Anundi H, Rask L, Sege K, Peterson PA. Source: The Journal of Biological Chemistry. 1980 October 10; 255(19): 9243-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7190975

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Orange fruit is more effective than are dark-green, leafy vegetables in increasing serum concentrations of retinol and beta-carotene in schoolchildren in Indonesia. Author(s): de Pee S, West CE, Permaesih D, Martuti S, Muhilal, Hautvast JG. Source: The American Journal of Clinical Nutrition. 1998 November; 68(5): 1058-67. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9808223

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Ossification of the posterior longitudinal ligament, diffuse, idiopathic skeletal hyperostosis, abnormal retinol and retinol binding protein: a familial observation. Author(s): De Bandt M, Meyer O, Fuster JM, Kahn MF. Source: The Journal of Rheumatology. 1995 July; 22(7): 1395-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7562783

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Pharmacokinetics of retinyl palmitate and retinol after intramuscular retinyl palmitate administration in severe malaria. Author(s): Davis TM, Binh TQ, Thu LT, Rossi R, Danh PT, Barrett PH, Beilby J. Source: Clinical Science (London, England : 1979). 2000 November; 99(5): 433-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11052924

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Plasma beta-carotene and retinol concentrations of children increase after a 30-d supplementation with the fruit Momordica cochinchinensis (gac). Author(s): Vuong le T, Dueker SR, Murphy SP. Source: The American Journal of Clinical Nutrition. 2002 May; 75(5): 872-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11976161

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Plasma carotenoids, retinol, tocopherols, and lipoproteins in preeclamptic and normotensive pregnant Zimbabwean women. Author(s): Williams MA, Woelk GB, King IB, Jenkins L, Mahomed K. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2003 August; 16(8): 665-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12878373

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Plasma concentrations of carotenoids, retinol, and tocopherols in preeclamptic and normotensive pregnant women. Author(s): Zhang C, Williams MA, Sanchez SE, King IB, Ware-Jauregui S, Larrabure G, Bazul V, Leisenring WM. Source: American Journal of Epidemiology. 2001 March 15; 153(6): 572-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11257065

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Plasma levels of retinol, carotenoids, and tocopherols in relation to dietary pattern among pregnant Tanzanian women. Author(s): Mulokozi G, Lietz G, Svanberg U, Mugyabuso JK, Henry JC, Tomkins AM. Source: Int J Vitam Nutr Res. 2003 October; 73(5): 323-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14639795

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Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in women. Author(s): Sesso HD, Buring JE, Norkus EP, Gaziano JM. Source: The American Journal of Clinical Nutrition. 2004 January; 79(1): 47-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684396

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Plasma retinol and alpha-tocopherol level and growth indices of 7 months old healthy Thai infants in Bangkok. Author(s): Sirivichayakul C, Changbumrung S, Chanthavanich P, Moungnoi P, Chokejindachai W, Attanath P, Pengsaa K. Source: Southeast Asian J Trop Med Public Health. 2001 June; 32(2): 408-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11556597

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Plasma retinol and tocopherol levels in greek elderly population from an urban and a rural area: associations with the dietary habits. Author(s): Leotsinidis M, Alexopoulos A, Schinas V, Kardara M, Kondakis X. Source: European Journal of Epidemiology. 2000; 16(11): 1009-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11421468

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Plasma retinol and tocopherol levels in relation to demographic, lifestyle and nutritional factors of plant origin in Greece. Author(s): Papas A, Stacewicz-Sapuntzakis M, Lagiou P, Bamia C, Chloptsios Y, Trichopoulou A. Source: The British Journal of Nutrition. 2003 January; 89(1): 83-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12568667

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Plasma retinol binding protein: structure and function of the prototypic lipocalin. Author(s): Newcomer ME, Ong DE. Source: Biochimica Et Biophysica Acta. 2000 October 18; 1482(1-2): 57-64. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11058747

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Plasma status of retinol, alpha- and gamma-tocopherols, and main carotenoids to first myocardial infarction: case control and follow-up study. Author(s): Ruiz Rejon F, Martin-Pena G, Granado F, Ruiz-Galiana J, Blanco I, Olmedilla B. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2002 January; 18(1): 26-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11827760

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Polymorphic variation at the -202 locus in IGFBP3: Influence on serum levels of insulin-like growth factors, interaction with plasma retinol and vitamin D and breast cancer risk. Author(s): Schernhammer ES, Hankinson SE, Hunter DJ, Blouin MJ, Pollak MN. Source: International Journal of Cancer. Journal International Du Cancer. 2003 October 20; 107(1): 60-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12925957

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Prediagnostic levels of serum beta-cryptoxanthin and retinol predict smoking-related lung cancer risk in Shanghai, China. Author(s): Yuan JM, Ross RK, Chu XD, Gao YT, Yu MC. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2001 July; 10(7): 767-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11440962

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Predictive value of urinary retinol binding protein for graft dysfunction after kidney transplantation. Author(s): Hosaka B, Park SI, Felipe CR, Garcia RG, Machado PG, Pereira AB, TedescoSilva H, Medina-Pestana JO. Source: Transplantation Proceedings. 2003 June; 35(4): 1341-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826154

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Prospective study of serum retinol, beta-carotene, beta-cryptoxanthin, and lutein/zeaxanthin and esophageal and gastric cancers in China. Author(s): Abneth CC, Qiao YL, Dawsey SM, Buckman DW, Yang CS, Blot WJ, Dong ZW, Taylor PR, Mark SD. Source: Cancer Causes & Control : Ccc. 2003 September; 14(7): 645-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14575362

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Prostatic levels of tocopherols, carotenoids, and retinol in relation to plasma levels and self-reported usual dietary intake. Author(s): Freeman VL, Meydani M, Yong S, Pyle J, Wan Y, Arvizu-Durazo R, Liao Y. Source: American Journal of Epidemiology. 2000 January 15; 151(2): 109-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10645812

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Provitamin A food sources and serum retinol. Author(s): Harrison EH, Smith JC. Source: The American Journal of Clinical Nutrition. 1999 October; 70(4): 575-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10500314

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Pulse radiolytic oxidation of beta-carotene with halogenated alkylperoxyl radicals in a quaternary microemulsion: formation of retinol. Author(s): Adhikari S, Kapoor S, Chattopadhyay S, Mukherjee T. Source: Biophysical Chemistry. 2000 December 15; 88(1-3): 111-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11152268

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Purification and characterization of a transmembrane domain-deleted form of lecithin retinol acyltransferase. Author(s): Bok D, Ruiz A, Yaron O, Jahng WJ, Ray A, Xue L, Rando RR. Source: Biochemistry. 2003 May 27; 42(20): 6090-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12755610

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Purification and fluorescent titration of cellular retinol-binding protein. Author(s): Malpeli G, Folli C, Cavazzini D, Sartori G, Berni R. Source: Methods in Molecular Biology (Clifton, N.J.). 1998; 89: 111-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9664323

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Quantitative assessment of total body stores of vitamin A in adults with the use of a 3-d deuterated-retinol-dilution procedure. Author(s): Ribaya-Mercado JD, Solon FS, Dallal GE, Solomons NW, Fermin LS, Mazariegos M, Dolnikowski GG, Russell RM. Source: The American Journal of Clinical Nutrition. 2003 March; 77(3): 694-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12600863

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Questionnaire assessment of antioxidants and retinol intakes in Mexican women. Author(s): Romieu I, Parra S, Hernandez JF, Madrigal H, Willett W, Hernandez M. Source: Archives of Medical Research. 1999 May-June; 30(3): 224-39. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10427874

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Rapid and sensitive high-performance liquid chromatographic method for simultaneous determination of retinol, alpha-tocopherol, 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 in human plasma with photodiode-array ultraviolet detection. Author(s): Alvarez JC, De Mazancourt P. Source: J Chromatogr B Biomed Sci Appl. 2001 May 5; 755(1-2): 129-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11393696

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Rapid and simple measurement of retinol in human dried whole blood spots. Author(s): Erhardt JG, Craft NE, Heinrich F, Biesalski HK. Source: The Journal of Nutrition. 2002 February; 132(2): 318-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11823598

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Rapid high-performance liquid chromatographic method for the simultaneous determination of retinol, alpha-tocopherol and beta-carotene in human plasma and low-density lipoproteins. Author(s): Gimeno E, Castellote AI, Lamuela-Raventos RM, de la Torre-Boronat MC, Lopez-Sabater MC. Source: J Chromatogr B Biomed Sci Appl. 2001 July 15; 758(2): 315-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11486843

98

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Retinoic acid homeostasis: retinoic acid regulates liver retinol esterification as well as its own catabolic oxidation in liver. Author(s): Wolf G. Source: Nutrition Reviews. 2001 December; 59(12): 391-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11766909

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Retinol analysis in dried blood spots by HPLC. Author(s): Craft NE, Haitema T, Brindle LK, Yamini S, Humphrey JH, West KP Jr. Source: The Journal of Nutrition. 2000 April; 130(4): 882-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10736346

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Retinol and alpha-tocopherol in serum of type 1 diabetic patients with intensive insulin therapy: a long term follow-up study. Author(s): Granado F, Olmedilla B, Botella F, Simal A, Blanco I. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2003 February; 19(2): 128-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591543

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Retinol and tocopherol content in primary and metastatic digestive neoplasms. Author(s): Rocchi E, Casalgrandi G, Ronzoni A, Rosa MC, Marri L, Gozzi C. Source: Anticancer Res. 2003 November-December; 23(6D): 5049-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14981966

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Retinol binding protein as a surrogate measure for serum retinol: studies in vitamin A-deficient children from the Republic of the Marshall Islands. Author(s): Gamble MV, Ramakrishnan R, Palafox NA, Briand K, Berglund L, Blaner WS. Source: The American Journal of Clinical Nutrition. 2001 March; 73(3): 594-601. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11237937

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Retinol binding protein expression is induced in HepG2 cells by zinc deficiency. Author(s): Satre MA, Jessen KA, Clegg MS, Keen CL. Source: Febs Letters. 2001 March 2; 491(3): 266-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11240140

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Retinol concentration in maternal and cord serum: its relation to birth weight in healthy mother-infant pairs. Author(s): Gazala E, Sarov B, Hershkovitz E, Edvardson S, Sklan D, Katz M, Friger M, Gorodischer R. Source: Early Human Development. 2003 February; 71(1): 19-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12614947

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Retinol equivalency ratio of beta-carotene. Author(s): Russell RM, Ross AC, Trumbo PR, West KP. Source: The Journal of Nutrition. 2003 September; 133(9): 2915-6; Author Reply 2917. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12949387

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Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study. Author(s): Promislow JH, Goodman-Gruen D, Slymen DJ, Barrett-Connor E. Source: Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research. 2002 August; 17(8): 1349-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12162487

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Retinol measurements and retinoid receptor gene expression in patients with multiple sclerosis. Author(s): Royal W 3rd, Gartner S, Gajewski CD. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 December; 8(6): 452-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12474982

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Retinol metabolism and lecithin:retinol acyltransferase levels are reduced in cultured human prostate cancer cells and tissue specimens. Author(s): Guo X, Knudsen BS, Peehl DM, Ruiz A, Bok D, Rando RR, Rhim JS, Nanus DM, Gudas LJ. Source: Cancer Research. 2002 March 15; 62(6): 1654-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11912136

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Retinol, alpha-tocopherol and carotenoids in diabetes. Author(s): Abahusain MA, Wright J, Dickerson JW, de Vol EB. Source: European Journal of Clinical Nutrition. 1999 August; 53(8): 630-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10477250

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Retinol, vitamin D, carotenes and alpha-tocopherol in serum of a moderately hypercholesterolemic population consuming sitostanol ester margarine. Author(s): Gylling H, Puska P, Vartiainen E, Miettinen TA. Source: Atherosclerosis. 1999 August; 145(2): 279-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10488954

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retSDR1, a short-chain retinol dehydrogenase/reductase, is retinoic acid-inducible and frequently deleted in human neuroblastoma cell lines. Author(s): Cerignoli F, Guo X, Cardinali B, Rinaldi C, Casaletto J, Frati L, Screpanti I, Gudas LJ, Gulino A, Thiele CJ, Giannini G. Source: Cancer Research. 2002 February 15; 62(4): 1196-204. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11861404

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Rod and cone visual cycle consequences of a null mutation in the 11-cis-retinol dehydrogenase gene in man. Author(s): Cideciyan AV, Haeseleer F, Fariss RN, Aleman TS, Jang GF, Verlinde CL, Marmor MF, Jacobson SG, Palczewski K. Source: Visual Neuroscience. 2000 September-October; 17(5): 667-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11153648

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Role of conserved residues in structure and stability: tryptophans of human serum retinol-binding protein, a model for the lipocalin superfamily. Author(s): Greene LH, Chrysina ED, Irons LI, Papageorgiou AC, Acharya KR, Brew K. Source: Protein Science : a Publication of the Protein Society. 2001 November; 10(11): 2301-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11604536

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RPE65 of retinal pigment epithelium, a putative receptor molecule for plasma retinolbinding protein, is expressed in human keratinocytes. Author(s): Hinterhuber G, Cauza K, Brugger K, Dingelmaier-Hovorka R, Horvat R, Wolff K, Foedinger D. Source: The Journal of Investigative Dermatology. 2004 February; 122(2): 406-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15009723

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Selective use of transthyretin and retinol-binding protein as markers in the postoperative assessment of protein nutritional status. Author(s): Ihara H, Matsumoto T, Shino Y, Hashizume N, Takase M, Nagao J, Sumiyama Y. Source: Journal of Clinical Laboratory Analysis. 2003; 17(1): 1-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12526015

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Serum ferritin, alpha-tocopherol, beta-carotene and retinol levels in lymphatic filariasis. Author(s): Friis H, Kaestel P, Nielsen N, Simonsen PE. Source: Transactions of the Royal Society of Tropical Medicine and Hygiene. 2002 March-April; 96(2): 151-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12055804

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Serum inhibitors for human mast cell growth: possible role of retinol. Author(s): Ishida S, Kinoshita T, Sugawara N, Yamashita T, Koike K. Source: Allergy. 2003 October; 58(10): 1044-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14510724

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Serum insulin-like growth factor (IGF) and IGF-binding protein levels and risk of lung cancer: a case-control study nested in the beta-Carotene and Retinol Efficacy Trial Cohort. Author(s): Spitz MR, Barnett MJ, Goodman GE, Thornquist MD, Wu X, Pollak M. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2002 November; 11(11): 1413-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12433720

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Serum levels of alpha-carotene, beta-carotene, and retinol in patients with multiple sclerosis. Author(s): de Bustos F, Jimenez-Jimenez FJ, Molina JA, de Andres C, Gasalla T, OrtiPareja M, Ayuso-Peralta L, Berbel A, Castellano-Millan F, Arenas J, Enriquez de Salamanca R. Source: Acta Neurol Belg. 2000 March; 100(1): 41-3. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10779861

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Serum retinol levels and fracture risk. Author(s): Chandra RK. Source: The New England Journal of Medicine. 2003 May 8; 348(19): 1927-8; Author Reply 1927-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12740968

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Serum retinol levels and fracture risk. Author(s): Boucher BJ. Source: The New England Journal of Medicine. 2003 May 8; 348(19): 1927-8; Author Reply 1927-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12736290

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Serum retinol levels and the risk of fracture. Author(s): Michaelsson K, Lithell H, Vessby B, Melhus H. Source: The New England Journal of Medicine. 2003 January 23; 348(4): 287-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12540641

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Serum retinol of Chadian nomadic pastoralist women in relation to their livestocks' milk retinol and beta-carotene content. Author(s): Zinsstag J, Schelling E, Daoud S, Schierle J, Hofmann P, Diguimbaye C, Daugla DM, Ndoutamia G, Knopf L, Vounatsou P, Tanner M. Source: Int J Vitam Nutr Res. 2002 July; 72(4): 221-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12214559

102

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Serum retinol, iron status and body composition of lactating women in Nandi, Kenya. Author(s): Ettyang GA, van Marken Lichtenbelt WD, Oloo A, Saris WH. Source: Annals of Nutrition & Metabolism. 2003; 47(6): 276-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14520023

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Short-term (intestinal) and long-term (postintestinal) conversion of beta-carotene to retinol in adults as assessed by a stable-isotope reference method. Author(s): Tang G, Qin J, Dolnikowski GG, Russell RM. Source: The American Journal of Clinical Nutrition. 2003 August; 78(2): 259-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12885706

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Significance of simultaneous determination of serum and seminal plasma alphatocopherol and retinol in infertile men by high-performance liquid chromatography. Author(s): Omu AE, Fatinikun T, Mannazhath N, Abraham S. Source: Andrologia. 1999 December; 31(6): 347-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10643509

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Simultaneous analysis of retinol, beta-carotene and tocopherol levels in serum of Vietnamese populations with different incomes. Author(s): Kieu NT, Yurie K, Hung NT, Yamamoto S, Chuyen NV. Source: Asia Pacific Journal of Clinical Nutrition. 2002; 11(2): 92-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12074187

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Simultaneous determination of tocotrienols, tocopherols, retinol, and major carotenoids in human plasma. Author(s): Lee BL, New AL, Ong CN. Source: Clinical Chemistry. 2003 December; 49(12): 2056-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14633878

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Stabilization of retinol through incorporation into liposomes. Author(s): Lee SC, Yuk HG, Lee DH, Lee KE, Hwang YI, Ludescher RD. Source: J Biochem Mol Biol. 2002 July 31; 35(4): 358-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12296993

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Substrate specificities and 13-cis-retinoic acid inhibition of human, mouse and bovine cis-retinol dehydrogenases. Author(s): Gamble MV, Mata NL, Tsin AT, Mertz JR, Blaner WS. Source: Biochimica Et Biophysica Acta. 2000 January 3; 1476(1): 3-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10606761

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The association between lung and prostate cancer risk, and serum micronutrients: results and lessons learned from beta-carotene and retinol efficacy trial. Author(s): Goodman GE, Schaffer S, Omenn GS, Chen C, King I. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 June; 12(6): 518-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12814997

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The mechanism of retinol-induced irritation and its application to anti-irritant development. Author(s): Kim BH, Lee YS, Kang KS. Source: Toxicology Letters. 2003 December 15; 146(1): 65-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14615068

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The molar ratio of retinol-binding protein to transthyretin in the assessment of vitamin A status in adults. Proposal of a cut-off point. Author(s): Zago LB, Dupraz H, Sarchi MI, Rio ME. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 December; 40(12): 1301-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12553434

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The molar ratio of serum retinol-binding protein (RBP) to transthyretin (TTR) is not useful to assess vitamin A status during infection in hospitalised children. Author(s): Donnen P, Dramaix M, Brasseur D, Bitwe R, Bisimwa G, Hennart P. Source: European Journal of Clinical Nutrition. 2001 December; 55(12): 1043-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11781669

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The relation of serum levels of antioxidant vitamins C and E, retinol and carotenoids with pulmonary function in the general population. Author(s): Schunemann HJ, Grant BJ, Freudenheim JL, Muti P, Browne RW, Drake JA, Klocke RA, Trevisan M. Source: American Journal of Respiratory and Critical Care Medicine. 2001 April; 163(5): 1246-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11316666

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The transfer of transthyretin and receptor-binding properties from the plasma retinolbinding protein to the epididymal retinoic acid-binding protein. Author(s): Sundaram M, van Aalten DM, Findlay JB, Sivaprasadarao A. Source: The Biochemical Journal. 2002 March 1; 362(Pt 2): 265-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11853533

104

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Three-dimensional structure of the transthyretin-retinol-binding protein complex. Author(s): Monaco HL. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 December; 40(12): 1229-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12553423

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Tolerance profile of retinol, retinaldehyde and retinoic acid under maximized and long-term clinical conditions. Author(s): Fluhr JW, Vienne MP, Lauze C, Dupuy P, Gehring W, Gloor M. Source: Dermatology (Basel, Switzerland). 1999; 199 Suppl 1: 57-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10473963

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Transcytosis of retinol-binding protein across renal proximal tubule cells after megalin (gp 330)-mediated endocytosis. Author(s): Marino M, Andrews D, Brown D, McCluskey RT. Source: Journal of the American Society of Nephrology : Jasn. 2001 April; 12(4): 637-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11274224

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Transthyretin, thyroxine, and retinol-binding protein in human cerebrospinal fluid: effect of lead exposure. Author(s): Zheng W, Lu YM, Lu GY, Zhao Q, Cheung O, Blaner WS. Source: Toxicological Sciences : an Official Journal of the Society of Toxicology. 2001 May; 61(1): 107-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11294981

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Ultraviolet irradiation depletes cellular retinol and alters the metabolism of retinoic acid in cultured human keratinocytes and melanocytes. Author(s): Andersson E, Rosdahl I, Torma H, Vahlquist A. Source: Melanoma Research. 1999 August; 9(4): 339-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10504051

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Urinary excretion of retinol in patients with multiple myeloma: a preliminary study. Author(s): Gavrilov V, Yermiahu T, Gorodischer R. Source: American Journal of Hematology. 2003 November; 74(3): 202-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14587052

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Urinary retinol binding protein in Indo-Asian patients with idiopathic interstitial nephritis. Author(s): Ball ST, Lapsley M, Norden AG, Cairns TD, Palmer AB, Taube DH. Source: Qjm : Monthly Journal of the Association of Physicians. 2003 May; 96(5): 363-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12702785

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Urinary retinol excretion in children with acute watery diarrhoea. Author(s): Mitra AK, Wahed MA, Chowdhury AK, Stephensen CB. Source: J Health Popul Nutr. 2002 March; 20(1): 12-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12022153

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Urinary retinol-binding protein (RBP) excretion and erythrocyte sodium-lithium countertransport (SLC) activity in a cohort of healthy normotensive subjects. Author(s): Hardman TC, Dubrey SW, Soni S, Clifford R, Chalkley S, Wierzbicki AS. Source: Journal of Human Hypertension. 1999 December; 13(12): 871-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10618681

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Urinary retinol-binding protein as a prognostic marker in glomerulopathies. Author(s): Kirsztajn GM, Nishida SK, Silva MS, Ajzen H, Moura LA, Pereira AB. Source: Nephron. 2002 April; 90(4): 424-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11961401

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Use of biomarkers of sub-clinical infection, nutrition and neonatal maturity to interpret plasma retinol in Nigerian neonates. Author(s): Adelekan DA, Northrop-Clewes CA, Owa JA, Oyedeji AO, Owoeye AA, Thurnham DI. Source: The British Journal of Nutrition. 2003 August; 90(2): 353-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12908896

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Use of serum retinol-binding protein for prediction of vitamin A deficiency: effects of HIV-1 infection, protein malnutrition, and the acute phase response. Author(s): Baeten JM, Richardson BA, Bankson DD, Wener MH, Kreiss JK, Lavreys L, Mandaliya K, Bwayo JJ, McClelland RS. Source: The American Journal of Clinical Nutrition. 2004 February; 79(2): 218-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14749226

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Use of the deuterated-retinol-dilution technique to assess total-body vitamin A stores of adult volunteers consuming different amounts of vitamin A. Author(s): Haskell MJ, Mazumder RN, Peerson JM, Jones AD, Wahed MA, Mahalanabis D, Brown KH. Source: The American Journal of Clinical Nutrition. 1999 November; 70(5): 874-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10539748

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Using denaturing HPLC for SNP discovery and genotyping, and establishing the linkage disequilibrium pattern for the all-trans-retinol dehydrogenase (RDH8) gene. Author(s): Han W, Yip SP, Wang J, Yap MK. Source: Journal of Human Genetics. 2004; 49(1): 16-23. Epub 2003 December 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14661078

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Vitamin A (retinol) status of first nation adults with non-insulin-dependent diabetes mellitus. Author(s): Basualdo CG, Wein EE, Basu TK. Source: Journal of the American College of Nutrition. 1997 February; 16(1): 39-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9013432

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Vitamin A and cancer prevention II: comparison of the effects of retinol and betacarotene. Author(s): de Klerk NH, Musk AW, Ambrosini GL, Eccles JL, Hansen J, Olsen N, Watts VL, Lund HG, Pang SC, Beilby J, Hobbs MS. Source: International Journal of Cancer. Journal International Du Cancer. 1998 January 30; 75(3): 362-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9455794

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Vitamin A supplementation of women postpartum and of their infants at immunization alters breast milk retinol and infant vitamin A status. Author(s): Bahl R, Bhandari N, Wahed MA, Kumar GT, Bhan MK; WHO/CHD Immunization-Linked Vitamin A Group. Source: The Journal of Nutrition. 2002 November; 132(11): 3243-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12421835

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Vitamin A transport for embryonic development: characterization of retinol binding protein & prealbumin from avian egg-yolk. Author(s): Sreekrishna K, Cama HR. Source: Indian J Biochem Biophys. 1978 August; 15(4): 255-9. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=570171

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Vitamin A transport in plasma of the non-mammalian vertebrates: isolation and partial characterization of piscine retinol-binding protein. Author(s): Shidoji Y, Muto Y. Source: Journal of Lipid Research. 1977 November; 18(6): 679-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=562910

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Vitamin A, retinol binding protein and lipids in type 1 diabetes mellitus. Author(s): Baena RM, Campoy C, Bayes R, Blanca E, Fernandez JM, Molina-Font JA. Source: European Journal of Clinical Nutrition. 2002 January; 56(1): 44-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11840179

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Vitamin A-sensitive tissues in transgenic mice expressing high levels of human cellular retinol-binding protein type I are not altered phenotypically. Author(s): Troen G, Eskild W, Fromm SH, De Luca LM, Ong DE, Wardlaw SA, Reppe S, Blomhoff R. Source: The Journal of Nutrition. 1999 September; 129(9): 1621-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10460195

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Vitamin D analogs affect the uptake and metabolism of retinol by human epidermal keratinocytes in culture. Author(s): Torma H, Rollman O, Binderup L, Michaelsson G. Source: The Journal of Investigative Dermatology. Symposium Proceedings / the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research. 1996 April; 1(1): 49-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9627692

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Vitamin-A reversal of abnormal dark adaptation in cirrhosis. Study of effects on the plasma retinol transport system. Author(s): Russell RM, Morrison SA, Smith FR, Oaks EV, Carney EA. Source: Annals of Internal Medicine. 1978 May; 88(5): 622-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=565608

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Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study. Author(s): Verhoeven DT, Assen N, Goldbohm RA, Dorant E, van 't Veer P, Sturmans F, Hermus RJ, van den Brandt PA. Source: British Journal of Cancer. 1997; 75(1): 149-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9000614

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Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations. Author(s): Myhre AM, Carlsen MH, Bohn SK, Wold HL, Laake P, Blomhoff R. Source: The American Journal of Clinical Nutrition. 2003 December; 78(6): 1152-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14668278

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Who has a high vitamin A intake from plant foods, but a low serum retinol concentration? Data from women in Indonesia. Author(s): de Pee S, Bloem MW, Tjiong R, Martini E, Satoto, Gorstein J, Shrimpton R, Muhilal. Source: European Journal of Clinical Nutrition. 1999 April; 53(4): 288-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10334655

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

Finding Nutrition Studies on Retinol 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 “retinol” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7

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

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The following is a typical result when searching for recently indexed consumer information on retinol: •

A 9-point guide to choosing the right supplement. Source: Tufts-University-diet-and-nutrition-letter (USA). (September 1993). volume 11(7) page 3-6.

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Avoiding breast cancer through food choices. Source: Tufts-University-diet-and-nutrition-letter (USA). (September 1993). volume 11(7) page 1.

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Blood pressure and nutrient intake in the United States. Source: McCarron, David A. Morris, Cynthia D. Henry, Holly H. Stanton, John L. Nutrition-today (USA). (Jul-August 1984). volume 19(4) page 14-17, 20-23.

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Cancer and your diet: the vital link. Source: MacGregor, R. Janeshutz, T. Weight-watchers (USA). (October 1985). volume 18(9) page 42, 44, 60.

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Changing nutrient requirements in older adults. Author(s): Tufts University, Boston, MA Source: Blumberg, J.B. Nutrition-today (USA). (October 1992). volume 27(5) page 15-20.

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Fat-soluble vitamins in human milk. Source: Lammi Keefe, Carol J. Jensen, Robert G. Nutrition-reviews (USA). (November 1984). volume 42(11) page 365-371.

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Micronutrient malnutrition: is it being eliminated? Author(s): Food and Nutrition Board, Institute of Medicine, Washington, DC. Source: Underwood, B.A. Nutrition-today (USA). (May-June 1998). volume 33(3) page 121-129.

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On behalf of the United Nations. Source: Nutrition-today (USA). (Sep-October 1985). volume 20(5) page 11-13.

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The state of the world's children 1998: a UNICEF report: malnutrition: causes, consequences, and solutions. Source: Nutrition-reviews (USA). (April 1998). volume 56(4,pt.1) page 115-123.

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Vitamin A and protective immunity. Author(s): Medical College of Pennsylvania, Philadelphia Source: Ross, A.C. Nutrition-today (USA). (August 1992). volume 27(4) page 18-26.

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Vitamin A toxicity. Source: Nutrition-and-the-M.D (USA). (May 1992). volume 18(5) page 4-5.

Additional consumer oriented references include: •

A case of human vitamin A deficiency caused by an inherited defect in retinolbinding protein without clinical symptoms except night blindness. Author(s): Department of Nutritional Sciences, University of California, Berkeley 947203104, USA. Source: Wolf, G Nutr-Revolume 1999 August; 57(8): 258-60 0029-6643

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A gene knockout corroborates the integral function of cellular retinol-binding protein in retinoid metabolism. Author(s): Department of Nutritional Sciences and Toxicology, University of California, Berkeley 94720-3104, USA.

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Source: Napoli, J L Nutr-Revolume 2000 August; 58(8): 230-6 0029-6643 •

A new metabolite of retinol: all-trans-4-oxo-retinol as a receptor activator and differentiation agent. Author(s): Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, MD 20892-4255, USA. Source: Ross, S A De Luca, L M Nutr-Revolume 1996 November; 54(11 Pt 1): 355-6 00296643

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A new morphogenic metabolite of retinol: 3,4-didehydroretinoic acid. Source: Anonymous Nutr-Revolume 1991 January; 49(1): 22-4 0029-6643

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A transporter specific for retinol in the brush border of rat small intestine. Author(s): University of California, Berkeley, CA. Source: Wolf, G. Nutrition-reviews (USA). (February 1995). volume 53(2) page 44-45. retinol digestive absorption binding proteins nutrients blood circulation rats 0029-6643

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Cellular retinol-binding protein functions in the regulation of retinoid metabolism. Author(s): Department of Nutritional Sciences, University of California, Berkeley 94720. Source: Wolf, G Nutr-Revolume 1992 July; 50(7): 197-9 0029-6643

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Effect of meal on retinol blood flow in IDDM patients. Source: Sullivan, P.M. Parfitt, V.J. Jagoe, R. Newsom, R. Kohner, E.M. Diabetes-Care. Alexandria, Va. : American Diabetes Association. August 1991. volume 14 (8) page 756758. 0149-5992

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Excess retinol intake may explain the high incidence of osteoporosis in northern Europe. Author(s): College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada. Source: Whiting, S J Lemke, B Nutr-Revolume 1999 June; 57(6): 192-5 0029-6643

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Function of an intestinal retinol-binding protein in the esterification of retinol. Source: Anonymous Nutr-Revolume 1987 July; 45(7): 221-3 0029-6643

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Hepatic retinol metabolism: role of the various cell types. Source: Blomhoff, R Nutr-Revolume 1987 September; 45(9): 257-63 0029-6643

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Low serum retinol is associated with increased severity of measles in New York City children. Author(s): Department of International Health, Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD 21205. Source: Caballero, B Rice, A Nutr-Revolume 1992 October; 50(10): 291-2 0029-6643

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Release of stored retinol from adipocytes. Author(s): Department of Nutritional Sciences, University of California, Berkeley 947203104, USA. Source: Wolf, G Nutr-Revolume 1998 January; 56(1 Pt 1): 29-30 0029-6643

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Retinoic acid biosynthesis from retinol. Source: Anonymous Nutr-Revolume 1988 January; 46(1): 30-1 0029-6643

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Retinoic acid homeostasis: retinoic acid regulates liver retinol esterification as well as its own catabolic oxidation in liver. Author(s): Department of Nutritional Sciences, University of California, Berkeley 94720, USA. Source: Wolf, G Nutr-Revolume 2001 December; 59(12): 391-4 0029-6643

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Retinol transport and metabolism in transthyretin-”knockout” mice. Author(s): Department of Nutritional Sciences, University of California, Berkeley 94720, USA. Source: Wolf, G Nutr-Revolume 1995 April; 53(4 Pt 1): 98-9 0029-6643

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The enzymes and kinetics of hepatic retinol metabolism. Source: Nutrition-reviews (USA). (September 1986). volume 44(9) page 311-314. rats retinol metabolism liver enzymes 0029-6643

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

Complimentary feeding - family foods for breastfed children. Source: Bulletin-of-the-Nutrition-Foundation-of-the-Philippines October 2000). volume 40(5) page 1-13. Issued February 2001.

(Philippines).

(Sep-

•

Effect of beta-carotene on health status and performance of sows and their litters. Source: Kostoglou, P. Kyriakis, S.C. Papasteriadis, A. Roumpies, N. Alexopoulos, C. Saoulidis, K. Journal-of-Animal-Physiology-and-Animal-Nutrition (Germany). (2000). volume 83(3) page 150-157.

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Impact on vitamins, nutrition and cancer in amphibian. Author(s): Alexandria Univ. (Egypt). Dept. of Zoology Source: Sadek, I.A. Pakistan-Journal-of-Biological-Sciences (Pakistan). (October 1999). volume 2(4) page 1655-1662.

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Versatile garlic. Source: Alvarez, R.C. Greenfields (Philippines). (April 2001). page 31-34. Received June 2001.

Additional physician-oriented references include: •

A prospective cohort study on intake of retinol, vitamins C and E, and carotenoids and prostate cancer risk (Netherlands). Author(s): Department of Epidemiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. Source: Schuurman, A G Goldbohm, R A Brants, H A van den Brandt, P A CancerCauses-Control. 2002 August; 13(6): 573-82 0957-5243

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A randomized, placebo-controlled trial of topical retinol in the treatment of cellulite. Author(s): Department of Dermatopathology, University Medical Center of Liege, Liege, Belgium. Source: Pierard Franchimont, C Pierard, G E Henry, F Vroome, V Cauwenbergh, G AmJ-Clin-Dermatol. 2000 Nov-December; 1(6): 369-74 1175-0561

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An isocratic liquid chromatographic method with diode-array detection for the simultaneous determination of alpha-tocopherol, retinol, and five carotenoids in human serum. Author(s): lnserm U525, Centre de Medecine Preventive, Vandoeuvre-les-Nancy, France. Source: Gueguen, Sonia Herbeth, Bernard Siest, Gerard Leroy, Pierre J-Chromatogr-Sci. 2002 February; 40(2): 69-76 0021-9665

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Carotenoids, alpha-tocopherols, and retinol in plasma and breast cancer risk in northern Sweden. Author(s): Department of Public Health and Clinical Medicine, Umea University, Sweden. [email protected] Source: Hulten, K Van Kappel, A L Winkvist, A Kaaks, R Hallmans, G Lenner, P Riboli, E Cancer-Causes-Control. 2001 August; 12(6): 529-37 0957-5243

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Changes in some innate defence parameters of seabream (Sparus aurata L.) induced by retinol acetate. Author(s): Department of Cell Biology, Faculty of Biology, University of Murcia, Spain. Source: Cuesta, A Ortuno, J Rodriguez, A Esteban, M A Meseguer, J Fish-ShellfishImmunol. 2002 October; 13(4): 279-91 1050-4648

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Determination of retinoic acid and retinol at physiological concentration by HPLC in Caucasians and Japanese women. Author(s): Department of Medicine, Monash Medical Centre, Monash University, Clayton Road, Clayton, Victoria 3168 (Australia) Source: Lo, C.S. Wahlqvist, M.L. Horie, Y. Asia-Pacific-Journal-of-Clinical-Nutrition (United Kingdom). (1996). volume 5(3) page 173-174.

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Effect of beta-lactoglobulin on plasma retinol and triglyceride concentrations, and fatty acid composition in calves. Author(s): Department of Animal Production, Tohoku National Agricultural Experimental Station, Morioka, Iwate, Japan. [email protected] Source: Kushibiki, S Hodate, K Kurisaki, J Shingu, H Ueda, Y Watanabe, A Shinoda, M JDairy-Res. 2001 November; 68(4): 579-86 0022-0299

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Effect of supplementation on haemoglobin and serum retinol levels and nutritional status of school children of northern India. Author(s): Department of Foods and Nutrition, CCS Haryana Agricultural University, Hisar-125004, India. Source: Jood, S Gupta, M Yadav, S K Khetarpaul, N Nutr-Health. 2001; 15(2): 97-111 0260-1060

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Elaboration and characterization of whey protein beads by an emulsification/cold gelation process: application for the protection of retinol. Author(s): STELA (Dairy Research Centre) and Groupe de recherche en nutrition humaine, Faculte des sciences de l'agriculture et de l'alimentation, Universite Laval, Quebec, Quebec, Canada G1K 7P4. Source: Beaulieu, Lucie Savoie, Laurent Paquin, Paul Subirade, Muriel Biomacromolecules. 2002 Mar-April; 3(2): 239-48 1525-7797

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Expression of cellular retinol- and retinoic acid-binding proteins in normal and pathologic human parathyroid glands. Author(s): Department of Medical Sciences, Uppsala University Hospital, S-751 85 Uppsala, Sweden. [email protected] Source: Melhus, H Li, Q Nordlinder, H Farnebo, L O Grimelius, L Endocr-Pathol. 2001 Winter; 12(4): 423-7 1046-3976

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Human choriocarcinoma cell line JEG-3 produces and secretes active retinoids from retinol. Author(s): INSERM U.384, Faculte de Medecine, BP 38, 63000 Clermont-Ferrand, France. Source: Blanchon, L Sauvant, P Bavik, C Gallot, D Charbonne, F Alexandre Gouabau, M C Lemery, D Jacquetin, B Dastugue, B Ward, S Sapin, V Mol-Hum-Reprod. 2002 May; 8(5): 485-93 1360-9947

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Immunolocalization of retinol-binding protein, cellular retinoic acid-binding protein I and retinoid X receptor beta in the porcine reproductive tract during the oestrous cycle. Author(s): Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrucke, Germany. [email protected] Source: Schweigert, F J Siegling, C Reprod-Fertil-Devolume 2001; 13(5-6): 421-6 10313613

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Inflammation-induced changes in the nutritional biomarkers serum retinol and carotenoids. Author(s): Institute of Nutritional Science, University of Potsdam, Germany. [email protected] Source: Schweigert, F J Curr-Opin-Clin-Nutr-Metab-Care. 2001 November; 4(6): 477-81 1363-1950

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Influence of high vitamin E dosages on retinol and carotinoid concentration in body tissues and eggs of laying hens. Author(s): Institute of Animal Nutrition of the Federal Agricultural Research Centre, Braunschweig (FAL), Germany. Source: Sunder, A Flachowsky, G Arch-Tierernahr. 2001; 55(1): 43-52 0003-942X

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Plasma retinol and alpha-tocopherol level and growth indices of 7 months old healthy Thai infants in Bangkok. Author(s): Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Source: Sirivichayakul, C Changbumrung, S Chanthavanich, P Moungnoi, P Chokejindachai, W Attanath, P Pengsaa, K Southeast-Asian-J-Trop-Med-Public-Health. 2001 June; 32(2): 408-12 0125-1562

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Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study. Author(s): Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, USA. Source: Promislow, J H Goodman Gruen, D Slymen, D J Barrett Connor, E J-Bone-MinerRes. 2002 August; 17(8): 1349-58 0884-0431

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Role of conserved residues in structure and stability: tryptophans of human serum retinol-binding protein, a model for the lipocalin superfamily. Author(s): Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, Florida 33101, USA. Source: Greene, L H Chrysina, E D Irons, L I Papageorgiou, A C Acharya, K R Brew, K Protein-Sci. 2001 November; 10(11): 2301-16 0961-8368

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Serum retinol levels and the risk of fracture. Author(s): Department of Surgical Sciences, Section of Orthopedics, University Hospital, Uppsala, Sweden. [email protected] Source: Michaelsson, K Lithell, H Vessby, B Melhus, H N-Engl-J-Med. 2003 January 23; 348(4): 287-94 1533-4406

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Simultaneous determination of serum retinol and various carotenoids: their distribution in middle-aged men and women. Source: Stacewicz Sapuntzakis, M. Bowen, P.E. Kikendall, J.W. Burgess, M. JMicronutrient-Anal. Barking, Essex : Elsevier Applied Science Publishers. 1987. volume 3 (1) page 27-45. ill., charts. 0266-349X

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The storage form of vitamin A in rat liver cells [Retinol]. Source: Olson, J.A. Gunning, D. J-Indian-Chem-Soc. Calcutta : The Society. July 1983. volume 60 (7) page 2184-2191. ill. 0019-4522

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Transfer of vitamin A from intestine to plasma in lambs fed low and high intakes of vitamin A [Retinol]. Source: Donoghue, S. Donawick, W.J. Kronfeld, D.S. J-Indian-Chem-Soc. Calcutta : The Society. July 1983. volume 60 (7) page 2197-2204. 0019-4522

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Urinary retinol excretion in children with acute watery diarrhoea. Author(s): University of Southern Mississippi, Center for Community Health, Hattiesburg 39406-5122, USA. [email protected] Source: Mitra, Amal K Wahed, Mohammad A Chowdhury, Ashish K Stephensen, Charles B J-Health-Popul-Nutr. 2002 March; 20(1): 12-7 1606-0997

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The following is a specific Web list relating to Retinol; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

Vitamins Multiple Vitamin-Mineral Supplements Source: Healthnotes, Inc.; www.healthnotes.com Provitamin A Source: Integrative Medicine Communications; www.drkoop.com Vitamin A Source: Healthnotes, Inc.; www.healthnotes.com Vitamin A Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin A Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10066,00.html

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Minerals Atorvastatin Source: Healthnotes, Inc.; www.healthnotes.com Fluvastatin Source: Healthnotes, Inc.; www.healthnotes.com Lovastatin Source: Healthnotes, Inc.; www.healthnotes.com Pravastatin Source: Healthnotes, Inc.; www.healthnotes.com Retinol Source: Integrative Medicine Communications; www.drkoop.com

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Simvastatin Source: Healthnotes, Inc.; www.healthnotes.com Vitamin A (Retinol) Source: Integrative Medicine Communications; www.drkoop.com Zinc Source: Prima Communications, Inc.www.personalhealthzone.com

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CHAPTER 3. CLINICAL TRIALS AND RETINOL Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning retinol.

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

Retinol Equivalence of Plant Carotenoids in Children Condition(s): Healthy; MedlinePlus consumer health information Study Status: This study is not yet open for patient recruitment. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); USDA; Tufts University Purpose - Excerpt: The experiments will be conducted in children (ages 6-8) with/without adequate vitamin A nutrition. As plant provitamin A carotenoids are a major and safe vitamin A source for a vast population in the world, it is essential to determine the efficiency of provitamin A carotenoid (mainly ß-C) conversion to vitamin A. By introducing ß-C into rice endosperm, Golden Rice may directly benefit consumers by providing vitamin A nutrition. Our investigation uses hydroponically grown, decadeuterium labeled spinach and Golden Rice, synthetic ß-C-d10 and a vitamin A isotope reference, decadeuterated retinyl acetate (RAc-d10), to evaluate the bioavailability and the bioconversion of plant provitamin A carotenes to retinol as compared with ß-C in oil capsules in vivo. Our objectives will be to test the following hypotheses and to make the following determinations: (1) The absorption and bioconversion of provitamin A carotenes taken by children are different between spinach, Golden Rice, and ß-C in oil capsules. (2) The absorption of provitamin A carotenes and their bioconversion to vitamin A are different in children with or without adequate vitamin A nutrition. (3) To define the vitamin A equivalence(s) of dietary spinach, Golden Rice, and a ß-C in oil dose by using an isotope reference method in children with

8

These are listed at www.ClinicalTrials.gov.

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or without adequate vitamin A nutrition and to compare those values with values derived from model based compartmental analysis. (4) To determine the number and time of blood samples needed for future studies in various field settings on the retinol equivalence of a large number of plant sources. This study will be of importance in planning vitamin A deficiency prevention strategies and also will provide useful information regarding the potential efficacy of a bioengineered crop to provide vitamin A nutrition. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00072696

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 “retinol” (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 4. PATENTS ON RETINOL 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 “retinol” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on retinol, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Retinol By performing a patent search focusing on retinol, 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 retinol: •

A and D vitamins and their metabolites: A new treatment for seasonal allergic rhinitis and atopy Inventor(s): Buttz; Angelina Pinal (7736 Iroquois Dr., El Paso, TX 79912) Assignee(s): None Reported Patent Number: 6,187,764 Date filed: February 1, 1999 Abstract: The present invention discloses a method of treating seasonal allergic rhinitis by administering retinol and ergocalciferol to individuals suffering from a hypersensitive immunological response to an allergen. Permanent, long-term relief and prevention of the recurring symptoms of seasonal allergic rhinitis is provided by the dosages and treatment regimens described herein. Excerpt(s): The present invention relates generally to the field of immunology. More specifically, the present invention relates to seasonal allergic rhinitis and the use of vitamins A and D for treatment of seasonal allergic rhinitis. Seasonal allergic rhinitis (SAR), commonly called hay fever, is a disease which was first described in ninth century Islamic and sixteenth century European texts. In Europe, the first case of hay fever was reported in 1595 (Emanuel, 1988). The actual cause of the symptoms in individual predisposed to hay fever was not suspected until 1833. That pollen plant was the sole cause of hay fever was proven experimentally in England in 1877. At about the same time, the pollen of Ambrosia artemisiaefolia, or common ragweed, was found to be the most active pollen which produced hay fever in America. Seasonal allergic rhinitis has now reached epidemic proportions. At the end of the nineteenth century in the United States alone, fifty thousand in a population of fifty million inhabitants suffer from seasonal allergic rhinitis. It is now the most common immunologic disorder in humans. Nearly one fifth of the inhabitants of the temperate zone are afflicted. Seasonal allergic rhinitis affects ten percent of children and twenty percent of adolescents and adults. The usual age of onset is between five and ten years and peaks between ten and twenty with males more often affected than females (Emanuel, M. B. Clinical Allergy, 18:295-304, 1988). In 1975, the United States National Health Survey reported twentyeight million restricted days and two million lost school days per year attributable to allergic rhinitis. Medical costs per year exceeded one billion dollars. With an increasing population and the rising costs of health care, it has become imperative to find an alternative approach for the treatment and prevention of seasonal allergic rhinitis. Web site: http://www.delphion.com/details?pn=US06187764__

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Anhydrous stable retinol based cosmetic or pharmaceutical composition Inventor(s): Laugier; Jean-Pierre (Antony, FR), Segot; Evelyne (Nogent sur Morne, FR) Assignee(s): L'oreal (paris, Fr) Patent Number: 6,015,568 Date filed: April 4, 1996 Abstract: Anhydrous, stable retinol-based cosmetic or pharmaceutical composition for the skin. This composition contains solubilized retinol in an organic solution which is

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liquid at ambient temperature and which is chosen from the group comprising:i) aliphatic fatty alcohols having a branched chain at C.sub.16 -C.sub.20,ii) saturated alcoxylated fatty alcohols having a straight or branched chain at C.sub.16 -C.sub.20,iii) the diesters of dicarboxylic esters at C.sub.6 -C.sub.14 and of isopropyl alcohol, and mixtures of these solvents.This composition is intended for the treatment of skin disorders, and of acne in particular. Excerpt(s): The present invention relates to an anhydrous, stable retinol- or vitamin Abased cosmetic or pharmaceutical composition for the skin and to the use thereof for the treatment of skin disorders, in particular for the treatment of acne, keratinization or scarring problems, light-related aging, and the prevention and softening of wrinkles. Retinol has previously been recommended in the treatment of these disorders: for example, in European Patent Application No. 224,504, which describes a stable composition containing retinol, a volatile silicone, and a solvent of the retinol and volatile silicone. The solvent used is preferably ethanol. However, studies of this type of composition revealed that retinol decomposed in the presence of ethanol. Web site: http://www.delphion.com/details?pn=US06015568__ •

Anti-inflammatory dental care agents Inventor(s): Jassoy; Claudia (Duesseldorf, DE), Leinen; Hans-Theo (Duesseldorf, DE), Wuelknitz; Peter (Leichlingen, DE) Assignee(s): Henkel Kommanditgesellschaft Auf Aktien (duesseldorf, De) Patent Number: 6,491,899 Date filed: April 6, 2001 Abstract: The present invention relates to a dental care composition containing (a) at least one panthenol compound, (b) at least one retinol compound, and (c) at least one antibacterial compound. The composition is particularly useful for reducing inflammation of the gums. Excerpt(s): This invention relates to dental care and cleaning preparations which counteract inflammation of the gums (gingivitis) through a special combination of active ingredients. Dental care preparations are primarily intended to remove food residues, discoloration and firmly adhering bacterial films from the surface of the teeth. In addition, attempts have been made to counteract diseases of the teeth and gums such as, for example, caries, gingivitis and parodontosis by incorporating special additives, for example fluorine compounds or antimicrobial agents, in dental care preparations. A particularly stubborn disease which, unless successfully treated, can lead to the loosening and loss of teeth is periodontitis which, in its initial stages, is manifested in inflammation and bleeding of the gums (gingivitis). It is caused by bacteria which colonise the dental pockets and which are difficult to control by mechanical cleaning of the teeth with a toothbrush. Web site: http://www.delphion.com/details?pn=US06491899__

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Assessing lipid metabolism Inventor(s): Barendse; William John (37 Ghost Gum Street, Bellowrie, QLD 4070, AU) Assignee(s): None Reported Patent Number: 6,383,751 Date filed: July 18, 2000 Abstract: This invention relates to methods and nucleic acid probes for assessing characteristics of lipid metabolism in animals, and in particular to methods of predicting fat levels in meat, milk, or other fat depots of animals. Thus the invention provides a method of assessing the fat metabolism characteristics of an animal, comprising the step of testing the animal for the presence or absence of one or more markers selected from the group consisting of: a) an allele of the 5' untranslated region of thyroglobulin; b) an allele of the DNA polymorphism CSSM34, associated with the gene encoding retinoic acid receptor gamma (RARG); and c) an allele of the DNA polymorphism ETH10, associated with 11-cis, 9-cis retinol dehydrogenase (RDH5). The invention is particularly applicable to predicting disposition of fat in muscle tissue, which produces the characteristic "marbling" of meat, and to assessment of milk fat content. The methods of the invention are useful in selection of animals, particularly cattle, for ability to produce high or low levels of milk fat content. Excerpt(s): This application claims priority to International Patent Application PCT/AU98/00882 filed Oct. 23, 1998, and Australian Patent Application No. PP0120 filed Oct. 30, 1997. This invention relates to methods and nucleic acid probes for assessing characteristics of lipid metabolism in animals, and in particular to methods of predicting fat levels in meat, milk, or other fat depots of animals. The invention is particularly applicable to predicting deposition of fat in muscular tissue, which produces the characteristic "marbling" of meat, and to assessment of milk fat content. The methods of the invention are useful in selection of animals, particularly cattle, for ability to produce or high levels of marbling in meat, and to produce high or low levels of milk fat content. The manner in which animals metabolise fat is of considerable economic significance in agriculture and animal husbandry. In some markets the high content of fat in meat, in the form of small fat deposits or "marbling", is regarded as highly desirable, and to induce heavy marbling of meat in cattle in particular the animals are grain fed for at least a short period prior to marketing and slaughter. In other markets a very lean meat is preferred. Similarly, a high fat content of milk is usually regarded as desirable. This can be particularly important if the milk is to be used for cheese production, and so these factors are important not only in cattle but also in sheep and goats. Recently generation of transgenic animals which secrete valuable proteins into their milk has been achieved, and in order to reduce the costs of purification of the desired protein a low content of fat in the milk is desirable. Web site: http://www.delphion.com/details?pn=US06383751__

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Combination of a retinoid with a polyamine polymer Inventor(s): Boussouira; Boudiaf (Paris, FR), Giacomoni; Paolo (Orsay, FR), Nguyen; Quang Lan (Antony, FR), Prince; Stephanie (Paris, FR) Assignee(s): L'oreal (paris, Fr) Patent Number: 6,162,448 Date filed: May 28, 1998

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Abstract: A composition comprising the combination of at least one retinoid selected from the group consisting of vitamin A (retinol) and the bioconvertible precursors of vitamin A and at least one polyamine polymer. Excerpt(s): The present invention relates to cosmetic and/or dermatological compositions, in particular compositions for use in skin care which comprise at least one compound of the retinoid family. More particularly, the present invention relates to stable compositions comprising at least one compound of the retinoid family and at least one polyamine polymer. Retinoid-based cosmetic and/or dermatological compositions have undergone a major development during the past few years. Among the retinoids, the use of retinoic acid in compositions for the treatment of acne is well-known. However, other derivatives of the retinoid family are also useful, both for the treatment of acne, as well as for skin care. These derivatives in particular are useful in limiting, even eliminating, the effects of skin ageing which include wrinkles, wizened appearance, yellowing, loss of elasticity, roughness, dryness, and the appearance of marks which are the usual manifestations of skin ageing. These manifestations are all the more pronounced the more frequently the skin has been exposed to sunlight or the more the skin is particularly sensitive to exposure to UV radiation. Web site: http://www.delphion.com/details?pn=US06162448__ •

Complexes of gamma-cyclodextrin and retinol or retinol derivatives, processes for their preparation and their use Inventor(s): Moldenhauer; Jens-Peter (Burghausen, DE), Regiert; Marlies (Munich, DE), Wimmer; Thomas (Marktl, DE) Assignee(s): Wacker-chemie Gmbh (muchen, De) Patent Number: 5,985,296 Date filed: March 20, 1998 Abstract: Complexes of.gamma.-cyclodextrin and retinol or retinol derivatives, along with processes for their preparation and compositions for their use. The complexes are useful in cosmetic formulations and in pharmaceutical formulations. Excerpt(s): The present invention relates to complexes of.gamma.-cyclodextrin and retinol or retinol derivatives, to processes for their preparation and to their use. Cyclodextrins are cyclic oligosaccharides which are composed of 6, 7 or 8.alpha.(1-4)linked anhydroglucose units. The.alpha.-,.beta.- or.gamma.-cyclodextrins prepared by the enzymatic conversion of starch differ in the diameter of their hydrophobic cavity and are generally suitable for inclusion of numerous lipophilic substances. Retinol (vitamin A) is a fat-soluble vitamin composed of a cyclohexene ring with a side chain containing conjugated polyunsaturation. It is essential for humans inter alia and plays an important role particularly for vision. The daily requirement is met almost exclusively by the intake of.beta.-carotene (provitamin A), which is converted into retinol enzymatically. Web site: http://www.delphion.com/details?pn=US05985296__

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Compositions and methods of treating abnormal cell proliferation Inventor(s): Achkar; Charles C. (North Bergen, NJ) Assignee(s): Gentrix Llc (north Bergen, Nj) Patent Number: 6,242,435 Date filed: July 12, 1999 Abstract: A composition is described comprising a vitamin D analog and a retinoid wherein: (a) the vitamin D analog is capable of binding a vitamin D receptor or being converted in vivo into a compound capable of binding a vitamin D receptor; and (b) the retinoid is selected from the group consisting of retinol in a concentration of at least about 1.0% and a retinoid characterized by having a substitution at the 4-position. Further, methods of treating disorders characterized by abnormal cell-proliferation and/or cell-differentiation are also described. Excerpt(s): The present invention relates to compositions comprising certain retinoids and vitamin D analogs useful in inducing differentiation and inhibiting undesirable proliferation of cells, such as cancer cells and skin cells. The present invention also relates to methods of using the above compositions in the treatment of diseases and conditions characterized by abnormal cell differentiation and/or cell proliferation. Abnormal cell differentiation and/or cell differentiation is associated with many conditions and diseases. For instance, hyperproliferation of epithelial cells is associated with psoriasis causes the skin to shed itself too rapidly, every three to four days. The goal in treating psoriasis is to reduce inflammation and to slow down rapid skin cell division. U.S. Pat. No. 4,866,048 discloses that certain vitamin D derivatives, in particular calcitriol (1 alpha,25-dihydroxy-vitamin D.sub.3 or) and calcipotriol are able to stimulate the differentiation of cells and inhibit excessive cell proliferation, and it has been suggested that these compounds are useful in the treatment of diseases characterized by abnormal cell differentiation and/or cell differentiation such as leukemia, myelofibrosis, psoriasis and acne. Web site: http://www.delphion.com/details?pn=US06242435__

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Cosmetic composition for skin care containing retinol and epidermal growth factor Inventor(s): Jo; Byoung Kee (Anyang-si, KR) Assignee(s): Coreana Cosmetics Co., Ltd. (kr) Patent Number: 6,589,540 Date filed: November 17, 2000 Abstract: A cosmetic composition for skin care containing retinol and epidermal growth factor is disclosed. In embodiments of the cosmetic composition, the epidermal growth factor is preferably present in an amount of 0.00001 to 1% by weight, and more preferably 0.0001 to 0.1% by weight, based on the total weight of the composition. The EGF-containing cosmetic composition of the present invention enhances the skin care effect of retinol and also alleviates adverse effects of retinol, such as skin irritation. Excerpt(s): Skin, which is the biggest organ of the human body, is composed of epidermis, dermis and subcutaneous fat. It performs various functions such as protection, barrier, temperature controlling, excretion and respiration. With the passage of time, however, those functions rapidly decline and a variety of changes occur to the skin. Physiological changes of the skin with aging, for example, include the decrease in

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thickness of epidermis, dermis and subcutaneous tissue; the dryness of skin resulting from the moisture reduction according to the changes of lipid composition and content in lipid barrier; and the occurrence of age spots, freckles, pigmentation or various skin lesions. Especially, the active oxygen species and free radicals, which can be generated by excess UV rays, air pollution, or fatigue or stress in modern life, oxidize or denature the bio-materials such as proteins, nucleic acids and membrane lipids, leading to the aging of the skin. Accordingly, there have been many studies on the occurrence of the wrinkles, age spots or freckles, the loss of skin elasticity, the pigmentation, and the dryness of skin. A variety of cosmetic compositions have been developed in order to solve the problems with aging of the skin and some visible results have been obtained in improving skin wrinkles. Various clinical studies have been reported on the effects of cosmetic compositions containing retinoids in improving wrinkles, freckles and deposited pigments, especially of the compositions containing retinol (vitamin A) in improving wrinkles, sagging and the reduction in elasticity of skin formed by sunlight. Japanese Patent Laid-open Publication No. Hei 5-246838 discloses a method for improving wrinkles of skin by the synthesis of collagen. It teaches that the activity of collagenase that decomposes collagen to promote collagen metabolism might be reduced with aging, leading to the increase of cross-link collagens and the increase of skin wrinkles. U.S. Pat. Nos. 4,603,146 and 4,877,805 also disclose methods for improving skin wrinkles by using retinol that is effective in the synthesis of collagen and the inhibition from the decomposition thereof. Retinol, an endogenous compound naturally present in the human body, is a lipo-soluble vitamin indispensable to the differentiation and growth of epithelial tissues. It is also believed to have an effect on the stimulation of physical growth and on the treatment of night blindness. In addition, when used in a cosmetic composition, retinol is believed to have an effect in enhancing the metabolism of skin cells, the differentiation and the resistance of the skin, and in inhibiting sebum secretion. Accordingly, there has been much interest in cosmetic compositions for skin care containing retinol. For example, various acne ointments containing retinol have been commercially available. Moreover, much effort has been invested in developing other uses of retinol, resulting in the application of retinol in treatment of UV damaged skin. Web site: http://www.delphion.com/details?pn=US06589540__ •

Cosmetic composition with a retinol fatty acid ester Inventor(s): Corey; Joseph (Waterbury, CT), Dorogi; Peter Ladislav (Norwalk, CT), Meyers; Alan Joel (Trumbull, CT), Vargas; Anthony (Monroe, CT) Assignee(s): Elizabeth Arden Co., Division of Conopco, Inc. (new York, Ny) Patent Number: 5,885,595 Date filed: April 7, 1997 Abstract: A method and composition is provided for enhancing skin radiance and treating chronoaging conditions including wrinkles and dermatological disorders including acne, follicular and lesional papules, actinic keratoses, oily skin and rosacea comprising: (i) a safe and effective amount of an unsaturated C.sub.18 -C.sub.30 fatty acid ester of retinol; and (ii) a safe and effective amount of a cosmetically acceptable carrier, the composition being stable for at least four weeks at 43.degree. C. An unsaturated C.sub.18 -C.sub.30 fatty acid ester of retinol is the active component which is applied to the skin in a cosmetically acceptable carrier. The most preferred

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unsaturated retinol fatty acid ester is retinyl linoleate. The composition is stable and remains active for at least four weeks at 43.degree. C. Excerpt(s): This application claims the benefits of U.S. Provisional Applications Nos. 60/017,559 filed May 13, 1996, and 60/025,803 filed Aug. 28, 1996. The present invention concerns a cosmetic composition containing specific long chain unsaturated retinol fatty acid esters useful for skin care treatment for chronoaging conditions and dermatologic disorders to provide skin radiance without substantial irritation. Skin is subject to deterioration through dermatologic disorders and normal aging (chronoaging) as well as extrinsic factors (environmental). Dermatologic disorders, other than chronoaging include acne, follicular and lesional papules, actinic keratoses, oily skin and rosacea. Web site: http://www.delphion.com/details?pn=US05885595__ •

Creating novel hematopoietic cell lines by expressing altered retinoic acid receptors Inventor(s): Collins; Steven J. (Seattle, WA), Tsai; Schickwann (Redmond, WA) Assignee(s): Fred Hutchinson Cancer Research Center (seattle, Wa) Patent Number: 5,830,760 Date filed: January 26, 1996 Abstract: Methods for establishing continuous SCF dependent lympho-hematopoietic progenitor cell lines capable of differentiating into erythroid, myeloid, and B lymphocytic lineages, and GM-CSF dependent neutrophil progenitor cell lines capable of differentiating into neutrophils but not into monocytes, mast cells, or basophils, by introducing into bone marrow, fetal spleen, fetal liver, or other hematopoietic myeloid cells nucleic acid encoding a dominant negative suppressor of a retinoic acid receptoralpha and a selectable marker, and culturing the recombinant cells in culture medium containing SCF or GM-CSF, agents allowing for selective growth of the recombinant cells, and a level of retinoic acid of less than about 10.sup.-8 M to about 10.sup.-9 M in the case of establishing neutrophilic progenitor cell lines. Addition of a retinol compound induces the latter cell line to differentiate into neutrophils. Excerpt(s): This invention relates to genetic engineering and particularly to hematopoietic cell lines bearing altered retinoic acid receptors. Abbreviations used herein include: APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; BFUE, burst-forming unit-erythroid; CAT, chloramphenicol acetyltransferase; CFU-E, colony-forming unit-erythroid; CFU-GM, colony-forming unitgranulocyte/macrophage; Epo, erythropoietin; GM-CSF, granulocyte-macrophage colony stimulating factor; IL-3, interleukin-3; IL-6, interleukin-6; IL-7, interleukin-7; IL11, interleukin-11; HS, horse serum; IgE R, immunoglobulin E receptor; RA, retinoic acid; RAR.alpha., retinoic acid receptor-.alpha.; RARs, retinoic acid receptors; RXR, retinoid X receptor; SCF, stem cell factor. Retinoic acid (RA), the natural acidic derivative of vitamin A (retinol), is a critical molecule regulating growth and differentiation of a wide variety of cells. RA is thought to be centrally involved in epithelial differentiation (37; see the appended citations), plays a critical role as a tissuespecific morphogen during embryogenesis (50) and as a suppressor of malignant transformation of epithelial cells both in vitro (39) and in vivo (29). These diverse and complex biologic effects of RA are mediated through a number of closely related nuclear RA receptors (RARs) that are members of the steroid/thyroid hormone receptor superfamily and possess discrete DNA-binding and RA (ligand) binding domains (22). Web site: http://www.delphion.com/details?pn=US05830760__

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DocosahexAenoic acid as retinoid X-receptor ligand and uses thereof Inventor(s): de Urquiza; Alexander Mata (Stockholm, SE), Griffiths; William (Stockholm, SE), Perlmann; Thomas (Stockholm, SE), Sjoberg; Maria (Stockholm, SE), Sjovall; Jan (Stockholm, SE), Suya; Liu (Stockholm, SE), Zetterstrom; Rolf (Stockholm, SE) Assignee(s): Ludwig Institute for Cancer Research (new York, Ny) Patent Number: 6,355,446 Date filed: March 24, 2000 Abstract: This invention involves the identification of a ligand for the retinol X receptor. Specifically docosahexaenoic has been identified as an RXR ligand. Various assays based upon this observation are a feature of this invention. Excerpt(s): This invention relates to the retinoid X receptor, referred to hereafter as "RXR." More particularly, it relates to the identification of its ligands, and the ramifications of this identification. The nuclear receptor (NR) superfamily comprises more than 150 different proteins, most of which are believed to function as ligand activated transcription factors, exerting widely different biological responses by regulating gene expression (for review, see Di Croce et al, EMBO J1 8:6201-6210 (1999); Mangelsdorf, et al Cell 83:825-839 (1995); Perlmann, et al, Cell 90:391-397 (1997)). Members of this family include receptors for endogenous small, lipophilic molecules, such as steroid hormones, retinoids, vitamin D and thyroid hormone. In addition, many members of this family lack known ligands and are therefore referred to as "orphan receptors" (for review, see Gigere, et al, Endocrine Rev 20:689-725 (1999); Kastner, et al, Cell 83:859-869 (1995)). During recent years small, lipophilic ligands and activators have been identified for several orphan receptors, leading to new insights of profound impact. These findings have dramatically increased understanding of endocrinology and disease (Forman, et al Cell 81:687-693 (1997); Xu, et al, Mol. Cell 3:397-403 (1999); Makashima et al., Science 284:1362-1365 (1999); Parks et al., Science 284:1365-1368 (1999); Wang et al., Mol Cell 3:543-553 (1999); Janowski et al., Nature 383:728-731 (1996); Kliewer et al., Cell 92:73-82 (1998); Blumberg et al., Genes Dev. 12:31953205 (1998)); however, ligands and biological functions of most orphan receptors remain to be elucidated, emphasizing the importance of unraveling previously uncharacterized signaling pathways by identifying novel endogenous ligands for NRs (for review, see Mangelsdorf et al, Cell 83:841-850 (1995); Giguere, et al, supra. Web site: http://www.delphion.com/details?pn=US06355446__

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Dual composition cosmetic product with a concentration sensitive and an incompatible active respectively placed within first and second compositions Inventor(s): Chandar; Prem (Closter, NJ), Hague; Jonathan David (Jakarta, ID), Scott; Ian Richard (Allendale, NJ), Sulistyowati; Endah (Jakarta, ID), Suryo; Dwiwahyu Haryo (Jakarta, ID), Weinkauf; Ronni Lynn (River Edge, NJ) Assignee(s): Unilever Home & Personal Care Usa, Division of Conopco, Inc. (greenwich, Ct) Patent Number: 6,585,984 Date filed: November 16, 2000 Abstract: A cosmetic product is provided packaged in a dispenser with separate first and second storage areas. The first of the areas contains a first cosmetic composition

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containing a first dermal active agent, preferably selected from keratolytic skin agents. Particularly preferred are alpha- and beta-hydroxy carboxylic acids as first dermal active placed in a composition having a pH from about 1 to about 5.5. The second area contains a second cosmetic composition with a second dermal agent incompatible with the first composition. Particularly preferred second dermal agents are retinoids, vitamins, enzymes and anti-oxidants. Most preferred is retinol. The dispenser allows transfer of the first and second compositions through an exit nozzle in a respective dispensing weight ratio of from about 30:1 to about 2:1. Excerpt(s): The invention concerns a cosmetic product with dual compositions, preferably stored in separate compartments, each composition containing a skin active with at least one of the actives being incompatible in a composition containing the other. A soft, supple and flexible skin has a marked cosmetic appeal. As human skin ages with advancing years, the epidermis can become folded, ridged or furrowed to form wrinkles. These signal loss of youthful appearance and herald the transition to old age. Exposure to excessive doses of sunlight accelerates the transition process. Moreover, the outer layer of the epidermis known as the stratum corneum can become dry and flaky following exposure to cold weather or excessive contact with detergents or solvents. Science has discovered a few active substances which can counter the aging process. Among these are the retinoids and the alpha-hydroxy carboxylic acids. Unfortunately these active substances can be incompatible under certain conditions. Retinol rapidly degrades in a acidic environment that may be most conducive to the alpha-hydroxys. Combinations of these actives have been reported in U.S. Pat. No. 5,935,589 (Mukhedjee et al.) which places the actives in separate emulsions within a single composition. Retinol is stabilized at a neutral pH in an oil-in-water emulsion. An alpha-hydroxy carboxylic acid such as glycolic acid is dispersed within a water-in-oil emulsion. Both of these emulsions are then carefully combined to form a single cosmetic composition. A problem for such compositions is that over time there will be leakage between the separate emulsions resulting in retinol degradation. Web site: http://www.delphion.com/details?pn=US06585984__ •

External skin treatment composition Inventor(s): Sakamoto; Okihiko (Yokohama, JP), Yanagida; Takeshi (Yokohama, JP) Assignee(s): Shiseido Company, Ltd. (tokyo, Jp) Patent Number: 6,024,941 Date filed: April 27, 1995 Abstract: An external skin treatment composition containing (I) vitamin A (retinol) and (II) as a stabilizer, a chelating agent/a polysaccharide, an oil, polyethylene (propylene) glycol, a hydroxy carboxylate, a neutral amino acid salt, an oil-soluble antioxidant/EDTA/a benzophenone compound, an oil-soluble antioxidant/an acid/a benzophenone compound, an inclusion compound of cyclodextrin including an antioxidant and/or an ultraviolet absorber, butanediol and/or an oil-soluble antioxidant, a water-soluble benzophenone compound, a basic amino acid and the salt thereof, an acidic amino acid and the salt thereof, a polar oil, a water-swellable clay mineral. Excerpt(s): The present invention relates to an external skin treatment composition in which the stability of vitamin A is extremely improved. It has been well known that vitamin A is effective for prevention or treatment of keratodermatitis and, prevention of

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and recovery from dermal aging. Vitamin A, however, is structurally very unstable and can readily cause isomerization, decomposition, polymerization, etc., with light, air, heat, metal ion, etc. Thus, it has been difficult to stably formulate vitamin A into an external skin treatment composition. Web site: http://www.delphion.com/details?pn=US06024941__ •

Genes and genetic markers for improved reproductive traits in animals Inventor(s): Messer; Lori A. (Lincoln, NE), Rothschild; Max F. (Ames, IA), Tuggle; Christopher K. (Ames, IA), Yu; Tun-Ping (Ames, IA) Assignee(s): Iowa State University Research Foundation, Inc. (ames, Ia) Patent Number: 5,939,264 Date filed: July 18, 1997 Abstract: Disclosed herein are genetic markers for favorable reproductive traits in animals such as litter size, and weaning weight. Methods for identifying such markers, and methods of screening animals to determine those more likely to produce favorable reproductive traits and preferably selecting those animals for future breeding purposes. The markers are based upon the presence or absence of certain polymorphisms in the pig reproductive genes, including retinol binding protein 4, retinoic acid receptor gamma, melatonin receptor 1a, and vascular cell adhesion molecule 1 Excerpt(s): This invention relates generally to the detection of genetic differences for reproductive efficiency among animals. More particularly the invention relates to genetic markers which have been identified in several genes indicative of heritable phenotypes associated with improved reproductive traits. Methods and compositions for use of these markers in genotyping of animals and selection are also disclosed. Reproductive efficiency, particularly as it relates to litter size, is the major limiting factor in the efficient production of pork as well as most other livestock animals. Genetic variability exists for several reproductive measures. Average litter size among breeds pigs varies from 4-16 pigs per litter. Mean age at puberty varies from 3 to 7 months of age. This genetic variability within breeds suggests that genetic improvement in reproduction is possible. The number of pigs born alive in the United States averages approximately 9.5 pigs per litter. Heritability for litter size is low (10%-15%), and standard genetic methods of selecting breeding females on the basis of past litter size have not been effective. Therefore, there is a need for an approach that deals with selection for reproductive traits at the cellular or DNA level. Chinese breeds are known for reaching puberty at an early age and for their large litter size. American breeds are known for their greater growth rates and leanness. Thus, it would be desirable to combine the best characteristics of both types of breeds, thereby improving the efficiency of U.S. pork production. These efforts would be greatly assisted by the discovery of genes or genetic markers that are associated with improved reproductive traits such as increased litter size in pigs. Web site: http://www.delphion.com/details?pn=US05939264__

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Human retinol dehydrogenase type II homolog Inventor(s): Bandman; Olga (Mountain View, CA), Corley; Neil C. (Mountain View, CA), Lal; Preeti (Santa Clara, CA) Assignee(s): Incyte Pharmaceuticals, Inc. (palo Alto, Ca) Patent Number: 5,858,750 Date filed: November 25, 1997 Abstract: The invention provides a human retinol dehydrogenase type II homolog (HRoDH) and polynucleotides which identify and encode HRoDH. The invention also provides expression vectors, host cells, agonists, antibodies and antagonists. The invention also provides methods for treating disorders associated with expression of HRoDH. Excerpt(s): This invention relates to nucleic acid and amino acid sequences of a human retinol dehydrogenase type II homolog and to the use of these sequences in the diagnosis, prevention, and treatment of disorders associated with immune response, cell proliferation, and development. Vitamin A is a pigment essential to vision. Vitamin A comes from the enzymatic conversion of carotenoids, yellow pigments common to carrots and other vegetables, to retinol. Deficiency of vitamin A and insufficient retinol production leads to a variety of maladies in humans and experimental animals. Symptoms of deficiency include vision related disorders such as xerophthalmia and night blindness; dry skin and dry mucous membranes; retarded development and growth; and sterility in male animals. Cleavage of.beta.-carotene yields two molecules of retinol; oxidation of retinol forms retinal. Retinal and opsin combine to produce rhodopsin, a visual pigment found in nature. The excitation of rhodopsin with visible light triggers a series of photochemical reactions and conformational changes in the molecule which result in the electrical signal to the brain that are the basis of visual transduction (Lehninger et al. (1993)Principles of Biochemistry, Worth Publishers, New York, N.Y.). Web site: http://www.delphion.com/details?pn=US05858750__

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Isolated proteins having retinol dehydrogenase activity, and which associate with retinol binding receptors Inventor(s): Eriksson; Ulf (Stockholm, SE), Romert; Anna (Stockholm, SE), Simon; Andras (Stockholm, SE) Assignee(s): Ludwig Institute for Cancer Research (new York, Ny) Patent Number: 6,399,344 Date filed: September 26, 1997 Abstract: Isolated membrane associated proteins which have a molecular weight of from about 30 kD to about 36 kilodaltons as determined by SDS-PAGE, are disclosed. The proteins have cis retinol dehydrogenase activity, such as 9, 11 or 13 cis retinol dehydrogenase activity, or cis activity at more than one position. Other trans-retinol dehydrogenases are also disclosed. Nucleic acid molecules which code for the proteins are also disclosed. Excerpt(s): This invention relates to proteins having retinol dehydrogenase activity, such as 9-cis, 11-cis or 13-cis retinol dehydrogenase activity, or trans retinol dehydrogenase activity and which form complexes with a specific portion of a

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membrane receptor for plasma retinol-binding protein (RBP) expressed, e.g., in retinal pigment epithelium (RPE), and, more specifically; proteins having cis retinol dehydrogenase activity, such as 9 or 11-cis retinol dehydrogenase activity, which form complexes with RBP-binding membrane proteins such as the 63 kDa RBP binding membrane protein found in RPE cells. The invention also involves isolation of the proteins, as well as nucleic acid molecules coding p32 or complementary to coding sequences therefor, in addition to various applications of these materials. Retinoids (vitamin A-derivatives) have important physiological functions in a variety of biological processes. During embryonic growth and development, as well as during growth and differentiation of adult organisms, retinoids act as hormones and participate in the regulation of gene expression in a number of cell types. See Lied et al. Trends Genet., 17:427-433 (1992). It is believed that these effects are mediated through two classes of nuclear ligand-controlled transcription factors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), Benbrook et al., Nature, 333:669-672 (1988); Brand et al., Nature, 332:850-853 (1988); Giguere et al., Nature, 330:624-629 (1987); Mangelsdorf et al., Nature, 345:224-229 (1990); Mangelsdorf, et al. Genes Dev. 6: 329-344 (1992); Petkovich et al. Nature 330:440-450 (1987); and Zelent et al., Nature 339:714-717 (1989). Apart from their role as hormones in cellular growth and differentiation, retinoids are also involved in the visual process as the stereo isomer of retinaldehyde, 11-cis retinaldehyde, is the chromophore of the visual pigments. See, e.g. Bridges, The Retinoids,. Vol. 2, pp 125176, Academic Press, Orlando, Fla., (1984). Web site: http://www.delphion.com/details?pn=US06399344__ •

Isolation, purification and cloning of retinol dehydratase Inventor(s): Buck; Jochen (New York, NY), Grun; Felix (Stamford, CT), Hammerling; Ulrich (New York, NY) Assignee(s): Cornell Research Foundation, Inc. (ithaca, Ny), Sloan-ketterin Institute for Cancer Research (new York, Ny) Patent Number: 5,928,931 Date filed: May 7, 1997 Abstract: The present invention relates to retinol dehydratase, the enzyme which synthesizes the retro-retinoid anhydroretinol in the Spodoptera frugiperda insect cell line Sf-21, as well as the DNA molecule encoding that enzyme. The DNA molecule can be incorporated in a DNA expression system and a host for recombinant production of anhydroretinol dehydratase. The isolated retinol dehydratase protein or polypeptide of the present invention can be combined with a pharmaceutically-acceptable carrier or used alone for administration to mammals, particularly humans, for preventing cell growth and/or uncontrolled cell growth in cells which are growth dependent on retinol and/or 14 hydroxy-4, 14-retro-retinol. Excerpt(s): The present invention relates to the isolation, purification, and cloning of retinol dehydratase. The diverse family of isoprenoid lipids, of which the retinoids represent one class, has been used in cellular signaling pathways since the beginning of multicellular life. Processes in vertebrates as diverse as growth, vision, and reproduction are "retinoid" dependent. The Retinoids, Vol. 2, eds. Spom, M. B., Roberts, A. B., & Goodman, D. S., pp. 289-286 ›Academic, Orlando 1984!. Retinoids are a group of compounds consisting of retinol (i.e. Vitamin A) and natural and synthetic derivatives thereof. Various metabolic derivatives of retinol have been identified. Retinoic acid has been found to be crucial for normal pattern formation during embryogenesis and in the

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regulation of the differentiation of a variety of cell types (Gudas L. J., J. Biol. Chem., 2679:15399-402 (1994)) , 11-cis retinal in vision (Wald, G. , Science, 162:230-32 (1968)) or 9-cis and all-trans retinoic acid for differentiation of a number of cellular systems (The Retinoids, Vol. 2, eds. Sporn, M. B., Roberts, A. B., & Goodman, D. S., pp. 289-286 ›Academic, Orlando 1984!). Web site: http://www.delphion.com/details?pn=US05928931__ •

Mouse and human 9-cis-retinol dehydrogenase Inventor(s): Blaner; William S. (New York, NY), Gamble; Mary V. (New York, NY), Mertz; James R. (New York, NY), Zott; Roseann Piantedosi (River Edge, NJ) Assignee(s): The Trustees of Columbia University in the City of New York (new York, Ny) Patent Number: 6,171,837 Date filed: September 29, 1997 Abstract: This invention provides an isolated nucleic acid molecule (SEQ ID NO:1) encoding a human 9-cis-retinol dehydrogenase. Also provided is a 9-cis-retinol dehydrogenase encoded by the isolated nucleic acid molecule, wherein the 9-cis-retinol dehydrogenase comprises the amino acid sequence of SEQ. ID NO: 2. This invention also provides isolated nucleic acid molecules comprising the nucleotide sequence shown in any of SEQ. ID NOS: 6, 7, and 8 encoding mouse 9-cis-retinol dehydrogenases. Excerpt(s): Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the claims. All-trans- and 9-cis-retinoic acid are active retinoids for regulating expression of retinoid responsive genes, serving as ligands for two classes of ligand-dependent transcription factors, the retinoic acid receptors and retinoid X receptors. Little is known, however, regarding 9-cis-retinoic acid formation. We have obtained a 1.4-kilobase cDNA clone from a normalized human breast tissue library, which when expressed in CHO cells encodes a protein that avidly catalyzes oxidation of 9-cis-retinol to 9-cis-retinaldehyde. This protein also catalyzes oxidation of 13-cis-retinol at a rate approximately 10% of that of the 9-cis isomer but does not catalyze all-trans-retinol oxidation. NAD+ was the preferred electron acceptor for oxidation of 9-cis-retinol, although NADP+ supported low rates of 9-cis-retinol oxidation. The rate of 9-cis-retinol oxidation was optimal at pHs between 7.5 and 8. Sequence analysis indicates that the cDNA encodes a protein of 319 amino acids that resembles members of the short chain alcohol dehydrogenase protein family. mRNA for the protein is most abundant in human mammary tissue followed by kidney and testis, with lower levels of expression in liver, adrenals, lung, pancreas, and skeletal muscle. We propose that this cDNA encodes a previously unknown stereospecific enzyme, 9-cisretinol dehydrogenase, which probably plays a role in 9-cis-retinoic acid formation. Retinoids (vitamin A and its analogs) are essential dietary substances that are needed by mammals for reproduction, normal embryogenesis, growth, vision, and maintaining normal cellular differentiation and the integrity of the immune system (1-5). Within cells, retinoids regulate gene transcription acting through ligand-dependent transcription factors, the retinoic acid receptors (RARs).sup.1, and the retinoid X receptors (RXRs) (6,7). All-trans-retinoic acid binds only to RARs with high affinity, whereas its 9-cis isomer binds with high affinity to both RARs and RXRs. The actions of

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all-trans- and 9-cis-retinoic acid in regulating cellular responses are distinct and not interchangeable. Web site: http://www.delphion.com/details?pn=US06171837__ •

Skin care compositions containing an n-substituted fatty acid amide and retinol or retinyl ester Inventor(s): Granger; Stewart Paton (Paramus, NJ), Rawlings; Anthony Vincent (Warrington, GB), Scott; Ian Richard (Allendale, NJ) Assignee(s): Elizabeth Arden Co., Division of Conopco, Inc. (new York, Ny) Patent Number: 5,955,092 Date filed: September 27, 1996 Abstract: N-substituted fatty acid amides which sufficiently inhibit LRAT or ARAT catalyzed esterification of retinol into inactive retinyl esters, have the same effect on keratinocytes as retinoic acid. Thus, effects of the retinol or retinyl esters in combination with N-substituted fatty acid amides are analogous to treatment with retinoic acid. Excerpt(s): The present invention relates to skin care compositions containing an Nsubstituted fatty acid amide and retinol or retinyl ester. Retinol (vitamin A) is an endogenous compound which occurs naturally in the human body and is essential for normal epithelial cell differentiation. Natural and synthetic vitamin A derivatives have been used extensively in the treatment of a variety of skin disorders and have been used as skin repair or renewal agents. Retinoic acid has been employed to treat a variety of skin conditions, e.g., acne, wrinkles, psoriasis, age spots and discoloration. See e.g., Vahlquist, A. et al., J. Invest. Dermatol., Vol.94, Holland D. B. and Cunliffe, W. J. (1990), pp. 496-498; Ellis, C. N. et al., "Pharmacology of Retinols in Skin", Vasel, Karger, Vol. 3, (1989), pp. 249-252; Lowe, N. J. et al., "Pharmacology of Retinols in Skin", Vol. 3, (1989), pp. 240-248; PCT Patent Application No. WO 93/19743. However, most of the endogenously applied retinol is rapidly converted into inactive fatty esters for storage in epidermal cells (keratinocytes). Esterification of retinol into inactive retinyl esters is achieved in cells by transfer of a fatty acyl group from an acyl CoA, catalyzed by the enzyme acyl CoA retinol transferase (ARAT), or by the transfer of an acyl group from phosphatidyl choline, catalyzed by the enzyme lecithin retinol acyl transferase (LRAT). These esterification reactions are very efficient in keratinocytes--the majority (95%) of cellular retinoids are in the form of retinyl fatty esters. Thus, unfortunately, although retinol and retinyl esters are safer to use than retinoic acid, they are less effective than retinoic acid at providing skin benefits. Web site: http://www.delphion.com/details?pn=US05955092__

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Skin care compositions containing fatty acid amides and retinol or retinyl ester Inventor(s): Granger; Stewart Paton (Paramus, NJ), Rawlings; Anthony Vincent (Wyckoff, NJ), Scott; Ian Richard (Allendale, NJ) Assignee(s): Elizabeth Arden Co., Division of Conopco, Inc. (new York, Ny) Patent Number: 5,811,110 Date filed: January 22, 1997

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Abstract: Fatty acid amides, but not free fatty acids or fatty acid esters, in combination with either retinol or retinyl ester resulted in a synergistic enhancement in keratinocyte proliferation and synergistic inhibition of keratinocyte differentiation. The effects of the retinol or retinyl esters in combination with fatty acid amides were analogous to treatment with retinoic acid. Excerpt(s): Retinol (vitamin A) is an endogenous compound which occurs naturally in the human body and is essential for normal epithelial cell differentiation. Natural and synthetic vitamin A derivatives have been used extensively in the treatment of a variety of skin disorders and have been used as skin repair or renewal agents. Retinoic acid has been employed to treat a variety skin conditions, e.g., acne, wrinkles, psoriasis, age spots and discoloration. See e.g., Vahlquist, A. et al., J. Invest. Dermatol., Vol. 94, Holland D. B. and Cunliffe, W. J. (1990), pp. 496-498; Ellis, C. N. et al., "Pharmacology of Retinols in Skin", Vasel, Karger, Vol. 3, (1989), pp. 249-252; Lowe, N. J. et al., "Pharmacology of Retinols in Skin", Vol. 3, (1989), pp. 240-248, PCT Patent Application No. WO 93/19743. Retinal and retinyl esters, such as retinyl acetate and retinyl palmitate, are easier to formulate/stabilize than retinoic acid. Unfortunately, retinol and retinyl esters are less effective than retinoic acid at providing skin benefits. The present invention is based, in part, on the discovery that certain combinations of retinol or retinyl esters with fatty acid amides result in a synergistic improvement in keratinocyte proliferation and differentiation. The effects of a fatty acid amide combined with retinol or a retinyl ester were analogous to the effects of retinoic acid. Thus, a mixture of fatty acid amides with retinol or retinyl esters mimics retinoic acid yet is easier to use than retinoic acid. Thornfeldt (U.S. Pat. No. 5,057,501) discloses a method for treatment of papulosquamous and eczematous diseases with a composition containing a sesquiterpene compound and from about 0.025% to about 35% of a monocarboxylic fatty acid, ester, or amide. The compositions may also include a retinoid; Thornfeldt teaches that certain retinoids, namely isotretinoin, tretinoin, etretin (all of which are stereoforms of retinoic acid) and etretinate (an ester of trimethoxyphenyl retinoic acid) have proven efficacy against papulosquamous diseases. PCT Application WO/9325177 (Procter and Gamble) discloses compositions for topical application to skin which contain a specific type of acyclic carboxamide coolant and may include retinoids such as retinoic acid and its derivatives (e.g., cis and trans). PCT application WO/9403156 (Rhone Poulenc) discloses a topical composition containing linoleic acid or a derivative as an active ingredient for treatment and prophylaxis of impure skin (e.g., skin affected by pimples, pustules, or comedones); the composition may also contain 0.025-0.1 wt. % of tretinoin. European Patent Application No. 0 388 275 (Pierre Fabre Cosmetique) discloses compositions for treating seborrhea containing alkyl carboxamide and a zinc salt which may be zinc retinoate. Klaus et al, (U.S. Pat. No. 5,216,148) disclose the use of specific complex carboxamides for treating and preventing neoplasms, dermatoses, and aging of skin. Van Scott et al. (U.S. Pat. No. 4,380,549) and Yu et al., (U.S. Pat. No. 4,363,815) disclose treatment of acne, dry, flaky, scaly skin with a hydroxyacid or the amide thereof. EP 582,458 discloses use of N,N-(1,4C alkyl) lauramide EP 559,304 disclose the use of an amide containing a hydrocarbyl chain of at least 25 carbon atoms as a skin smoothening agent. Beauquey et al. (U.S. Pat. No. 5,308,551) disclose a skin washing and conditioning composition containing, among other ingredients, a 1-4C alkanolamide of a 8-16C fatty acid. Great Britain Patent Specification No. 1,126,289 (Hoffman-La Roche) discloses a stock vitamin preparation containing vitamin A alcohol or a vitamin A ester, an emulsifier and a solvent which is selected from an alcohol or a dialkyl amide of a monocarboxylic acid (e.g., N,N-diethyl-acetamide, N,N-dimethyl acetamide or N,Ndimethyl formamide). The vitamin preparation has a very high vitamin content, i.e., the

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minimum concentration is 250,000 I.U. vitamin A/ml. Further, the amides disclosed in the '289 application do not fall within the scope of the present invention. Web site: http://www.delphion.com/details?pn=US05811110__ •

Skin care compositions containing geranyl geraniol and retinol or retinyl esters Inventor(s): Burger; Allan Robert (Passaic, NJ), Granger; Stewart Paton (Paramus, NJ), Rawlings; Anthony Vincent (Warrington, GB2), Scott; Ian Richard (Allendale, NJ), Zhang; Kelly Hua (Piscataway, NJ) Assignee(s): Chesebrough-pond's Usa Co., Division of Conopco, Inc. (greenwich, Ct) Patent Number: 5,756,109 Date filed: September 27, 1996 Abstract: Geranyl geraniol inhibits esterification of retinol into inactive retinyl esters. Thus, effects of the retinol or retinyl esters in combination with geranyl geraniol are analogous to treatment with retinoic acid. Excerpt(s): The present invention relates to skin care compositions containing geranyl geraniol and retinol or retinyl esters. Retinol (vitamin A) is an endogenous compound which occurs naturally in the human body and is essential for normal epithelial cell differentiation. Natural and synthetic vitamin A derivatives have been used extensively in the treatment of a variety of skin disorders and have been used as skin repair or renewal agents. Retinoic acid has been employed to treat a variety of skin conditions, e.g., acne, wrinkles, psoriasis, age spots and discoloration. See e.g., Vahlquist, A. et al., J. Invest. Dermatol., Vol. 94, Holland D. B. and Cunliffe, W. J. (1990), pp. 496-498; Ellis, C. N. et al., "Pharmacology of Retinols in Skin", Vasel, Karger, Vol. 3, (1989), pp. 249-252; Lowe, N. J. et al., "Pharmacology of Retinols in Skin", Vol. 3, (1989), pp. 240-248; PCT Patent Application No. WO 93/19743. The present invention is based, in part, on the discovery that geranyl geraniol inhibits these esterification reactions and thus potentiates the action of retinyl ester on retinol by increasing the amount of retinol available for conversion to retinoic acid. Thus, a mixture of geranyl geraniol with retinol or retinyl esters mimics retinoic acid yet is safer to use than retinoic acid. Web site: http://www.delphion.com/details?pn=US05756109__

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Skin cream Inventor(s): McElwain; Elizena A. (125 Picnic La., Hardinsburg, KY 40143) Assignee(s): None Reported Patent Number: 6,261,603 Date filed: April 10, 2000 Abstract: Topical skin rejuvenation cream and lotion compositions for dry, damaged or aging skin comprising deionized water, mink oil, vitamin E, retinol acetate (vitamin A), ginseng, aloe vera, glycerin, lanolin (hydrous), gotu kola, soybean oil, fish liver oil, hydrolyzed animal protein, dl-alpha tocopherol acetate, stearic acid, cetyl alcohol, citric acid, silicon, isopropylmyristate, propylene glycol, stearyl alcohol, glycerol stearate, dimethicone, lactic acid, quaternium-15, propylparaben, carbomer 934 and 940, triethanolamine, methylparaben, tetrasodium ethylenediaminetetraacetic acid (EDTA), DMDM hydantoin, diazolidinyl urea and fragrance.

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Excerpt(s): The present invention relates to a skin rejuvenation cream and lotion especially beneficial for dry, damaged or aging skin. The need for anti-aging creams/lotions and moisturizers without a prescription is strongly felt. RETIN-A is used to reduce wrinkles but has a high incidence of side effects and requires a prescription. Over-the-counter skin care preparations generally do not suffice, and often make the skin feel greasy. Their moisturizing qualities also tend to vanish quickly, resulting in dry, cracked skin. U.S. Pat. No. 5,153,230 issued to Jaffery on Oct. 6, 1992 discloses a topical skin cream composition. The skin cream of Jaffery is designed to prevent and treat aging skin. The active ingredient is glycolic acid in concentrations up to 3.5 weight percent. The composition also may include vitamin A palmitate and/or vitamin E acetate. Preservatives are included in the composition to increase shelf life. Other ingredients may be included in the composition but no natural ingredients such as mink oil, soybean oil, fish liver oil, or gotu kola are included in the composition. Web site: http://www.delphion.com/details?pn=US06261603__ •

Softgel-compatible composition containing retinol Inventor(s): Rinaldi; Marie A. (St. Petersburg, FL), Saxena; Subhash J. (Belmont, CA), Tutschek; Paul C. (Largo, FL) Assignee(s): Enhanced Derm Technologies, Inc. (dublin, Oh), R. P. Scherer Corporation (troy, Mi) Patent Number: 6,228,894 Date filed: March 19, 1999 Abstract: A softgel-compatible composition containing retinol comprises retinolimpregnated microparticles. The composition may include an optionally thickened silicone oil, or may include an emulsion comprising a silicone oil. Ascorbic acid may be present as ascorbic acid-impregnated microparticles and/or within the emulsion. Such compositions are compatible with softgels, and may also be used in other dispensing containers, such as sachets, tubes, and airless pumps. Excerpt(s): This invention relates to a softgel-compatible composition containing retinol, and to a softgel-compatible composition containing both retinol and ascorbic acid; and to dispensing containers containing such compositions. Retinol, along with other retinoids, has enjoyed increasing popularity as an active ingredient in skin care compositions, especially for acne, photoaging, and sun damage. However, more so than other retinoids, retinol tends to decompose on exposure to light, heat, and oxygen. The problem of decomposition has been addressed to some extent by formulating retinol with antioxidants and chelating agents, and storing it in opaque or colored containers, and several patents and published applications, for example, PCT International Application Publication No. WO 93/00085 and European Patent Application Publication Nos. 0 440 398 and 0 586 106, all to Johnson & Johnson, describe water-in-oil emulsions containing retinol, which are asserted to be stable. European Patent Application Publication No. 0 781 551, to Advanced Polymer Systems, discloses an oil-in-water emulsion containing retinol, in which the retinol is entrapped within the pores of solid porous polymeric microparticles. The disclosures of these and other documents referred to in this application are incorporated herein by reference. Softgel (soft gelatin capsule) formulations have recently become of greater interest in the formulation of products for topical application to the skin, because the softgels provide an attractive single use method for dispensing the product. Typically, these softgels contain 0.1 mL to 2 mL of a fill material, and have a "twist-off" or other removable feature at one end for dispensing

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the fill material. Such softgels can be prepared by methods well known for the preparation of softgels for oral dosage formulations, i.e. by encapsulating the fill material between two sheets of gelatin as it passes between a pair of die rolls having surface cavities shaped to form the desired shape of the resulting softgel. Web site: http://www.delphion.com/details?pn=US06228894__ •

Stabilizing vitamin A derivatives by encapsulation in lipid vesicles formed with alkylammonium fatty acid salts Inventor(s): Aust; Duncan T. (Ridge, NY), Hayward; James A. (Stony Brook, NY), Ross; Michael A. (Jericho, NY), Wilmott; James M. (Shoreham, NY) Assignee(s): Collaborative Laboratories, Inc. (east Setauket, Ny) Patent Number: 6,183,774 Date filed: August 17, 1999 Abstract: The present invention provides for vitamin A derivative selected from the group consisting of retinol, retinyl ester and any combination thereof incorporated into liposomes formed with alkylammonium fatty acid salts, and methods for manufacturing same. The liposomes of the invention may deliver vitamin A derivative materials at the occurrence of a preset triggering condition. Preferred liposomes of the invention are cationic liposomes. The preferred liposomes of the invention are formed with alkylammonium fatty acid salts, e.g., trialkylammonium fatty acid salts of long chain amides. The encapsulated vitamin A derivative is thus stabilized by the liposomes. The present invention thus also provides a method of stabilizing vitamin A derivative be encapsulation in such liposomes. The liposomes of the invention are used to provide topical skin treatment formulations useful in the treatment of skin. Excerpt(s): The present invention relates to the stabilization of vitamin A derivatives by encapsulation in lipid vesicles formed with long chain alkylammonium fatty acid salts. The present invention also relates to compositions comprising such liposomes for the cosmetic or dermatological treatment of imperfections or complaints of the skin, including the scalp. More particularly, the invention relates to a composition for treating the skin comprising at least one vitamin A derivative as an active agent encapsulated in the long chain alkylammonium fatty acid salt liposomes of the invention and methods of using such compositions. Liposome formation is a natural result of the amphipathic nature of the molecules of which they are comprised. Amphipathic molecules are those molecules with distinct regions of the molecule having hydrophilic character and distinct regions of the same molecule having hydrophobic character. When dispersed in water, amphipathic molecules form three types of macro-molecular structure: micelles, hexagonal phase and lipid bilayers. The exact macromolecular structure which is formed depends on the relative sizes of the hydrophilic and hydrophobic regions of the molecule. Liposomes may be formed as a single bilayer enclosing a single aqueous space (small unilamellar vesicles; SUVS) or may be composed of concentric bilayers with many aqueous spaces alternating with the bilayers (multilamellar vesicles; MLVS). Liposomes can be used to encapsulate both hydrophobic and hydrophilic materials. Hydrophobic payloads are typically partitioned within the bilayers whereas hydrophilic payloads are typically trapped within the aqueous compartments. The advantages of using liposomes as a carrier/encapsulation system is that they are stable and can protect their payload from degradation, e.g., by oxygen, digestive enzymes, etc. Web site: http://www.delphion.com/details?pn=US06183774__

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Stable W/O/W emulsion and its use as cosmetic and/or dermatological composition Inventor(s): Afriat; Isabelle (Paris, FR), Chanvin; Florence (Soisy/S/Seine, FR), Guiramand; Carole (Linas, FR) Assignee(s): L'oreal S.a. (paris, Fr) Patent Number: 6,149,900 Date filed: October 5, 1998 Abstract: A composition in the form of a water/oil/water triple emulsion comprising an outer aqueous phase and an oily phase constituting, with an inner aqueous phase, a W/O primary emulsion, the outer aqueous phase comprising, in combination, an emulsifying copolymer of carboxylic acid with a fatty chain, and a crosslinked poly(acrylamidomethylpropane-sulfonic acid). The emulsion remains stable, even in the presence of an acidic active agent, and is particularly appropriate as vehicle for watersensitive and/or oxygen-sensitive active agents, in particular in a cosmetic or dermatological composition. The active agent can be, in particular, a vitamin, such as ascorbic acid or retinol, an enzyme and an.alpha.- or.beta.-hydroxy acid. The emulsion obtained can constitute, in particular, a composition for cleaning and/or treating and/or protecting the skin and/or mucous membranes and/or keratinous fibers. Excerpt(s): The present invention relates to a composition which is provided in the form of a W/O/W triple emulsion and to its applications in the cosmetic and dermatological fields, in particular for the controlled release of active agent, more particularly of watersensitive and/or oxygen-sensitive active agent and of acidic active agents, in particular for the purpose of cleaning and/or treating and/or protecting the skin and/or mucous membranes and/or keratinous fibers. It is known to introduce active agents into cosmetic and/or dermatological compositions for the purpose of contributing specific treatments to the skin, for example for combating drying, ageing or pigmentation of the skin, for treating acne or certain skin diseases (eczema, psoriasis), for combating excess weight, for promoting restructuring of the skin or its cell renewal, or for coloring the skin. For example, ascorbic acid (or vitamin C) is known to stimulate the growth of the connective tissue and in particular that of collagen. It also makes it possible to strengthen the defenses of cutaneous tissue against external attacks, such as ultraviolet radiation or pollution. Ascorbic acid is also used for removing blotches and pigmentation of the skin and also for promoting healing of the skin. Web site: http://www.delphion.com/details?pn=US06149900__

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Treatment for onychomycosis topically applying salicylic acid, optionally in combination with a retinoid Inventor(s): Caswell; Michael L. (Poway, CA), Dever; Gerald R. (Cordova, TN), Hayes, Jr.; Jesse Calvin (Cleveland, TN), Laughlin; Thomas J. (Germantown, TN), Schroer, Jr.; Charles F. (Bartlett, TN), Wildman; Gary C. (Germantown, TN) Assignee(s): Schering-plough Healthcare Products, Inc. (memphis, Tn) Patent Number: 6,416,749 Date filed: August 10, 1994 Abstract: A method and a medicament for treating onychomycosis. The active ingredient is salicylic acid or a salt, ester or mixture thereof in a medicament, such as a plaster preparation or a liquid preparation, optionally with a retinoid compound such as

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tretinoin, adapalene, manoalide, retinol, tretinate or mixtures thereof. The method comprises topically administering the active ingredient to the afflicted nail. The medicament is applied without drilling holes in the nail or periodic scraping of the nail and in the absence of an imidazole antimycotic compound. Excerpt(s): In a similar manner, the book, "Diseases of the Nail" by V. Pardo-Castello, Thomas Books, Baltimore, Maryland, (1936), pp. 22-40 describes several treatments for onychomycosis, including the following: "Craik (43) has reported two cases treated with success by means of daily applications of a solution of 4 grams of salicylic acid in 45 c.c. of methylated spirit, after thoroughly scraping the nail. The cited reference, R.Craik, "A Simple Treatment of Ringworm of the Nails", Brit. M. J. February 1920, p. 185 describes a procedure wherein a lotion containing salicylic acid was ". to be painted on after scraping [the finger nail] every night, and without scraping every morning, and to be used for three months or longer." Scraping a finger nail each day for three months or more has effect of thinning or completely removing the nail plate. Avulsion or surgical approaches for treating onychomycosis have also been used. Infected nails are treated by surgically or chemically removing the nail and treating the exposed nailbed with topical antifungals. These treatments must be continuted until the nail grows out, typically 6 months or more. Although the surgical approach generally results in cure rates significantly higher than those reported for topical treatments, most patients dislike undergoing surgery, which can result in permanent nail loss. International Application WO 88/06884 teaches treating nail mycosis with a pharmaceutically effective amount of a topical antimycotic such as an imidazole compound, optionally with an antiseptic as exemplified using about 5% salicylic acid in a liquid preparation. There is no suggestion in this reference that salicylic acid, by itself, can serve as the antimycotic active ingredient. Nor does this reference suggest the unexpected and surprising discovery that salicylic acid, applied topically, will penetrate into the nail and exert an antifungal effect, in the absence of an imidazole antimycotic agent. Web site: http://www.delphion.com/details?pn=US06416749__ •

Vaccine compositions and method for induction of mucosal immune response via systemic vaccination Inventor(s): Araneo; Barbara A. (Salt Lake City, UT), Daynes; Raymond A. (Park City, UT) Assignee(s): University of Utah Research Foundation (salt Lake City, Ut) Patent Number: 5,824,313 Date filed: June 7, 1995 Abstract: The invention relates to a vaccine which comprises an antigen and a lymphoid organ modifying agent. Suitable lymphoid organ modifying agents include, but are not limited to, 1,25-dihydroxy Vitamin D.sub.3, biologically active Vitamin D.sub.3 derivatives which are capable of activating the intracellular Vitamin D.sub.3 receptor, all trans-retinoic acid, retinoic acid derivatives, retinol, retinol derivatives and glucocorticoid. The vaccine composition may further comprise an immune response augmenting agent. The immune response augmenting agent enhances T cell lymphokine production. Suitable immune response augmenting agents include, but are not limited to, dehydroepiandrosterone (DHEA), DHEA congeners and DHEAderivatives. The invention also relates to a method for inducing an antigen-specific mucosal immune response in a subject vertebrate animal which comprises administering a vaccine which comprises an antigen and a lymphoid organ modifying

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agent to a site which drains into a peripheral lymph compartment. Alternatively, the method comprises separately administering the lymphoid organ modifying agent and a vaccine containing an antigen to the same site. The method may further comprise additionally administering an immune response augmenting agent which enhances T cell lymphokine production. The immune response augmenting agent may be administered sequentially or contemporaneously with the lymphoid organ modifying agent. Excerpt(s): The invention relates to vaccine compositions and methods of vaccination which provide for the induction of mucosal immune responses. The publications and other materials used herein to illuminate the background of the invention, or provide additional details respecting its practice, are incorporated by reference. The vast majority of agents of infection in vertebrates enter the host across a mucosal surface, including generally the mucosa of the alimentary canal (including oral mucosa), the respiratory tract (including olfactory and conjunctival mucosa), the mammary glands, and the genitourinary tract. The common mucosal immune system, by way of the secretory immunoglobulin response, provides a first line of resistance to infection across mucosal surfaces in vertebrates (J. Mestecky (1987). J Clin. Immunol. 7:265-75). Web site: http://www.delphion.com/details?pn=US05824313__ •

Water-in-oil emulsion containing retinol, its use and its packaging Inventor(s): Collin; Nathalie (Sceaux, FR), Quemin; Eric (Villepinte, FR) Assignee(s): L'oreal (paris, Fr) Patent Number: 5,800,596 Date filed: January 13, 1997 Abstract: A device for packaging a product comprising: i) a dispensing device such that the product is not brought into contact with the environment, ii) constituent walls which are impermeable to gases and to visible-ultraviolet light, wherein a surface of the walls in contact with the product is non-metallic; and iii) an oxygen-trapping device. Excerpt(s): The present invention relates to a water-in-oil emulsion containing stabilized retinol, this emulsion being particularly intended for the cosmetic and/or dermatological fields. The invention also relates to a use of this emulsion for treating the skin and to packaging which is perfectly suitable for this emulsion. Retinol is known for its beneficial effects on the skin, in particular in topical application. Retinol has for a long time been used in the treatment of acne. However, it is in the field of repair of damage caused either by age or by over-exposure to the sun that retinol has proven to be extremely active. Web site: http://www.delphion.com/details?pn=US05800596__

Patent Applications on Retinol 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

10

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

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several years.) The following patent applications have been filed since December 2000 relating to retinol: •

Composition containing a retinoid and a benzotriazole silicone Inventor(s): Martin, Guenaelle; (Paris, FR), Touzan, Philippe; (Paris, FR) Correspondence: Oblon Spivak Mcclelland Maier & Neustadt PC; Fourth Floor; 1755 Jefferson Davis Highway; Arlington; VA; 22202; US Patent Application Number: 20020081271 Date filed: October 30, 2001 Abstract: The present invention relates to a composition containing a retinoid, in particular retinol, and a specific benzotriazole silicone. Excerpt(s): The present invention relates to compositions, preferably cosmetic and/or dermatological compositions, more preferably compositions intended for caring for the skin, comprising, preferably in a physiologically acceptable medium, a retinoid and a benzotriazole silicone. The uses of such compositions similarly makes up a part of the invention, as does their preparation. Retinoid-based cosmetic and/or dermatological compositions have experienced significant growth in recent years, in particular for the treatment of acne and cutaneous imperfections, because of the ability of retinoids to regulate the differentiation of keratinocytes, and for the prevention and treatment of certain signs of intrinsic or photoinduced cutaneous ageing, such as the formation of wrinkles and the loss of firmness of the skin, due in particular to their ability to modulate the synthesis of collagen. Among the derivatives of the retinoids family, retinol, also known under the name of vitamin A, is of very particular advantage. This is because retinol is a natural endogenous constituent of the human body which is well tolerated on application to the skin up to higher levels than retinoic acid. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Compositions and methods for use in modulating immune system function Inventor(s): Chambon, Pierre; (Blaesheim, FR), Durandy, Anne; (Paris Cedex 15, FR), Dy, Michel; (Paris Cedex 15, FR), Geissmann, Frederick; (Paris, FR), Lepelletier, Yves; (Savigny-sur-Orge, FR), Revy, Patrick; (Paris Cedex 15, FR) Correspondence: Sterne, Kessler, Goldstein & Fox Pllc; 1100 New York Avenue, N.W., Suite 600; Washington; DC; 20005-3934; US Patent Application Number: 20020090352 Date filed: April 12, 2001 Abstract: Vitamin A (retinol) deficiency results in impaired response to infection and increased mortality. By the present invention, we show that retinol activates immature dendritic cells (DC) and enhances antigen presentation via a cross-talk with inflammatory cytokines, whereas it increases DC death in the absence of these cytokines. These effects, that are mediated through retinoic acids and distinct nuclear retinoid receptor pathways, can be dissociated from each other with selective synthetic retinoids. The present invention identifies a novel cellular target and function for retinoids, provides compositions and methods for modulating the immune system and for treating or preventing various physical disorders in animals, preferably via controlling activation and/or apoptosis in antigen-presenting cells using selective retinoids.

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Excerpt(s): The present application claims the benefit of U.S. Provisional Application No. 60/196,921, filed Apr. 13, 2000, the contents of which are entirely incorporated herein by reference. The present invention relates to the fields of mammalian immunology, retinoid receptor biology and mammalian disease therapeutics. More particularly, the invention relates to compositions and methods useful in modulating the activity and function of the immune system of an animal. Specifically, the present invention provides compositions and methods for modulating the function of the immune system in an animal, particularly by activating antigen-presenting cells or by inhibiting/delaying apoptosis of antigen-presenting cells, the methods comprising administering to the animal an effective amount of a composition comprising at least one retinoid and at least one cytokine. In related aspects, the present invention provides compositions and methods for modulating the function of the immune system in an animal, particularly by inducing apoptosis of antigen-presenting cells, the methods comprising administering to the animal an effective amount of a composition comprising at least one synthetic retinoid. The methods and compositions of the present invention are useful in treating and/or preventing a variety of physical disorders in mammals including infectious (bacterial or viral) diseases, parasitic diseases, cancers (particularly carcinomas), immune system dysfunctions, and the like. A number of studies have demonstrated that retinoids (vitamin A derivatives) are essential for normal growth, vision, tissue homeostasis, reproduction and overall survival (for reviews and references, See Sporn et al., The Retinoids, Vols. 1 and 2, Sporn et al., eds., Academic Press, Orlando, Fla. (1984)). For example, retinoids have been shown to be vital to the maintenance of skin homeostasis and barrier function in mammals (Fisher, G. J., and Voorhees, J. J., FASEB J. 10:1002-1013 (1996)). Retinoids are also apparently crucial during embryogenesis, since offspring of dams with vitamin A deficiency (VAD) exhibit a number of developmental defects (Wilson, J. G., et al., Am. J. Anat. 92:189-217 (1953); Morriss-Kay, G. M., and Sokolova, N., FASEB J. 10:961-968 (1996)). With the exceptions of those on vision (Wald, G., et al., Science 162:230-239 (1968)) and spermatogenesis in mammals (van Pelt, H. M. M., and De Rooij, D. G., Endocrinology 128:697-704 (1991)), most of the effects generated by VAD in animals and their fetuses can be prevented and/or reversed by retinoic acid (RA) administration (Wilson, J. G., et al., Am. J. Anat. 92:189-217 (1953); Thompson et al., Proc. Royal Soc. 159:510-535 (1964); Morriss-Kay, G. M., and Sokolova, N., FASEB J. 10:961-968 (1996)). The dramatic teratogenic effects of maternal RA administration on mammalian embryos (Shenefelt, R. E., Teratology 5, 103-108 (1972); Kessel, M., Development 115:487-501 (1992); Creech Kraft, J., In Retinoids in Normal Development and Teratogenesis, G. M. Morriss-Kay, ed., Oxford University Press, Oxford, UK, pp. 267-280 (1992)), and the marked effects of topical administration of retinoids on embryonic development of vertebrates and limb regeneration in amphibians (Mohanty-Hejmadi, et al., Nature 355:352-353 (1992); Tabin, C. J., Cell 66:199-217 (1991)), have contributed to the notion that RA may have critical roles in morphogenesis and organogenesis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

COMPOSITIONS AND METHODS OF TREATING SKIN CONDITIONS Inventor(s): ACHKAR, CHARLES; (NORTH BERGEN, NJ) Correspondence: Charles C Achkar; 7855 Boulevard East # 26g; North Bergen; NJ; 07047 Patent Application Number: 20010002396 Date filed: July 16, 1998

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Abstract: A composition is described comprising a vitamin D analog and a retinoid, wherein: (a) the vitamin D analog is capable of binding a vitamin D receptor or being converted in vivo into a compound capable of binding a vitamin D receptor; and (b) the retinoid is selected from the group consisting of a compound capable of binding a retinoic acid receptor, retinol in a concentration of at least about 0.1% and a compound in a concentration of at least about 0.% capable of being converted in vivo into retinol. Further, methods of treating disorders characterized by abnormal cell-proliferation and/or cell-differentiation are also described. Excerpt(s): The present invention relates to compositions comprising certain retinoids and vitamin D analogs useful in inducing differentiation and inhibiting undesirable proliferation of cells, such as cancer cells and skin cells. The present invention also relates to methods of using the above compositions in the treatment of diseases and conditions characterized by abnormal cell differentiation and/or cell proliferation. Abnormal cell differentiation and/or cell differentiation is associated with many conditions and diseases. For instance, hyperproliferation of epithelial cells is associated with psoriasis causes the skin to shed itself too rapidly, every three to four days. The goal in treating psoriasis is to reduce inflammation and to slow down rapid skin cell division. U.S. Pat. No. 4,866,048 discloses that certain vitamin D derivatives, in particular calcitriol (1 alpha,25-dihydroxy-vitamin D.sub.3 or) and calcipotriol are able to stimulate the differentiation of cells and inhibit excessive cell proliferation, and it has been suggested that these compounds are useful in the treatment of diseases characterized by abnormal cell differentiation and/or cell differentiation such as leukemia, myelofibrosis, psoriasis and acne. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Cosmetic material containing triple- encapsulated retinol Inventor(s): Jo, Byoung Kee; (Kyungki-do, KR), Lee, Chun Mong; (Chungcheongnamdo, KR), Lee, Seung Ji; (Chungcheongnam-do, KR), Lee, Young Jin; (Chungcheongnamdo, KR) Correspondence: J. Rodman Steele, JR; Akerman, Senterfitt & Eidson, P.A.; Post Office Box 3188; West Palm Beach; FL; 33402-3188; US Patent Application Number: 20030118616 Date filed: December 7, 2001 Abstract: The present invention concerns stabilized cosmetic material containing tripleencapsulated retinal. Unstable, fat-soluble retinal is stabilized firstly by addition into vesicles consisting of nonionic surface-active agent, cholesterol and cholesteryl ester. The firstly stabilized retinol (vesicle) is subsequently inserted into sphingosomes (a kind of multi lamellar liposome) consisting of lecithin and ceramide. Finally the doubleencapsulated retinal (sphingosome) is inserted into lamellar liquid-crystal emulsifying base, thereby being triply encapsulated. Excerpt(s): The present invention concerns stabilized cosmetic material containing triple encapsulated retinol. In concrete terms, unstable and fat-soluble retinol is stabilized firstly by addition into vesicles consisting of nonionic surface-active agent, cholesterol and cholesteryl ester. The firstly stabilized retinol(vesicle) is subsequently inserted into sphingosomes (a kind of multi lamellar liposome) consisting of lecithin and ceramide. Finally the double encapsulated retinol (sphingosome) is added into a lamellar liquidcrystal emulsifying base. Thusly, useful cosmetic material, which diminishes wrinkling,

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skin irritation and improves moisturizing effect, is obtained. Chronoaging results in general degradation of the skin. Wrinkling and thickening of the skin induced by solar light result in sagging, reduced elasticity of skin, dry skin and mottling, and other harmful effects are additively increased by exposure to sunlight and this phenomenon is called "photoaging". Deterioration of the epidermis and dermis, wrinkling, yellowing, thickening and reduced elasticity of skin are all associated with photoaging. To solve this problem, uses of retinoid (vitamin A) have been reported in U.S. Pat. Nos. 4,603,146 and 4,877,805. There are Retinol (Vitamin A alcohol), Retinal (Vitamin A aldehyde), Retinyl acetate, Retinyl propionate, Retinyl linoleate and Retinyl palmitate in the Retinoid group. Among elements of retinoid group, retinol is a compound which can be naturally found in the human body and is essential in the specialization and growth of epithelium. Moreover, retinol is superior to other retinoids (such as retinoic acid) in terms of safety for living creatures, so retinol is suitable for skin-care cosmetic material. In case of excessive intake, retinol is chiefly stored as an inactive form of retinyl palmitate, and a small quantity is stored as an inactive form of retinyl acetate in the human body. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Cosmetic skin conditioning compositions containing high performing retinyl esters Inventor(s): Barratt, Marieann; (Oak Ridge, NJ), DeFlorio, Victor; (Cranford, NJ), Granger, Stewart Paton; (Sharnbrook Bedford, GB), Iobst, Susanne Teklits; (Maywood, NJ), Kosturko, Richard John; (Nutley, NJ), Scott, Ian Richard; (Allendale, NJ) Correspondence: Unilever; Patent Department; 45 River Road; Edgewater; NJ; 07020; US Patent Application Number: 20020001603 Date filed: April 18, 2001 Abstract: Cosmetic skin care compositions containing a high performing retinyl ester which is an ester of retinol with C.sub.18, unsaturated, non-essential, cis-6 and/or cis-12 fatty acid. The ester is preferably selected from the group consisting of gamma-retinyl linolenate, retinyl petroselinate, and retinyl cis-12-octadecenoate. Excerpt(s): Cosmetic methods and compositions for conditioning human skin by topical application to the skin of cosmetic compositions containing selected retinyl esters. Cosmetic products which improve the appearance of skin are increasingly popular with consumers. These products aim to alleviate or delay the signs of aged or photoaged skin, such as fine lines and wrinkles, dry and sagging skin. Although the marketplace offers a variety of products, cosmetic manufacturers continue the quest for alternative actives, in order to provide a consumer with a choice of products. A number of retinyl esters are disclosed in prior art. See for example U.S. Pat. No. 5,723,139; U.S. Pat. No. 5,885,595; WO 94/09756; EP 0 512 814; U.S. Pat. No. 5,723,139; EP 0710 478; U.S. Pat. No. 5,037,850; U.S. Pat. No. 4,992,265; U.S. Pat. No. 5,605,933. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Cosmetic skin conditioning compositions containing red yeast rice extract Inventor(s): Bajor, John Steven; (Ramsey, NJ), Januario, Thomas Eugene; (Middletown, NY), Mahajan, Manisha Narayan; (Westwood, NJ), Pillai, Sreekumar; (Wayne, NJ), Santhanam, Uma; (Tenafly, NJ) Correspondence: Unilever; Patent Department; 45 River Road; Edgewater; NJ; 07020; US Patent Application Number: 20020041883 Date filed: December 14, 2000 Abstract: Cosmetic methods and compositions for conditioning human skin by topical application to the skin of cosmetic compositions containing red yeast rice extract. Cosmetic compositions containing red yeast rice extract in combination with ascorbyl palmitate, or sodium ascorbyl phosphate, or retinol, or retinyl ester are also disclosed. Excerpt(s): This application claims the benefit of U.S. provisional application no. 60/170,669 filed Dec. 1, 1999. Cosmetic methods and compositions for conditioning human skin by topical application to the skin of cosmetic compositions containing red yeast rice extract. Cosmetic products which improve the appearance of skin are increasingly popular with consumers. Frequently, consumers seek to alleviate or delay the signs of aged or photoaged skin, such as fine lines and wrinkles, dry and sagging skin. Consumers also frequently seek other benefits in addition to anti-aging. A frequent, undesirable skin condition is "oily skin," the condition which results from the excessive amount of sebum on the skin. Sebum is skin oil which is produced by sebocytes (cells of the sebaceous glands in the skin) and is then secreted to the skin surface. Oily skin is associated with a shiny, undesirable appearance and a disagreeable tactile sensation. Oily skin affects various age groups. Cosmetic actives which are able to provide both anti-aging benefits and sebum control are highly desirable, both from the manufacturer's and consumer's perspective. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Isolated nucleic acid molecule which codes for a 32 kDa protein having 11-CIS retinol dehydrogenase activity, and which associates with p63, a portion of a retinol binding protein receptor Inventor(s): Eriksson, Ulf; (Stockholm, SE), Romert, Anna; (Stockholm, SE), Simon, Andras; (Stockholm, SE) Correspondence: Fulbright & Jaworski, Llp; 666 Fifth Ave; New York; NY; 10103-3198; US Patent Application Number: 20030032169 Date filed: May 4, 2001 Abstract: In accordance with this invention, an RPE cell membrane associated protein which has a molecular weight of about 32 kd, as determined by SDS-PAGE, has been discovered. This protein, referred to an "p32," forms an oligomeric protein complex with the previously characterized p63 protein, a component of the membrane receptor for RBP. A nucleic acid molecule which codes for the p32 protein has also been isolated and sequence analysis shows that the p32 protein belongs to the family of short chain alcohol dehydrogenases, and exhibits 11-cis retinol dehydrogenase activity, the enzyme which catalyzes conversion of 11-cis-retinol into 11-cis retinaldehyde.

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Excerpt(s): This application is a continuation-in-part of copending application Serial Number 08/375,962, filed Jan. 20, 1995, which is itself a continuation in part of copending application, Serial No. 08/258,418 filed Jun. 10, 1994. Both applications are incorporated by reference. This invention relates to a protein having 11-cis retinol dehydrogenase activity, and which forms a complex with a specific portion of a membrane receptor for plasma retinol-binding protein (RBP) expressed, e.g., in retinal pigment epithelium (RPE), and more specifically a 32 kDa protein having 11-cis retinol dehydrogenase activity, which forms a complex with a 63 kDa RBP-binding membrane protein. The invention also involves isolation of the 32 kDa protein (p32), as well as nucleic acid molecules coding for p32 or complimentary to coding sequences therefor, in addition to various applications of these materials. Retinoids (vitamin A-derivatives) have important physiological functions in a variety of biological processes. During embryonic growth and development, as well as during growth and differentiation of adult organisms, retinoids act as hormones and participate in the regulation of gene expression in a number of cell types. See Lied et al. Trends Genet., 17:427-433 (1992). It is believed that the effects of these molecules are mediated through two classes of nuclear ligand-controlled transcription factors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), Benbrook et al., Nature, 333:669-672 (1988); Brand et al., Nature, 332:850-853 (1988); Giguere et al., Nature, 330:624-629 (1987); Mangelsdorf et al., Nature, 345:224-229 (1990); Mangelsdorf, et al. Genes Dev. 6:329-344 (1992); Petkovich et al. Nature 330:440-450 (1987); and Zelent et al., Nature 339:714-717 (1989). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

METHODS AND COMPOSITIONS FOR PREVENTING CHRONOLOGICAL AGING IN HUMAN SKIN

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TREATING

Inventor(s): FISHER, GARY J.; (ANN ARBOR, MI), KANG, SEWON; (ANN ARBOR, MI), VARANI, JAMES; (ANN ARBOR, MI), VOORHEES, JOHN J.; (ANN ARBOR, MI) Correspondence: Hopgood Calimafde Kalil & Judlowe; 60 East 42nd Street; New York; NY; 10165 Patent Application Number: 20010053347 Date filed: February 24, 1998 Abstract: The deleterious effects of the passage of time on human skin (i.e., chronological aging of human skin) can be prevented and treated with the topical application of a retinoid, preferably retinol. We have found that some of the same pathways (namely the stress-activated pathways, SAPs) activated in photoaging of human skin (i.e., sun-induced premature skin aging) are similarly elevated in the skin of elderly people. We have also found that other pathways (namely the mitogen-activated ERK pathway) is depressed in the same skin. Treatment of chronologically-aged skin with a retinoid both inhibits degradation of dermal collagen and promotes procollagen synthesis. Biopsied sections from skin of elderly (80+ years old) show that a single treatment can increase epidermal thickness, improve the dermal collagen density, and promote the formation of rete pegs and dermal papillae (see FIG. 13), and can decrease the amount of c-Jun and increase the amounts of Types I and III procollagen (see FIG. 18). Such benefits are also helpful in preventing bruising, tearing, and ulceration of elderly skin. Excerpt(s): This application is based in part on copending provisional applications Nos. 60/040,594, filed Feb. 25, 1997, and 60/042,976, filed Apr. 7,1997, the disclosures of which are incorporated herein by reference. This invention relates to methods and

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compositions, especially those comprising retinoids, preferably topically applied, which are useful for improving keratinocyte and fibroblast proliferation, decreasing matrix metalloproteinase (MMP) expression, and improving collagen synthesis in elderly skin, thus providing as an effect the rejuvenation of aged skin. As far as mammals go, humans are essentially hairless; that is, most of the skin of the human body can be seen without interference from hair. The skin is thus exposed to whatever insults (natural and man-made) the environment harbors. Since it was first understood that the sun caused erythema, people have taken measures to avoid its "harmful rays." A century ago, in Elizabethan England, it was the fashion to avoid the sun at all costs. Yet the skin of those Elizabethans still wrinkled and displayed other signs of chronological aging. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods and compositions for the treatment of macular and retinal degenerations Inventor(s): Travis, Gabriel H.; (Los Angeles, CA) Correspondence: Gina N. Shishima; Fulbright & Jaworski L.L.P.; Suite 2400; 600 Congress Avenue; Austin; TX; 78701; US Patent Application Number: 20030032078 Date filed: June 19, 2001 Abstract: The present invention is a method for screening and identifying therapeutic agents for the treatment of macular or retinal degeneration. The candidate substances preferably reduces the activity of 11-cis-retinol dehydrogenase. In vitro and in vivo studies administering the inhibitor molecules to abcr knockout mice and analyzing for the inhibition of lipofuscin (A2E) accumulation are contemplated. Excerpt(s): The present application claims the benefit of U.S. Provisional Application Serial No. 60/263,837 filed on Jan. 23, 2001. The entire text of the above-referenced disclosure is herein incorporated by reference. The government may own rights in the present invention pursuant to grant number R01 EY11713 from The National Institutes of Health. 1. Field of the Invention The present invention relates generally to the field of optical disease, such as macular and retinal degenerations. More particularly, it concerns modulators of dehydrogenases, such as 11-cis-retinol dehydrogenase, which are involved in the visual pathway and can be used for the prevention or treatment of macular or retinal degeneration. The macular degenerations are a group of inherited blinding diseases that cause destruction of the central retina. Age-related macular degeneration (AMD), for example, is the leading cause of blindness in the elderly and affects ten million people in the United States. Little is understood about the cause of macular degeneration, and there exists no effective treatment. The macula contains a central structure called the fovea, populated exclusively with cone photoreceptors. Death of these foveal cones results in devastating loss of central vision. Although cones are far more important than rods for human vision, most of what is known about photoreceptor function comes from the study of rod-dominant retinas. For example, the majority of genes identified for inherited retinal degenerations encode proteins expressed specifically in rods. The current invention focuses on cones and diseases of the macula. Fifteen distinct loci for inherited diseases involving abnormal cone function and macular degenerations have been mapped but not yet cloned. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods for the treatment of hyperpigmentation of skin Inventor(s): Carmichael, Robin; (Redmond, WA), Patt, Leonard M.; (Seattle, WA) Correspondence: Seed Intellectual Property Law Group Pllc; 701 Fifth Ave; Suite 6300; Seattle; WA; 98104-7092; US Patent Application Number: 20030134781 Date filed: October 4, 2002 Abstract: Methods for treating hyperpigmentation of skin employ topical application of compositions to skin in need thereof, where the compositions comprise at least one peptide copper complex, or at least one peptide copper complex in combination with retinol, at least one retinol derivative, or a mixture thereof. Also disclosed are methods that use such compositions further comprising active agents selected from active drug substances, emollients, sunscreen agents, skin-lightening agents, skin protectants, skin conditioning agents, and humectants. Excerpt(s): This application claims the benefit of U.S. Provisional Patent Application No. 60/364,657 filed Mar. 14, 2002 and U.S. Provisional Patent Application No. 60/327,640 filed Oct. 5, 2001, where the two provisional applications are incorporated herein by reference in their entireties. The present invention generally relates to the treatment of dermatological conditions, more specifically, of those conditions related to hyperpigmentation, by means of the topical application of compositions, effective therefor. Melanin is a dark pigment found in the skin of humans that is responsible for the darkening of the skin. Melanin is produced by specialized cells in the skin called malanocytes through a complicated series of chemical and enzymatic reactions, mainly involving the copper containing enzyme tyrosinase. The melanin pigments are packaged in granules called melanosomes. Melanosomes are transferred to the outer layer of the skin where they are responsible for the darkening of the skin, the degree of darkening being associated with skin type, sun exposure, and/or certain dermatological conditions. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Mutations in nucleic acid molecules encoding 11-CIS retinol dehydrogenase, the mutated proteins, and uses thereof Inventor(s): Berson, Eliot L.; (Boston, MA), Dryja, Thaddeus P.; (Boston, MA), Eriksson, Ulf; (Stockholm, SE), Simon, Andras; (Stockholm, SE), Yamamoto, Hioyuji; (Boston, MA) Correspondence: Fulbright & Jaworski Llp; 666 Fifth Avenue; New York; NY; 10103; US Patent Application Number: 20020042116 Date filed: June 13, 2001 Abstract: The invention relates to mutations in the gene encoding 11-cis retinal dehyrogenase. The mutations in the gene and in the resulting encoded protein are correlated to ocular disorders, such as fundus albipunctatus. Excerpt(s): This invention relates to mutations in nucleic acid molecules encoding the protein 11-cis retinol dehydrogenase, or "RDH5," and the resulting mutated protein. These mutations are implicated in ocular disorders, such as fundus albipunctatus. The diagnostic and therapeutic ramifications of these mutations are also discussed and are features of the invention. Retinoids (vitamin A-derivatives) have important physiological functions in a variety of biological processes. During embryonic growth

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and development, as well as during growth and differentiation of adult organisms, retinoids act as hormones and participate in the regulation of gene expression in a number of cell types. See Lied et al. Trends Genet., 17:427-433 (1992). It is believed that these effects are medicated through two classes of nuclear ligand-controlled transcription factors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), Benbrook et al., Nature, 333:669-672 (1988); Brand et al., Nature, 332:850-853 (1988); Giguere et al., Nature, 330:624-629 (1987); Mangelsdorf et al., Nature, 345:224-229 (1990); Mangelsdorf, et al. Genes Dev. 6:329-344 (1992); Petkovich et al. Nature 330:440450 (1987); and Zelent et al., Nature 339:714-717 (1989). Apart from their function as hormones in cellular growth and differentiation, retinoids are also involved in the visual process, as the stereo isomer 11-cis retinaldehyde is the chromophore of the visual pigments. See, e.g. Bridges, The Retinoids, Vol. 2, pp 125-176, Academic Press, Orlando, Fla., (1984). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel sulfone derivatives and process for producing these Inventor(s): Kimura, Kazutaka; (Shizuoka, JP), Seko, Shinzo; (Osaka, JP), Takahashi, Toshiya; (Osaka, JP) Correspondence: Birch Stewart Kolasch & Birch; PO Box 747; Falls Church; VA; 220400747; US Patent Application Number: 20040034257 Date filed: December 30, 2002 Abstract: There are provided production processes for cyclic sulfone compounds of formula (2) or (4): 1wherein the dashed lines represent that a double bond is present at one of three positions indicated; Ar and the wavy line are as defined below, characterized in that compounds of formula (1) or (3): 2wherein Ar is aryl optionally having a substituent(s) and the wavy line represents either one of E/Z geometrical isomers or their mixture, is subjected to cyclization in the presence of an acid catalyst. These processes are excellent processes as the production processes for retinol from the viewpoints of raw material costs, intermediate purification, the number of steps, and the like. Excerpt(s): The present invention relates to disulfone derivatives and conjugated triene derivatives, which are useful as the intermediates of pharmaceuticals, feed additives, and food additives, e.g., as the intermediates of retinol derivatives and carotenoids, as well as their production processes. There have not been known so far the linear disulfone compounds of the following formula (11) and the conjugated triene compounds of the following formula (10). The present inventors have found sulfone derivatives as the important intermediates of retinol by the coupling reaction of cyclic sulfones and allyl halides derived from C10 alcohols (e.g., geraniol), as disclosed in JP-A 11-222479. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Oil-in-water emulsion formulation containing free and entrapped hydroquinone and retinol Inventor(s): Beausoleil, Marie-Helene; (Issy-Les-Moulineaux, FR), Saxena, Subhash J.; (Bedminister, NJ), Singh, B. Sandhya; (Bedminister, NJ) Correspondence: Kim Diliberti; 1430 Waukegan Road; Mchaw Park; IL; 60085-6787; US Patent Application Number: 20030032680 Date filed: May 16, 2002 Abstract: An oil-in-water emulsion formulation containing hydroquinone and retinol, which comprises an oil-in-water emulsion containing free hydroquinone, hydroquinone entrapped in absorbent micro-agglomerates and/or impregnated in porous microparticles; and retinol-impregnated microparticles. Excerpt(s): This application is a continuation-in-part of application Ser. No. 09/565,321 filed May 5, 2000, now abandoned. This invention relates to an oil-in-water emulsion formulation containing hydroquinone and retinol. More specifically this invention relates to oil-in-water emulsions that contain hydroquinone entrapped in microagglomerates and/or impregnated in porous microparticles and in free form; and retinol-impregnated porous microparticles. Hydroquinone is a reduced quinone, wellrecognized as an efficacious skin-lightening agent. When topically applied, it produces a reversible depigmentation of the skin by inhibiting the enzymatic oxidation of tyrosine to 3,4-dihydroxyphenylalanine, as well as suppressing other metabolic processes of melanocytes. In a clinical setting, hydroquinone is employed to treat hypermelanosis. It has likewise been utilized to bleach hyperpigmented skin conditions including chloasma, melasma, freckles, and senile lentigines. Hydroquinone is available in overthe-counter and prescription products. Although hydroquinone is considered a mild irritant, it displays minimal toxicity in humans. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Polyester polyol nanocapsules, compositions thereof, and methods of use Inventor(s): Guerin, Gilles; (Eaubonne, FR), Simonnet, Jean-Thierry; (Paris, FR) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20030224060 Date filed: February 12, 2003 Abstract: The present invention relates generally to nanocapsules having a coreenvelope structure where the core contains a lipophilic active agent and the envelope contains at least one polyester polyol obtained by polycondensation of an aliphatic dicarboxylic acid with at least two alkanediols or with at least one alkanediol and at least one hydroxyalkyl alkanediol. These nanocapsules make it possible to stabilize lipophilic active agents that are difficult to stabilize, especially retinol esters such as retinyl propionate. Excerpt(s): This application is based on, and claims priority to, U.S. provisional application 60/361,707, filed Mar. 6, 2002 and French patent application 0202290, filed Feb. 22, 2002, both of which are incorporated by reference herein. The present invention relates to nanocapsules having a lipid core forming or containing a lipophilic active agent, and a water-insoluble envelope, comprising at least one polyester polyol.

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Preferably, this polyester polyol is obtained by polycondensation of an aliphatic dicarboxylic acid with at least two alkanediols or with at least one alkanediol and at least one hydroxyalkyl alkanediol. The aliphatic dicarboxylic acid is preferably adipic acid (hexane-1,6-dioic acid). These nanocapsules make it possible to stabilize lipophilic active agents that are difficult to stabilize, and especially retinol esters such as retinyl propionate. The invention also relates to cosmetic and/or dermatological compositions containing the invention nanocapsules, and to a process for preparing these nanocapsules. The term "nanoparticles" mainly encompasses two different systems: "nanospheres" consisting of a porous polymer matrix in which the active principle is absorbed and/or adsorbed, and "nanocapsules" with a structure of core-envelope type, i.e. a structure with a lipid core forming or comprising the active principle, this core being encapsulated in a water-insoluble, preferably continuous, protective envelope. The present invention relates exclusively to this second vesicular type of nanoparticles, i.e. nanocapsules with a lipid core surrounded by a polymer membrane. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Process for producing retinol and intermediate compounds for producing the same Inventor(s): Doi, Noriyuki; (Osaka, JP), Kimura, Kazutaka; (Osaka, JP), Konya, Naoto; (Osaka, JP), Seko, Shinzo; (Osaka, JP), Takahashi, Toshiya; (Osaka, JP) Correspondence: Birch Stewart Kolasch & Birch; PO Box 747; Falls Church; VA; 220400747; US Patent Application Number: 20020058844 Date filed: October 18, 2001 Abstract: There are disclosed a disulfone compound of formula (1): 1wherein Ar denotes an aryl group that may have a substituent, R1 denotes a hydrogen atom or a protective group of a hydroxyl group and the wavy line means that the disulfone compound is an E or Z geometrical isomer or a mixture thereof,a method for producing the same,intermediate compounds therefore anda process for producing retinol through the disulfone compound. Excerpt(s): The present invention relates to sulfone compounds that are useful intermediate compounds for the production of pharmaceuticals, feed additives or food additives such as retinal, and production methods for producing the same, and a process for the production of retinol using the same. There has been disclosed a process for producing retinol by reacting a sulfone of formula (6) shown below with a C10 aldehyde compound derived from linalool by a plurality of steps to obtain a C20 hydroxy sulfone compound, and derivatizing the same by a plurality of steps (U.S. Pat. No. 4,825,006). However, there is a demand for the development of a further improved industrial production process for producing retinol. According to the present invention, retinol can be readily obtained by using novel sulfone compounds and a readily available C5 allyl halide compound. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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RETINOL STABILIZED CLEANSING COMPOSITIONS Inventor(s): DUBOIS, JENNIFER; (PRINCETON, NJ), NYSTRAND, GLENN; (LEBANON, NJ) Correspondence: Darby & Darby PC; 805 Third Avenue; New York; NY; 10022 Patent Application Number: 20010001783 Date filed: May 14, 1999 Abstract: The present invention provides compositions which include (A) a skin enhancing agent; (B) glycerin; (C) one or more emollients; and (D) a salt of cocoyl isethionate, a mono alkyl phosphate or a salt thereof, or a combination thereof, neutralized to a pH ranging from about 5 to about 8. In an alternate embodiment, the present invention provides compositions described above which further include (E) water; (F) a gum; (G) a gum neutralized to a pH ranging from about 5 to about 8; (H) a detergent additive selected from the group consisting of sodium lauryl sulfate, a sodium salt of fatty acid taurate, an acyl glutamate, an alpha-olefin sulfonate, a sarcosinate, or any combination of any of the foregoing; (I) a mixture of diosodium cocamido monoethanolamine sulfosuccinate and cocamido betaine; (J) an anti-microbial agent; (K) microcrystalline wax; (L) a foam booster; (M) an antioxidant; (N) a UV stabilizer; (O) a sun screen; (P) a colorant; (Q) a fragrance; (R) a preservative; (S) a chelating agent; (T) a physical exfolliant; or (U) any combination of any of the foregoing. These compositions are useful in preparing stable formulations containing pH dependent active agents including, but not limited to, retinol. Also provided are methods of delivering skinenhancing agents, such as retinol, to an animal, preferably a mammal, and most preferably a human, by topically applying the compositions of the present invention to the skin of an animal in need of the skin enhancing agent. Excerpt(s): This invention relates to cosmetically aesthetic, stable cleansing preparations containing skin-enhancing agents such as, for example, retinol. A mild depositing cleanser is disclosed in Ramirez et al., U.S. Pat. No. 5,409,706. This cleanser is an essentially anhydrous oil and surfactant mixture dispersed in a continuous glycerin phase. However, this formulation exhibits poor aesthetics including excess firmness and an occasional granular texture. This formulation also exhibits poor in-use aesthetics such as, for example, poor spreadability when contacted with water (which leads to the floating chunks of the cleanser) and low amounts of foam. This cleanser also exhibits poor stability in that it often develops syneresis of both oils (at the top of the cream) and glycerin (at the bottom). Even when left at room temperature for relatively short periods of time, tube samples ooze clear liquids. See also, U.S. Pat. No. 5,254,334. See also, U.S. Pat. No. 5,602,087 which discloses a low water content composition in solid form. Moreover, certain active agents such as, for example, retinol are unstable at low pH such as the pH of the given thickened compositions of U.S. Pat. No. 5,409,706. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Retinyl carbonate derivatives, preparation process and uses Inventor(s): Dalko, Maria; (Gif S/yvette, FR), Rubinstenn, Gilles; (Paris, FR), Tuloup, Remy; (Paris, FR) Correspondence: Oblon Spivak Mcclelland Maier & Neustadt PC; Fourth Floor; 1755 Jefferson Davis Highway; Arlington; VA; 22202; US Patent Application Number: 20020019547 Date filed: August 31, 2001 Abstract: The present invention relates to novel retinol derivatives having the formula (I): 1and to processes for preparing them. The invention also relates to the use of these compounds in or for the preparation of compositions intended for treating conditions of the skin or scalp, for example in preventing or combating acne and/or chronological or actinic ageing of the skin. Excerpt(s): The present invention relates to novel retinyl carbonate derivatives. The invention also relates to the use of these compounds in or for the preparation of compositions intended in particular for preventing or combating acne and/or chronological or actinic ageing of the skin. Retinoid-based cosmetic and/or dermatological compositions have undergone considerable development in recent years. The reason for this is that it has been found that certain compounds of the retinoid family, derived from retinoic acid, are advantageous in skin care, in particular in the treatment of acne and for limiting, or even eliminating altogether, the effects of ageing on the skin such as wrinkles, a weathered appearance, yellowing, loss of elasticity, a ruddy complexion and dryness of the skin, as well as the appearance of blemishes. These signs of ageing are all the more accentuated when the skin is frequently exposed to sunlight or is particularly sensitive to exposure to UV radiation. Thus, the effects of intrinsic ageing of the skin (age-related) and of light-induced ageing (due to exposure to sunlight) can be cumulative. The manifestations of ageing usually appear at an advanced age; however, their prevention should be undertaken from the start of adult life by suitable care treatments. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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SKIN CARE COMPOSITION Inventor(s): COLE, CURTIS A.; (LANGHORNE, PA), FLACK, LAURA E.; (OVERLAND PARK, KS), KAMINSKI, CLAUDIA; (MILFORD, NJ) Correspondence: Philip S. Johnson; One Johnnson & Johnson Plaza; New Brunswick; NJ; 08933-7003; US Patent Application Number: 20020048591 Date filed: June 3, 1999 Abstract: There are provided compositions which include a retinoid and preferably retinol; an acid; and an acid neutralizing effective amount of ammonium hydroxide. There are also provided compositions which include a retinoid and a neutralized ammonium salt of an acid. Further provided are methods for reducing fine lines and wrinkles and for increasing the clarity of a skin surface, cellular turnover, skin radiance, skin smoothness, skin permeation or collagen synthesis in a mammal in need thereof. Compositions as described above are administered topically to the skin of the animal.

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Excerpt(s): This invention relates to skin care compositions which include, in a single formulation, the beneficial ingredients for aging or photodamaged skin, retinol and an acid. Retinol or vitamin A alcohol is useful in the reduction of fine lines, wrinkles, and mottled hyperpigmentation in skin. Hydroxy acids, and particularly alpha-hydroxy acids, are useful in increasing the clarity of the skin surface, increasing cellular turnover, and increasing skin radiance and smoothness. Ascorbic acid has skin permeation and collagen synthesis activity. However, retinol is physically unstable and rapidly degrades when stored at a pH below about 5. Acids such as hydroxy acids, and particularly alpha-hydroxy acids and ascorbic acid, on the other hand, are not active in increasing skin cell turnover, exfoliation, skin permeation, and/or collagen synthesis at pHs above about 5, however. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Skin care compositions containing peptide copper complexes and retinol, retinol derivatives, or a mixture thereof Inventor(s): Patt, Leonard M.; (Seattle, WA) Correspondence: Seed Intellectual Property Law Group Pllc; 701 Fifth Ave; Suite 6300; Seattle; WA; 98104-7092; US Patent Application Number: 20030134780 Date filed: October 4, 2002 Abstract: Compositions, generally useful for preserving the skin and/or improving its health and appearance, comprise a peptide copper complex and retinol, a retinol derivative, or a mixture thereof. In another embodiment, the disclosed compositions further comprise additives, including emollients, sunscreen agents, skin protectants, skin conditioning agents, and/or humectants. Also disclosed is a method for treating skin to accomplish such preservation and/or improvement thereof, where the method comprises the step of topically applying a disclosed composition to an area of skin in need of such treatment. Excerpt(s): This application claims the benefit of U.S. Provisional Patent Application No. 60/327,640 filed Oct. 5, 2001, where this provisional application is incorporated herein by reference in its entirety. The present invention generally relates to skin care compositions, and pharmaceutical and cosmetic preparations for skin, and more particularly, to compositions and preparations comprising peptide copper complexes and retinol, a retinol derivative, or a mixture thereof, as well as to methods for treating or preventing dermatological conditions related to photodamaged and aging skin. The use of chemical compositions to treat aged or photodamaged skin has been reported. For example the topical use of retinol (viatamin A) and retinol derivatives had been described for such treatment. More specifically, the retinol derivative, retonoic acid (present in Retin-A and Renova, Ortho Pharmaceuticals, Skillman, N.J.), has been shown to reduce the signs of photoaging (see J. Invest. Dermatology 104(4): 518-522, 1995). Retinoic acid compositions useful in skin treatment and cosmetic preparations have been disclosed, for example, in U.S. Pat. Nos. 5,955,109; 5,719,195; and 4,126,693. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Skincare agents Inventor(s): De Moragas, Maria; (Argentona, ES), Viladot Petit, Josep-Lluis; (Barcelona, ES) Correspondence: Cognis Corporation; 2500 Renaissance BLVD., Suite 200; Gulph Mills; PA; 19406 Patent Application Number: 20030044469 Date filed: August 28, 2002 Abstract: Skin care compositions containing microcapsules with a mean diameter of from 0.1 to 5 mm are disclosed. The microcapsules are prepared by a process comprising: (a) providing an o/w emulsion prepared by combining an aqueous preparation of a component selected from the group consisting of retinol and retinolic acid with an oil component in the presence of an emulsifier; (b) combining the emulsion and an aqueous solution of an anionic polymer to form a matrix; (c) contacting the matrix with an aqueous chitosan solution such that membrane-encapsulated products are formed in an aqueous phase; and (d) separating the products from the aqueous phase. Excerpt(s): This invention relates generally to cosmetics and more particularly to skin care preparations containing an effective quantity of retinol or retinolic acid encapsulated in a particular manner. Retinol, also known as vitamin A, is a fat-soluble isoprenoid of which the advantageous effects in skin care have been known for some time. These effects are largely attributable to the fact that retinol promotes the growth, the differentiation and the preservation of the epithelial tissue. Accordingly, the use of retinol-containing products, particularly in so-called anti-ageing products such as, for example, Roc's "Retinol-concentre bi-actif with AHA" or Vichy's "Reti-C concentre with vitamin C", is very popular. However, the disadvantage of retinol is that it is photochemically unstable and is rapidly degraded under the influence of light, especially at relatively high temperatures. In the cosmetics field, attempts have hitherto been made to tackle the problem of the inadequate stability of retinol in very different ways, for example by storage under inert conditions, by addition of antioxidants (for example vitamin E or BHT) or by the use of lightproof packs. However, only the encapsulation of retinol in a more or less stable matrix has proved to be of any practical value. For example, so-called "thalasspheres" or "cylaspheres" which contain 1% by weight retinol encapsulated in a collagen matrix are marketed by Coletica. Sphere Tech Co. market phospholipid-based liposomes which contain 4.5% by weight retinol; the percentage content of retinol in ROVI's "rovisomes" (matrix: lecithin) or Lipotec's sphingosomes (basis: sphingolipids) is between 0.3 and 2% by weight. However, none of these systems shows totally satisfactory stability. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Topical agent for dermatological use Inventor(s): Kuriki, Takashi; (Osaka, JP), Nakae, Takashi; (Hyogo, JP), Nakayama, Hiroki; (Tokyo, JP), Nishimura, Takahisa; (Nara, JP) Correspondence: Pennie And Edmonds; 1155 Avenue OF The Americas; New York; NY; 100362711 Patent Application Number: 20030198610 Date filed: June 4, 2003

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Abstract: The objetive of the present invention was to enhance the skin whitening effects and blackening prevention effects and supply safe and stable topical agents for dermatological use. For that purpose 4-Hydroxyphenyl-.alpha.-D-glucopyranoside was combined with auxiliary agents such as ascorbic acid and its derivatives, crude drugs and its extracts, hydroxycarboxylic acid and its salts, oil soluble glycyrrhiza extract, gentian extract, phenol derivatives and their salts, placenta extract, kojic acid and its derivative, glucosamine and its derivatives, azelaic acid and its derivatives, retinol and its derivatives, pyridoxin and its derivatives, tocopherol and its derivatives, chitosan and its decomposition products, caffeic acid derivatives, hydroxycinnamate and its derivatives, Umbelliferae plant extracts, mycelial cultures and their extracts, plant leaves and their extracts. Excerpt(s): The present invention is related to topical agents for dermatological use which whiten the skin color or prevent its blackening and prevent or relieve liver spots, freckles, etc. and which show generally desirable formulation properties in terms of the safety and stability. Various melanin formation preventing agents have been used to whiten the skin color or prevent its blackening and prevent or relieve skin troubles such as liver spots and freckles caused due to excessive exposure to UV rays. These agents include 1,4-dihydroxybenzene,.beta.-arbutin, vitamin C and its derivatives, and kojic acid. However, vitamin C, 1,4-dihydroxybenzene and kojic acid are extremely unstable with respect to heat and oxidation in water. When added to topical agents for dermatological use, therefore, these compounds decompose over time and cause coloration. Their derivatives, such as phosphate-ascorbyl magnesium and.beta.-arbutin, which is obtained as a result of the.beta.-binding of glucose to one of the hydroxy groups of 1,4-dihydroxybenzene, are not necessa-rily satisfactory in terms of efficacy although they are more stable than their parent compounds with respect to heat and oxidation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Topical preparation for treating acne and hirsutism Inventor(s): Goodman, David S.; (Naples, FL) Correspondence: Robert I. Pearlman, ESQ.; Riker, Danzig, Scherer, Hyland & Perretti Llp; Headquarters Plaza; One Speedwell Avenue; Morristown; NJ; 07962; US Patent Application Number: 20020155180 Date filed: March 13, 2002 Abstract: An improved method and preparation for the treatment of acne and hirsutism comprises topically applying an effective amount of a saw palmetto berry extract, and preferably one or more low irritability constituents that enhance penetration of the extract into hair follicle sebaceous glands. The low irritability penetration aid may be selected from the group consisting of adapalene, tretinoin, tretinoin gel microsponges, retinaldehyde, retinol, tazarotene, beta hydroxy acids (salicylic acid), azelaic acid, and alpha hydroxy acids (glycolic acid) as well as polyolprepolymer-2. Excerpt(s): This application is a Continuation-in-Part of U.S. Ser. No. 09/563,555 filed May 3, 2000 for the instant inventor. This invention relates to an improved preparation and method for treating both acne and hirsutism, or unwanted facial and body hair in women; and more particularly to a preparation comprising a topically active extract of saw palmetto berries, with one or more compounds which exhibit low irritability and enhance penetration of the extract into hair follicles and sebaceous glands. Acne is

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caused by a complex interaction of excessive sebum production colonization of hair follicles by Proprionibasterium acnes, and follicular plugging or comedone formation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Treatment of hyperproliferative diseases Inventor(s): Bavik, Claes; (Sheffield S. Yorks, GB), Cork, Michael; (Sheffield S. Yorks, GB), Tazi-Aahnini, Rachid; (Sheffield S. Yorks, GB), Ward, Simon; (Sheffield S. Yorks, GB) Correspondence: Frommer Lawrence & Haug; 745 Fifth Avenue- 10th FL.; New York; NY; 10151; US Patent Application Number: 20030119715 Date filed: February 27, 2002 Abstract: We describe methods and compositions for treating a patient suffering from a hyperproliferative disorder or photoageing. Our methods involve blocking the activity of a retinol binding protein receptor (RBPr) in cells of the patient, and/or administering to the patient an antagonist of a retinol binding protein receptor (RBPr) and/or lowering the endogenous level of retinoic acid (RA) in cells of said patient. Excerpt(s): This application is a continuation-in-part of international application PCT/GB01/03694, filed Aug. 17, 2001 and claims priority from Great Britian Application No. 0020351.3, filed Aug. 17, 2000. The above-mentioned applications, as well as all documents cited herein and documents referenced or cited in documents cited herein, are hereby incorporated herein by reference. This invention relates to the treatment of diseases associated with cellular hyperproliferation in a patient, including psoriasis and cancer. The invention also relates to the treatment or alleviation of symptoms associated with photoageing. A number of diseases are associated with hyperproliferation of cells, including psoriasis, the ichthyoses, cancer and cutaneous viral infections. Psoriasis is a chronic inflammatory disease characterised by hyperproliferation and impaired differentiation of keratinocytes. Currently, the symptoms of psoriasis are treated in a number of ways, including topical administration of retinoids to the patient. Other diseases such as acne vulgaris and photoageing also respond to retinoid therapy and are believed to involve additional retinoid-mediated mechanisms. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of retinol in assisted-reproduction protocols Inventor(s): Eberhardt, Dawn M.; (Knoxville, TN), Godkin, James D.; (Knoxville, TN) Correspondence: Stanley A. Kim; Akerman, Senterfitt & Eidson, P.A.; 222 Lakeview Avenue, Suite 400; P.O. Box 3188; West Palm Beach; FL; 33402-3188; US Patent Application Number: 20020028849 Date filed: April 17, 2001 Abstract: Disclosed is the use of retinoids such as retinol, all trans retinoic acid, and 9-cis retinoic acid to enhance the success of assisted-reproduction. Administration of retinol to superovulated animals dramatically improved embryo viability and development as well as the pregnancy rates of animals implanted with embryos derived from such

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animals. Culturing presumptive embryos in vitro in the presence of retinol enhanced development of embryos from the presumptive zygotes compared to presumptive embryos not treated with retinol. Excerpt(s): The present application claims the benefit of U.S. provisional patent application number 60/198,061 filed Apr. 18, 2000. Not applicable. The invention relates the field of sexual reproduction. More particularly, the invention relates to the use of retinoids to improve assisted-reproduction protocols. 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 retinol, 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 “retinol” (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 retinol. You can also use this procedure to view pending patent applications concerning retinol. 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 5. BOOKS ON RETINOL Overview This chapter provides bibliographic book references relating to retinol. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on retinol include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Chapters on Retinol In order to find chapters that specifically relate to retinol, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and retinol 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 “retinol” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on retinol: •

Trace Elements and Vitamins in Renal Disease Source: in Mitch, W.E., and Klahr, S., eds. Nutrition and the Kidney. 2nd ed. Boston, MA: Little, Brown and Company. 1993. p. 114-131. Contact: Available from Lippincott-Raven Publishers. 12107 Insurance Way, Hagerstown, MD 21740. (800) 777-2295. Fax (301) 824-7390. E-mail: [email protected]. Website: http://www.lrpub.com. PRICE: $94.95. ISBN: 0316575003. Summary: This chapter, from a medical textbook on nutrition and the kidney, reviews the metabolism, concentrations, and requirements of trace elements and vitamins in patients with chronic renal failure (CRF) prior to the onset of dialysis and during treatment with either hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Topics include the alteration of trace element metabolism in kidney failure, including aluminum, iron, zinc, copper, selenium, and ultra trace elements; and vitamins, including thiamine (B1), riboflavin (B2), pyridoxine (B6), cobalamin (B12), folic

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acid, biotin, niacin, pantothenic acid, ascorbic acid (vitamin C), retinol (vitamin A), and tocopherol (vitamin E). The authors briefly discuss recommendations for supplementation. 4 tables. 101 references.

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CHAPTER 6. PERIODICALS AND NEWS ON RETINOL Overview In this chapter, we suggest a number of news sources and present various periodicals that cover retinol.

News Services and Press Releases One of the simplest ways of tracking press releases on retinol 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 “retinol” (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 retinol. 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 “retinol” (or synonyms). The following was recently listed in this archive for retinol: •

Retinol binding protein lost in some breast cancers Source: Reuters Medical News Date: March 16, 2000

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The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “retinol” (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 “retinol” (or synonyms). If you know the name of a company that is relevant to retinol, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “retinol” (or synonyms).

Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly

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to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “retinol” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on retinol: •

Does Excess Vitamin A Cause Hip Fracture? Source: Harvard Women's Health Watch. 9(7): 1-3. March 2000. Contact: Available from Harvard Women's Health Watch. Department SR, P.O. Box 380, Boston, MA 02117. (800) 829-5921. E-mail: [email protected]. Summary: This newsletter article provides women with information on the role of excess vitamin A in hip fracture. Researchers at Harvard Medical School who were studying the relationship between postmenopausal hip fracture and vitamin A intake found that women with an intake of 3,000 micrograms (mcg) or more per day had a 48 percent greater risk for hip fracture compared to women with an intake of 1,250 mcg or less per day. The increased risk was mainly due to a form of vitamin A known as retinol. In contrast, consumption of high levels of beta carotene, also a source of vitamin A, had a negligible impact on hip fracture risk. Women taking hormone replacement therapy were somewhat protected from the effects of too much retinol. A Swedish study also found a higher occurrence of hip fracture among women who consumed more than 1,500 mcg of retinol per day than women whose intake was less than 500 mcg daily. The study also found a consistent association between bone mineral density loss and retinol intake. No significant relationship was found between beta carotene intake and hip fracture. The article suggests some simple precautions women can take to prevent excess vitamin A in the body, including learning the source of vitamin A in fortified foods and multivitamins, avoiding exceeding the recommended dietary allowance of vitamin A, and eating fruits and vegetables. 2 figures and 1 table.

Academic Periodicals covering Retinol Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to retinol. In addition to these sources, you can search for articles covering retinol 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 Institute11: •

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

11

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

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•

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

•

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

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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

•

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

•

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

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 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:13 •

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

•

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

•

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

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

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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

•

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

12

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

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

•

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

The NLM Gateway14 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.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “retinol” (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 29954 307 760 86 81 31188

HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 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.18 Simply search by “retinol” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

14

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

15

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

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 Biologists19 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.20 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.21 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 Retinol In the following section, we will discuss databases and references which relate to the Genome Project and retinol. 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).22 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. 19 Adapted 20

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. 21 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. 22 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 “retinol” (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 retinol: •

Lecithin Retinol Acyltransferase Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604863

•

Retinol Dehydrogenase 10 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607599

•

Retinol Dehydrogenase 11 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607849

•

Retinol Dehydrogenase 5 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601617

•

Retinol-binding Protein 1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=180260

•

Retinol-binding Protein 2 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=180280

•

Retinol-binding Protein 3 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=180290

•

Retinol-binding Protein 4 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=180250 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

•

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,

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paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html •

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

•

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

•

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

•

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

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

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

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•

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

•

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 “retinol” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database23 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 Database24 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.

23

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 24 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

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To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “retinol” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

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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 retinol 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 retinol. 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 retinol. 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 “retinol”:

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Antioxidants http://www.nlm.nih.gov/medlineplus/antioxidants.html Cancer Alternative Therapy http://www.nlm.nih.gov/medlineplus/canceralternativetherapy.html Osteoporosis http://www.nlm.nih.gov/medlineplus/osteoporosis.html Vitamins and Minerals http://www.nlm.nih.gov/medlineplus/vitaminsandminerals.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “retinol” (or synonyms). The following was recently posted: •

Acne Source: Finnish Medical Society Duodecim - Professional Association; 2001 April 30; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3389&nbr=2615&a mp;string=Retinol

•

Clinical practice guidelines for nutrition in chronic renal failure Source: National Kidney Foundation - Disease Specific Society; 2000 June; 121 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2545&nbr=1771&a mp;string=Retinol

•

Lung cancer prevention: the guidelines Source: American College of Chest Physicians - Medical Specialty Society; 2003 January; 12 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3636&nbr=2862&a mp;string=Retinol

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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 retinol. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

•

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 retinol. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with retinol. 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 retinol. 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

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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 “retinol” (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 “retinol”. 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 “retinol” (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 “retinol” (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.25

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

25

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)26: •

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

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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

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California: Gateway Health Library (Sutter Gould Medical Foundation)

•

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

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

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

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

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

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

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

•

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/

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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/

26

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

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

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

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

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

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

•

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

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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

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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/

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•

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).

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

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

•

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

•

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

•

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

193

RETINOL DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 2-Hydroxy-5-nitrobenzyl Bromide: A chemical reagent that reacts with and modifies chemically the tryptophan portion of protein molecules. Used for 'active site' enzyme studies and other protein studies. Sometimes referred to as Koshland's reagent. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Abortion: 1. The premature expulsion from the uterus of the products of conception - of the embryo, or of a nonviable fetus. The four classic symptoms, usually present in each type of abortion, are uterine contractions, uterine haemorrhage, softening and dilatation of the cervix, and presentation or expulsion of all or part of the products of conception. 2. Premature stoppage of a natural or a pathological process. [EU] Abrasion: 1. The wearing away of a substance or structure (such as the skin or the teeth) through some unusual or abnormal mechanical process. 2. An area of body surface denuded of skin or mucous membrane by some unusual or abnormal mechanical process. [EU] Abscess: A localized, circumscribed collection of pus. [NIH] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Accommodation: Adjustment, especially that of the eye for various distances. [EU] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylgalactosamine: The N-acetyl derivative of galactosamine. [NIH] Acetylglucosamine: The N-acetyl derivative of glucosamine. [NIH] Acidity: The quality of being acid or sour; containing acid (hydrogen ions). [EU] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Acne Vulgaris: A chronic disorder of the pilosebaceous apparatus associated with an increase in sebum secretion. It is characterized by open comedones (blackheads), closed comedones (whiteheads), and pustular nodules. The cause is unknown, but heredity and age are predisposing factors. [NIH] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute

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myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenomatous Polyposis Coli: An autosomal dominant polyposis syndrome in which the colon contains few to thousands of adenomatous polyps, often occurring by age 15 to 25. [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] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adsorption: The condensation of gases, liquids, or dissolved substances on the surfaces of solids. It includes adsorptive phenomena of bacteria and viruses as well as of tissues treated with exogenous drugs and chemicals. [NIH] Adsorptive: It captures volatile compounds by binding them to agents such as activated carbon or adsorptive resins. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH]

Dictionary 195

Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Aged, 80 and Over: A person 80 years of age and older. [NIH] Ageing: A physiological or morphological change in the life of an organism or its parts, generally irreversible and typically associated with a decline in growth and reproductive vigor. [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] Air Sacs: Thin-walled sacs or spaces which function as a part of the respiratory system in birds, fishes, insects, and mammals. [NIH] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Alcohol Dehydrogenase: An enzyme that catalyzes reversibly the final step of alcoholic fermentation by reducing an aldehyde to an alcohol. In the case of ethanol, acetaldehyde is reduced to ethanol in the presence of NADH and hydrogen. The enzyme is a zinc protein which acts on primary and secondary alcohols or hemiacetals. EC 1.1.1.1. [NIH] Aldehyde Dehydrogenase: An enzyme that oxidizes an aldehyde in the presence of NAD+ and water to an acid and NADH. EC 1.2.1.3. Before 1978, it was classified as EC 1.1.1.70. [NIH]

Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps

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to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [NIH] Aloe: A genus of the family Liliaceae containing anthraquinone glycosides such as aloinemodin or aloe-emodin (emodin). [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Aluminum: A metallic element that has the atomic number 13, atomic symbol Al, and atomic weight 26.98. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Amaurosis: Partial or total blindness from any cause. [NIH] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid 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-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amphetamines: Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopression, bronchodilation, and to

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varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] 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] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] 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] Angiogenesis Factor: Substance causing proliferation of new blood vessels. It is found in tissues with high metabolic requirements, such as the retina, and in certain cancers. The factor is also released by hypoxic macrophages at the edges or outer surfaces of wounds and initiates revascularization in wound healing. [NIH] Anhydrous: Deprived or destitute of water. [EU] Animal Husbandry: The science of breeding, feeding, and care of domestic animals; includes housing and nutrition. [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] Anionic: Pertaining to or containing an anion. [EU] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or

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positive pole during electrolysis. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Anoxia: Clinical manifestation of respiratory distress consisting of a relatively complete absence of oxygen. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Anterior chamber: The space in front of the iris and behind the cornea. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticarcinogenic: Pertaining to something that prevents or delays the development of cancer. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antidepressant: A drug used to treat depression. [NIH] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-infective: An agent that so acts. [EU] Anti-Infective Agents: Substances that prevent infectious agents or organisms from spreading or kill infectious agents in order to prevent the spread of infection. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antimycotic: Suppressing the growth of fungi. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU]

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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] Antiseptic: A substance that inhibits the growth and development of microorganisms without necessarily killing them. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Aphakia: Absence of crystalline lens totally or partially from field of vision, from any cause except after cataract extraction. Aphakia is mainly congenital or as result of lens dislocation and subluxation. [NIH] 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] Aqueous: Having to do with water. [NIH] Arachidonate 15-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 15-hydroperoxyarachidonate (15-HPETE) which is rapidly converted to 15-hydroxy5,8,11,13-eicosatetraenoate (15-HETE). The 15-hydroperoxides are preferentially formed in neutrophils and lymphocytes. EC 1.13.11.33. [NIH] Arachidonate Lipoxygenases: Enzymes catalyzing the oxidation of arachidonic acid to hydroperoxyarachidonates (HPETES). These products are then rapidly converted by a peroxidase to hydroxyeicosatetraenoic acids (HETES). The positional specificity of the enzyme reaction varies from tissue to tissue. The final lipoxygenase pathway leads to the leukotrienes. EC 1.13.11.- . [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Archaea: One of the three domains of life (the others being bacteria and Eucarya), formerly called Archaebacteria under the taxon Bacteria, but now considered separate and distinct. They are characterized by: 1) the presence of characteristic tRNAs and ribosomal RNAs; 2) the absence of peptidoglycan cell walls; 3) the presence of ether-linked lipids built from branched-chain subunits; and 4) their occurrence in unusual habitats. While archaea resemble bacteria in morphology and genomic organization, they resemble eukarya in their method of genomic replication. The domain contains at least three kingdoms: crenarchaeota, euryarchaeota, and korarchaeota. [NIH] Aromatic: Having a spicy odour. [EU] Arsenic trioxide: An anticancer drug that induces programmed cell death (apoptosis) in certain cancer cells. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU]

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Arteries: The vessels carrying blood away from the heart. [NIH] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Asbestos: Fibrous incombustible mineral composed of magnesium and calcium silicates with or without other elements. It is relatively inert chemically and used in thermal insulation and fireproofing. Inhalation of dust causes asbestosis and later lung and gastrointestinal neoplasms. [NIH] Asbestosis: A lung disorder caused by constant inhalation of asbestos particles. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, star-shaped cells called astrocytes. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] 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] Autocrine Communication: Mode of communication wherein a bound hormone affects the function of the cell type that produced the hormone. [NIH]

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Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Avian: A plasmodial infection in birds. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacterial Proteins: Proteins found in any species of bacterium. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Beta 2-Microglobulin: An 11 kDa protein associated with the outer membrane of many cells including lymphocytes. It is the small subunit of the MHC class I molecule. Association with beta 2-microglobulin is generally required for the transport of class I heavy chains from the endoplasmic reticulum to the cell surface. Beta 2-microglobulin is present in small amounts in serum, csf, and urine of normal people, and to a much greater degree in the urine and plasma of patients with tubular proteinemia, renal failure, or kidney transplants. [NIH] Beta carotene: A vitamin A precursor. Beta carotene belongs to the family of fat-soluble vitamins called carotenoids. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its

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composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biochemical reactions: In living cells, chemical reactions that help sustain life and allow cells to grow. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] 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] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH]

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Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blastomeres: The undifferentiated cells formed by cleavage of the fertilized ovum. This includes cells in the cleavage, morula, and blastula stages of the embryo. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Coagulation Factors: Endogenous substances, usually proteins, that are involved in the blood coagulation process. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood Proteins: Proteins that are present in blood serum, including serum albumin, blood coagulation factors, and many other types of proteins. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [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] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

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]

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Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchopulmonary: Pertaining to the lungs and their air passages; both bronchial and pulmonary. [EU] Bronchopulmonary Dysplasia: A chronic lung disease appearing in certain newborn infants treated for respiratory distress syndrome with mechanical ventilation and elevated concentration of inspired oxygen. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cadmium: An element with atomic symbol Cd, atomic number 48, and atomic weight 114. It is a metal and ingestion will lead to cadmium poisoning. [NIH] Cadmium Poisoning: Poisoning occurring after exposure to cadmium compounds or fumes. It may cause gastrointestinal syndromes, anemia, or pneumonitis. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcifediol: The major circulating metabolite of vitamin D3 produced in the liver and the best indicator of the body's vitamin D stores. It is effective in the treatment of rickets and osteomalacia, both in azotemic and non-azotemic patients. Calcifediol also has mineralizing properties. [NIH] Calcitriol: The physiologically active form of vitamin D. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [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] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH]

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Carbenoxolone: An agent derived from licorice root. It is used for the treatment of digestive tract ulcers, especially in the stomach. Antidiuretic side effects are frequent, but otherwise the drug is low in toxicity. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboxy: Cannabinoid. [NIH] Carboxylic Acids: Organic compounds containing the carboxy group (-COOH). This group of compounds includes amino acids and fatty acids. Carboxylic acids can be saturated, unsaturated, or aromatic. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carotenoids: Substance found in yellow and orange fruits and vegetables and in dark green, leafy vegetables. May reduce the risk of developing cancer. [NIH] Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Caspases: A family of intracellular cysteine endopeptidases. They play a key role in inflammation and mammalian apoptosis. They are specific for aspartic acid at the P1 position. They are divided into two classes based on the lengths of their N-terminal prodomains. Caspases-1,-2,-4,-5,-8, and -10 have long prodomains and -3,-6,-7,-9 have short prodomains. EC 3.4.22.-. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule,

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especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] 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 Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellar Diseases: Diseases that affect the structure or function of the cerebellum. Cardinal manifestations of cerebellar dysfunction include dysmetria, gait ataxia, and muscle hypotonia. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH]

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Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Ceroid: A naturally occurring lipid pigment with histochemical characteristics similar to lipofuscin. It accumulates in various tissues in certain experimental and pathological conditions. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chelating Agents: Organic chemicals that form two or more coordination bonds with a central metal ion. Heterocyclic rings are formed with the central metal atom as part of the ring. Some biological systems form metal chelates, e.g., the iron-binding porphyrin group of hemoglobin and the magnesium-binding chlorophyll of plants. (From Hawley's Condensed Chemical Dictionary, 12th ed) They are used chemically to remove ions from solutions, medicinally against microorganisms, to treat metal poisoning, and in chemotherapy protocols. [NIH] Chemoprevention: The use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the development or recurrence of, cancer. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chloasma: Melasma c. hepaticum a term formerly used to refer to circumscribed facial hyperpigmentation resembling melasma that may occur as a cutaneous manifestation of chronic liver disease. [EU] Chlormethiazole: A sedative and anticonvulsant often used in the treatment of alcohol withdrawal. Chlormethiazole has also been proposed as a neuroprotective agent. The mechanism of its therapeutic activity is not entirely clear, but it does potentiate gaba receptors response and it may also affect glycine receptors. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholecalciferol: An antirachitic oil-soluble vitamin. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially

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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] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Chondrocytes: Polymorphic cells that form cartilage. [NIH] Choriocarcinoma: A malignant tumor of trophoblastic epithelium characterized by secretion of large amounts of chorionic gonadotropin. It usually originates from chorionic products of conception (i.e., hydatidiform mole, normal pregnancy, or following abortion), but can originate in a teratoma of the testis, mediastinum, or pineal gland. [NIH] Chorioretinitis: Inflammation of the choroid in which the sensory retina becomes edematous and opaque. The inflammatory cells and exudate may burst through the sensory retina to cloud the vitreous body. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic 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] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] Citric Acid: A key intermediate in metabolism. It is an acid compound found in citrus fruits. The salts of citric acid (citrates) can be used as anticoagulants due to their calcium chelating ability. [NIH] Citrus: Any tree or shrub of the Rue family or the fruit of these plants. [NIH] C-kit receptor: A protein on the surface of some cells that binds to stem cell factor (a substance that causes certain types of cells to grow). Altered forms of this receptor may be associated with some types of cancer. [NIH]

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Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

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

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] Cochlea: The part of the internal ear that is concerned with hearing. It forms the anterior part of the labyrinth, is conical, and is placed almost horizontally anterior to the vestibule. [NIH]

Cod Liver Oil: Oil obtained from fresh livers of the cod family, Gadidae. It is a source of vitamins A and D. [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colon Polyps: Small, fleshy, mushroom-shaped growths in the colon. [NIH]

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Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Concentric: Having a common center of curvature or symmetry. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] 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] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a

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fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [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] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Consumption: Pulmonary tuberculosis. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contralateral: Having to do with the opposite side of the body. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and

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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] Cotinine: 1-Methyl-5-(3-pyridyl)-2-pyrrolidinone antidepressant. Synonym: Scotine. [NIH]

fumarate.

Stimulant

proposed

as

Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] 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] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] CSF: Cerebrospinal fluid. The fluid flowing around the brain and spinal cord. CSF is produced in the ventricles of the brain. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclin E: A 50-kD protein that complexes with cdk2 in the late G1 phase of the cell cycle. [NIH]

Cyclodextrins: A homologous group of cyclic glucans consisting of alpha-1,4 bound glucose units obtained by the action of cyclodextrin glucanotransferase on starch or similar substrates. The enzyme is produced by certain species of Bacillus. Cyclodextrins form inclusion complexes with a wide variety of substances. [NIH] Cysteine Endopeptidases: Endopeptidases which have a cysteine involved in the catalytic process. This group of enzymes is inactivated by sulfhydryl reagents. EC 3.4.22. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it

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(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] Cytotoxic chemotherapy: Anticancer drugs that kill cells, especially cancer cells. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Dark Adaptation: Adjustment of the eyes under conditions of low light. The sensitivity of the eye to light is increased during dark adaptation. [NIH] Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [NIH]

De novo: In cancer, the first occurrence of cancer in the body. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Dehydroepiandrosterone: DHEA. A substance that is being studied as a cancer prevention drug. It belongs to the family of drugs called steroids. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]

Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Care: The total of dental diagnostic, preventive, and restorative services provided to meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] Dental Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [NIH]

Depigmentation: Removal or loss of pigment, especially melanin. [EU] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss

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of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermal: Pertaining to or coming from the skin. [NIH] Dermatitis: Any inflammation of the skin. [NIH] Dermatologic Agents: Drugs used to treat or prevent skin disorders or for the routine care of skin. [NIH] Dermatosis: Any skin disease, especially one not characterized by inflammation. [EU] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [NIH] Developmental Biology: The field of biology which deals with the process of the growth and differentiation of an organism. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Foot: Ulcers of the foot as a complication of diabetes. Diabetic foot, often with infection, is a common serious complication of diabetes and may require hospitalization and disfiguring surgery. The foot ulcers are probably secondary to neuropathies and vascular problems. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Dietary Fats: Fats present in food, especially in animal products such as meat, meat

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products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. [NIH]

Diethylnitrosamine: A nitrosamine derivative with alkylating, carcinogenic, and mutagenic properties. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilatation: The act of dilating. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Dispenser: Glass, metal or plastic shell fitted with valve from which a pressurized formulation is dispensed; an instrument for atomizing. [NIH] Disposition: A tendency either physical or mental toward certain diseases. [EU] Dissection: Cutting up of an organism for study. [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] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diuresis: Increased excretion of urine. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several

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systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetics. It is a hydroxy derivative of daunorubicin and is used in treatment of both leukemia and solid tumors. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Ectoderm: The outer of the three germ layers of the embryo. [NIH] Ectopic: Pertaining to or characterized by ectopia. [EU] Eczema: A pruritic papulovesicular dermatitis occurring as a reaction to many endogenous and exogenous agents (Dorland, 27th ed). [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] 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] Eicosanoids: A class of oxygenated, endogenous, unsaturated fatty acids derived from arachidonic acid. They include prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acid compounds (HETE). They are hormone-like substances that

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act near the site of synthesis without altering functions throughout the body. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Electroretinography: Recording of electric potentials in the retina after stimulation by light. [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] Emodin: Purgative anthraquinone found in several plants, especially Rhamnus frangula. It was formerly used as a laxative, but is now used mainly as tool in toxicity studies. [NIH] Emollient: Softening or soothing; called also malactic. [EU] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [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] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles

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or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endoderm: The inner of the three germ layers of the embryo. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]

Endometriosis: A condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Activators: Compounds or factors that act on a specific enzyme to increase its activity. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are

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uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] 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] Epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. [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] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] ERV: The expiratory reserve volume is the largest volume of gas that can be expired from the end-expiratory level. [NIH] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [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] Esterification: The process of converting an acid into an alkyl or aryl derivative. Most frequently the process consists of the reaction of an acid with an alcohol in the presence of a trace of mineral acid as catalyst or the reaction of an acyl chloride with an alcohol. Esterification can also be accomplished by enzymatic processes. [NIH] Estrogen: One of the two female sex hormones. [NIH]

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Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Etretinate: An oral retinoid used in the treatment of keratotic genodermatosis, lichen planus, and psoriasis. Beneficial effects have also been claimed in the prophylaxis of epithelial neoplasia. The compound may be teratogenic. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excipients: Usually inert substances added to a prescription in order to provide suitable consistency to the dosage form; a binder, matrix, base or diluent in pills, tablets, creams, salves, etc. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excrete: To get rid of waste from the body. [NIH] Exfoliation: A falling off in scales or layers. [EU] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Expiratory: The volume of air which leaves the breathing organs in each expiration. [NIH] Expiratory Reserve Volume: The extra volume of air that can be expired with maximum effort beyond the level reached at the end of a normal, quiet expiration. Common abbreviation is ERV. [NIH] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]

External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous

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and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Facial: Of or pertaining to the face. [EU] Facial Expression: Observable changes of expression in the face in response to emotional stimuli. [NIH] Faecal: Pertaining to or of the nature of feces. [EU] Fallopian tube: The oviduct, a muscular tube about 10 cm long, lying in the upper border of the broad ligament. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Fenretinide: A synthetic retinoid that is used orally as a chemopreventive against prostate cancer and in women at risk of developing contralateral breast cancer. It is also effective as an antineoplastic agent. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fetal Alcohol Syndrome: A disorder occurring in children born to alcoholic women who continue to drink heavily during pregnancy. Common abnormalities are growth deficiency (prenatal and postnatal), altered morphogenesis, mental deficiency, and characteristic facies - small eyes and flattened nasal bridge. Fine motor dysfunction and tremulousness are observed in the newborn. [NIH] Fetal Blood: Blood of the fetus. Exchange of nutrients and waste between the fetal and maternal blood occurs via the placenta. The cord blood is blood contained in the umbilical vessels at the time of delivery. [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] Fibril: Most bacterial viruses have a hollow tail with specialized fibrils at its tip. The tail fibers attach to the cell wall of the host. [NIH] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH]

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Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filariasis: Infections with nematodes of the superfamily Filarioidea. The presence of living worms in the body is mainly asymptomatic but the death of adult worms leads to granulomatous inflammation and permanent fibrosis. Organisms of the genus Elaeophora infect wild elk and domestic sheep causing ischaemic necrosis of the brain, blindness, and dermatosis of the face. [NIH] Flatus: Gas passed through the rectum. [NIH] Flavopiridol: Belongs to the family of anticancer drugs called flavinols. [NIH] Flavoring Agents: Substances added to foods and medicine to improve the quality of taste. [NIH]

Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluorine: A nonmetallic, diatomic gas that is a trace element and member of the halogen family. It is used in dentistry as flouride to prevent dental caries. [NIH] Fluorine Compounds: Inorganic compounds that contain fluorine as an integral part of the molecule. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Follicles: Shafts through which hair grows. [NIH] Follicular Fluid: A fluid consisting of sex steroid hormones, plasma proteins, mucopolysaccharides, and electrolytes that is present in the vesicular ovarian follicle (Graafian follicle) surrounding the ovum. [NIH] Food Additives: Substances which are of little or no nutritive value, but are used in the processing or storage of foods or animal feed, especially in the developed countries; includes antioxidants, food preservatives, food coloring agents, flavoring agents, anti-infective agents

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(both plain and local), vehicles, excipients and other similarly used substances. Many of the same substances are pharmaceutic aids when added to pharmaceuticals rather than to foods. [NIH]

Food Preservatives: Substances capable of inhibiting, retarding or arresting the process of fermentation, acidification or other deterioration of foods. [NIH] Foot Ulcer: Lesion on the surface of the skin of the foot, usually accompanied by inflammation. The lesion may become infected or necrotic and is frequently associated with diabetes or leprosy. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fovea: The central part of the macula that provides the sharpest vision. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact. [NIH] Fundus: The larger part of a hollow organ that is farthest away from the organ's opening. The bladder, gallbladder, stomach, uterus, eye, and cavity of the middle ear all have a fundus. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] GABA: The most common inhibitory neurotransmitter in the central nervous system. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body

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through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Mucosa: Surface epithelium in the stomach that invaginates into the lamina propria, forming gastric pits. Tubular glands, characteristic of each region of the stomach (cardiac, gastric, and pyloric), empty into the gastric pits. The gastric mucosa is made up of several different kinds of cells. [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 Neoplasms: Tumors or cancer of the gastrointestinal system. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene 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] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] 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] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gestational Age: Age of the conceptus. In humans, this may be assessed by medical history, physical examination, early immunologic pregnancy tests, radiography, ultrasonography, and amniotic fluid analysis. [NIH] Gingivitis: Inflammation of the gingivae. Gingivitis associated with bony changes is referred to as periodontitis. Called also oulitis and ulitis. [EU] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH]

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Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioblastoma: A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. They may arise in any region of the central nervous system, with a predilection for the cerebral hemispheres, basal ganglia, and commissural pathways. Clinical presentation most frequently occurs in the fifth or sixth decade of life with focal neurologic signs or seizures. [NIH] Glioblastoma multiforme: A type of brain tumor that forms from glial (supportive) tissue of the brain. It grows very quickly and has cells that look very different from normal cells. Also called grade IV astrocytoma. [NIH] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucans: Polysaccharides composed of repeating glucose units. They can consist of branched or unbranched chains in any linkages. [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 occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucosinolates: Substituted thioglucosides. They are found in rapeseed (Brassica campestris) products and related Cruciferae. They are metabolized to a variety of toxic products which are most likely the cause of hepatocytic necrosis in animals and humans. [NIH]

Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glucuronides: Glycosides of glucuronic acid formed by the reaction of uridine diphosphate glucuronic acid with certain endogenous and exogenous substances. Their formation is important for the detoxification of drugs, steroid excretion and bilirubin metabolism to a more water-soluble compound that can be eliminated in the urine and bile. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system.

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[NIH]

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

Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [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] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Glycyrrhetinic Acid: 3-beta-Hydroxy-11-oxoolean-12-en-30-oic acid. A product from Glycyrrhiza glabra L. Leguminosae with some antiallergic, antibacterial, and antiviral properties. It is used topically for allergic or infectious skin inflammation and orally for its aldosterone effects in electrolyte regulation. [NIH] Glycyrrhiza: A genus of leguminous herbs or shrubs whose roots yield glycyrrhetinic acid and its derivatives, carbenoxolone for example. Licorice toxicity is manifested as hypokalemia, low blood potassium. Licorice is used as flavoring and aromatic in pharmaceuticals and as candy. [NIH] Goats: Any of numerous agile, hollow-horned ruminants of the genus Capra, closely related to the sheep. [NIH] Gonadal: Pertaining to a gonad. [EU] 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] Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH]

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Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [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] Hay Fever: A seasonal variety of allergic rhinitis, marked by acute conjunctivitis with lacrimation and itching, regarded as an allergic condition triggered by specific allergens. [NIH]

Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains. [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]

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Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [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] Heterodimers: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] Hirsutism: Excess hair in females and children with an adult male pattern of distribution. The concept does not include hypertrichosis, which is localized or generalized excess hair. [NIH]

Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]

Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic

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cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydatidiform Mole: A trophoblastic disease characterized by hydrops of the mesenchymal portion of the villus. Its karyotype is paternal and usually homozygotic. The tumor is indistinguishable from chorioadenoma destruens or invasive mole ( = hydatidiform mole, invasive) except by karyotype. There is no apparent relation by karyotype to choriocarcinoma. Hydatidiform refers to the presence of the hydropic state of some or all of the villi (Greek hydatis, a drop of water). [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolases: Any member of the class of enzymes that catalyze the cleavage of the substrate and the addition of water to the resulting molecules, e.g., esterases, glycosidases (glycoside hydrolases), lipases, nucleotidases, peptidases (peptide hydrolases), and phosphatases (phosphoric monoester hydrolases). EC 3. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxy Acids: Organic compounds containing both the hydroxyl and carboxyl radicals. [NIH]

Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperostosis: Increase in the mass of bone per unit volume. [NIH] Hyperpigmentation: Excessive pigmentation of the skin, usually as a result of increased melanization of the epidermis rather than as a result of an increased number of melanocytes. Etiology is varied and the condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. [NIH] Hyperreflexia: Exaggeration of reflexes. [EU] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions

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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] Hypertrichosis: Localized or generalized excess hair. The concept does not include hirsutism, which is excess hair in females and children with an adult male pattern of distribution. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypervitaminosis: A condition due to ingestion of an excess of one or more vitamins; called also supervitaminosis. [EU] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypoxic: Having too little oxygen. [NIH] 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] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] 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] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH]

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Immunology: The study of the body's immune system. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] 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] Infant, Newborn: An infant during the first month after birth. [NIH] 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]

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] Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical

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and surgical treatment. [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] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-11: Lymphohematopoietic cytokine that has the ability to modulate antigenspecific antibody responses, potentiate megakaryocytes, and regulate bone marrow adipogenesis. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-3: A multilineage cell growth factor secreted by lymphocytes, epithelial cells, and astrocytes which stimulates clonal proliferation and differentiation of various types of blood and tissue cells. Also called multi-CSF, it is considered one of the hematopoietic colony stimulating factors. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different

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cells including T-cells, monocytes, and fibroblasts. [NIH] Interleukin-7: Hematopoietic growth factor that promotes growth of B-cell precursors and also is co-mitogenic with Interleukin-2 for mature T-cell activation. It is produced by bone marrow stromal cells. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intramuscular injection: IM. Injection into a muscle. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Invertebrates: Animals that have no spinal column. [NIH] 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] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells.

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This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoprenoid: Molecule that might anchor G protein to the cell membrane as it is hydrophobic. [NIH]

Isopropyl: A gene mutation inducer. [NIH] Isothiocyanates: Organic compounds with the general formula R-NCS. [NIH] Isotretinoin: A topical dermatologic agent that is used in the treatment of acne vulgaris and several other skin diseases. The drug has teratogenic and other adverse effects. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Keratoconjunctivitis: Simultaneous inflammation of the cornea and conjunctiva. [NIH] Keratoconjunctivitis Sicca: Drying and inflammation of the conjunctiva as a result of insufficient lacrimal secretion. When found in association with xerostomia and polyarthritis, it is called Sjogren's syndrome. [NIH] Keratolytic: An agent that promotes keratolysis. [EU] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH]

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Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kidney Transplantation: The transference of a kidney from one human or animal to another. [NIH] Kilobase: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [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] Laceration: 1. The act of tearing. 2. A torn, ragged, mangled wound. [EU] Lacrimal: Pertaining to the tears. [EU] Lacrimal gland: The small almond-shaped structure that produces tears; located just above the outer corner of the eye. [NIH] Lactation: The period of the secretion of milk. [EU] Lanolin: A yellow fat obtained from sheep's wool. It is used as an emollient, cosmetic, and pharmaceutic aid. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Leiomyosarcoma: A tumor of the muscles in the uterus, abdomen, or pelvis. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Leprosy: A chronic granulomatous infection caused by Mycobacterium leprae. The granulomatous lesions are manifested in the skin, the mucous membranes, and the peripheral nerves. Two polar or principal types are lepromatous and tuberculoid. [NIH] 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] Leukoplakia: A white patch that may develop on mucous membranes such as the cheek, gums, or tongue and may become cancerous. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

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Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligase: An enzyme that repairs single stranded discontinuities in double-stranded DNA molecules in the cell. Purified DNA ligase is used in gene cloning to join DNA molecules together. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Bilayers: Layers of lipid molecules which are two molecules thick. Bilayer systems are frequently studied as models of biological membranes. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipofuscin: A naturally occurring lipid pigment with histochemical characteristics similar to ceroid. It accumulates in various normal tissues and apparently increases in quantity with age. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [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] Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution to the tumor site is improved. [NIH]

Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [NIH]

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Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]

Litter: Appliance consisting of an oblong frame over which is stretched a canvas or other material, used for carrying an injured or disabled person. [NIH] Litter Size: The number of offspring produced at one birth by an animal. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]

Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] 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] Lubricants: Oily or slippery substances. [NIH] Lubrication: The application of a substance to diminish friction between two surfaces. It may refer to oils, greases, and similar substances for the lubrication of medical equipment but it can be used for the application of substances to tissue to reduce friction, such as lotions for skin and vaginal lubricants. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH]

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Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokine: A soluble protein produced by some types of white blood cell that stimulates other white blood cells to kill foreign invaders. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macula: A stain, spot, or thickening. Often used alone to refer to the macula retinae. [EU] Macula Lutea: An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the superior pole of the eye and slightly below the level of the optic disk. [NIH] Macular Degeneration: Degenerative changes in the macula lutea of the retina. [NIH] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Manic: Affected with mania. [EU] Man-made: Ionizing radiation emitted by artificial or concentrated natural, radioactive material or resulting from the operation of high voltage apparatus, such as X-ray apparatus or particle accelerators, of nuclear reactors, or from nuclear explosions. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH]

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Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]

Meat Products: Articles of food which are derived by a process of manufacture from any portion of carcasses of any animal used for food (e.g., head cheese, sausage, scrapple). [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [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 color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melanophores: Chromatophores (large pigment cells of fish, amphibia, reptiles and many invertebrates) which contain melanin. Short term color changes are brought about by an active redistribution of the melanophores pigment containing organelles (melanosomes). Mammals do not have melanophores; however they have retained smaller pigment cells known as melanocytes. [NIH] Melanosomes: Melanin-containing organelles found in melanocytes and melanophores. [NIH]

Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Lipids: Lipids, predominantly phospholipids, cholesterol and small amounts of glycolipids found in membranes including cellular and intracellular membranes. These lipids may be arranged in bilayers in the membranes with integral proteins between the layers and peripheral proteins attached to the outside. Membrane lipids are required for active transport, several enzymatic activities and membrane formation. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental deficiency: A condition of arrested or incomplete development of mind from inherent causes or induced by disease or injury. [NIH]

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Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metaplasia: A condition in which there is a change of one adult cell type to another similar adult cell type. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [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] Micelles: Electrically charged colloidal particles or ions consisting of oriented molecules; aggregates of a number of molecules held loosely together by secondary bonds. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Micronuclei: Nuclei, separate from and additional to the main nucleus of a cell, produced during the telophase of mitosis or meiosis by lagging chromosomes or chromosome fragments derived from spontaneous or experimentally induced chromosomal structural changes. This concept also includes the smaller, reproductive nuclei found in multinucleate protozoans. [NIH] Micronutrients: Essential dietary elements or organic compounds that are required in only small quantities for normal physiologic processes to occur. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living

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organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microsomal: Of or pertaining to microsomes : vesicular fragments of endoplasmic reticulum formed after disruption and centrifugation of cells. [EU] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Miscible: Susceptible of being mixed. [EU] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitomycin: An antineoplastic antibiotic produced by Streptomyces caespitosus. It acts as a bi- or trifunctional alkylating agent causing cross-linking of DNA and inhibition of DNA synthesis. [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] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monocular: Diplopia identified with one eye only; it may be induced with a double prism, or it may occur either as a result of double imagery due to an optical defect in the eye, or as a result of simultaneous use of normal and anomalous retinal correspondence. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus

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surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]

Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Morula: The early embryo at the developmental stage in which the blastomeres, resulting from repeated mitotic divisions of the fertilized ovum, form a compact mass. [NIH] 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] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] 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] Mutagenic: Inducing genetic mutation. [EU] Mutate: To change the genetic material of a cell. Then changes (mutations) can be harmful, beneficial, or have no effect. [NIH] Myalgia: Pain in a muscle or muscles. [EU] Mycosis: Any disease caused by a fungus. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelodysplastic syndrome: Disease in which the bone marrow does not function normally. Also called preleukemia or smoldering leukemia. [NIH] Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [NIH] Myelotoxic: 1. Destructive to bone marrow. 2. Arising from diseased bone marrow. [EU] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH]

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Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myopia: That error of refraction in which rays of light entering the eye parallel to the optic axis are brought to a focus in front of the retina, as a result of the eyeball being too long from front to back (axial m.) or of an increased strength in refractive power of the media of the eye (index m.). Called also nearsightedness, because the near point is less distant than it is in emmetropia with an equal amplitude of accommodation. [EU] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] 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] Nearsightedness: The common term for myopia. [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] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephropathy: Disease of the kidneys. [EU] Nephrosis: Descriptive histopathologic term for renal disease without an inflammatory component. [NIH] Nephrotic: Pertaining to, resembling, or caused by nephrosis. [EU] Nephrotic Syndrome: Clinical association of heavy proteinuria, hypoalbuminemia, and generalized edema. [NIH] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural Crest: A strip of specialized ectoderm flanking each side of the embryonal neural

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plate, which after the closure of the neural tube, forms a column of isolated cells along the dorsal aspect of the neural tube. Most of the cranial and all of the spinal sensory ganglion cells arise by differentiation of neural crest cells. [NIH] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Night Blindness: Anomaly of vision in which there is a pronounced inadequacy or complete absence of dark-adaptation. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] Normotensive: 1. Characterized by normal tone, tension, or pressure, as by normal blood pressure. 2. A person with normal blood pressure. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the

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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] Nucleic Acid Probes: Nucleic acid which complements a specific mRNA or DNA molecule, or fragment thereof; used for hybridization studies in order to identify microorganisms and for genetic studies. [NIH] Nucleotidases: A class of enzymes that catalyze the conversion of a nucleotide and water to a nucleoside and orthophosphate. EC 3.1.3.-. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Nutritive Value: An indication of the contribution of a food to the nutrient content of the diet. This value depends on the quantity of a food which is digested and absorbed and the amounts of the essential nutrients (protein, fat, carbohydrate, minerals, vitamins) which it contains. This value can be affected by soil and growing conditions, handling and storage, and processing. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oligohydramnios: Presence of less than 300 ml of amniotic fluid at term. Principal causes include malformations of fetal urinary tracts, intra-uterine growth retardation, high maternal blood pressure, nicotine poisoning, and prolonged pregnancy. [NIH] Oligosaccharides: Carbohydrates consisting of between two and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Onychomycosis: Mycosis of the nails, possibly due to some extent to humidity. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic 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] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Organogenesis: Clonal propagation which involves culturing explants from roots, leaves, or stems to form undifferentiated callus tissue; after the cells form shoots, they are separated and rooted. Alternatively, if the callus is put in liquid culture, somatic embryos form. [NIH] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] 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] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [NIH] Ovarian Follicle: Spheroidal cell aggregation in the ovary containing an ovum. It consists of an external fibro-vascular coat, an internal coat of nucleated cells, and a transparent, albuminous fluid in which the ovum is suspended. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overall survival: The percentage of subjects in a study who have survived for a defined period of time. Usually reported as time since diagnosis or treatment. Often called the survival rate. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Ovum Implantation: Endometrial implantation of the blastocyst. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

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Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH] 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] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parasitic Diseases: Infections or infestations with parasitic organisms. They are often contracted through contact with an intermediate vector, but may occur as the result of direct exposure. [NIH] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [NIH] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle Accelerators: Devices which accelerate electrically charged atomic or subatomic

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particles, such as electrons, protons or ions, to high velocities so they have high kinetic energy. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Hydrolases: A subclass of enzymes from the hydrolase class that catalyze the hydrolysis of peptide bonds. Exopeptidases and endopeptidases make up the sub-subclasses for this group. EC 3.4. [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] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [NIH]

Peripheral blood: Blood circulating throughout the body. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneal Dialysis: Dialysis fluid being introduced into and removed from the peritoneal cavity as either a continuous or an intermittent procedure. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH]

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Peritonitis: Inflammation of the peritoneum; a condition marked by exudations in the peritoneum of serum, fibrin, cells, and pus. It is attended by abdominal pain and tenderness, constipation, vomiting, and moderate fever. [EU] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [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] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Pharmaceutic Aids: Substances which are of little or no therapeutic value, but are necessary in the manufacture, compounding, storage, etc., of pharmaceutical preparations or drug dosage forms. They include solvents, diluting agents, and suspending agents, and emulsifying agents. Also, antioxidants; preservatives, pharmaceutical; dyes (coloring agents); flavoring agents; vehicles; excipients; ointment bases. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] 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] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenylbutyrate: An anticancer drug that belongs to the family of drugs called differentiating agents. [NIH] 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] Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3. [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] Photoreceptor: Receptor capable of being activated by light stimuli, as a rod or cone cell of

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the eye. [NIH] Phototransduction: The transducing of light energy to afferent nerve impulses, such as takes place in the retinal rods and cones. After light photons are absorbed by the photopigments, the signal is transmitted to the outer segment membrane by the cyclic GMP second messenger system, where it closes the sodium channels. This channel gating ultimately generates an action potential in the inner retina. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigmentation: Coloration or discoloration of a part by a pigment. [NIH] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]

Pineal gland: A tiny organ located in the cerebrum that produces melatonin. Also called pineal body or pineal organ. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Placental tissue: The tissue intervening between fetal blood and maternal blood in the placenta; it acts as a selective membrane regulating the passage of substances from the maternal to the fetal blood. [NIH] Plant Oils: Oils derived from plants or plant products. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Platelet-Derived Growth Factor: Mitogenic peptide growth hormone carried in the alphagranules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form.

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Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]

Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Pollen: The male fertilizing element of flowering plants analogous to sperm in animals. It is released from the anthers as yellow dust, to be carried by insect or other vectors, including wind, to the ovary (stigma) of other flowers to produce the embryo enclosed by the seed. The pollens of many plants are allergenic. [NIH] Polyarthritis: An inflammation of several joints together. [EU] 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] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]

Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyp: A growth that protrudes from a mucous membrane. [NIH] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [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] Postoperative: After surgery. [NIH] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH]

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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] Prealbumin: A tetrameric protein, molecular weight between 50,000 and 70,000, consisting of 4 equal chains, and migrating on electrophoresis in 3 fractions more mobile than serum albumin. Its concentration ranges from 7 to 33 per cent in the serum, but levels decrease in liver disease. [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Pregnancy Tests: Tests to determine whether or not an individual is pregnant. [NIH] Preleukemia: Conditions in which the abnormalities in the peripheral blood or bone marrow represent the early manifestations of acute leukemia, but in which the changes are not of sufficient magnitude or specificity to permit a diagnosis of acute leukemia by the usual clinical criteria. [NIH] Premalignant: A term used to describe a condition that may (or is likely to) become cancer. Also called precancerous. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presumptive: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [NIH] Primary tumor: The original tumor. [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] Procollagen: A biosynthetic precursor of collagen containing additional amino acid sequences at the amino-terminal ends of the three polypeptide chains. Protocollagen, a precursor of procollagen consists of procollagen peptide chains in which proline and lysine have not yet been hydroxylated. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU]

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Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [NIH] Promyelocytic leukemia: A type of acute myeloid leukemia, a quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. [NIH]

Prophylaxis: An attempt to prevent disease. [NIH] Propylene Glycol: A clear, colorless, viscous organic solvent and diluent used in pharmaceutical preparations. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandins: A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. [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] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] 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] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [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]

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Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pruritic: Pertaining to or characterized by pruritus. [EU] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Pupil: The aperture in the iris through which light passes. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis,

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caused by hemorrhage into the tissues. [NIH] Pustular: Pertaining to or of the nature of a pustule; consisting of pustules (= a visible collection of pus within or beneath the epidermis). [EU] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU]

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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] Recurrence: The return of a sign, symptom, or disease after a remission. [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] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractive Errors: Deviations from the average or standard indices of refraction of the eye through its dioptric or refractive apparatus. [NIH] Refractive Power: The ability of an object, such as the eye, to bend light as light passes through it. [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Reproductive system: In women, this system includes the ovaries, the fallopian tubes, the uterus (womb), the cervix, and the vagina (birth canal). The reproductive system in men includes the prostate, the testes, and the penis. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Residual disease: Cancer cells that remain after attempts have been made to remove the cancer. [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,

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4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Response Elements: Nucleotide sequences, usually upstream, which are recognized by specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promotor and enhancer regions. [NIH]

Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinae: A congenital notch or cleft of the retina, usually located inferiorly. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Detachment: Separation of the inner layers of the retina (neural retina) from the pigment epithelium. Retinal detachment occurs more commonly in men than in women, in eyes with degenerative myopia, in aging and in aphakia. It may occur after an uncomplicated cataract extraction, but it is seen more often if vitreous humor has been lost during surgery. (Dorland, 27th ed; Newell, Ophthalmology: Principles and Concepts, 7th ed, p310-12). [NIH] Retinal pigment epithelium: The pigment cell layer that nourishes the retinal cells; located just outside the retina and attached to the choroid. [NIH] Retinaldehyde: A carotenoid constituent of visual pigments. It is the oxidized form of retinol which functions as the active component of the visual cycle. It is bound to the protein opsin forming the complex rhodopsin. When stimulated by visible light, the retinal component of the rhodopsin complex undergoes isomerization at the 11-position of the double bond to the cis-form; this is reversed in "dark" reactions to return to the native transconfiguration. [NIH] Retinitis: Inflammation of the retina. It is rarely limited to the retina, but is commonly associated with diseases of the choroid (chorioretinitis) and of the optic nerve (neuroretinitis). The disease may be confined to one eye, but since it is generally dependent on a constitutional factor, it is almost always bilateral. It may be acute in course, but as a rule it lasts many weeks or even several months. [NIH] Retinitis Pigmentosa: Hereditary, progressive degeneration of the neuroepithelium of the retina characterized by night blindness and progressive contraction of the visual field. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH]

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Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retinol-Binding Proteins: Proteins which bind with retinol. The retinol-binding protein found in plasma has an alpha-1 mobility on electrophoresis and a molecular weight of 21,000-22,000. The protein has one binding site for retinol and is responsible for the transport of Vitamin A. The retinol-protein complex (molecular weight 80,000 to 90,000) circulates in plasma in the form of a protein-protein complex with prealbumin. The retinol-binding protein found in tissue has a molecular weight of 14,000 and carries retinol as a noncovalently-bound ligand. [NIH] Retinyl palmitate: A drug being studied in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [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] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Ruminants: A suborder of the order Artiodactyla whose members have the distinguishing feature of a four-chambered stomach. Horns or antlers are usually present, at least in males. [NIH]

Salicylic: A tuberculosis drug. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saponification: The hydrolysis of an ester into an alcohol and acid. [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]

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Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Sebaceous gland: Gland that secretes sebum. [NIH] Seborrhea: Hypersecretion of sebum with excessive oily secretion from the sweat glands. [NIH]

Sebum: The oily substance secreted by sebaceous glands. It is composed of keratin, fat, and cellular debris. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] 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] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semicircular canal: Three long canals of the bony labyrinth of the ear, forming loops and opening into the vestibule by five openings. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [NIH]

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Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Sicca: Failure of lacrimal secretion, keratoconjunctivitis sicca, failure of secretion of the salivary glands and mucous glands of the upper respiratory tract and polyarthritis. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Silicon: A trace element that constitutes about 27.6% of the earth's crust in the form of silicon dioxide. It does not occur free in nature. Silicon has the atomic symbol Si, atomic number 14, and atomic weight 28.09. [NIH] Silicon Dioxide: Silica. Transparent, tasteless crystals found in nature as agate, amethyst, chalcedony, cristobalite, flint, sand, quartz, and tridymite. The compound is insoluble in water or acids except hydrofluoric acid. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin Aging: The process of aging due to changes in the structure and elasticity of the skin over time. It may be a part of physiological aging or it may be due to the effects of ultraviolet radiation, usually through exposure to sunlight. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer. [NIH]

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Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoldering leukemia: Disease in which the bone marrow does not function normally. Also called preleukemia or myelodysplastic syndrome. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Channels: Cell membrane glycoproteins selective for sodium ions. Fast sodium current is associated with the action potential in neural membranes. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solar radiation: Sunbathing as a therapeutic measure. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Soybean Oil: Oil from soybean or soybean plant. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spermatids: Male germ cells derived from spermatocytes and developing into spermatozoa. [NIH]

Spermatocytes: Male germ cells derived from spermatogonia and developing into spermatids. [NIH] Spermatogenesis: Process of formation and development of spermatozoa, including

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spermatocytogenesis and spermiogenesis. [NIH] Spermatogonia: The spermatocytes. [NIH]

primitive

differentiated

male

gametes

which

give

rise

to

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] Spinous: Like a spine or thorn in shape; having spines. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [NIH] Stabilization: The creation of a stable state. [EU] Stabilizer: A device for maintaining constant X-ray tube voltage or current. [NIH] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Steady state: Dynamic equilibrium. [EU] Stellate: Star shaped. [NIH] Stem Cell Factor: Hematopoietic growth factor and the ligand of the c-kit receptor CD117 (proto-oncogene protein C-kit). It is expressed during embryogenesis and provides a key signal in multiple aspects of mast-cell differentiation and function. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

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Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] 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] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [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] Sunburn: An injury to the skin causing erythema, tenderness, and sometimes blistering and resulting from excessive exposure to the sun. The reaction is produced by the ultraviolet radiation in sunlight. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppositories: A small cone-shaped medicament having cocoa butter or gelatin at its basis and usually intended for the treatment of local conditions in the rectum. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface

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tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]

Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sweat Glands: Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. [NIH] Symphysis: A secondary cartilaginous joint. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synthetic retinoid: A substance related to vitamin A that is produced in a laboratory. [NIH] Systemic: Affecting the entire body. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telophase: The final phase of cell division, in which two daughter nuclei are formed, the cytoplasm divides, and the chromosomes lose their distinctness and are transformed into chromatin networks. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Teratogen: A substance which, through immediate, prolonged or repeated contact with the skin may involve a risk of subsequent non-hereditable birth defects in offspring. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Teratogenicity: The power to cause abnormal development. [NIH] Teratoma: A type of germ cell tumor that may contain several different types of tissue, such as hair, muscle, and bone. Teratomas occur most often in the ovaries in women, the testicles in men, and the tailbone in children. Not all teratomas are malignant. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetani: Causal agent of tetanus. [NIH] Tetanic: Having the characteristics of, or relating to tetanus. [NIH] Tetanus: A disease caused by tetanospasmin, a powerful protein toxin produced by Clostridium tetani. Tetanus usually occurs after an acute injury, such as a puncture wound or laceration. Generalized tetanus, the most common form, is characterized by tetanic muscular contractions and hyperreflexia. Localized tetanus presents itself as a mild condition with manifestations restricted to muscles near the wound. It may progress to the generalized form. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it

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is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Theophylline: Alkaloid obtained from Thea sinensis (tea) and others. It stimulates the heart and central nervous system, dilates bronchi and blood vessels, and causes diuresis. The drug is used mainly in bronchial asthma and for myocardial stimulation. Among its more prominent cellular effects are inhibition of cyclic nucleotide phosphodiesterases and antagonism of adenosine receptors. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thiamine: 3-((4-Amino-2-methyl-5-pyrimidinyl)methyl)-5-(2methylthiazolium chloride. [NIH]

hydroxyethyl)-4-

Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] 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]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] 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] 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]

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Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Toxoid: The material resulting from the treatment of toxin in such a way that the toxic properties are inactivated whilst the antigenic potency remains intact. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer

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both local and systemic cellular immunity to nonimmune recipients. [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] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [NIH] Tretinoin: An important regulator of gene expression, particularly during growth and development and in neoplasms. Retinoic acid derived from maternal vitamin A is essential for normal gene expression during embryonic development and either a deficiency or an excess can be teratogenic. It is also a topical dermatologic agent which is used in the treatment of psoriasis, acne vulgaris, and several other skin diseases. It has also been approved for use in promyelocytic leukemia. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Trophoblast: The outer layer of cells of the blastocyst which works its way into the endometrium during ovum implantation and grows rapidly, later combining with mesoderm. [NIH] 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] Tumor model: A type of animal model which can be used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Tumor-derived: Taken from an individual's own tumor tissue; may be used in the development of a vaccine that enhances the body's ability to build an immune response to the tumor. [NIH] Tumorigenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH]

Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [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]

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Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10 megahertz. [NIH] Ultraviolet radiation: Invisible rays that are part of the energy that comes from the sun. UV radiation can damage the skin and cause melanoma and other types of skin cancer. UV radiation that reaches the earth's surface is made up of two types of rays, called UVA and UVB rays. UVB rays are more likely than UVA rays to cause sunburn, but UVA rays pass deeper into the skin. Scientists have long thought that UVB radiation can cause melanoma and other types of skin cancer. They now think that UVA radiation also may add to skin damage that can lead to skin cancer and cause premature aging. For this reason, skin specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Uridine Diphosphate: A uracil nucleotide containing a pyrophosphate group esterified to C5 of the sugar moiety. [NIH] Uridine Diphosphate Glucuronic Acid: A nucleoside diphosphate sugar which serves as a source of glucuronic acid for polysaccharide biosynthesis. It may also be epimerized to UDP iduronic acid, which donates iduronic acid to polysaccharides. In animals, UDP glucuronic acid is used for formation of many glucosiduronides with various aglycones. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Uvea: The middle coat of the eyeball, consisting of the choroid in the back of the eye and the ciliary body and iris in the front of the eye. [NIH] Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] Vaccination: Administration of vaccines to stimulate the host's immune response. This

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includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] VE: The total volume of gas either inspired or expired in one minute. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventricles: Fluid-filled cavities in the heart or brain. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [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] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Visual field: The entire area that can be seen when the eye is forward, including peripheral vision. [NIH] Visual Perception: The selecting and organizing of visual stimuli based on the individual's past experience. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitamin D: The vitamin that mediates intestinal calcium absorption, bone calcium

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metabolism, and probably muscle activity. It usually acts as a hormone precursor, requiring 2 stages of metabolism before reaching actual hormonal form. It is isolated from fish liver oils and used in the treatment and prevention of rickets. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitreous Humor: The transparent, colorless mass of gel that lies behind the lens and in front of the retina and fills the center of the eyeball. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Volvulus: A twisting of the stomach or large intestine. May be caused by the stomach being in the wrong position, a foreign substance, or abnormal joining of one part of the stomach or intestine to another. Volvulus can lead to blockage, perforation, peritonitis, and poor blood flow. [NIH] Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] Xerophthalmia: Dryness of the eye surfaces caused by deficiency of tears or conjunctival secretions. It may be associated with vitamin A deficiency, trauma, or any condition in which the eyelids do not close completely. [NIH] Xerostomia: Decreased salivary flow. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a

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radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zebrafish: A species of North American fishes of the family Cyprinidae. They are used in embryological studies and to study the effects of certain chemicals on development. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

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INDEX 4 4-Nitroquinoline-1-oxide, 48 A Abdomen, 193, 203, 219, 233, 235, 237, 247, 248, 262, 263 Abdominal, 193, 194, 247, 248, 249 Aberrant, 27, 52, 193 Abortion, 193, 208 Abrasion, 53, 193 Abscess, 193, 259 Acatalasia, 193, 205 Acceptor, 136, 193, 236, 246 Acetylcholine, 193, 208, 244 Acetylgalactosamine, 193, 226 Acetylglucosamine, 193, 226 Acidity, 193, 249 Acne, 125, 127, 128, 129, 130, 137, 138, 139, 140, 142, 144, 145, 147, 157, 160, 161, 182 Acne Vulgaris, 161, 193, 234, 267 Acute myelogenous leukemia, 193, 194 Acute myeloid leukemia, 36, 50, 194, 253 Acute nonlymphocytic leukemia, 194 Acyl, 7, 38, 39, 48, 77, 137, 156, 194, 219 Adaptability, 194, 206 Adaptation, 32, 38, 44, 48, 55, 194, 213, 244 Adenine, 92, 194, 254 Adenocarcinoma, 194, 228, 244 Adenomatous Polyposis Coli, 11, 194 Adenosine, 194, 204, 249, 265 Adipocytes, 37, 111, 194, 211 Adjustment, 193, 194, 213 Adjuvant, 194, 224 Adoptive Transfer, 52, 194 Adrenal Glands, 194, 197 Adsorption, 71, 194 Adsorptive, 194 Adverse Effect, 128, 194, 234, 260 Aerobic, 194, 241 Afferent, 195, 250 Affinity, 25, 38, 50, 80, 136, 195, 200, 236, 261 Age Groups, 149, 195 Age of Onset, 124, 195 Aged, 80 and Over, 195 Ageing, 84, 127, 142, 145, 157, 159, 195 Agonist, 49, 195, 216, 244 Air Sacs, 195, 196 Airway, 69, 195

Albumin, 11, 63, 195, 246, 250 Alcohol Dehydrogenase, 18, 19, 49, 69, 70, 79, 80, 82, 86, 91, 136, 149, 195 Aldehyde Dehydrogenase, 20, 195 Aldehydes, 47, 195 Alertness, 195, 204 Algorithms, 195, 202 Alimentary, 89, 144, 196, 247 Alkaloid, 196, 209, 242, 244, 265 Alleles, 196, 228, 236 Allergen, 124, 196, 214 Allergic Rhinitis, 124, 196, 227 Aloe, 139, 196 Alpha Particles, 196, 255 Alpha-1, 196, 212, 258 Alternative medicine, 166, 196 Aluminum, 163, 196 Alveoli, 7, 57, 196, 269 Amaurosis, 50, 196 Amino Acid Sequence, 88, 134, 136, 196, 198, 224, 252 Amino-terminal, 196, 252 Ammonia, 196, 264, 268 Amniotic Fluid, 196, 224, 245 Amphetamines, 196, 209 Amputation, 53, 197 Amyloid, 26, 197 Amyloidosis, 61, 197 Anaesthesia, 197, 231 Anal, 114, 144, 197, 237 Analgesic, 197, 242, 245 Analog, 7, 128, 147, 197 Analogous, 137, 138, 139, 197, 251, 266 Anaplasia, 197 Anatomical, 197, 207, 231, 259 Androgenic, 90, 197 Anemia, 85, 177, 197, 204, 222, 238, 242 Anesthesia, 195, 197 Angiogenesis, 8, 14, 33, 197, 238 Angiogenesis Factor, 33, 197 Anhydrous, 124, 125, 156, 197 Animal Husbandry, 126, 197 Animal model, 5, 6, 9, 12, 24, 46, 48, 50, 197, 267 Anionic, 159, 197 Anions, 195, 197, 233, 260 Anomalies, 198, 264 Anoxia, 92, 198

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Antagonism, 198, 204, 265 Anterior chamber, 33, 198, 233 Antibacterial, 125, 198, 226, 261 Antibiotic, 198, 213, 216, 241, 261, 265 Antibodies, 8, 42, 51, 58, 134, 198, 227, 229, 230, 237, 250, 255 Antibody, 58, 195, 198, 210, 227, 228, 230, 231, 232, 234, 241, 255, 261, 271 Anticarcinogenic, 30, 198 Anticoagulant, 198, 253 Anticonvulsant, 198, 207 Antidepressant, 198, 212 Antifungal, 143, 198 Antigen, 12, 22, 26, 52, 143, 145, 146, 195, 198, 210, 213, 228, 229, 230, 231, 232 Antigen-presenting cell, 145, 146, 198, 213 Anti-infective, 198, 222, 229, 233 Anti-Infective Agents, 198, 222 Anti-inflammatory, 125, 198, 225 Antimicrobial, 125, 198, 214 Antimycotic, 143, 198 Antineoplastic, 198, 216, 221, 241, 247 Antioxidant, 15, 34, 35, 72, 73, 103, 132, 156, 199, 200, 246, 247 Antiseptic, 143, 199 Anuria, 199, 234 Anus, 197, 199, 203, 209 Aphakia, 199, 257 Apolipoproteins, 199, 236 Apoptosis, 6, 7, 13, 18, 22, 25, 36, 40, 145, 146, 199, 205 Aqueous, 141, 142, 159, 199, 201, 212, 217, 229, 235, 236 Arachidonate 15-Lipoxygenase, 199, 236 Arachidonate Lipoxygenases, 199, 236 Arachidonic Acid, 17, 75, 199, 216, 235, 253 Archaea, 199, 240 Aromatic, 199, 205, 226, 249 Arsenic trioxide, 16, 199 Arterial, 199, 200, 208, 230, 253 Arteries, 199, 200, 203, 211, 237, 240, 242, 265 Arteriosclerosis, 200, 230 Asbestos, 34, 88, 200 Asbestosis, 200 Ascorbic Acid, 3, 140, 142, 158, 160, 164, 200, 229 Aseptic, 200, 246, 262 Aspartic, 200, 205, 218 Aspartic Acid, 200, 205 Assay, 16, 21, 39, 56, 69, 72, 78, 87, 200, 230

Astrocytes, 200, 232 Astrocytoma, 200, 225 Asymptomatic, 193, 200, 222 Ataxia, 177, 200, 206, 265 Atrophy, 176, 177, 200 Autocrine Communication, 7, 200 Autoimmune disease, 52, 201, 242 Avian, 106, 201 B Bacteria, 125, 194, 198, 199, 201, 202, 210, 213, 218, 221, 240, 241, 250, 261, 266, 269 Bacterial Physiology, 194, 201 Bacterial Proteins, 51, 201 Bactericidal, 201, 220 Bacteriophage, 201, 266 Bacterium, 201, 210 Basal Ganglia, 200, 201, 223, 225 Basal Ganglia Diseases, 200, 201 Base, 11, 147, 194, 201, 213, 220, 224, 234, 235, 249, 251, 264 Basement Membrane, 201, 220 Basophils, 130, 201, 226, 235 Benign, 201, 223, 227, 243, 255 Beta 2-Microglobulin, 71, 201 Beta carotene, 34, 167, 201 Beta-pleated, 197, 201 Bilateral, 201, 257 Bile, 28, 65, 201, 202, 223, 225, 228, 234, 237, 262 Bile Acids, 202, 262 Bile Acids and Salts, 202 Bilirubin, 71, 195, 202, 225, 229 Bioassay, 19, 37, 202 Bioavailability, 21, 23, 45, 62, 78, 119, 202 Bioavailable, 35, 202 Biochemical, 5, 9, 26, 29, 31, 32, 33, 35, 37, 38, 39, 41, 53, 57 Biochemical reactions, 38, 202 Biological response modifier, 202, 232 Biological therapy, 202, 227 Biomarkers, 9, 53, 76, 77, 78, 79, 86, 88, 96, 101, 103, 105, 114, 202 Biotechnology, 59, 61, 166, 173, 175, 176, 177, 178, 202 Biotin, 38, 164, 202 Biotransformation, 35, 202 Bladder, 31, 64, 203, 223, 242, 253, 268 Blastocyst, 203, 210, 246, 250, 267 Blastomeres, 203, 242 Blood Coagulation, 203, 204, 265 Blood Coagulation Factors, 203 Blood Glucose, 203, 227, 232

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Blood Platelets, 203, 239, 260, 265 Blood pressure, 110, 203, 205, 230, 241, 244, 245, 261 Blood Proteins, 11, 203 Blood vessel, 197, 203, 205, 207, 218, 225, 234, 237, 240, 248, 261, 263, 264, 265, 269 Blot, 8, 96, 203 Body Composition, 30, 102, 203 Body Fluids, 202, 203, 204, 216, 261, 267 Body Mass Index, 30, 203 Bone Marrow, 85, 130, 193, 194, 203, 219, 230, 232, 233, 237, 239, 241, 242, 252, 253, 261, 263 Bowel, 197, 203, 215, 233, 248, 263 Bowel Movement, 203, 215, 263 Brachytherapy, 203, 233, 234, 255, 270 Branch, 29, 189, 203, 217, 237, 248, 254, 261, 265 Breakdown, 203, 215, 223, 245 Breeding, 133, 197, 203 Bronchi, 204, 219, 265, 266 Bronchial, 21, 41, 204, 265 Bronchioles, 196, 204 Bronchopulmonary, 7, 57, 204 Bronchopulmonary Dysplasia, 7, 57, 204 Buccal, 16, 204 Bypass, 50, 204 C Cadmium, 9, 204 Cadmium Poisoning, 204 Caffeine, 62, 204, 254 Calcifediol, 204 Calcitriol, 128, 147, 204 Calcium, 200, 204, 208, 210, 238, 247, 264, 269 Callus, 204, 217, 246 Capillary, 204, 225 Capsules, 45, 58, 119, 204, 224, 225 Carbenoxolone, 205, 226 Carbohydrate, 205, 226, 245, 251, 259 Carbon Dioxide, 205, 250, 256 Carboxy, 205 Carboxylic Acids, 132, 205 Carcinogen, 6, 15, 205 Carcinogenesis, 5, 6, 15, 48, 53, 76, 111, 205, 207 Carcinogenic, 6, 41, 54, 205, 215, 232, 253, 262, 267 Carcinoma, 15, 27, 47, 48, 76, 205, 244 Cardiac, 18, 33, 89, 204, 205, 219, 224, 243, 262 Cardiovascular, 34, 94, 205, 235, 260

Cardiovascular disease, 94, 205 Carotene, 5, 14, 15, 23, 34, 35, 36, 45, 53, 112, 127, 134, 167 Carotenoids, 15, 16, 31, 35, 45, 53, 112, 113, 114, 119, 134, 153 Case-Control Studies, 16, 205 Caspases, 36, 205 Catabolism, 6, 29, 205 Catalase, 17, 193, 205 Cataract, 199, 205, 257 Caudal, 206, 251 Cell Adhesion, 8, 133, 206 Cell Death, 32, 36, 199, 206 Cell Differentiation, 10, 128, 137, 138, 139, 147, 206, 262 Cell Division, 128, 147, 176, 201, 206, 227, 239, 241, 250, 259, 264 Cell membrane, 17, 149, 206, 234, 249, 261 Cell proliferation, 6, 18, 42, 128, 134, 147, 200, 206 Cell Respiration, 206, 241, 257 Cell Size, 206, 222 Cell Survival, 19, 25, 206, 227 Central Nervous System, 193, 196, 204, 206, 209, 223, 225, 227, 235, 242, 246, 260, 265 Centrifugation, 206, 241 Ceramide, 33, 147, 206 Cerebellar, 200, 206, 256, 267 Cerebellar Diseases, 200, 206, 267 Cerebral, 200, 201, 206, 207, 219, 220, 225, 238 Cerebral Cortex, 200, 206, 220 Cerebral hemispheres, 201, 206, 207, 225 Cerebrospinal, 104, 207, 212 Cerebrospinal fluid, 104, 207, 212 Cerebrovascular, 201, 205, 207, 265 Cerebrum, 206, 207, 250, 267 Ceroid, 207, 236 Cervical, 10, 207 Cervix, 10, 193, 207, 256 Character, 141, 207, 213 Chelating Agents, 140, 207 Chemoprevention, 7, 14, 21, 29, 35, 36, 41, 54, 207 Chemopreventive, 6, 7, 11, 21, 36, 53, 207, 221 Chemotherapeutic agent, 7, 11, 207 Chemotherapy, 7, 13, 16, 33, 51, 75, 207 Chin, 207, 239 Chloasma, 154, 207 Chlormethiazole, 6, 207

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Chlorophyll, 207, 223 Cholecalciferol, 75, 207 Cholesterol, 74, 147, 202, 207, 208, 211, 236, 237, 239, 262 Cholesterol Esters, 208, 236 Choline, 137, 208 Chondrocytes, 208, 221 Choriocarcinoma, 82, 113, 208, 229 Chorioretinitis, 208, 257 Choroid, 27, 208, 257, 268 Chromatin, 199, 208, 218, 264 Chromosomal, 49, 208, 240, 250 Chromosome, 49, 64, 87, 208, 210, 228, 236, 240, 259 Chronic Disease, 23, 208 Chronic renal, 163, 182, 208, 251 Chylomicrons, 208, 236 Cirrhosis, 83, 107, 208, 227 Cisplatin, 33, 208 Citric Acid, 139, 208 Citrus, 200, 208 C-kit receptor, 208, 262 Clear cell carcinoma, 209, 214 Clinical Medicine, 113, 209, 252 Clinical study, 209, 211 Clinical trial, 4, 13, 27, 30, 33, 39, 40, 43, 58, 69, 119, 120, 173, 209, 211, 216, 254, 255 Clone, 9, 29, 39, 40, 48, 136, 209 Cloning, 59, 68, 70, 87, 135, 202, 209, 236 Coca, 209 Cocaine, 43, 209 Cochlea, 209, 232 Cod Liver Oil, 209, 217 Coenzyme, 200, 209 Cofactor, 209, 253, 265 Collagen, 41, 129, 142, 145, 150, 151, 157, 158, 159, 196, 201, 209, 220, 221, 224, 238, 252, 253 Colloidal, 195, 209, 217, 240, 249, 260 Colon, 11, 34, 176, 194, 209, 210, 235 Colon Polyps, 11, 34, 209 Colorectal, 72, 210 Colorectal Cancer, 72, 210 Complement, 210, 224, 250 Complete remission, 210, 256 Computational Biology, 173, 175, 210 Concentric, 141, 210 Conception, 193, 208, 210, 221, 262 Cone, 24, 38, 43, 49, 100, 151, 210, 249, 263 Congestion, 210, 219 Conjugated, 127, 153, 202, 210, 212

Conjugation, 202, 210 Conjunctiva, 211, 231, 234 Conjunctivitis, 211, 227 Connective Tissue, 53, 142, 200, 203, 209, 211, 214, 222, 223, 224, 237, 240, 253, 263 Connective Tissue Cells, 211 Consciousness, 197, 211, 213, 215 Constitutional, 211, 257 Consumption, 20, 49, 167, 211, 214, 245, 247 Contamination, 31, 211 Contraindications, ii, 211 Contralateral, 211, 221, 256 Control group, 3, 211 Controlled clinical trial, 57, 211 Coordination, 207, 211, 242 Cornea, 51, 198, 211, 234, 259, 268 Corneum, 132, 211, 219 Coronary, 205, 211, 240, 242 Coronary heart disease, 205, 211 Coronary Thrombosis, 211, 240, 242 Corticosteroids, 211, 225 Cortisol, 195, 212 Cotinine, 53, 212 Cranial, 212, 227, 244, 245 Creatinine, 4, 10, 71, 212, 234 Crossing-over, 212, 256 Cross-Sectional Studies, 31, 212 CSF, 43, 130, 201, 207, 212, 232 Cultured cells, 21, 51, 212 Curative, 212, 244, 258, 265 Cutaneous, 142, 145, 161, 207, 212 Cyclic, 127, 153, 204, 212, 250, 265 Cyclin, 41, 212 Cyclin E, 41, 212 Cyclodextrins, 127, 212 Cysteine Endopeptidases, 205, 212, 218 Cytochrome, 29, 75, 212 Cytokine, 43, 58, 146, 212, 232 Cytoplasm, 199, 201, 206, 212, 218, 242, 258, 264 Cytosine, 82, 213, 255 Cytotoxic, 33, 213, 255 Cytotoxic chemotherapy, 33, 213 Cytotoxicity, 50, 208, 213 D Dark Adaptation, 44, 54, 91, 107, 213 Daunorubicin, 213, 216 De novo, 31, 213 Deamination, 213, 268 Decidua, 213, 250 Degenerative, 213, 228, 238, 257

277

Dehydration, 17, 213 Dehydroepiandrosterone, 143, 213 Deletion, 44, 46, 199, 213 Dementia, 4, 213 Dendrites, 213, 244 Dendritic, 12, 145, 213, 239 Dendritic cell, 12, 145, 213 Density, 37, 99, 114, 150, 167, 203, 206, 213, 222, 236, 245, 251 Dental Care, 125, 213 Dental Caries, 213, 222 Depigmentation, 154, 213 Depressive Disorder, 213, 237 Deprivation, 27, 214 Dermal, 53, 71, 90, 132, 133, 150, 214 Dermatitis, 214, 216 Dermatologic Agents, 214 Dermatosis, 214, 222 Dermis, 128, 148, 214, 264 DES, 113, 214 Desensitization, 55, 214 Detergents, 132, 214 Detoxification, 31, 44, 214, 225 Deuterium, 214, 229 Developed Countries, 214, 222 Developing Countries, 22, 58, 214 Developmental Biology, 28, 214 Diabetes Mellitus, 3, 81, 106, 214, 225, 227 Diabetic Foot, 53, 214 Diagnostic procedure, 123, 166, 214 Dialyzer, 214, 227 Diarrhoea, 105, 115, 214 Dietary Fats, 37, 214, 236 Diethylnitrosamine, 6, 215 Digestion, 65, 83, 196, 202, 203, 215, 233, 236, 237, 263, 269 Digestive system, 121, 215, 242 Digestive tract, 205, 215, 261, 262 Dihydrotestosterone, 47, 215, 256 Dihydroxy, 128, 143, 147, 215 Dilatation, 193, 215, 252 Dilution, 14, 64, 97, 105, 215 Dimethyl, 138, 215 Direct, iii, 14, 33, 39, 46, 54, 56, 72, 209, 215, 216, 247, 256 Discrete, 23, 130, 215 Disease Progression, 37, 215 Disinfectant, 215, 220 Dispenser, 131, 215 Disposition, 67, 126, 215 Dissection, 56, 74, 215 Dissociation, 26, 195, 215

Dissociative Disorders, 215 Distal, 57, 215, 254 Diuresis, 204, 215, 265 Dopamine, 209, 215, 244, 249 Dorsal, 18, 216, 244, 251 Double-blind, 62, 216 Doxorubicin, 50, 216 Drug Resistance, 33, 216 Drug Tolerance, 216, 266 Duct, 216, 220, 258, 264 Duodenum, 201, 216, 263 Dyes, 197, 201, 216, 222, 249 Dysplasia, 7, 57, 177, 216 Dystrophy, 91, 177, 216 E Ectoderm, 216, 243 Ectopic, 48, 216 Eczema, 142, 216 Edema, 216, 243 Effector, 36, 52, 193, 210, 216 Efficacy, 7, 13, 15, 22, 27, 33, 34, 36, 37, 40, 45, 50, 54, 120, 138, 160 Eicosanoids, 17, 216 Elastic, 57, 217, 264 Elasticity, 127, 129, 148, 157, 200, 217, 260 Elastin, 57, 84, 209, 217, 220 Elective, 100, 217 Electrolyte, 217, 226, 235, 251, 261 Electrophoresis, 42, 217, 252, 258 Electrophysiological, 47, 217 Electroretinography, 25, 217 Embryo, 44, 45, 61, 161, 193, 203, 206, 216, 217, 218, 221, 224, 231, 240, 242, 251 Embryogenesis, 5, 35, 46, 60, 77, 130, 135, 136, 146, 217, 262 Emodin, 196, 217 Emollient, 217, 226, 235, 245 Emulsion, 132, 140, 142, 144, 154, 159, 217 Encapsulated, 141, 147, 155, 159, 217, 236 Endemic, 217, 238, 262 Endocrine Glands, 217, 247 Endocrine System, 217 Endocrinology, 83, 131, 146, 217 Endocytosis, 104, 217 Endoderm, 44, 218 Endogenous, 9, 18, 29, 39, 45, 56, 76, 81, 129, 131, 137, 138, 139, 145, 161, 203, 215, 216, 218, 225, 246, 253, 266 Endometrial, 218, 246 Endometriosis, 56, 218 Endometrium, 213, 218, 267 Endopeptidases, 212, 218, 248, 253

278

Retinol

Endothelial cell, 8, 218, 221, 265 Endothelium, 57, 218 Endothelium, Lymphatic, 218 Endothelium, Vascular, 218 Endotoxic, 218, 236 End-stage renal, 208, 218, 251 Enhancer, 218, 257 Environmental Exposure, 218, 245 Environmental Health, 172, 174, 218 Enzymatic, 18, 19, 35, 63, 127, 134, 152, 154, 196, 204, 205, 210, 213, 218, 219, 239, 257 Enzyme Activators, 42, 218 Eosinophils, 218, 226, 235 Epidemic, 124, 219, 262 Epidermal, 77, 87, 107, 128, 137, 150, 219, 234, 239 Epidermal Growth Factor, 128, 219 Epidermis, 128, 132, 148, 211, 214, 219, 228, 229, 234, 252, 254, 255 Epidermoid carcinoma, 219, 262 Epigastric, 219, 247 Epinephrine, 216, 219, 244, 267 Epithelial Cells, 5, 10, 11, 21, 39, 41, 44, 48, 63, 82, 86, 89, 128, 130, 147, 219, 232 Epithelium, 10, 22, 29, 32, 38, 39, 51, 54, 55, 57, 66, 71, 92, 135, 148, 150, 201, 208, 218, 219, 224, 233, 257 ERV, 174, 219, 220 Erythema, 151, 219, 263 Erythrocytes, 197, 203, 219 Erythropoietin, 130, 219 Esophageal, 96, 219 Esophagus, 16, 215, 219, 249, 263 Essential Tremor, 177, 219 Esterification, 48, 76, 77, 90, 98, 111, 137, 139, 219 Estrogen, 39, 55, 219, 220 Estrogen receptor, 39, 220 Ethanol, 6, 18, 19, 49, 70, 82, 86, 92, 125, 195, 220, 221 Etretinate, 138, 220 Eukaryotic Cells, 220, 231, 246, 268 Evoke, 5, 220, 263 Excipients, 220, 223, 249 Excitation, 32, 55, 134, 196, 220, 222, 244 Excrete, 199, 220, 234 Exfoliation, 158, 220 Exhaustion, 198, 220, 238 Exocrine, 10, 220, 247 Exogenous, 30, 47, 194, 202, 216, 218, 220, 225, 253

Expiration, 220, 256 Expiratory, 219, 220 Expiratory Reserve Volume, 219, 220 Extensor, 220, 254 External-beam radiation, 220, 233, 255, 270 Extracellular, 21, 27, 41, 48, 57, 197, 200, 211, 217, 220, 221, 238, 261, 264 Extracellular Matrix, 27, 41, 57, 211, 220, 221, 238 Extracellular Matrix Proteins, 220, 238 Extracellular Space, 21, 220 Extraction, 72, 199, 221, 257 F Facial, 4, 160, 207, 221 Facial Expression, 4, 221 Faecal, 214, 221 Fallopian tube, 221, 256 Family Planning, 173, 221 Fatigue, 129, 221 Fatty acids, 5, 138, 195, 205, 216, 221, 236, 253 Feces, 221, 263 Fenretinide, 13, 77, 78, 221 Fermentation, 195, 221, 223 Ferritin, 100, 221 Fetal Alcohol Syndrome, 18, 20, 70, 221 Fetal Blood, 221, 250 Fetal Development, 35, 57, 221 Fetus, 35, 193, 219, 221, 250, 252, 268 Fibril, 26, 221 Fibroblast Growth Factor, 19, 221 Fibroblasts, 27, 71, 83, 85, 90, 211, 221, 233 Fibrosis, 41, 177, 222, 259 Filariasis, 100, 222 Flatus, 222, 224 Flavopiridol, 34, 222 Flavoring Agents, 222, 249 Flow Cytometry, 58, 222 Fluorescence, 54, 78, 222 Fluorescent Dyes, 222 Fluorine, 125, 222 Fluorine Compounds, 125, 222 Folate, 4, 15, 31, 50, 64, 222 Fold, 24, 39, 222 Folic Acid, 3, 164, 222 Follicles, 161, 222 Follicular Fluid, 70, 222 Food Additives, 153, 155, 222 Food Preservatives, 222, 223 Foot Ulcer, 53, 214, 223 Forearm, 203, 223

279

Fovea, 151, 223 Fractionation, 23, 223 Free Radicals, 129, 199, 215, 223 Friction, 223, 237 Fundus, 66, 91, 93, 152, 223 Fungi, 198, 210, 223, 227, 240, 241, 271 Fungus, 223, 242 G GABA, 207, 223 Gallbladder, 193, 215, 223 Gamma Rays, 223, 255 Ganglia, 193, 201, 223, 243 Ganglion, 223, 244, 245 Gas, 14, 45, 196, 205, 219, 222, 223, 229, 244, 269 Gastric, 92, 96, 219, 224 Gastric Mucosa, 92, 224 Gastrin, 224, 228 Gastrointestinal, 63, 200, 204, 219, 220, 224, 235, 238, 260, 263, 267 Gastrointestinal Neoplasms, 200, 224 Gastrointestinal tract, 220, 224, 235, 260, 267 Gelatin, 140, 224, 226, 263, 265 Gene, 5, 8, 11, 16, 17, 18, 20, 26, 29, 32, 35, 39, 42, 44, 46, 48, 49, 54, 56, 57, 59, 60, 61, 64, 66, 68, 69, 73, 79, 80, 83, 87, 88, 91, 92, 93, 99, 100, 105, 110, 126, 131, 135, 136, 150, 152, 153, 178, 196, 202, 224, 234, 236, 245, 257, 259, 267 Gene Expression, 18, 20, 29, 35, 42, 48, 49, 54, 57, 60, 131, 135, 150, 153, 178 Genetic Code, 224, 244 Genetic Engineering, 130, 202, 209, 224 Genetic Markers, 133, 224 Genetics, 28, 52, 64, 77, 91, 105, 210, 224 Genital, 209, 224, 268 Genitourinary, 144, 224, 268 Genotype, 30, 224, 249 Germ Cells, 56, 224, 239, 246, 261, 264 Germ Layers, 216, 218, 224 Gestation, 18, 58, 224, 250 Gestational, 18, 35, 224 Gestational Age, 35, 224 Gingivitis, 125, 224 Ginseng, 139, 224 Gland, 39, 42, 51, 225, 237, 247, 250, 253, 259, 263, 264, 265 Glioblastoma, 13, 225 Glioblastoma multiforme, 13, 225 Glioma, 13, 225 Glomerular, 71, 225, 233, 234, 256

Glomerular Filtration Rate, 71, 225, 234 Glomerulus, 225, 243 Glucans, 212, 225 Glucocorticoid, 35, 36, 143, 225 Glucose, 160, 176, 200, 203, 212, 214, 225, 226, 227, 232, 258 Glucose Intolerance, 214, 225 Glucosinolates, 15, 225 Glucuronic Acid, 225, 268 Glucuronides, 7, 225 Glutamate, 156, 225 Glutamic Acid, 222, 225, 244, 253 Glutathione Peroxidase, 226, 259 Glycerol, 139, 226, 249 Glycine, 196, 202, 207, 226, 244, 260 Glycoprotein, 50, 219, 226, 265 Glycosaminoglycans, 24, 220, 226, 253 Glycoside, 226, 229, 258 Glycosidic, 226, 245 Glycyrrhetinic Acid, 226 Glycyrrhiza, 160, 226 Goats, 126, 226 Gonadal, 226, 262 Gonadotropin, 208, 226 Governing Board, 226, 252 Grade, 225, 226 Graft, 96, 226, 228, 231 Graft Rejection, 226, 231 Granulocyte, 130, 226 Grasses, 222, 227 Growth factors, 19, 57, 95, 227 H Habitual, 207, 227 Hair follicles, 160, 214, 227, 270 Haptens, 195, 227 Hay Fever, 124, 196, 227 Headache, 204, 227, 231 Health Status, 112, 227 Heart attack, 205, 227 Heme, 17, 202, 212, 227 Hemochromatosis, 83, 227 Hemodialysis, 163, 214, 227, 234, 235 Hemoglobin, 197, 207, 219, 227 Hemoglobin A, 207, 227 Hemoglobinuria, 177, 227 Hemorrhage, 227, 255, 263 Hepatic, 6, 21, 24, 26, 28, 37, 41, 58, 72, 80, 83, 87, 111, 112, 195, 227 Hepatitis, 58, 228 Hepatocellular, 6, 68, 89, 228 Hepatocellular carcinoma, 68, 89, 228 Hepatocyte, 26, 46, 228

280

Retinol

Hereditary, 23, 228, 257 Heredity, 33, 193, 224, 228 Heterodimers, 40, 228 Heterogeneity, 195, 228 Heterozygote, 62, 228 Hirsutism, 160, 228, 230 Histone Deacetylase, 27, 228 Homeostasis, 5, 35, 46, 98, 111, 146, 228 Homodimer, 46, 228 Homologous, 10, 24, 30, 44, 196, 212, 228, 259 Hormonal, 35, 200, 228, 270 Hormone Replacement Therapy, 167, 228 Horny layer, 219, 228 Host, 12, 134, 135, 144, 201, 221, 228, 230, 231, 235, 268, 269 Humoral, 58, 226, 228 Humour, 228 Hybrid, 209, 228, 229 Hybridization, 8, 9, 19, 55, 228, 245 Hybridomas, 228, 232 Hydatidiform Mole, 208, 229 Hydrogen, 155, 193, 195, 201, 205, 214, 220, 226, 229, 236, 241, 244, 245, 246, 249, 254 Hydrogen Peroxide, 205, 226, 229, 236 Hydrolases, 20, 41, 229, 249 Hydrolysis, 7, 20, 41, 200, 202, 208, 229, 248, 249, 258 Hydrophilic, 141, 214, 229 Hydrophobic, 24, 81, 127, 141, 214, 229, 234, 236 Hydroxy Acids, 158, 160, 229 Hydroxylation, 204, 229 Hydroxylysine, 209, 229 Hydroxyproline, 196, 209, 229 Hyperbilirubinemia, 71, 229, 234 Hyperglycemia, 37, 229 Hyperlipidemia, 37, 229 Hyperostosis, 93, 229 Hyperpigmentation, 152, 158, 207, 229 Hyperreflexia, 229, 264, 265 Hypersensitivity, 83, 196, 214, 229, 235 Hypertension, 94, 105, 205, 227, 230 Hypertrichosis, 228, 230 Hypertriglyceridemia, 37, 88, 230 Hypervitaminosis, 26, 85, 230 Hypoplasia, 57, 230 Hypoxic, 197, 230 I Id, 115, 176, 182, 183, 188, 190, 230 Idiopathic, 83, 93, 104, 230

Imidazole, 143, 202, 230 Immune function, 57, 230 Immune response, 12, 22, 43, 58, 134, 143, 144 Immune Sera, 230 Immune system, 12, 58, 136, 144, 145, 146 Immunity, 70, 110, 230, 267 Immunization, 12, 52, 58, 106, 194, 230, 231 Immunoassay, 70, 72, 86, 230 Immunodeficiency, 176, 230 Immunofluorescence, 42, 230 Immunogenic, 230, 236 Immunoglobulin, 130, 144, 198, 230, 241 Immunohistochemistry, 8, 230 Immunologic, 124, 194, 224, 230, 255 Immunology, 13, 22, 52, 124, 146, 194, 195, 222, 231 Immunosuppressive, 225, 231 Immunosuppressive therapy, 231 Immunotherapy, 12, 194, 202, 214, 231 Impairment, 43, 57, 200, 231, 240 Implant radiation, 231, 233, 234, 255, 270 In situ, 8, 9, 19, 29, 55, 64, 231 In Situ Hybridization, 8, 9, 19, 55, 64, 231 In vitro, 13, 19, 20, 26, 37, 39, 42, 47, 49, 51, 55, 61, 130, 151, 162 Incision, 231, 233 Indicative, 14, 133, 231, 248, 269 Induction, 6, 13, 37, 39, 40, 51, 56, 143, 144, 231 Infancy, 58, 231, 258 Infant, Newborn, 195, 231 Infarction, 231 Infection, 30, 37, 43, 58, 144, 145 Influenza, 84, 231 Informed Consent, 10, 231 Ingestion, 204, 230, 232, 251, 264 Initiation, 6, 7, 32, 39, 232, 253, 266 Inlay, 232, 257 Inner ear, 18, 232 Inorganic, 31, 208, 222, 232 Insight, 8, 9, 232 Insulator, 232, 242 Insulin, 3, 21, 37, 95, 98, 101, 106, 232 Insulin-dependent diabetes mellitus, 106, 232 Insulin-like, 21, 95, 101, 232 Interferon, 27, 232 Interferon-alpha, 232 Interleukin-1, 130, 232 Interleukin-11, 130, 232

281

Interleukin-2, 232, 233 Interleukin-3, 130, 232 Interleukin-6, 130, 232 Interleukin-7, 130, 233 Intermittent, 233, 248 Internal Medicine, 10, 71, 107, 217, 233 Internal radiation, 233, 234, 255, 270 Interstitial, 104, 203, 220, 233, 234, 243, 256, 270 Intestinal, 23, 28, 37, 102, 111, 204, 205, 233, 238, 269 Intestine, 28, 111, 115, 202, 203, 210, 233, 235, 270 Intracellular, 21, 27, 28, 41, 58, 64, 65, 143, 204, 205, 231, 233, 239, 251, 259 Intracellular Membranes, 233, 239 Intramuscular, 58, 94, 233, 247 Intramuscular injection, 58, 233 Intravenous, 233, 247 Intrinsic, 20, 145, 157, 195, 201, 233 Inulin, 225, 233 Invasive, 36, 62, 229, 230, 233 Invertebrates, 25, 233, 239 Involuntary, 201, 219, 233, 243 Iodine, 36, 233 Ionizing, 196, 218, 233, 238, 255 Ions, 193, 201, 207, 215, 217, 229, 233, 240, 241, 248, 261 Iris, 198, 211, 233, 254, 268 Irradiation, 104, 233, 271 Ischemia, 200, 234 Isoprenoid, 135, 159, 234 Isopropyl, 125, 234 Isothiocyanates, 16, 234 Isotretinoin, 138, 234 J Jaundice, 229, 234 Joint, 47, 234, 264 K Kb, 49, 172, 234, 235 Keratin, 234, 259 Keratinocytes, 10, 65, 67, 100, 104, 107, 137, 145, 161, 234 Keratoconjunctivitis, 51, 234, 260 Keratoconjunctivitis Sicca, 51, 234, 260 Keratolytic, 132, 213, 234 Kidney Disease, 119, 121, 172, 177, 234 Kidney Failure, 163, 218, 234, 235 Kidney Failure, Acute, 234 Kidney Failure, Chronic, 234, 235 Kidney Transplantation, 96, 235 Kilobase, 136, 235

Kinetic, 17, 24, 26, 86, 233, 235, 248 L Labyrinth, 209, 232, 235, 259, 269 Laceration, 235, 264 Lacrimal, 51, 234, 235, 260 Lacrimal gland, 51, 235 Lactation, 14, 235 Lanolin, 139, 235 Large Intestine, 210, 215, 233, 235, 256, 261, 270 Lectin, 235, 239 Leiomyosarcoma, 81, 235 Lens, 27, 60, 79, 199, 205, 235, 270 Leprosy, 223, 235 Leukemia, 16, 36, 51, 60, 128, 130, 147, 176, 194, 216, 235, 252 Leukocytes, 201, 203, 218, 232, 235, 241 Leukoplakia, 53, 235 Leukotrienes, 199, 216, 235 Library Services, 188, 235 Life cycle, 14, 223, 236 Ligament, 93, 221, 236, 253 Ligands, 5, 33, 36, 42, 46, 81, 131, 136, 236 Ligase, 41, 236 Ligation, 36, 236 Linkage, 68, 87, 105, 224, 236 Linkage Disequilibrium, 105, 236 Lipase, 42, 65, 236 Lipid, 11, 21, 28, 41, 66, 80, 87, 106, 126, 129, 141, 154, 199, 200, 207, 208, 226, 232, 236, 242, 247, 267 Lipid A, 28, 236 Lipid Bilayers, 141, 236 Lipid Peroxidation, 11, 236, 247 Lipofuscin, 32, 39, 151, 207, 236 Lipophilic, 127, 131, 154, 236 Lipopolysaccharide, 24, 236 Lipoprotein, 28, 37, 236, 237 Liposomal, 27, 50, 236 Liposome, 50, 141, 147, 236 Lipoxygenase, 17, 199, 235, 236 Lithium, 105, 237 Litter, 133, 237 Litter Size, 133, 237 Liver cancer, 6, 237 Localization, 8, 39, 49, 60, 230, 237 Localized, 17, 21, 193, 197, 213, 217, 228, 230, 231, 237, 250, 264, 268 Longitudinal Studies, 212, 237 Longitudinal study, 37, 237 Low-density lipoprotein, 97, 236, 237 Lubricants, 237

282

Retinol

Lubrication, 51, 237 Lymph, 144, 207, 218, 228, 237, 263 Lymph node, 207, 237 Lymphatic, 100, 218, 231, 237, 240, 261, 262, 265 Lymphatic system, 237, 261, 262, 265 Lymphocyte, 25, 31, 198, 237 Lymphocytic, 130, 238 Lymphoid, 36, 143, 198, 211, 238 Lymphokine, 143, 238 Lymphoma, 176, 238 Lysine, 229, 238, 252 M Macrophage, 130, 232, 238 Macula, 151, 223, 238 Macula Lutea, 238 Macular Degeneration, 32, 39, 151, 238 Maintenance therapy, 54, 238 Malabsorption, 82, 176, 238 Malaria, 89, 94, 238 Malaria, Falciparum, 238 Malaria, Vivax, 238 Malignant, 5, 13, 34, 71, 130, 176, 194, 198, 208, 225, 237, 238, 242, 243, 255, 264 Malignant tumor, 208, 238, 242 Malnutrition, 45, 105, 110, 195, 200, 238, 242 Mammary, 5, 7, 39, 42, 63, 82, 89, 136, 144, 238 Manic, 237, 238 Man-made, 151, 238 Matrix metalloproteinase, 27, 53, 151, 238 Meat, 126, 214, 239 Meat Products, 215, 239 Mediate, 10, 14, 39, 40, 51, 52, 216, 239 Medicament, 142, 239, 263 MEDLINE, 173, 175, 177, 239 Megakaryocytes, 232, 239 Megaloblastic, 222, 239 Meiosis, 239, 240 Melanin, 152, 160, 213, 233, 239, 249, 267 Melanocytes, 65, 104, 154, 229, 239 Melanoma, 104, 176, 239, 268 Melanophores, 239 Melanosomes, 152, 239 Membrane Lipids, 129, 239, 249 Membrane Proteins, 135, 239 Memory, 58, 213, 239 Menopause, 239, 251 Mental, iv, 4, 121, 172, 174, 178, 206, 207, 213, 215, 221, 239, 240, 254, 268 Mental deficiency, 221, 239

Mental Disorders, 121, 240 Mental Health, iv, 4, 121, 172, 174, 240, 254 Mental Processes, 215, 240, 254 Mercury, 222, 240 Mesenchymal, 57, 219, 229, 240 Mesoderm, 240, 267 Meta-Analysis, 22, 34, 75, 240 Metabolite, 7, 82, 111, 202, 204, 215, 240 Metaplasia, 10, 240 Metastasis, 6, 238, 240 Metastatic, 27, 98, 240, 259 Methionine, 46, 215, 240, 263 MI, 38, 103, 150, 151, 191, 240 Micelles, 141, 240 Microbe, 240, 266 Microbiology, 52, 194, 240 Micronuclei, 53, 240 Micronutrients, 15, 22, 25, 30, 42, 53, 103, 240 Microorganism, 209, 240, 248, 270 Micro-organism, 213, 241, 250 Microscopy, 8, 26, 37, 42, 201, 241 Microsomal, 29, 47, 67, 73, 241 Microtubules, 241, 247 Migration, 35, 241 Miscible, 107, 241 Mitochondria, 9, 241, 246 Mitomycin, 33, 241 Mitosis, 199, 240, 241 Mitotic, 241, 242 Mobility, 241, 258 Mobilization, 20, 241 Modification, 80, 90, 196, 224, 241 Molecular Structure, 141, 241 Monitor, 22, 27, 36, 212, 241, 244 Monoclonal, 229, 234, 241, 255, 271 Monocular, 27, 241 Monocytes, 130, 232, 233, 235, 241, 242 Mononuclear, 43, 241, 242 Morphine, 43, 242, 243, 245 Morphogenesis, 18, 47, 146, 221, 242 Morphological, 20, 195, 217, 223, 239, 242 Morphology, 54, 199, 206, 242 Morula, 44, 203, 242 Mucosa, 144, 224, 242, 263 Mucositis, 88, 242 Multiple Myeloma, 104, 242 Multiple sclerosis, 99, 101, 242 Muscle Fibers, 242 Muscular Atrophy, 177, 242 Muscular Dystrophies, 216, 242

283

Mutagenic, 38, 215, 242 Mutate, 56, 242 Myalgia, 231, 242 Mycosis, 143, 242, 245 Myelin, 242 Myelodysplastic syndrome, 16, 242, 261 Myelofibrosis, 128, 147, 242 Myeloid Cells, 12, 130, 242 Myelotoxic, 16, 242 Myocardial infarction, 95, 211, 240, 242 Myocardium, 44, 240, 242, 243 Myopia, 26, 243, 256, 257 Myotonic Dystrophy, 177, 243 N Naive, 58, 243 Narcotic, 242, 243 Nasal Mucosa, 231, 243 NCI, 1, 34, 120, 171, 208, 243 Nearsightedness, 243 Need, 3, 11, 20, 21, 36, 133, 140, 152, 156, 157, 158, 163, 166, 184 Neonatal, 35, 58, 79, 92, 105, 243 Neonatal period, 58, 243 Neoplasia, 176, 220, 243 Neoplasm, 243 Neoplastic, 11, 41, 76, 197, 228, 238, 243 Nephritis, 104, 243 Nephropathy, 234, 243 Nephrosis, 243 Nephrotic, 72, 243 Nephrotic Syndrome, 72, 243 Nerve, 197, 200, 207, 213, 223, 242, 243, 244, 245, 250, 258, 259, 263 Nervous System, 43, 177, 195, 206, 243, 244, 263 Neural, 18, 20, 195, 197, 228, 243, 257, 261 Neural Crest, 18, 243 Neuroblastoma, 99, 244 Neurologic, 43, 225, 244 Neurons, 33, 209, 213, 223, 244 Neuroretinitis, 244, 257 Neurotransmitter, 193, 194, 196, 200, 215, 223, 225, 226, 244, 263 Neutrons, 196, 233, 244, 255 Neutrophil, 130, 244 Niacin, 164, 244, 267 Nicotine, 244, 245 Night Blindness, 8, 32, 61, 110, 129, 134, 244, 257 Nitrogen, 196, 220, 234, 244, 267 Non-small cell lung cancer, 21, 244 Normotensive, 94, 105, 244

Nuclear, 5, 7, 19, 29, 36, 40, 42, 43, 46, 51, 60, 130, 131, 135, 145, 150, 153 Nuclei, 196, 211, 224, 240, 241, 244, 245, 254, 264 Nucleic acid, 126, 129, 130, 134, 135, 136, 149, 150, 152 Nucleic Acid Hybridization, 228, 245 Nucleic Acid Probes, 126, 245 Nucleotidases, 229, 245 Nucleus, 199, 201, 208, 212, 214, 218, 220, 223, 239, 240, 241, 242, 244, 245, 254, 265 Nutritional Status, 30, 31, 74, 100, 113, 245 Nutritive Value, 222, 245 O Ocular, 19, 51, 62, 152, 245 Ointments, 129, 245 Oligohydramnios, 57, 245 Oligosaccharides, 127, 245 Oliguria, 234, 245 Oncogene, 6, 176, 245, 262 Onychomycosis, 142, 143, 245 Opacity, 205, 213, 245 Opiate, 43, 242, 245 Opium, 242, 245 Opsin, 32, 43, 48, 50, 134, 245, 257, 258 Optic Nerve, 244, 245, 257, 259 Organ Culture, 21, 27, 53, 246, 266 Organelles, 206, 212, 239, 242, 246 Organogenesis, 146, 246 Osmosis, 246 Osmotic, 25, 195, 246, 260 Osteoporosis, 111, 182, 246 Ovalbumin, 52, 246 Ovarian Follicle, 222, 246 Ovaries, 246, 256, 260, 264 Ovary, 246, 251, 263 Overall survival, 146, 246 Ovum, 203, 213, 222, 224, 236, 242, 246, 252, 267, 270 Ovum Implantation, 246, 267 Oxidants, 132, 246 Oxidation, 20, 25, 44, 47, 50, 111, 134, 136, 154, 160 Oxidation-Reduction, 202, 246, 247 Oxidative Stress, 15, 37, 53, 247 Oxygen Consumption, 247, 257 P Paclitaxel, 33, 247 Palate, 45, 247 Palliative, 247, 265 Pancreas, 9, 136, 193, 202, 215, 227, 232, 236, 247, 267

284

Retinol

Pancreatic, 9, 176, 247 Pancreatic cancer, 9, 176, 247 Parasite, 247 Parasitic, 146, 247 Parasitic Diseases, 146, 247 Parathyroid, 77, 113, 204, 247, 258, 264 Parathyroid Glands, 77, 113, 247, 258 Parathyroid hormone, 204, 247 Parenteral, 57, 247 Paroxysmal, 177, 247 Partial remission, 247, 256 Particle Accelerators, 238, 247 Patch, 235, 248 Pathogen, 22, 248 Pathogenesis, 19, 248 Pathologic, 19, 77, 113, 199, 211, 229, 248, 254, 256 Pathologic Processes, 199, 248 Pathophysiology, 57, 248 Pelvic, 218, 248, 253 Pelvis, 193, 235, 246, 248, 268 Penis, 248, 256 Peptide, 79, 152, 158, 196, 218, 221, 229, 234, 248, 250, 252, 253 Peptide Hydrolases, 218, 229, 248 Perception, 38, 210, 248 Perforation, 248, 270 Perfusion, 248, 266 Periodontitis, 125, 224, 248 Peripheral blood, 27, 43, 232, 248, 252 Peritoneal, 163, 248 Peritoneal Cavity, 248 Peritoneal Dialysis, 163, 248 Peritoneum, 248, 249 Peritonitis, 249, 270 Petrolatum, 217, 249 PH, 37, 38, 94, 249 Phagocyte, 246, 249 Pharmaceutic Aids, 223, 249 Pharmaceutical Preparations, 220, 224, 249, 253 Pharmacokinetic, 13, 51, 249 Pharmacologic, 23, 33, 197, 249, 266 Pharynx, 231, 249 Phenolphthalein, 217, 249 Phenotype, 8, 20, 23, 26, 32, 39, 48, 249 Phenylalanine, 249, 267 Phenylbutyrate, 33, 249 Phospholipids, 221, 236, 239, 249 Phosphoric Monoester Hydrolases, 229, 249 Phosphorus, 204, 247, 249

Phosphorylation, 40, 41, 249 Photoreceptor, 8, 19, 32, 39, 43, 55, 83, 151, 249, 258 Phototransduction, 8, 44, 250 Physical Examination, 224, 250 Physiologic, 8, 21, 35, 195, 221, 233, 240, 250, 256, 267 Physiology, 11, 28, 35, 47, 63, 89, 90, 93, 112, 217, 250, 269 Pigmentation, 129, 142, 229, 250 Pigments, 8, 32, 49, 129, 134, 135, 152, 153, 205, 234, 250, 257 Pineal gland, 208, 250 Pituitary Gland, 221, 250 Placenta, 160, 221, 250, 252 Placental tissue, 35, 250 Plant Oils, 245, 250 Plants, 196, 200, 203, 205, 207, 208, 209, 217, 224, 225, 226, 233, 235, 242, 250, 251, 258, 266 Plasma cells, 198, 242, 250 Plasma protein, 195, 218, 222, 250, 260 Plasmid, 33, 250, 269 Platelet-Derived Growth Factor, 19, 250 Platelets, 250 Platinum, 208, 251 Pneumonia, 211, 251 Point Mutation, 26, 251 Poisoning, 204, 207, 240, 245, 251 Pollen, 124, 251 Polyarthritis, 234, 251, 260 Polycystic, 177, 251 Polyethylene, 132, 251 Polymorphism, 68, 126, 251 Polyp, 11, 251 Polyposis, 11, 194, 210, 251 Polysaccharide, 132, 198, 251, 253, 268 Polyunsaturated fat, 80, 251, 265 Posterior, 93, 197, 200, 208, 216, 233, 247, 251, 259 Postmenopausal, 167, 246, 251 Postnatal, 57, 58, 221, 251, 262 Postoperative, 100, 251 Postprandial, 23, 37, 251 Potassium, 226, 251 Potentiate, 207, 232, 251 Practice Guidelines, 174, 182, 252 Prealbumin, 11, 64, 78, 90, 93, 106, 252, 258 Precancerous, 37, 207, 252 Preclinical, 36, 41, 53, 252 Precursor, 9, 11, 35, 55, 199, 201, 208, 216, 218, 249, 252, 267, 270

285

Pregnancy Tests, 224, 252 Preleukemia, 242, 252, 261 Premalignant, 21, 37, 53, 252 Prenatal, 18, 217, 221, 252 Presumptive, 162, 252 Prevalence, 11, 23, 31, 37, 75, 252 Prickle, 234, 252 Primary tumor, 21, 252 Probe, 19, 52, 252 Procollagen, 150, 252 Progesterone, 252, 262 Progression, 6, 12, 13, 27, 28, 31, 37, 56, 197, 252, 267 Progressive, 206, 208, 213, 216, 227, 235, 242, 243, 252, 256, 257 Proline, 209, 229, 252, 253 Promoter, 11, 19, 33, 40, 48, 56, 63, 79, 253 Promotor, 253, 257 Promyelocytic leukemia, 16, 36, 130, 253, 267 Prophylaxis, 138, 220, 253, 269 Propylene Glycol, 139, 253 Prospective study, 96, 237, 253 Prostaglandins, 75, 199, 216, 253 Prostate, 15, 34, 47, 62, 64, 76, 99, 103, 112, 176, 202, 221, 253, 256, 267 Protease, 37, 253 Protease Inhibitors, 37, 253 Protein Binding, 253, 266 Protein C, 28, 50, 74, 104, 149, 195, 196, 199, 201, 221, 234, 236, 253, 258, 268 Protein Conformation, 50, 196, 234, 253 Protein S, 59, 90, 100, 177, 178, 193, 202, 224, 253, 258, 265 Proteinuria, 242, 243, 253 Proteoglycan, 27, 57, 253 Protocol, 33, 254 Protons, 196, 229, 233, 248, 254, 255 Proto-Oncogene Proteins, 247, 254 Proto-Oncogene Proteins c-mos, 247, 254 Protozoan, 238, 254 Proximal, 27, 104, 215, 254, 259 Pruritic, 216, 254 Psoriasis, 128, 137, 138, 139, 142, 147, 161, 220, 254, 267 Psychic, 239, 254, 259 Psychology, 215, 254 Puberty, 133, 254 Public Health, 22, 35, 78, 95, 111, 113, 114, 174, 254 Public Policy, 173, 254

Pulmonary, 36, 103, 203, 204, 211, 234, 235, 254, 264, 269 Pulmonary Artery, 203, 254 Pulmonary Edema, 234, 254 Pulse, 96, 241, 254 Pupil, 211, 254 Purines, 254, 260 Purpura, 75, 254 Pustular, 193, 255 Pyridoxal, 30, 255 Pyrimidines, 255, 260 Q Quaternary, 96, 253, 255 R Race, 10, 15, 241, 255 Radiation, 40, 53, 127, 142, 157, 218, 220, 222, 223, 233, 238, 255, 268, 270 Radiation therapy, 220, 223, 233, 234, 255, 270 Radioactive, 37, 229, 231, 233, 234, 238, 244, 255, 267, 270 Radiography, 224, 255 Radioimmunotherapy, 255 Radioisotope, 255, 266 Radiolabeled, 23, 234, 255, 271 Radiological, 13, 255 Radiology, 255 Radiotherapy, 13, 203, 234, 255, 271 Randomized, 13, 22, 30, 34, 53, 57, 58, 62, 112, 216, 255 Reagent, 193, 255 Recombinant, 24, 47, 52, 54, 69, 90, 130, 135, 256, 269 Recombination, 10, 44, 210, 224, 256 Rectum, 199, 203, 209, 210, 215, 222, 224, 235, 253, 256, 263 Recurrence, 207, 256 Red Nucleus, 200, 256 Reductase, 66, 69, 70, 99, 256 Refer, 1, 204, 207, 210, 223, 237, 238, 243, 244, 255, 256, 266 Refraction, 243, 256, 261 Refractive Errors, 26, 256 Refractive Power, 243, 256 Refractory, 51, 256 Regeneration, 8, 29, 32, 39, 43, 48, 55, 146, 221, 256 Regimen, 216, 256 Relapse, 17, 256 Remission, 16, 53, 238, 256 Renal failure, 163, 182, 201, 256 Reproductive cells, 224, 256

286

Retinol

Reproductive system, 56, 256 Resection, 21, 256 Residual disease, 16, 256 Resorption, 204, 256 Respiration, 128, 205, 241, 256 Respiratory distress syndrome, 204, 257 Response Elements, 9, 42, 257 Restoration, 6, 257, 270 Retinae, 238, 257 Retinal Detachment, 19, 27, 32, 257 Retinal pigment epithelium, 29, 32, 38, 39, 54, 55, 65, 80, 100, 135, 150, 257 Retinaldehyde, 17, 38, 104, 135, 136, 149, 153, 160, 257 Retinitis, 32, 50, 54, 92, 257 Retinitis Pigmentosa, 32, 50, 54, 92, 257 Retinoblastoma, 73, 176, 257 Retinol-Binding Proteins, 71, 88, 92, 258 Retinyl palmitate, 41, 53, 58, 63, 94, 138, 148, 258 Rheumatoid, 246, 258 Rhinitis, 124, 258 Rhodopsin, 19, 32, 38, 43, 54, 134, 245, 257, 258 Riboflavin, 3, 163, 258 Ribosome, 258, 267 Rickets, 204, 258, 270 Risk factor, 15, 27, 37, 253, 258 Rod, 30, 38, 43, 49, 54, 100, 151, 201, 249, 258 Ruminants, 226, 258 S Salicylic, 142, 143, 160, 258 Salivary, 215, 247, 258, 260, 263, 270 Salivary glands, 215, 258, 260 Saponification, 85, 258 Saponins, 258, 262 Scatter, 259, 268 Sclera, 27, 208, 211, 259, 268 Sclerosis, 99, 177, 200, 242, 259 Screening, 31, 55, 58, 133, 151, 209, 259 Sebaceous, 149, 160, 214, 259, 270 Sebaceous gland, 149, 160, 214, 259, 270 Seborrhea, 138, 259 Sebum, 129, 149, 161, 193, 259 Secondary tumor, 240, 259 Secretion, 8, 20, 25, 28, 58, 129, 193, 208, 219, 228, 232, 234, 235, 259, 260, 269 Secretory, 144, 259 Sedative, 207, 259 Segregation, 256, 259 Seizures, 225, 247, 259

Selenium, 16, 69, 163, 259 Semen, 253, 259 Semicircular canal, 232, 259 Senile, 154, 246, 259 Septal, 7, 259 Sequence Analysis, 20, 54, 149, 259 Sequencing, 59, 260 Serine, 25, 218, 254, 260 Serologic, 230, 260 Serotonin, 244, 260, 267 Serous, 218, 260 Serum Albumin, 82, 203, 252, 260 Sex Characteristics, 254, 260, 264 Sex Determination, 177, 260 Sicca, 51, 260 Side effect, 50, 140, 194, 202, 205, 260, 266 Signs and Symptoms, 256, 260 Silicon, 139, 260 Silicon Dioxide, 260 Skeletal, 93, 136, 242, 260 Skeleton, 234, 260 Skin Aging, 150, 260 Skull, 45, 260, 264 Small cell lung cancer, 21, 260 Small intestine, 111, 208, 216, 228, 233, 261, 269 Smoldering leukemia, 242, 261 Smooth muscle, 197, 204, 211, 242, 261, 263 Sodium, 39, 105, 149, 156, 250, 261, 264 Sodium Channels, 250, 261 Soft tissue, 203, 260, 261 Solar radiation, 53, 261 Solid tumor, 197, 216, 261 Solvent, 24, 125, 138, 220, 226, 246, 253, 261 Soma, 261 Somatic, 56, 60, 217, 228, 239, 241, 246, 261 Somatic cells, 56, 239, 241, 261 Soybean Oil, 139, 140, 251, 261 Specialist, 183, 261 Species, 32, 38, 129, 201, 212, 219, 228, 238, 239, 241, 247, 255, 261, 263, 267, 269, 270, 271 Specificity, 20, 40, 42, 47, 86, 195, 199, 218, 252, 261, 266 Spectrum, 40, 261 Sperm, 208, 251, 256, 261 Spermatids, 56, 261 Spermatocytes, 56, 261, 262 Spermatogenesis, 56, 146, 261 Spermatogonia, 56, 261, 262

287

Spinal cord, 200, 206, 207, 208, 212, 223, 243, 262 Spinous, 219, 234, 262 Spleen, 130, 197, 237, 262 Sporadic, 11, 257, 262 Squamous, 10, 36, 48, 90, 219, 244, 262 Squamous cell carcinoma, 36, 48, 90, 219, 244, 262 Squamous cells, 262 Stabilization, 102, 141, 262 Stabilizer, 132, 156, 262 Staging, 12, 262 Steady state, 8, 262 Stellate, 21, 30, 41, 61, 262 Stem Cell Factor, 130, 208, 262 Stem Cells, 11, 36, 51, 60, 219, 262 Sterile, 200, 247, 262 Sterility, 56, 134, 262 Steroid, 7, 9, 47, 76, 90, 130, 131, 202, 212, 222, 225, 258, 262 Stimulant, 204, 212, 262 Stimulus, 40, 220, 263 Stomach, 16, 193, 205, 215, 219, 223, 224, 228, 248, 249, 258, 261, 262, 263, 270 Stool, 22, 209, 235, 263 Stress, 15, 37, 53, 129, 150, 212, 247, 263 Stroke, 16, 121, 172, 205, 263 Stromal, 7, 218, 233, 263 Stromal Cells, 233, 263 Subacute, 231, 263 Subclinical, 75, 231, 259, 263 Subcutaneous, 128, 194, 216, 247, 263 Submaxillary, 219, 263 Subspecies, 261, 263 Substance P, 240, 259, 263 Substrate, 17, 20, 42, 47, 54, 68, 74, 102, 229, 263 Substrate Specificity, 20, 42, 47, 74, 263 Sulfur, 220, 240, 263 Sunburn, 263, 268 Supplementation, 22, 30, 31, 34, 53, 57, 58, 69, 74, 75, 76, 84, 94, 106, 113, 164, 263 Suppositories, 224, 263 Suppression, 6, 41, 91, 263 Suppressive, 21, 43, 263 Surfactant, 156, 263 Survival Rate, 246, 264 Sweat, 214, 259, 264 Sweat Glands, 214, 259, 264 Symphysis, 207, 253, 264 Synergistic, 138, 264

Synthetic retinoid, 7, 13, 77, 145, 146, 221, 264 Systemic, 143, 197, 203, 219, 231, 234, 255, 264, 267, 270 T Telangiectasia, 177, 264 Telophase, 240, 264 Temporal, 18, 60, 238, 264 Teratogen, 18, 264 Teratogenic, 7, 18, 19, 146, 220, 234, 264, 267 Teratogenicity, 7, 264 Teratoma, 208, 264 Testicular, 56, 264 Testis, 56, 136, 208, 264 Testosterone, 256, 264 Tetani, 264 Tetanic, 264 Tetanus, 58, 264, 265 Tetany, 247, 264 Tetracycline, 19, 48, 265 Thalamic, 200, 265 Thalamic Diseases, 200, 265 Theophylline, 36, 254, 265 Therapeutics, 13, 89, 146, 265 Thermal, 200, 215, 244, 265 Thiamine, 163, 265 Threonine, 25, 254, 260, 265 Thrombin, 253, 265 Thrombocytopenia, 85, 265 Thrombomodulin, 253, 265 Thrombosis, 253, 263, 265 Thromboxanes, 199, 216, 265 Thymus, 230, 237, 265 Thyroid, 9, 26, 39, 60, 61, 130, 131, 233, 247, 265, 267 Thyroid Gland, 247, 265 Thyroxine, 104, 195, 249, 265 Tissue Culture, 21, 25, 266 Tissue Distribution, 7, 68, 266 Tolerance, 92, 104, 194, 225, 266 Tomography, 37, 266 Tone, 244, 266 Tooth Preparation, 194, 266 Toxic, iv, 7, 14, 46, 53, 107, 211, 213, 218, 225, 227, 230, 244, 259, 266 Toxicity, 7, 14, 21, 26, 31, 39, 58, 75, 110, 154, 205, 217, 226, 240, 266 Toxicology, 9, 40, 103, 104, 110, 174, 266 Toxin, 218, 264, 266 Toxoid, 58, 266 Trace element, 163, 222, 260, 266

288

Retinol

Tracer, 24, 266 Trachea, 204, 249, 265, 266 Transcription Factors, 4, 5, 49, 131, 135, 136, 150, 153, 257, 266 Transduction, 33, 50, 55, 134, 266 Transfection, 21, 202, 266 Transfer Factor, 230, 266 Translation, 25, 26, 196, 267 Transplantation, 85, 89, 96, 208, 230, 267 Trauma, 201, 227, 265, 267, 270 Tremor, 177, 267 Tretinoin, 138, 143, 160, 267 Triglyceride, 38, 74, 113, 230, 267 Trophoblast, 35, 203, 267 Tryptophan, 90, 193, 209, 260, 267 Tuberous Sclerosis, 177, 267 Tumor marker, 202, 267 Tumor model, 50, 267 Tumor-derived, 12, 267 Tumorigenic, 36, 267 Tunica, 242, 267 Tyrosine, 154, 216, 267 U Ubiquitin, 41, 268 Ulcer, 53, 268 Ulceration, 53, 150, 268 Ultrasonography, 224, 268 Ultraviolet radiation, 142, 260, 263, 268 Unconscious, 230, 268 Urea, 139, 234, 264, 268 Uremia, 234, 256, 268 Urethra, 248, 253, 268 Uridine Diphosphate, 225, 268 Uridine Diphosphate Glucuronic Acid, 225, 268 Urinary, 23, 70, 72, 85, 88, 89, 92, 96, 104, 105, 115, 224, 245, 268 Urinary tract, 245, 268 Urine, 9, 16, 23, 65, 79, 199, 201, 203, 212, 215, 219, 225, 227, 234, 245, 253, 258, 268 Urogenital, 224, 268 Uterus, 55, 193, 207, 213, 218, 223, 235, 246, 252, 256, 268, 269 Uvea, 268 Uveitis, 52, 268 V Vaccination, 143, 144, 268 Vaccine, 34, 58, 84, 143, 144, 194, 254, 267, 269 Vacuoles, 217, 246, 269 Vagina, 207, 214, 256, 269

Vaginal, 237, 269 Vascular, 53, 57, 133, 208, 214, 218, 231, 246, 250, 265, 268, 269 Vascular endothelial growth factor, 57, 269 VE, 52, 67, 269 Vector, 247, 266, 269 Vein, 233, 244, 269 Venous, 253, 269 Ventilation, 204, 269 Ventricles, 207, 212, 269 Vesicular, 155, 222, 241, 269 Vestibule, 209, 232, 259, 269 Veterinary Medicine, 173, 269 Villi, 24, 229, 269 Viral, 146, 161, 231, 266, 267, 269 Virulence, 266, 269 Virus, 43, 201, 218, 224, 232, 266, 269 Visual field, 257, 269 Visual Perception, 38, 269 Vitamin D, 12, 107, 143, 258, 269 Vitreous, 208, 235, 257, 270 Vitreous Body, 208, 257, 270 Vitreous Humor, 257, 270 Vitro, 13, 19, 20, 26, 37, 39, 42, 47, 49, 51, 55, 61, 65, 75, 80, 81, 85, 90, 130, 151, 162, 231, 266, 270 Vivo, 7, 10, 17, 19, 26, 32, 37, 40, 41, 42, 45, 47, 51, 52, 54, 55, 60, 119, 128, 130, 147, 151 Volvulus, 59, 70, 270 Vulgaris, 161, 270 W White blood cell, 198, 226, 235, 237, 238, 244, 250, 270 Windpipe, 249, 265, 270 Withdrawal, 207, 270 Womb, 256, 268, 270 Wound Healing, 197, 221, 238, 270 X Xenograft, 28, 197, 267, 270 Xerophthalmia, 134, 270 Xerostomia, 234, 270 X-ray, 17, 24, 60, 71, 84, 222, 223, 233, 238, 244, 255, 262, 270 X-ray therapy, 234, 270 Y Yeasts, 223, 249, 271 Z Zebrafish, 24, 68, 83, 271 Zymogen, 253, 271

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