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

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

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VITAMIN K 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., 1960Vitamin K: 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: 0-597-84235-3 1. Vitamin K-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 vitamin K. 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 VITAMIN K................................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Vitamin K ..................................................................................... 5 E-Journals: PubMed Central ....................................................................................................... 30 The National Library of Medicine: PubMed ................................................................................ 33 CHAPTER 2. NUTRITION AND VITAMIN K ...................................................................................... 77 Overview...................................................................................................................................... 77 Finding Nutrition Studies on Vitamin K .................................................................................... 77 Federal Resources on Nutrition ................................................................................................... 79 Additional Web Resources ........................................................................................................... 80 CHAPTER 3. ALTERNATIVE MEDICINE AND VITAMIN K................................................................ 85 Overview...................................................................................................................................... 85 National Center for Complementary and Alternative Medicine.................................................. 85 Additional Web Resources ........................................................................................................... 97 General References ..................................................................................................................... 104 CHAPTER 4. DISSERTATIONS ON VITAMIN K................................................................................ 105 Overview.................................................................................................................................... 105 Dissertations on Vitamin K ....................................................................................................... 105 Keeping Current ........................................................................................................................ 106 CHAPTER 5. CLINICAL TRIALS AND VITAMIN K .......................................................................... 107 Overview.................................................................................................................................... 107 Recent Trials on Vitamin K ....................................................................................................... 107 Keeping Current on Clinical Trials ........................................................................................... 108 CHAPTER 6. PATENTS ON VITAMIN K .......................................................................................... 111 Overview.................................................................................................................................... 111 Patents on Vitamin K ................................................................................................................ 111 Patent Applications on Vitamin K............................................................................................. 140 Keeping Current ........................................................................................................................ 148 CHAPTER 7. BOOKS ON VITAMIN K .............................................................................................. 151 Overview.................................................................................................................................... 151 Book Summaries: Online Booksellers......................................................................................... 151 The National Library of Medicine Book Index ........................................................................... 152 Chapters on Vitamin K .............................................................................................................. 153 CHAPTER 8. MULTIMEDIA ON VITAMIN K ................................................................................... 157 Overview.................................................................................................................................... 157 Bibliography: Multimedia on Vitamin K ................................................................................... 157 CHAPTER 9. PERIODICALS AND NEWS ON VITAMIN K ................................................................ 159 Overview.................................................................................................................................... 159 News Services and Press Releases.............................................................................................. 159 Newsletter Articles .................................................................................................................... 162 Academic Periodicals covering Vitamin K................................................................................. 162 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 163 Overview.................................................................................................................................... 163 U.S. Pharmacopeia..................................................................................................................... 163 Commercial Databases ............................................................................................................... 164 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 167 Overview.................................................................................................................................... 167 NIH Guidelines.......................................................................................................................... 167 NIH Databases........................................................................................................................... 169

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Other Commercial Databases..................................................................................................... 171 The Genome Project and Vitamin K .......................................................................................... 171 APPENDIX B. PATIENT RESOURCES ............................................................................................... 175 Overview.................................................................................................................................... 175 Patient Guideline Sources.......................................................................................................... 175 Finding Associations.................................................................................................................. 177 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 179 Overview.................................................................................................................................... 179 Preparation................................................................................................................................. 179 Finding a Local Medical Library................................................................................................ 179 Medical Libraries in the U.S. and Canada ................................................................................. 179 ONLINE GLOSSARIES................................................................................................................ 185 Online Dictionary Directories ................................................................................................... 186 VITAMIN K DICTIONARY ........................................................................................................ 187 INDEX .............................................................................................................................................. 257

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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 vitamin K is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about vitamin K, 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 vitamin K, 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 vitamin K. 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 vitamin K, 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 vitamin K. The Editors

1

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

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

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

Bones and Crohn's: Problems and Solutions Source: Inflammatory Bowel Diseases. 5(3): 212-227. August 1999. Contact: Available from Lippincott Williams and Wilkins, Inc. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-3030. Fax (301) 824-7390. Summary: Inflammatory bowel disease (IBD) may manifest in various extra intestinal ways. In this review article, the author describes the various manifestations of skeletal abnormalities associated with IBD, their possible pathophysiology, and possible methods of prevention and treatment. The author notes that much of the experience on solutions to the problem is based on the extrapolation from studies in patients with other systemic inflammatory conditions (such as rheumatoid arthritis) because in some cases the data available from patients with IBD is limited or nonexistent. The author

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Vitamin K

focuses on osteopenia (subnormally mineralized bone), noting that osteopenia and various arthropathies may be very debilitating. These may be related to the disease itself, patient genetics, lifestyle, or disease treatment. Calcium and vitamin D malabsorption, vitamin K deficiency, malnutrition, corticosteroid and other immunosuppressive medications, smoking, lack of exercise, and postmenopausal state may all play important roles. Treatment may be undertaken to correct nutrient deficiencies, inhibit bone resorption, and increase bone formation. 2 figures. 3 tables. 214 references. •

Bleeding Problems in Patients with Liver Disease: Ways to Manage the Many Hepatic Effects on Coagulation Source: Postgraduate Medicine. 106(4): 187-190, 193-195. October 1, 1999. Contact: Available from McGraw-Hill, Inc. 1221 Avenue of the Americas, New York, NY 10020. (612) 832-7869. Summary: Liver disease is a significant cause of morbidity and mortality in the United States and around the world. Considering that an estimated 3 to 5 million people in the United States are infected with hepatitis C virus, the number of patients with cirrhosis, hepatoma, and liver failure can be expected to increase. The liver has a pivotal role in the coagulation process, so it is not surprising that clotting abnormalities are a prominent feature of acute and chronic liver disease. In this article, the authors review these hepatic effects on coagulation and suggest an approach to dealing with coagulation abnormalities that may result from liver disease. The authors caution that therapeutic intervention for coagulation problems in liver disease is difficult, in part because patients are often critically ill and may be malnourished. Methods to correct hemostatic abnormalities in these patients include vitamin K supplementation, fresh frozen plasma infusion, plasma exchange, platelet transfusion, cryoprecipitate infusion, heparin administration, and fibrinolysis inhibitor use. The authors recommend that, to ensure the best care of patients with liver disease and bleeding, primary care physicians should not hesitate to enlist the assistance of specialists in clotting disorders and a reliable coagulation laboratory. 1 figure. 3 tables. 14 references.

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Parenteral Nutrition: A Clinician's Perspective Source: Dietitian's Edge. 2(1): 53-57. January-February 2001. Contact: Available from Dietitian's Edge. 70 Hilltop Road, 3rd Floor, Ramsey, NJ 07446. (201) 825-2552. Fax (201) 825-0553. E-mail: [email protected]. Summary: Until recently, the provision and management of parenteral (outside the gastroenteral tract) nutrition (PN) has been relegated to specialists such a nutrition support teams. However, with the changing face of health care, more registered dietitians are required to oversee PN provision. This article is intended to increase a dietitian's comfort level and interest in becoming more involved with patients receiving PN. The author stresses that PN should not be the feeding modality of choice when the patient can tolerate enteral nutrition. The author reviews the indications and contraindications for PN, noting that the overall goal of PN is to minimize weight loss, maintain lean body mass, and promote anabolism. The nutrition assessment for PN should evaluate the route of administration, indications for parenteral support, macronutrient and micronutrient requirements, nutrient tolerances and limitations as well as nutritional goals. PN requires central intravenous (IV) access. The Harris Benedict Equation and calories per kilogram are the most commonly used formulas to estimate caloric requirements. The author covers the role of dextrose, lipid (fat), amino

Studies

5

acids (protein), and fluid volume. In addition, electrolytes and minerals can be added to PN. The Food and Drug Administration (FDA) has mandated an increase in vitamins C, thiamin, riboflavin, folic acid, and the addition of vitamin K to adult multivitamin infusion products (by early 2002). Medications often added to PN include heparin, H2 antagonists, insulin, metoclopramide and octreotide. Dietitians are advised to monitor patients on PN closely for adequacy of nutrition support and tolerance to the regimen. Overall improvement in the patient's medical status, as shown by wound healing and increased functional capacity, is the best 'nutrition indicator.' 1 figure. 5 tables. 23 references. •

Why Getting the Right Amount of Vitamins is Important for the Renal Disease Patient Source: For Patients Only. 16(2): 12-16. March/April 2003. Contact: Available from For Patients Only. 18 East 41st Street, New York, NY 10017. (818) 704-5555. Fax (818) 704-6500. Summary: Vitamins are important for everyone's good health. For patients with end stage renal (kidney) disease (ESRD) and those on dialysis, restrictions of the renal diet sometimes make it difficult for them to get the appropriate vitamins and in the right amounts. This article, from a patient education newsletter, reviews these concerns about vitamins and nutrition for the patient with renal disease. Topics include uremia (build up of waste products in the blood); dialysis, vitamin interaction, and medications; fatsoluble vitamins; vitamin A; vitamin D; vitamin E; vitamin K; water soluble vitamins; erythropoiesis, folic acid, B6, and B12; cardiovascular mortality (death), folic acid, B6 and B12; high flux dialyzers and B6; vitamin C; and zinc. The article concludes by recommending a daily renal multivitamin that contains the B vitamins and vitamin C. One table summarizes the product information for six different renal vitamin preparations (prescription). 1 figure. 1 table. 27 references.

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

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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Vitamin K

Project Title: ACTIVATION OF PROTHROMBIN Principal Investigator & Institution: Mann, Kenneth G.; Professor and Chair; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2001; Project Start 30-SEP-1991; Project End 31-AUG-2006 Summary: This research program is aimed at understanding how thrombin is generated and how thrombin generation is regulated. Our approach to these questions comes via the convergence of four separate directions associated with 1) the physical properties of coagulation enzyme complexes, their constituents and how these complexes can assemble into efficient enzyme catalysts. 2) Studies in which multiple coagulation catalysts/inhibitors are mixed to attempt to duplicate the performance of the combined catalyst system associated with the tissue factor pathway of thrombin expression. 3) To study this process in minimally modified biological systems (whole blood) to evaluate the correctness of hypothesis derived from purified systems. 4) To create mathematical models which can be used to define, on a quantitative basis, the process of blood clotting and its regulation both to aid in experimental designs 1,2,3, and also to aid in the evaluation of the pharmacologic agents and the diagnosis and treatment of hemostatic and thrombotic diseases. The aim of the present investigation is to understand the nature of procoagulant and anticoagulant vitamin-K dependent complexes and their regulation during the process of thrombin generation. Studies will employ physical chemistry techniques including hydrodynamics and fluorescence spectroscopy, (the latter both in solution and on surfaces) in closed systems and under flow to study complexes on synthetic membranes and cells. Reactions will be followed using both synthetic and natural substrates to monitor both presteady state and steady state kinetic events. Natural and recombinant inhibitors will be used to study the regulation of procoagulant and anticoagulant processes associated with thrombin generation. We will integrate the detailed information available through studies of individual reactions with that obtained from multi-reaction center systems. Conversely, the processes noted to occur in the whole blood system will direct appropriate attention in the purified system analyses. We anticipate developing a quantitative evaluation of the biologically relevant chemistry associated with the complex reactions which occur simultaneously during a blood clotting event. These data have significance in interpreting normal physiology and in developing approaches to correct the coagulation pathology associated with thrombosis and hemophilia. The techniques we develop will provide tools for the evaluation of potential pharmacological intervention in hemostatic and thrombotic disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOLOGICAL ROLES OF FACTORS X AND XA Principal Investigator & Institution: High, Katherine A.; Professor of Pediatrics; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: This application focuses on the biology of blood coagulation factor X (F.X), and builds on work carried out in the previous funding cycles of this grant. F.X occupies a central role in coagulation, since it can be activated either through the extrinsic pathway (Vlla/tissue factor), or through the intrinsic pathway (IXa/VIIla). In earlier work, we had delineated a number of naturally occurring mutations in the F.X gene, and had carried out structure-function studies on the mutant proteins. More recently, we developed an in vitro expression system for production of recombinant F.X variants. Finally, using homologous recombination techniques, we have generated a F.X-deficient

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mouse that is characterized by mid-embryonic lethality of uncertain etiology in about half of the affected mice, and neonatal death from bleeding complications in the remainder. The mid-embryonic lethality is of interest in light of recent studies suggesting that F.X and its activated form F.Xa may have a plethora of biological functions unrelated to clot formation, including mitogenic activity, promotion of cytokine release and up-regulation of transcription factors. Consistent with these reports is our observation that FX, in contrast to other vitamin K-dependent clotting factors, is expressed in a variety of tissues in adult humans and in the developing mouse embryo. The objective of the first aim is to evaluate the pathophysiology of the mid-embryonic lethality, and determine the structural, functional and tissue-specific characteristics of a F.X molecule capable of rescuing the mid-embryonic lethality. Specifically, we will determine the sites and level of expression required and will also determine whether an active site is required (since some F.X-mediated signaling events an active site is not required). The goal of aims 2 and 3 is to develop a better understanding of the relative roles of the intrinsic and extnnsic pathways of blood coagulation, using both recombinant proteins and mice transgenic for variant FX species. We and others have reported the existence of FX variants with markedly asymmetric activation in the intrinsic (IXa/VIIla) and extrinsic (Vlla-TF) pathways. The existence of these variants is consistent with current data suggesting that macromolecular substrate recognition by the extrinsic and intrinsic tenases is determined to a large extent by contact surfaces distinct from the scissile bond and different for the intrinsic versus the extrinsic tenase. Blocking of these exosites may represent a novel approach to anticoagulation. We intend to synthesize these asymmetrically activated variants, characterize them in purified component assays, and test their in vivo effects by creating mice carrying these variants that can be activated through one or the other pathway but not through both. We will characterize both baseline hemostasis and response to prothrombotic stimuli in these animals. This application represents a synthesis of two longstanding areas of investigation in this laboratory. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOMIMETIC OXYGENATIONS--ANALOGY FROM VITAMIN K OXIDATIO Principal Investigator & Institution: Verma, Sharad K.; Chemistry; University of California Berkeley Berkeley, Ca 94720 Timing: Fiscal Year 2001; Project Start 01-APR-2001 Summary: Presented herein is a methodology for the oxygenation of alpha- beta unsaturated ketones (enones) based on a mechanistic analogy from vitamin K oxidation. The primary thrust of this transformation lies in its potential ability for the concise introduction of contiguous stereocenters in which the C-O bonds of a newly generated epoxy alcohol have a cis relationship. A previously developed non-enzymatic model which mimics vitamin K oxidation is utilized for this proposal. Because many chemical compounds used as pharmaceuticals and therapeutics for the treatment of various medical ailments bear stereocenters, the development of synthetic methods that enable the concise introduction of asymmetry are highly coveted, and merit such investigation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOSYNTHESIS OF BLOOD CLOTTING PROTEINS Principal Investigator & Institution: Furie, Bruce; Chief, Coagulation Unit; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215

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Vitamin K

Timing: Fiscal Year 2001; Project Start 01-APR-1987; Project End 31-AUG-2003 Summary: (Adapted from investigator's abstract) The vitamin K-dependent blood coagulation proteins undergo co- or post-translational processing that includes gamma carboxylation. This protein modification is required for calcium-dependent membrane binding. The propeptide of the molecule contains the gamma carboxylation recognition site which directs gamma carboxylation, and a propeptide cleavage consensus sequence. The current proposal aims to define the consensus sequence for the gamma carboxylation recognition site using combinatorial chemical peptide synthesis and combinatorial phage display. The three dimensional structure of a synthetic fully carboxylated profactor IX analog will be solved to determine the structure of the propeptide and its relationship to the Gla domain. To prove that the propeptide is sufficient to direct gamma carboxylation, in vivo carboxylation of chimeras of prothrombin propeptide joined to truncated P-selectin and PSGL-1 will be studied to assess carboxylation of glutamic acids in proteins that normally do not undergo gamma carboxylation. The cDNA encoding a protein required for gamma carboxylation in a CHO cell line characterized by defective carboxylation but with normal carboxylase activity will be identified by expression cloning. The physiological roles of furin and proprotein convertase 7 (PC7) in propeptide cleavage of the vitamin K-dependent proteins will be determined using furin deficient CHO cells, and experiments will be performed to identify the consensus sequence of PC7-mediated peptide bond cleavage. Experiments in this proposal will extend understanding of the role of the propeptide in vitamin K-dependent carboxylation and the identification of the enzymes that cleave the propeptide during the biosynthesis of these gamma carboxyglutamic acid-containing proteins. Gamma carboxylation and propeptide cleavage are the posttranslational events that limit the expression of the biologically active recombinant proteins and define protein expression levels for gene therapy of hemophilia B. Detailed knowledge of these processes will improve our understanding of the biology of these proteins and has potential for improvements in hemophilia therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BLOOD CLOTTING FACTORS & PLATELETS IN DEEP VEIN THROMBOSIS DEVELOPMENT Principal Investigator & Institution: Hultin, Mae B.; Associate Professor; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001 Summary: Previous studies from our laboratory suggested the possible importance of the Vitamin k-dependent procoagulant proteins in the thrombotic process that is involved in premature ischemic heart disease (IHD). This study proposes to examine whether an elevated plasma prothrombin level, associated with a variant prothrombin gene, is a risk factor for the development of premature IHD. The prothrombin gene mutation or variant is a G to A nucleotide transition at 20210 in the 3'untranslated(3'UTR) region of the prothrombin gene, which is associated with a 25-30% increase in plasma prothrombin activity and with 3-fold increased risk of deep venous thrombosis. Other objectives of the proposal will be to prove whether this increase in prothrombin activity is associated with lipid metabolism or with an increase in any of the other three procoagulant Vitamin K-dependent proteins, in order to clarify the mechanism responsible for the elevated plasma prothrombin activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BLOOD INTERACTIONS

COAGULATION

PROTEIN

METAL

ION

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LIPID

Principal Investigator & Institution: Castellino, Francis J.; Dean, College of Science; Chemistry and Biochemistry; University of Notre Dame 511 Main Bldg Notre Dame, in 46556 Timing: Fiscal Year 2001; Project Start 01-DEC-1976; Project End 31-MAY-2004 Summary: The overall objective of this research is to understand the structure- function relationships of the vitamin K-dependent proteins that are involved in hemostasis, and the genes that encode these proteins. Some of the focus in this application will be placed on murine proteins and genes, since most targeted gene alterations, which have considerably advanced this field, are performed in mouse models. Proteins of specific interest that are contained in this general class, viz., factors (f) VII, IX, X, and protein C (PC), are assembled through similar domains, which include the gammacarboxyglutamic acid (Gla) domain, a hydrophobic stretch, two consecutive epidermal growth factor-like (EGF) motifs, an activation peptide module, and a serine protease domain. These regions incorporate different properties of these proteins, and appear to function independently. It is hypothesized that by closely defining the critical regions of these protein domains, and their genes, that are essential to their various functions, it will be possible to regulate their specific features, and, likely, to transfer specific functions of one protein into another. Five specific aims are proposed to achieve these goals: (1) to identify and assess the functional roles of transcriptional regulatory of the murine genes, fVII, fX, PC, and the endothelial cell PC receptor (EPCR), through in vitro and in vivo methodology; (2) to employ a synthetic peptide library to determine sequences that are most effectively cleaved by fVIIa and the fVIIa/TF complex, by thrombin and the thrombin/TM complex, and by aPC and the aPC/EPCR complex. To exchange various optimized peptide sequences identified for each enzyme with comparable residues in another protein (fIX) to determine whether cleavages by these enzymes occur as predicted from the peptide study; (3) to express wild-type and variants of the first growth factor-like domain (EGF1) of human PC and to characterize their divalent cation binding proteins. TO determine, by NMR, the solution structures and backbone dynamics of EGF1-PC in the presence and absence of Ca2+, along with a variant of this module lacking its extra disulfide loop sequence; (4) to chemically synthesize variants of the gamma-carboxyglutamic acid (Gla) domain of human PC and to characterize their Ca2+-dependent properties. Peptides that are selectively-labeled with 13C-Gla will be emphasized to evaluate divalent cation binding to peptides mutated in the same manners as variant proteins that show defective Ca2+-related properties; and (5) to investigate amino acid determinants of the binding of human PC to EPCR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARBOXYLASE

CHARACTERIZATION

OF

DEFECTIVE

G-GLUTAMYL

Principal Investigator & Institution: Baker, Dale; Microbiology, Immunology & Pathology; Colorado State University Fort Collins, Co 80523 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2006 Summary: (provided by applicant): This application is a request for R24 funding through the National Center for Research Resources (NCRR) of the project entitled "Characterization of Defective Gamma-Glutamyl Carboxylase in Rambouillet Sheep." Human patients with hereditary deficiencies of gamma-glutamyl carboxylase have

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Vitamin K

severe bleeding clinically, but more recently, acquired defects of carboxylation have been implicated in degenerative diseases of the aged such as vascular mineralization and osteoporosis. While hereditary deficiency of gamma-glutamyl carboxylase is uncommon, atherosclerosis and osteoporosis are significant diseases of the aged. A model of defective gamma-glutamyl carboxylation does not exist despite previous efforts to produce one through knockout mouse technology. The Specific Aims of this project are: (1) Develop and maintain a flock of sheep with defective gamma-glutamyl carboxylase activity equivalent to human gamma-glutamyl carboxylase deficiency, and provide affected lambs and tissue to investigators of gamma-glutamyl carboxylase; (2) verify that the genetic defects identified in the gamma-glutamyl carboxylase gene is responsible for diminished function, and develop a heterozygous carrier detection test for identification of carrier animals; (3) characterize the skeletal phenotype in defective gamma-glutamyl carboxylase of homozygous affected lambs; and (4) develop an in vitro gene therapy technique that may eventually be applied in vivo to this and other models of defective coagulation. Specific Aims 1, 2, and 4 will be performed at CSU under the supervision of Drs. Baker and Jennifer MacLeay, and Specific Aim 3 will be carried out at Yale University by Dr. Caren Gundberg. Preliminary studies in these sheep have identified the coagulation defect that occurs in homozygous affected lambs, and the underlying cause of this coagulopathy is markedly decreased gamma-glutamyl carboxylase activity. Genetic mutations of the gamma-glutamyl carboxylase gene have also been identified. These sheep represent the only known model of this defect in existence, but much of the underlying genetic and functional aspects of the abnormalities other than defective hemostasis are unknown. One ram and seven ewes are known heterozygous carriers of the gene. The investigators plan to identify and increase the numbers of known carrier rams to three and ewes to 24 to produce six homozygous affected lambs per year, and make rams and ewes available to investigators of gamma-glutamyl carboxylase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHARACTERIZATION OF THE BACTERIAL ARC SYSTEM. Principal Investigator & Institution: Beckwith, Jonathan R.; Professor of Microbiology and Molecular; Microbiol & Molecular Genetics; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2004 Summary: (provided by applicant) The Arc two-component signal transduction system of Escherichia coil modulates the expression of numerous operons according to the redox condition of growth. This system comprises ArcB as the sensor kinase and ArcA as the response regulator. Under reducing conditions, dimeric ArcB undergoes ATPdependent autophosphorylation and catalyzes the phosphorylation of ArcA by a HisAsp-His-Asp phosphorelay. Phosphorylated ArcA represses transcription of numerous operons involved in aerobic respiration and activates a small number of operons involved in fermentation. D-lactate, pyruvate, and acetate stimulate ArcB autophosphorylation. Under oxidizing conditions, the accumulating ubiquinone or menaquinone inhibits ArcB autophosphorylation, thereby allowing ArcB to catalyze net dephosphorylation of ArcA-P via an Asp-His-Asp reverse relay. Characterization of the Arc system will deepen our understanding of how bacteria optimize their strategy for energy metabolism.The proposed project has three main aims. The first is to locate the quinone reception site in ArcB and define the mode of action of the signal. The second is to determine which phosphotransfer step in signal transmission and signal decay occurs intermolecularly between the two subunits of ArcB. The last objective is to explore the

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true role of the cytosolic PAS domain in ArcB, erroneously reported to be the receptor site for the redox signal.This research will be done primarily in Mexico as an extension of NIH grant #R01 GM40993. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMBINATORIAL SYNTHESIS OF BIOLOGICAL LIBRARIES BY CR Principal Investigator & Institution: Martinez, Luis E.; Assistant Professor; University of Texas El Paso El Paso, Tx 79968 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--MOLECULAR BIOLOGY AND PROTEIN EXPRESSION Principal Investigator & Institution: Krishnaswamy, Sriram; Associate Professor of Pediatrics; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: The molecular biology and protein expression core is organized on the basis of the pooling of the resources and expertise of all four project leaders in the program. This centralized resource provides service and assistance in molecular biology, particularly the ability to rapidly subclone the gene of interest or a mutagenized derivative into one or more expression vectors without the need for restriction digestion. The core also provides the facilities and hardware for mammalian expression, selection of stable cell lines and large scale cell growth for collection of serum-free conditioned media. The core will provide facilities for large scale isolation of recombinant proteins, the appropriate chromatography strategies and will maintain the affinity columns necessary for this activity. Assistance and facilities will also be provided for the largescale isolation of coagulation proteins from plasma. Finally, the core will provide some quality control services particularly the quantitation of 7 carboxy-glutamic acid content to verify the integrity of expressed vitamin K-dependent proteins. The Co-Directors will be responsible for the oversight and efficient conduct of these activities and for ensuring equitable service to the projects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEVELOPMENT OF SOLVATED 3D STRUCTURES OF VKD PROTEINS Principal Investigator & Institution: Pedersen, Lee G.; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001 Summary: We propose to exploit the recent explosion of structural data that has recently become available on the Vitamin K-dependent coagulation proteins by utilizing theoretical techniques to a) complete the structures where domains or loops are missing, b) test the models by performing simulations on variant proteins of human disease importance, and c) to model activation complexes on Factor VIIa/Tissue Factor with Factor IX and X. The key structural sets that now exist are partial structures for Factor Xa, IXa, Protein Ca (The EGF and catalytic domains), the Gla and first Kringle domains of pro-thrombin (Factor II) (as well as a number of structures of inhibited complexes of thrombin), and the almost complete structure of factor VIIa complexed to soluble Tissue

12

Vitamin K

Factor. The first of these structures was published in 1992. An essential component of our confidence that the bulk of these studies can be successfully addressed is the recent advanced in simulation technology of the Particle Mesh Ewald method (PME). This development, which took place in our collaboration with T. Darden (NIEHS, RTP, NC), makes possible the accurate computation of the ion-ion interactions; PME is rapidly being implemented into a number of simulation codes around the world. The planned research is thus an integration of experiment and theory to gain complete pictures of the structure and functions of the Vitamin K-dependent coagulation proteins. The complete solvated structures developed will be made available on the internet web and will retain value as new experimental structures become available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF VITAMIN K ON AGE-RELATED BONE LOSS Principal Investigator & Institution: Booth, Sarah L.; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 30-JUN-2006 Summary: (Scanned from the applicant's description): Usual dietary intakes of vitamin K among adults are low. These intakes do not support complete carboxylation of osteocalcin, a vitamin K-dependent protein in bone, and short-term dietary vitamin K deficiency may increase bone turnover in adults. Epidemiological evidence has shown associations between biochemical markers of vitamin K nutrition and age-related bone loss in elderly men and women. However it is not known if these markers of vitamin K nutrition are indicators of generalized poor total nutritional status in these studies. Furthermore, the impact of long-term vitamin K supplementation on bone mineral density (BMD) and bone turnover has not been examined. In a 3-year, double-blind, placebo controlled trial, we propose to study the effect of vitamin K supplementation (500 ug/d on femoral neck BMD and markers of bone turnover in 450 men and women, aged 60-80 years. All participants will also be receiving calcium and vitamin D supplements, in addition to a multivitamin, to prevent any potential bone loss associated with dietary inadequacy of these nutrients. We will measure plasma vitamin K concentrations and percent undercarboxylated osteocalcin (markers of vitamin K status), serum osteocalcin and collagen Type-1-crosslink N-telopeptides (markers of bone turnover) and BMD of the hip, as well as the heel, spine and total body at 1, 6, 12, 24, and 36 months of vitamin K supplementation. Plasma 25-hydroxyvitamin D and 1, 25-dihydroxyvitamin D concentrations and urinary calcium will be measured at the same time points to be used as covanates in this assessment. Other covariates collected through the course of the study include age, anthropometric data, physical activity, medication used, smoking, and dietary intakes of energy, protein, alcohol and caffeine. The proposed trial provides a unique opportunity to determine if supplemental vitamin K will reduce age-related bone loss in elderly men and women, above that achieved by supplemental calcium and vitamin D alone. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENHANCED VITAMIN K DEPENDENT PROTEINS Principal Investigator & Institution: Nelsestuen, Gary L.; Professor; Biochem/Mole Biol/Biophysics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 15-JUL-1998; Project End 30-JUN-2003

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Summary: (Investigator's abstract) This study will examine vitamin K-dependent proteins that display improved membrane affinity. The vitamin K-dependent plasma proteins function in both pro- and anti-coagulation pathways. Membrane contact is important for nearly all of the steps of these reactions. Calcium and membrane binding by vitamin K-dependent proteins depend on several gamma-carboxyglutamic acid (Gla) residues in amino acids 1-45 of these proteins. Gla is synthesized in the liver in a vitamin K-dependent reaction. Administration of vitamin K antagonists, which lower the level of Gla-containing proteins in the circulation, is a common biomedical application for persons subject to thrombosis. In addition, administration of intact proteins is important to treatment for some bleeding disorders. A major goal of this project is to establish the membrane contact mechanisms of the vitamin K-dependent proteins and to use that knowledge to generate proteins with improved function. This proposal presents a new hypothesis for membrane contact. Seven specific aims include: 1. Design mutants of protein C and factor VII that have improved membrane contact sites. 2. Determine the relationship between amino acids in the Gla domain and membrane binding affinity. 3. Characterize the relationship between membrane affinity and the ability of a zymogen protein to function as substrate for activation by other membrane-bound enzymes. 4. Determine the impact of membrane affinity (specific aim 1) on the enzyme activity of the activated forms of these proteins (factor VIIa and activated protein C, APC), including the impact of cofactor proteins, membrane content, and other properties. 5. Determine the mechanisms of membrane contact by vitamin K proteins. 6. Determine the role of the hydrophobic residues in the Gla domain. 7. Determine the structures responsible for greatest folding stability of the Gla domain. Methods used include expression of mutant proteins and their characterization by enzyme and coagulation assays, spectroscopic assays by fluorescence, and biophysical characterization with NMR and calorimetry. The use of carefully prepared membrane vesicles is required in most areas of this project. This study should reveal structure/function relationships of gammacarboxyglutamic acid, and its ultimate function in creating a membrane-contact site. It will increase knowledge of the role that membranes play in enzymatic events of coagulation and in biological systems. It may ultimately provide new and/or improved materials for biomedical applications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FACTOR XI PHYSIOLOGY AND MOLECULAR BIOLOGY Principal Investigator & Institution: Gailani, David; Associate Professor; Pathology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2001; Project Start 01-JUL-1997; Project End 30-JUN-2005 Summary: (provided by applicant): The plasma protease factor XI is a key component of the intrinsic pathway of coagulation. Originally thought to be required for initiation of fibrin clot formation, an abundance of clinical and biochemical evidence now suggests that factor XI is required for consolidation and protection of the clot after initial fibrin formation. This is most important with severe bleeding or at sites with high fibrinolytic activity. Furthermore, recent studies in humans and mice suggest that factor XI may influence thrombotic disease processes. The molecular structure of factor XI differs substantially from those of other coagulation proteases. In contrast to the vitamin Kdependent proteins (prothrombin and factors VII, IX, and X), factor XI lacks a calcium binding Gla domain. and phospholipid has little influence on its activity. Properties of factor XI therefore, are not easily extrapolated from observations made on the vitamin K-dependent proteases. The goals of this proposal are to understand the mechanism by which factor XI attaches to platelets during normal hemostasis, to study its contribution

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Vitamin K

to factor IX activation, and to determine the factors that regulate plasma factor XI levels. We have expressed recombinant factor XII molecules containing domain substitutions from the structurally related protein prekallikrein, as well as factor XI molecules with specific site-directed mutations. These have been used to identify binding sites on factor XI for factor IX, activated platelets, and heparin. We propose to use these, and additional recombinant proteins to study the mechanism by which factor XI interacts with high molecular weight kininogen and prothrombin while binding to platelets, and to study the mechanism by which factor IX is activated on the platelet surface. We have cloned the promoter regions for the factor XI and prekallikrein genes, and identified common polymorphisms that may influence function. We will identify areas of the promoters required for tissue specific expression, identify transcription factors involved in expression, and study the influences of polymorphisms on plasma factor XII levels. Finally, we have demonstrated that factor XI deficiency partially rescues protein C deficient mice from early death due to disseminated thrombosis. We will test the effect of factor XI deficiency on the phenotypes of mice with ApoE deficiency, and with PAl-1 over-expression. This work will substantially increase our understanding of a relatively poorly characterized part of the coagulation mechanism, and will provide a firmer knowledge base from which to assess the contribution of factor XI and the intrinsic pathway to thromboembolic disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FASEB K&SYNTHESIS,STRUCTURE,FUNCTION

CONFERENCE:VITAMIN

Principal Investigator & Institution: Lian, Jane B.; Professor; Federation of Amer Soc for Exper Biology Bethesda, Md 208143998 Timing: Fiscal Year 2001; Project Start 04-AUG-2001; Project End 03-AUG-2002 Summary: (provided by applicant) This proposal is for partial support of a conference on Vitamin K and Vitamin K-Dependent Proteins that is being held under the auspices of the Federation of American Scientists for Experimental Biology (FASEB) from August 4-9, 2001, at the Vermont Academy in Saxtons River, VT. This conference will represent multi-disciplinary fields spanning nutrition, application of vitamin K for intervention of osteoporosis and cardiovascular disorders, blood coagulation, skeletal development, and the conotoxin Gla neuroactive peptides. Fundamental biochemical and molecular mechanisms provide the basis for assimilating the common regulatory parameters of vitamin K mediated biological activity. Knowledge of the vitamin K dependent carboxylase, the structural requirements of Gla peptide substrate and enzyme interactions, regulation of propeptide and mature protein synthesis, the requirements for vitamin K, and interactions of calcium bound-Gla domains with phospholipid membrane components that reflect the shared properties of the vitamin K-dependent proteins will be evaluated. The meeting will focus on the most recent developments in vitamin K research. Participation will be limited to 150 applicants who will be selected on the basis of expertise and ability to contribute to a stimulating and productive meeting. The conference will consist of nine scientific sessions, two afternoon roundtable discussions, and poster sessions. The major session topics will be: (1) vitamin K and nutrition, (2) structure-function relationships of vitamin dependent proteins and membrane interactions, (3) molecular mechanisms mediating gen expression/developmental regulation of vitamin k dependent proteins with aging, (4) matrix Gla proteins and tissue functions, (5) matrix Gla proteins and cardiovascular disease, (6) vitamin K status: skeletal pathophysiologies an therapeutic intervention, (7) the Conotoxin family of Gla neuropeptides and recently discovered Gla containing

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proteins, (8) the family of vitamin K carboxylase enzymes, (9) vitamin K and warfarin. Exchange of ideas and insights among these investigators from diverse fields will provide the opportunity for new scientific collaboration and new research directions with potential for impact on neurologic, cardiovascular and bone diseases. The program includes leaders in the field and new/junior investigators, postdoctoral fellows, and scientists from Europe and Asia with exciting and unique findings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: K VITAMINS--A NEW CLASS OF LIVER CELL GROWTH INHIBITORS Principal Investigator & Institution: Carr, Brian I.; Professor; Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 08-APR-2000; Project End 31-MAR-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: KETAMINE INJECTION AND HIV RISK AMONG HIGH RISK YOUTH Principal Investigator & Institution: Lankenau, Stephen E.; Sociomedical Sciences; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 30-APR-2007 Summary: (provided by applicant): Parochially known as "Special K," "Vitamin K," or simply "K," ketamine is a conger of phencyclidine (PCP). Used for many years as an anesthetic in emergency and veterinary medicine, ketamine has recently emerged in a non-clinical context as one of several synthetic substances classified as "club drugs." Like other so-called "club drugs," such as MDMA, GHB, and Methamphetamine, most available information about ketamine stems from studies focused on "club drug" environments and populations, notably MSM venues. Much of this data has presumed non-injected modes of administrating ketamine, and HIV risk has been assessed in relation to increased risk for sexual transmission. However, pilot data from our R03 study indicates that ketamine is prevalent among non-MSM populations and venues, notably in diverse sub-populations of high risk youth. Moreover, pilot data also indicate the previously unrecognized use of injection as a mode of administration. While ketamine injection practices have yet to be systematically described, preliminary data indicate the use of an array of drug preparation and injection techniques that may pose increased risk for transmission of blood-borne pathogens, notably HIV-1, HBV, and HCV. Following a comparative research design that we have successfully applied in previous studies of out-of-treatment populations, we propose a descriptive epidemiological study of ketamine injection among high risk youth in three cities - New York City, New Orleans, and Los Angles. We will employ methods of ethnographic observation to develop a systematic description of the behavioral practices used to prepare and inject ketamine. Following our prior work in modeling injection practices, we will identify discrete features of ketamine injection that may exacerbate or attenuate risk for viral transmission, including variability in these practices that may be associated with different forms of ketamine and various of patterns of ketamine acquisition. Finally, we will recruit a cohort of high risk youth in NYC who have recently initiated injection of ketamine and describe the social course and unintended medical consequences associated with the use of injection as a mode of administration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MATRIX GLA PROTEIN AND ARTERY CALCIFICATION Principal Investigator & Institution: Price, Paul A.; Professor; Biology; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 30-JUN-2003 Summary: (Adapted from Investigator's Abstract): The objectives of this investigation are to define the contribution of warfarin treatment and of dietary vitamin K deficiency to the arterial calcification process in humans and in a rat model of the disease. The Principal Investigator will assess the molecular mechanism by which matrix Gla proteins, which are vitamin K dependent, can inhibit the arterial calcification process. The applicant will identify those risk factors which act synergistically with warfarin to accelerate arterial calcification in a rat model. He will establish the extent to which arterial calcification is arrested or reversed. Within the context of this specific aim, he will investigate the effect of dietary deficiency on the carboxylation of the Gla protein and the calcification in arteries in the rat. Dr. Price will also determine the effect of warfarin on the calcification of the intima in animal models of atherosclerosis and investigate the ability of the Gla protein infusion the arterial calcification that is induced by warfarin. The second aim, is designed to investigate the relationship between defective carboxylation of serum Gla protein and arterial calcification using isoelectric focusing and terminal protein sequencing; mineral binding activity will be done to measure carboxylation status. He will also look at the structure and functional associations of Gla protein and calcification sites in the human artery. The principal investigator will also investigate the mechanism by which the Gla proteins inhibit the calcification of elastin in the human aortic media when elastin is added to solutions that contain physiological concentrations of calcium and phosphate. He will also determine the role of Gla protein as an inhibitor of the growth of crystallites isolated by the human aortic media. These experiments are being done to establish the importance of vitamin K deficiency and of warfarin treatment as risk factors for the calcification of human arteries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEW THERAPIES FOR HEMOPHILIA Principal Investigator & Institution: Key, Nigel S.; Associate Professor; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 05-SEP-2000; Project End 31-JUL-2005 Summary: The theme of this Program Project proposal is to develop novel therapies for hemophilia. In particular, the focus will be on the most significant complication of the disease, namely the occurrence of inhibitory antibodies to the clotting factors that are normally used to treat bleeding episodes. The development of an inhibitory is a devastating event, which leads inevitably to increased morbidity, and cost of therapy (which is already exceptionally high for patients without this complication). Furthermore, development of inhibitors remains one of the principal concerns surrounding gene therapy for hemophilia. We will adopt a multi- disciplinary approach to this problem, concentrating on bio-engineered clotting factors (mutants of factor VIIa with enhanced pro-coagulant activity, and human-porcine factor VIII hybrid molecules with reduced immunogenicity and antigenicity. Although not part of this proposal, clinical trials involving these proteins can be realistically anticipated as a longer term goal. In Project 1 ("The Role of Tissue trials involving these proteins can be realistically anticipated as a longer term goal. In Project 1 ("The Role of Tissue Factor in Hemophilia"), we will examine the biochemical basis for tissue factor encryption in

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vitro, and develop methods to measure expression of both the encrypted and procoagulant forms of tissue factor in vivo. In Project ("Enhanced Vitamin K- dependent Proteins in Hemophilia"), recombinant factor VII molecules that have been mutated at specific residues in the membrane contact region will be characterized with respect to their pro-coagulant activity. The anti-hemorrhagic efficacy (and potential undesirable thrombogenicity) of selected mutants will be tested in animal models of hemophilia. In Project 3 ("CD4+ T Cell Response to Porcine Factor VIII"), CD4+ T cell responses to human-porcine hybrid FVIII molecules will be examined, primarily in the murine model of hemophilia A with a FVIII inhibitor. It is our hypotheses that these hybrid molecules may be less immunogenic than human FVIII. Finally, in Project 4 ("Chimeraplasty for Factor IX and Factor VII Gene Expression"), we will use chimeric RNA/DNA constructs to "repair" the point mutation in the factor IX gene in canine hemophilia, and deliberately induce a selected point mutation in the factor VII gene to promote expression of high activity FVII(a) in vivo that will "by-pass" the need for factor VIII (or IX) in patients with inhibitors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROGRAM

NUTRITION

&

CARDIOVASCULAR

DISEASE

TRAINING

Principal Investigator & Institution: Lichtenstein, Alice H.; Professor; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The objective of this Training Grant application is to generate support for well qualified students to earn a doctoral degree in the area nutrition and cardiovascular disease at the Gerald J. & Dorothy R. Friedman School of Nutrition Science & Policy at Tufts University. The specific aims of the training program are to: 1) provide trainees with rigorous didactic training in the areas of nutrition, cardiovascular disease, basic sciences and medical ethics; 2) create a supportive environment within which trainees are guided through the process of conducting independent research; 3)develop in each trainee communication skills necessary to effectively disseminate research data in both oral and written form; 4) enable the acquisition to multidisciplinary training to make each trainee competitive upon conclusion of their formal training; 5) instill the skills necessary to become an independent investigator capable of generating research funding; 6) develop a thorough understanding of what constitutes responsible conduct of research; and 7) secure a postdoctoral position on completion of the program. The Program Faculty is drawn from a broad range of disciplines; each member currently directs a vibrant research program and has an extensive history of inter-investigator collaboration. They contribute expertise in the areas of lipids and lipoproteins, genetics, folate/homocysteine (epidemiology and basic science), obesity, cardiovascular disease risk factors and mechanisms, vitamin K, immunology, vascular biology, nutrition assessment, cardiac function and oxidative stress, and atherosclerotic plaque stability. This environment is supplemented by the combined resources of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Tufts University School of Medicine, and the Sackler School of Graduate Biomedical Sciences that together provide a fertile environment in which predoctoral students can fulfill the aforementioned aims. The symposia, seminars and meetings of institutions in the greater Boston area further serve to supplement these resources. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OSTEOCALCIN SYNTHESIS AND CATABOLISM Principal Investigator & Institution: Gundberg, Caren M.; Associate Professor; Orthopedics and Rehabilitation; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-JUL-1986; Project End 31-AUG-2008 Summary: (provided by applicant): Vitamin K is involved in the physiological activation of various proteins involved in hemostasis and bone and cartilage metabolism. Osteocalcin is a vitamin K-dependent Ca2+binding protein found in the organic matrix of bone and dentin. Circulating osteocalcin is a highly specific osteoblastic marker and it has been widely used for assessing bone turnover. The studies proposed here seek to verify new methods for the measurement of osteocalcin or its fragments as indicators of vitamin K status and bone turnover. These studies will evaluate: (1) the relationship between circulating levels of osteocalcin fragments and bone accretion and resorption via calcium kinetics; and (2) the effect of vitamin K intake on the profile of circulating forms of osteocalcin and their correlation with other measures of bone turnover. Although, the function of osteocalcin has not been precisely defined, studies in mice suggest that osteocalcin may play a role in bone remodeling. The proposed studies will (1) rescue the osteocalcin null mouse (OC-/-) with an uncarboxylated variant such that osteocalcin will not accumulate in bone but circulating levels will be elevated. The effects of 1,25(OH)2D3 and ovariectomy in wt, OC-/- and rescued animals will be evaluated by bone density, mineral content, bone turnover markers histomorphometric parameters and osteoclast development. Osteoclast and/or osteoblast progenitors will be evaluated in bone marrow cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHOSPHOLIPID BINDING SPECIFICITY OF FACTOR IX Principal Investigator & Institution: Falls, Lisa A.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-JUL-2001 Summary: The overall goal of this proposal is to characterize the phospholipid binding specificity of factor IX. Factor IXa cleaves factor X to produce Xa in a vitamin Kdependent reaction. The absence of factor Ix causes hemophilia B. The factor IXa reaction is one of many in the coagulation cascade requiring a membrane surface for assembly of the enzyme, substrate, and cofactor. The central hypothesis of this proposal is that phospholipid composition affects the binding of factor IX and the factor IXa catalyzed conversion of factor X to factor Xa. The effect of phospholipid composition on the enzymatic function of factor IXa will be examined by measuring factor Xa generation in the presence of phospholipid vesicles and soluble phospholipids of varying compositions. In addition, the binding specificity of factor DC for phospholipid vesicles will be determined using light scattering. Identification of the portions of the phospholipids important in the binding will be discovered by using soluble phospholipids to compete with phospholipid vesicles for the binding of fluorescently labeled factor IX in flow cytometry experiments. These studies will be complemented by 1H NMR spectroscopy experiments examining molecular contacts between factor IX( 147) and l ,2-dihexanoic-sn-glycero~3 phospho-L-serine. Ultimately, the structure of the factor IX(l47)-phosphatidylserine complex will be determined by two- dimensional NMR analysis. The results of this proposal will lead to new information about how phospholipid membranes contribute to the vitamin K-dependent coagulation reactions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PREDICTORS OF ANTICOAGULATION CONTROL ON WARFARIN Principal Investigator & Institution: Kimmel, Stephen E.; Associate Professor; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 19-MAR-2001; Project End 31-JAN-2005 Summary: Thromboembolism (TE) can occur in the venous or arterial system and is associated with substantial morbidity and mortality in a large proportion of the population. Although most of these thromboembolic events can be prevented using warfarin sodium, proper levels of anticoagulation (AC) with warfarin are very difficult to maintain. Because the drug has a narrow therapeutic range, inadequate levels of AC can lead to failure of therapy and life threatening thromboembolic complications, while excessive levels can lead to life threatening bleeding complications. In addition, improper AC can lead to increased medical costs, reduced quality of life, patient dissatisfaction, and discontinuation of a highly efficacious therapy. However, the reason for the marked intrapatient and interpatient variability in response to warfarin often remains unknown. Recently discovered genetic variants that affect warfarin pharmacokinetics (the CYP2C9 enzyme, via reduced warfarin metabolism) may explain at least some of this variability. In addition, patient adherence with warfarin, and its interaction with genotype, are likely to be important, but have not been rigorously studied. The objective of this study is to determine the effects of these genetic variants and adherence on AC control. A prospective cohort study is proposed in patients requiring AC at one of three AC clinics, representing a broad spectrum of patients. Patients presenting for AC will be identified at the start of therapy and followed throughout their course of therapy. Genotype of CYP2C9 and apolipoprotein E will be determined via cheek swabs, and adherence with medications will be measured throughout the study using state-of-the-art electronic pill cap monitoring. Detailed information on important time-varying confounders also will be collected. The outcomes will be over-AC and under-AC, analyzed separately because different genotypic variants and adherence patterns are likely to affect each differently. Univariate and multivariate analyses will focus on genotype, adherence, and the interactions between genotypes and between genotype and adherence. The interaction of other risk factors with genotype also will be explored as will other outcomes, including bleeding and TE. By understanding the effects of genetic polymorphisms and adherence on AC control via the merger of the disciplines of pharmacogenetics and pharmacoepidemiology, this study hopes to provide critical information to apply clinically (patient pre-screening) and scientifically (development and application of specific strategies targeted at specific patient groups based on the cause of their poor AC control). The ultimate goal is to improve the use of a highly efficacious, but underused, drug and reduce morbidity and mortality in the large proportion of the population at risk for TE. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROTEIN Z DEPENDENT PROTEINASE INHIBITOR Principal Investigator & Institution: Broze, George J.; Professor; Barnes-Jewish Hospital Ms 90-94-212 St. Louis, Mo 63110 Timing: Fiscal Year 2001; Project Start 08-SEP-1998; Project End 31-AUG-2002 Summary: (Investigator's abstract) Protein Z is a vitamin K-dependent plasma protein of previously unknown function. The goals of this proposal are to biochemically characterize: 1) the interaction between protein Z and factor Xa at the surface of phospholipids; 2) the protein mediated enhancement of factor Xa inhibition by tissue

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Vitamin K

factor pathway inhibitor; and 3) the protein Z-dependent inhibition of factor Xa produced by an additional, previously unrecognized plasma protein. In additional studies, the in vivo consequences of protein Z deficiency will be determined in mice. The experiments are designed to provide information, now lacking, concerning the function of protein Z. These results should enhance our understanding of both hemostasis and pathological thromboembolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTON & ELECTRON TRANSFER & ENERGY COUPLING IN SIT I Principal Investigator & Institution: Ohnishi, Tomoko; Research Professor; Biochemistry and Biophysics; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-FEB-1983; Project End 31-JAN-2005 Summary: The NADH-quinone oxidoreductase (complex I) is the largest (M.W. = approximately 1 mega-daltons) and most complicated (43 subunits) energy-transducing system in mitochondria. Many mitochondria-linked genetic diseases have been discovered, and the majority of them originate from a complex I defect(s). The elucidation of the structure-function relationship of complex I is vital not only for the study of bioenergetics, but also for the understanding of the nature of these diseases, in order to develop therapies. Based upon our previous findings, we will extend our studies in the following directions: (1) The NADH-binding site, one FMN molecule, and a majority of iron-sulfur clusters with low midpoint potential are localized in the hydrophilic promontory domain of complex I. In contrast, the iron-sulfur cluster N2 (which has the highest midpoint redox potential) and three distinct ubisemiquinone species are located within the membrane domain. We hypothesized that cluster N2 and these semiquinones play key roles in the proton and electron transfer in complex I. We found that cluster N2 resides in either of TYKY or PSST subunits. Both subunits are at least partially buried within the membrane. Determining the subunit location and ligand structure of cluster N2 has been one of the most important yet difficult tasks in complex I study. Recently, we have developed systems with much simpler bacterial complex I counterparts in which these two candidate subunits can be separated. Using these systems, we will identify which subunit harbors cluster N2. Furthermore, we will study the unique functions of cluster N2 employing site-directed mutagenesis techniques. (2) The subunit PSST (not TYKY) contains a specific and tight binding site for various complex I inhibitors. We have discovered that the distinct ubisemiquinone species respond differently to these inhibitors. Using vari9us inhibitors with different specificity, we will study the functional roles of both cluster N2 and the three quinone species in the energy-coupling mechanism in complex I. (3) We have found that the complex I counterpart in Thermus thermophilus has extreme thermo-stability and that its purified subunits are very stable. We will use this bacterium for crystallization and Xray crystallographic studies. (4) We will determine physicochemical properties and spatial organization of all important redox components by combining state-of-the-art molecular genetic technology with sophisticated physical techniques such as EPR, ENDOR, ESEEM, and cyclic voltammetry as collaborative efforts. (5) We have developed an exciting bacterial model system, which allows us to study mechanisms of mitochondria-linked diseases by making clinically significant point mutations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF MACROPHAGE DEPENDENT ANGIOGENIC ACTIVITY Principal Investigator & Institution: Leibovich, Samuel Joseph.; Professor; Anat/Cell Biology/Injury Sci; Univ of Med/Dent Nj Newark Newark, Nj 07103 Timing: Fiscal Year 2001; Project Start 01-MAY-1999; Project End 30-APR-2003 Summary: (Adapted from Investigator's Abstract): Macrophages play a key role in mediating the induction of angiogenesis in wound repair, fibroproliferative diseases and solid tumor development, by producing macrophage-derived angiogenic activity (MDAA). VEGF is an important component of MDAA. The bio-activity of VEGF is regulated in macrophages by the iNOS pathway, by hypoxia and by lactate. The applicant's previous studies indicate that regulation of the angiogenic activity of VEGF by macrophages is controlled in part by the process of mono-ADP-ribosylation. The primary hypothesis is that VEGF is produced by macrophages in either the unmodified or the ADP-ribosylated form. Unmodified VEGF is angiogenic; while ADP- ribosylated VEGF is non-angiogenic. ADP-ribosylation is regulated by the iNOS pathway and by hypoxia. The Specific Aims of this application are designed to analyze the mechanisms that regulate the mono-ADP-ribosylation of VEGF, and the role of the mono-ADPribosylation in the process of macrophage-dependent angiogenesis. The role of the iNOS pathway in controlling VEGF ADP-ribosylation will also be examined. Specific Aim 1 is directed at characterizing molecular and cellular aspects of ADP-ribose incorporation into VEGF in macrophages. Two experimental protocols will be used to monitor covalent modification of VEGF. First, macrophages will cytoplasmically loaded with 32P-NAD+ using the "Influx"TM pinocytic cell loading system. Second, the substrate availability to exogenous ADP-ribosylation will be monitored using a "Back ADPribosylation" approach. In addition, specific antibodies to ADP- Ribose will be obtained and used to analyze the incorporation of ADP-Ribose into VEGF, using SDS-PAGE and Western blotting. Specific Aim 2 focuses on determining the effects of ADP-ribosylation on the angiogenic properties of VEGF. Initial experiments have shown that rVEGF165 can be ADP-ribosylated with cholera toxin or macrophage cytoplasmic extracts, and that the ADP-ribosylated VEGF is non- angiogenic in the rat corneal bio-assay of angiogenesis. Further studies will examine the angiogenic activity of ADP-ribosylated VEGF in additional assays of angiogenesis in vivo and in vitro. Specific Aim 3 will examine the role of the iNOS pathway and its products in the regulation of VEGF ADPribosylation by macrophages. The goal will be to determine whether the iNOS pathway effects ADP- ribosyl transferase activity or expression directly, or alters the availability of the NAD+ required as a substrate for the enzyme. Specific Aim 4 examines the role of ADP-ribosylarginine hydrolases in the regulation of VEGF ribosylation. Enzyme activity and steady state mRNA expression levels will be determined in macrophages cultured under various conditions. The effects of iNOS-derived products on the activity and expression of ADP ribosylarginine hydrolase will then be analyzed. Specific Aim 5 examines ADP- ribosylation and its regulation by NO in macrophages from iNOS knockout mice. This will be a continuation of earlier results indicating that macrophages from iNOS knockout mice show markedly reduced production of MDAA, with no reduction in VEGF production. Specific Aim 6 focuses on the effect of inhibitors of ADPribosylation on wound repair in normal and iNOS knockout mice. Novobiocin, VitaminK1, and Vitamin-K3 will be tested. Taken together, these studies should elucidate an important control mechanism involved in the regulation of macrophage-dependent angiogenic activity, and lead to potential therapeutic modalities for the treatment of chronic wounds. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Vitamin K

Project Title: STRUCTURE AND FUNCTION OF THE GAMMA-GLUTAMYL CARBOXYLASE Principal Investigator & Institution: Furie, Barbara C.; Director; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001 Summary: The vitamin K-dependent gamma-glutamyl carboxylase post-translationally converts glutamic acids in its substrate proteins to gamma carboxyglutamic acid (Gla). This modification is critical for normal blood coagulation, through multiple vitamin Kdependent proteins, and for calcium homeostasis, through participation of matrix Gla protein. It is likely that other critical roles for this post-translational modification will be discovered. Here we explore the structure and function of the carboxylase. We have been shown that the ability of the carboxylase to activate vitamin K to the highly reactive cofactor intermediate is regulated by the presence of glutamate containing substrate. This regulation results from modification, at least in part, of the environment of a critical free cysteine residue in the enzyme. In specific Aim 1 we identify the mechanistically important cysteine(s) and determine the disulfide bonding pattern in carboxylase. In Specific Aim 2, we determine the topology of the carboxylase within the endoplasmic reticulum membrane. We will determine the potential N-linked glycosylation sites in the enzyme that are occupied, perform glycosylation scanning mutagenesis and use cell free transcription and translation in conjunction with protease protection assays. In Specific Aim 3 we use innovative methods of tandem mass spectrometry that spares gamma-carboxyl groups during ion fragmentation to determine if the carboxylase is processive or distributive, if distributive, is it directional or random? We developed a transgenic mouse model in which, on the background of a carboxylase null mouse, we introduced a wild-type carboxylase transgene under the regulation of a liver specific promoter. This rescues the fetal phenotype of the carboxylase null mouse. In Specific Aim 4 we will use this model to identify additional critical gamma-carboxylated proteins. We will also use the mouse model to determine the relationship of kinetic parameters of various carboxylase substrates to in vivo carboxylation of these substrates. The vitamin K-dependent carboxylase performs a post-translational modification critical for blood coagulation and for calcium homeostasis. The studies proposed will elucidate important aspects of carboxylase mechanism and provide a topologic structure to unify the mechanistic information already available for this enzyme. The performance of these studies will be enhanced by other aspects of the Program: the availability of Core services, information about regulation of carboxylase gene expression from Project II as well as the technical expertise of Drs. David Roth and Bruce Furie in various aspects of these studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRUCTURE FUNCTION RELATIONSHIPS OF FACTOR IX Principal Investigator & Institution: Roberts, Harold R.; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001 Summary: The purpose of this project is to understand the function of the gammacarboxyglutamic (Gla) domain of vitamin K-dependent coagulation factor IX. Understanding the Gla domain, the location both of factor IX binding to collagen IV and platelets and also of carboxylation, can advance knowledge about hemostasis. A better understanding of the molecular basis of factor IX's activity could have clinical applications in the treatment of thrombosis. First we will attempt to determine the

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physiological relevance of factor IX's binding to collagen IV by examining the phenotype of a mouse with a mutant factor IX unable to bind collagen IV. Second, to determine if collagen IV is intracellular or is actually found on the surface of endothelial cells lining the lumen of both arteries and veins where it is (uniquely among vitamin Kdependent clotting factors) co-localized with factor IX, we will utilize monoclonal antibodies together with colloidal gold and electron microscopy. Third, to identify residues of collagen IV to which factor IX binds, we will utilize chemical cross-linking techniques. Fourth, since a specific region of the factor IX Gla domain binds to platelets, we propose to use the photochemical cross-linker benzoyl- phenylanine to identify and purify the receptor. Fifth, we will continue our studies on substrates for the carboxylase by examining several new constructs for their activity in an in-vitro carboxylase assay and determining if a specific sequence is required for the carboxylation of vitamin Kdependent protein in-vivo. A plausible mechanism to explain the defects in conditional hemophilia B patients identified during the tenure of our current project will be very important to understanding how these pro-peptide mutations are leading to hemophilia B in the presence of warfarin. Moreover, knowledge of the mechanism of carboxylation and the importance of each residue of the pro-peptide in carboxylation may allow the development of anticoagulents specific for a particular vitamin K- dependent coagulation factor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURE/FUNCTION CARBOXYLASE

OF

THE

GAMMA-GLUTAMYL

Principal Investigator & Institution: Stafford, Darrel W.; Pathology and Lab Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 01-APR-1992; Project End 31-JUL-2006 Summary: (Applicant's Description Verbatim): The broad biological objective of this project is to continue studies to understand the complete vitamin K cycle, which is important for blood coagulation, bone formation, and a number of other physiological processes. The primary effort will continue to be studying the structure and function of gamma-glutamyl carboxylase and the mechanism of carboxylation. Another major element of the study will be to purify the microsomal enzyme vitamin K epoxide reductase, which is essential for regenerating vitamin K. The long-term goal of the research is to replicate not only the carboxylation process but the entire vitamin K cycle in vitro in order to understand the roles that carboxylase, vitamin K epoxide reductase, and any other essential components in the vitamin K cycle play in blood coagulation. Most of the research proposed in this application is devoted to understanding how the structure of the human gamma-glutamyl carboxylation enzyme is related to its function. Some overarching goals of the proposed research are: (1) determine the ways carboxylase recognizes and interacts with substrates and ligands: (2) identify and characterize catalytic residues crucial for gamma-glutamyl carboxylation; (3) elucidate the role of regulatory sites on the mechanism of gamma-glutamyl carboxylation; and (4) define a structural organization of the carboxylase enzyme by 2-dimensional electron diffraction. In particular, the Specific Aims are: Specific Aim 1: Identify sequences in the carboxylase that bind propeptide, investigate the role of carboxylase residues surrounding L394, which may constitute part of the gla domain-binding site, and determine which residues mediate linkage between these two sites. Specific Aim 2: Identify cysteine residues important for catalysis and functionally important disulfide bonds. Specific Aim 3: Investigate the relationship of the carboxylase's putative internal

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Vitamin K

propeptide sequence to control of enzyme activity. Specific Aim 4: Examine what factors determine the substrate's rate of dissociation from the carboxylase in vitro and whether the rate of dissociation of substrate/product affects the extent of carboxylation of proteins expressed in cell culture. Specific Aim 5: Identify the gene for the vitamin K epoxide reductase. Specific Aim 6: Continue our collaboration with Dr. Kuhlbrandt's laboratory to obtain structural information about gamma-glutamyl carboxylase. The pursuit of these goals will include making chimeras of human and Drosophila carboxylases, using fluorescence spectroscopy to measure on- and off-rates of substrates used in carboxylation, and using the power of Drosophila genetics to attempt to identify the gene for epoxide reductase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURE/FUNCTION OF CONTAINING PROTEINS PRGP1 AND PRG

TWO

PROLINE

RICH

GLA

Principal Investigator & Institution: Xie, Ling; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2001 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURE/FUNCTION STUDY OF THE ANTICOAGULANT PROTEIN S Principal Investigator & Institution: Rigby, Alan C.; Assistant Professor; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: Blood coagulation involves the assembly of calcium- dependent macromolecular complexes on phospholipid membranes. The penultimate step in blood coagulation is the conversion of prothrombin to thrombin, which is then responsible for the conversion of fibrinogen to fibrin. Uncontrolled or excessive thrombin generation leads to thrombosis, a major cause of morbidity and mortality. The protein C anticoagulant pathway is an essential mechanism for regulating thrombin formation, whereby activated protein C (APC) in association with its cofactor protein S enhances the inactivation of factor Va (FVa) and factor VIIIa (FVIIIa). Protein S, is a vitamin Kdependent protein that possesses both APC-dependent and APC-independent anticoagulant activity. The APC-independent activity of protein S has been ascribed to its ability to inhibit the "prothrombinase" and "tenase" procoagulant complexes. The major goals of this research proposal are to elucidate the structural and/or functional significance of the N-terminal domains of protein S including: the Gla domain, the thrombin sensitive region and the first epidermal growth factor domain. Initially, we will characterize the Gla domain of human protein S, PS(1-45), in the APC-independent mechanism of anticoagulation. PS (1-45) will be chemically synthesized and its calcium binding, phospholipid binding and functional properties investigated. We will then evaluate the ability of this domain to inhibit the FVa- and FX- dependent prothrombinase activity. Finally, we will determine the three-dimensional structure of PS(1-45) in the presence and absence of calcium using NMR spectroscopy. We believe that a comparison between these two structures will identify residues that are critical for calcium binding and thus involved in the calcium-dependent conformational perturbation. The other major goal of this proposal involves the APC-dependent cofactor activity of protein S, which requires the thrombin sensitive region (TSR) and

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first epidermal growth factor domain (EGF1). Initially, we will characterize the structural and functional properties of recombinantly expressed TSR-EGF1 (rhTSREGF1), to ensure this protein is properly folded. Simultaneously, we will uniformly 15N and 13C label rhTSR-EGF1 allowing us to determine the three-dimensional structure of TSR-EGF1 using heteronuclear NMR spectroscopy. We will then investigate the proteinprotein interaction between rhTSR-EGF1 and APC or FXa using fluorescence spectroscopy, isothermal calorimetry and NMR spectroscopy. This structural information will identify the critical epitopes involved in complex formation and provide valuable information necessary to understand the mechanisms involved in regulating thrombus formation, which is of considerable clinical and basic science interest. New insights into these mechanisms may identify novel methods for the intervention in pathologic thrombus formation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURE-FUNCTION CARBOXYLASE

ANALYSIS

OF

THE

GAMMA-

Principal Investigator & Institution: Berkner, Kathleen L.; Assistant Professor; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2003; Project Start 01-APR-1997; Project End 30-NOV-2006 Summary: (provided by applicant): Vitamin K dependent (VKD) proteins require carbolylation for activity and so the VKD carboxylase plays a critical role in hemostasis. The carboxylase converts Glu's to Gla's using the energy of vitamin K oxygenation. At least 10 different VKD proteins in liver engage a single carboxylase in the endoplasmic reticulum to become fully carboxylated (9-12 Gla's per molecule). Under normal conditions full carboxylation occurs, however how the process is regulated to achieve such remarkable fidelity is not known. A method that mimics the normal physiological process was developed to study protein carboxylation, which showed conclusively that carboxylase processivity can account for comprehensive carboxylation in vivo and also provided new insights into the mechanism. The carboxylase active site was identified in studies that led to a hypothesis of substrate-regulated carboxylation. The long standing question of why carboxylation is saturated when VKD proteins are expressed in mammalian cells was addressed and showed the importance of the secretory machinery in facilitating carboxylation. Two modifications, carboxylase carboxylation and phosphorylation, were discovered. The long term goal is to understand the mechanism of carboxylation, including how multiple VKD proteins compete for one carboxylase in tissue to become fully carboxylated. The specific aims proposed for the next funding period are to: 1) Determine how the active site facilitates carboxylation. The hypotheses for how carboxylation is regulated will be tested by characterizing a newly discovered second site of VKD protein-carboxylase interaction and determining how vitamin K is oxygenated to initiate carboxylation. 2) Define the mechanism of VKD protein carboxylation, The hypothesis that vitamin K availability, competing VKD proteins and carboxylase carboxylation affect carboxylase processivity will be tested. 3) Determine how carboxylase carboxylation and phosphorylation regulate carboxylation. The hypothesis that these modifications regulate how secretory events facilitate carboxylation will be tested by analyzing effects on carboxylase trafficking, stability, chaperone association and fIX carboxylation. These studies will make fundamental contributions towards understanding the mechanism of carboxylation, which will be important for developing improved anticoagulants, determining how changes in diet and anticoagulation affect hemostasis and producing therapeutic amounts of VKD proteins.

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Vitamin K

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

Project Title: STUDIES ON VITAMIN K BIOSYNTHESIS Principal Investigator & Institution: Meganathan, Rangaswamy; Biological Sciences; Northern Illinois University De Kalb, Il 60115 Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 28-FEB-2005 Summary: DESCRIPITON (provided by applicant): Humans and animals cannot synthesize vitamin K (K). K dependent, hypoprothrombia is an important clinical problem under a number of conditions. The K requirement in human and animal nutrition is met by green plants and intestinal bacteria. Because K plays an important role in human well being, it is important to understand its biosynthesis and regulation. The vitamin K biosynthetic pathway may be summarized as follows: chorismate -menF-> isochorismate --menD--> 2-succinyl-6-hydroxy-2, 4-cyclohexadiene-1 -carboxylate (SHCHC) ---menC---->o-succinylbenzoic acid (OSB)-menE-> o-succinylbenzoyl-CoA (OSB-CoA) --menB-->{ 1, 4-dihydroxy-2-naphthoyl-CoA (DHNA-CoA)}---menH---> 1, 4dihydroxy-2-naphthoic acid (DHNA) ---menA---> demethylmenaquinone (DMK) --ubiE --> menaquinone (MK). Seven ORFs (six of which have been shown to be menaquinone biosynthetic genes) lie in a cluster in the order orf1O1, menF, menD, menH, menB, menC, and menE. Transcription of all the genes are initiated from a single strong promoter site, 26 bp 5' to orfiOl was detected under anaerobic conditions. The menA gene is located at 89 min on the chromosome and is linked to an unidentified orf (orf161). In this study, we propose 1) to determine the role of orf101; 2) to study the regulation of the men operon using lacZ fusions; 3) to determine the structure of a proposed intermediate (DHNA-CoA); 4) to identify the methyltranferase involved in the DMK-->MK conversion, and 5) to characterize the active site mutants of OSB synthase, whose three dimensional structure was recently solved by us. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SUPPRESSION OF LUNG GROWTH BY MATRIX GLA PROTEIN Principal Investigator & Institution: Rannels, Stephen R.; Cellular/Molecular Physiology; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, Pa 17033 Timing: Fiscal Year 2001; Project Start 16-AUG-1999; Project End 30-JUN-2003 Summary: Matrix Ga protein (MGP), a vitamin K-dependent protein first isolated from the matrix of bone, is also abundant in developing and adult lung. Although its function in any tissue is unknown, we have recently obtained evidence that MGP restricts embryonic lung branching and alveolar sac formation in a spatial and temporal manner. Treatment of day 14 rat lung explants with MGP antibodies doubles the number of terminal lung buds that are formed during culture. Addition of vitamin K to explants stimulates the carboxylation and secretion of mature MGP in the distal aspects of the lung and restricts normal branching and budding. Other factors that influence morphogenesis and adult lung growth, including retinoic acid, dexamethasone, TGFbeta and EGF also have an appropriate influence on MGP expression. That is, when MGP is increased, growth is restricted. We propose to study the expression of MGP in both epithelial and mesenchymal compartments of developing lungs using both explant and isolated cell models to establish that MGP is a key modulator of morphogenesis and is a common mediate of the above mentioned factors. Manipulation of the expression of MGP will identify strategies to increase alveolization during development and in adult lung. These studies will employ the use of antibody and anti-sense RNA blocking

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strategies, peptide competition and protein addition protocols, and the selective administration of growth factors and agents into mesenchymal and epithelial compartments of the lung. We will also selectively restrict vitamin K function in the lung to allow growth to accelerate in the absence of MGP. This approach will incorporate a combination of treatment protocols which should optimize differentiation and growth and focus on autocrine and paracrine relationships in MGP action. The hypothesis of the of these studies is that MGP is tightly regulated in a cell-specific and temporal manner to restrict growth and alveolization in developing and adult lung. It's expression, and therefore function, is tightly controlled by numerous growth-promoting and restricting factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VENOUS THROMBOEMBOLISM: GENES, RISK, MANAGEMENT Principal Investigator & Institution: Bovill, Edwin G.; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2001; Project Start 30-SEP-1991; Project End 31-AUG-2006 Summary: We propose to investigate gene-gene and gene-environmental interactions in venous thrombosis with the goal of better defining individualized clinical risk profiles, optimal, optimal clinical management practices and underlying pathophysiology. Our study population is a group of extended, related thrombophilic pedigrees of French/French Canadian descent (n=1400), living in France, Quebec and Vermont, which share type I protein C deficiency due to a rare 3363 C insertion mutation. The mutation exhibits haplotypic identity across the Quebec, Vermont and probably French families. Thus, the abnormal allele is identical across the population with respect to not only protein C coding and intronic sequence but also related nearby regulatory or coregulated elements. Therefore, our study population creates a unique opportunity to study the multicausal nature of thrombosis with one of the major modifying loci held constant. Some of these families have been studied by investigators for up to 15 years. We will study the following hypotheses in this study population by a combination of an ambispective longitudinal familial cohort study and molecular biologic strategies focused on gene discovery: 1. The risk for venous thrombosis is a function of a definable subset of oligogenic and environmental factors and their interaction. 2. Clinical management will be improved by better understanding of individual global risk profiles. 3. Quality of life will be affected to varying degrees by the knowledge of an individual's risk profile as well as the presence of disease. 4. Expression of many individual and composite biochemical risk factors, characterized as continuous variables, will reflect the inheritance of single genes that can be localized within the genome. This collaborative clinical study will bring together complementary expertise from five major academic centers, with existing collaborative relationships, in North America and Europe. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VITAMIN K AND BONE TURNOVER IN POSTMENOPAUSAL WOMEN Principal Investigator & Institution: Binkley, Neil C.; Assistant Professor; Institute on Aging; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: Accumulating data suggest that vitamin K (K) insufficiency may contribute to osteoporosis development by causing by causing increased bone turnover. However,

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Vitamin K

currently available data do not permit definitive conclusions to be drawn regarding a role of K in bone metabolism. Much of the evidence implicating K in bone health utilizes measurement of serum undercarboxylated osteocalcin (ucOC) as a sensitive indicator of K status. When ucOC elevation is used to define K inadequacy, insufficiency is extremely common. However, whether this "insufficiency has skeletal relevance, or if elevated ucOC concentration is simply a surrogate for generalized inadequate nutrition, is unknown. To clarify the role of K insufficiency in skeletal health, we propose a 14 month, prospective, randomized, double-blind, placebo controlled trial of K1 supplementation in 226 postmenopausal women. We hypothesize that K1 supplementation reduces skeletal turnover. To test this hypothesis we will use a K1 dose (1000 mcg/day) that produces maximal reduction in serum ucOC. Our specific objective is to assess skeletal turnover by measuring serum osteocalcin, bone specific alkaline phosphatase, and N-telopeptides of type l collagen, as well as urinary pyridinoline and deoxypyridinoline. If K insufficiency causes high bone turnover, a known risk factor for low bone mass and osteoporotic fracture, the recommended K intake should be increased and K1 supplementation become part of standard preventative medical care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VITAMIN K STATUS IN PREMATURE INFANTS Principal Investigator & Institution: Kumar, Deepak; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001 Summary: Full term newborns are in a state of relative vitamin K deficiency. Only recently, the vitamin K status of full term infants has been reliably described. Similiar information on premature infants is not available. This pilot study is proposed to prospectively investigate the vitamin K status of premature infants especially the very low birth weight infants. A cohort of premature newborns will be enrolled. Their vitamin K status will be assessed by measuring plasma vitamin K concentrations, PIVKA II, osteocalcin, calcium, phosphate and alkaline phosphatase levels in their blood at birth (cord blood), two, and six weeks of age. In addition urine calcium, hydroxyproline and creatinine excretion will be measured at the same times. An assessment of their vitamin K intake will be made from their daily parenteral, formula and breast milk intake. Amount of vitamin K given at birth as prophylaxis will also be noted. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VITAMIN K, METABOLISM AND FUNCTION Principal Investigator & Institution: Wallin, Reidar; Internal Medicine; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 30-SEP-2003 Summary: Understanding vitamin K-dependent proteins will require insight into their biosynthesis and regulation. Unique for these proteins is their vitamin K-dependent post-translational modification. The modification is carried out by the _-carboxylase, an integral protein of the ER membrane which uses the reduced form of vitamin K (vitamin KH2) as cofactor. The reduced cofactor is produced by the enzyme Vitamin K 3,4-Epoxide reductase (VKOR) which is the target for the anticoagulant drug warfarin. Despite numerous attempts to purify VKOR, the molecular components that constitute the enzyme have not been identified. The applicants have been able to show that VKOR is an enzyme complex in the ER membrane and they propose that assembly of the

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complex is similar to assembly of the lipoxygenase complex on the nuclear envelope membrane. Both enzymes incorporates a member of the glutathione-S-transferase gene family as part of the lipid-protein enzyme complex. Experiments are proposed to complete the model of the VKOR enzyme complex and unveil the basis for genetic resistance to warfarin. Recombinant VKOR will be used to increase the capacity of cell lines to produce functional clotting factors VII and IX. It is our hypothesis that vitamin KH2 cofactor production by VKOR is a limiting factor in cellular production of these recombinant proteins. Although 8-10 different vitamin K-dependent proteins have been shown to be made extrahepatically only some have been identified. They include the coagulation factors prothrombin and protein S, the growth arrest specific gene 6 product Gas6 and the bone and cartilage resident proteins, osteocalsin and matrix GLA protein (MGP). In the last specific aim of this application experiments are proposed to identify new vitamin K-dependent proteins by vitamin K-dependent radioactive labeling. The proposed experiments will provide a better understanding of vitamin K metabolism and vitamin K function and have an impact on prophylactic medicine concerned with recombinant vitamin K-dependent coagulation factors and warfarin anticoagulation. The experiments should also contribute to the exciting, rapidly expanding area of research on extra-hepatic vitamin K-dependent proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VITAMIN DEVELOPMENT

K-DEPENDENT

PROTEINS

IN

BLOOD

AND

Principal Investigator & Institution: Roth, David A.; Assistant Professor of Medicine; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-SEP-1997; Project End 28-FEB-2003 Summary: In what is the only known biological process dependent on vitamin K, the vitamin K-dependent lambda-glutamyl carboxylase catalyzes the posttranslational modification of glutamate to lambda-carboxyglutamate in the vitamin K-dependent proteins during their synthesis. This modification is essential for the biological activities of all known vitamin K-dependent proteins. Substrates of the carboxylase include several proteins involved in blood coagulation as well as bone matrix proteins and Gas6. Gas6, a cell cycle regulated protein is a ligand for receptor tyrosine kinases and has been implicated in the prevention of apoptosis of growth arrested cells. While we have previously focused our studies on the role of vitamin K-dependent carboxylation in hemostasis, we have recently demonstrated extrahepatic expression of the vitamin Kdependent carboxylase gene in adult and embryonic rat tissues, supporting the hypothesis that vitamin K has an important physiological role outside of blood coagulation. Warfarin, a potent vitamin K antagonist, is a widely used anticoagulant which indirectly inhibits the activity of the vitamin K-dependent carboxylase. Warfarin is also a teratogen. Human maternal exposure to warfarin during pregnancy is associated with developmental abnormalities in the fetus, the warfarin embryopathy, suggesting critical developmental functions for the carboxylase enzyme and its substrates. New data from our laboratory demonstrates temporal variations in tissue specific expression of vitamin K-dependent carboxylase mRNA in developing rat embryonic tissues, supporting the hypothesis that vitamin K-dependent carboxylation is a developmentally regulated posttranslational modification important for normal embryogenesis. In the current application, studies are proposed to clarify the role of vitamin K in development by examining the developmental and tissue specific expression of the vitamin K-dependent carboxylase in rat embryos. The regulation of vitamin K-dependent carboxylase gene transcription will be evaluated in vitro to study

30

Vitamin K

the factors that regulate vitamin K- dependent protein activity during development. An animal model of warfarin embryopathy will be developed, to direct future in vivo studies for testing the functions of carboxylase substrates in development of the normal embryo. Vitamin K-dependent carboxylation will serve as a model for other developmentally regulated posttranslational modifications of proteins important in fetal development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VITAMIN K-DEPENDENT TRANSMEMBRANE GLA PROTEINS Principal Investigator & Institution: Davie, Earl W.; Professor and Chairman; Biochemistry; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2003; Project Start 15-DEC-2002; Project End 30-NOV-2007 Summary: (provided by applicant): Vitamin K-dependent proteins have been shown to play a major role in vertebrates in blood coagulation and its regulation, as well as in bone resorption and tissue mineralization. The vitamin K-dependent proteins contain gamma carboxyglutamic acid residues that are generated in a post-translation event within the lumen of the endoplasmic reticulum. This reaction is catalyzed by a gamma glutamyl carboxylase that is widely distributed in numerous vertebrate and nonvertebrate tissues. This investigation will focus on gaining insight into the biological role of four novel vitamin K-dependent proteins that are single transmembrane proteins. These proteins range in size from 17 kDa to 25 kDa and contain from nine to thirteen gammacarboxyglutamic acid residues. They have been called PRGP1, PRGP2, TMG3, and TMG4. Genes for two of these transmembrane proteins, PRGP1 and TMG3 are located on the X chromosome, while genes for PRGP2 and TMG4 are found on chromosome 19 and 11, respectively. Studies with transfected mammalian cells have now shown that they require vitamin K for their post-translational modification in a reaction that is inhibited by warfarin. The carboxyl region of the four transmembrane proteins bind to Nedd4-like proteins, suggesting that they may play a role in the ubiquitin cycle. Nedd4-like proteins have a C2 domain, two to four WW domains, and a HECT domain that functions as an E3 ubiquitin ligase in the ubiquitin cycle. The mechanism and specificity of these reactions will be examined in detail in these investigations. 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 “vitamin K” (or synonyms) into the search box. This search gives you access to full-

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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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text articles. The following is a sample of items found for vitamin K in the PubMed Central database: •

Anaerobic biosynthesis of enterobactin Escherichia coli: regulation of entC gene expression and evidence against its involvement in menaquinone (vitamin K2) biosynthesis. by Kwon O, Hudspeth ME, Meganathan R.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=178078

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Comparative effects of cefoxitin and cefotetan on vitamin K metabolism. by Sieradzan RR, Bottner WA, Fasco MJ, Bertino JS Jr.; 1988 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=175889

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Effects of aztreonam on fecal flora and on vitamin K metabolism. by Sakata H, Kakehashi H, Fujita K, Yoshioka H.; 1990 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=171755

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Expression of Bovine Vitamin K-Dependent Carboxylase Activity in BaculovirusInfected Insect Cells. by Roth DA, Rehemtulla A, Kaufman RJ, Walsh CT, Furi B, Furie BC.; 1993 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47358

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Identification and Purification to Near Homogeneity of the Vitamin K- Dependent Carboxylase. by Wu S, Morris DP, Stafford DW.; 1991 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51205

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Identification of the vitamin K-dependent carboxylase active site: Cys-99 and Cys-450 are required for both epoxidation and carboxylation. by Pudota BN, Miyagi M, Hallgren KW, West KA, Crabb JW, Misono KS, Berkner KL.; 2000 Nov 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27173

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In vitro and in vivo Functional Characterization of Bovine Vitamin K- Dependent [gamma]-Carboxylase Expressed in Chinese Hamster Ovary Cells. by Rehemtulla A, Roth DA, Wasley LC, Kuliopulos A, Walsh CT, Furie B, Furie BC, Kaufman RJ.; 1993 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46562

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Manipulation of the membrane binding site of vitamin K-dependent proteins: Enhanced biological function of human factor VII. by Shah AM, Kisiel W, Foster DC, Nelsestuen GL.; 1998 Apr 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22471

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Mechanism of Cyanide Inhibition of the Blood-Clotting, Vitamin K-Dependent Carboxylase. by Dowd P, Ham S.; 1991 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52973

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Menaquinone (vitamin K2) biosynthesis: cloning, nucleotide sequence, and expression of the menC gene from Escherichia coli. by Sharma V, Meganathan R, Hudspeth ME.; 1993 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=204947

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Menaquinone (vitamin K2) biosynthesis: conversion of o-succinylbenzoic acid to 1,4dihydroxy-2-naphthoic acid by Mycobacterium phlei enzymes. by Meganathan R, Bentley R.; 1979 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=216783

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Menaquinone (vitamin K2) biosynthesis: evidence that the Escherichia coli menD gene encodes both 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylic acid synthase and alpha-ketoglutarate decarboxylase activities. by Palaniappan C, Sharma V, Hudspeth ME, Meganathan R.; 1992 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=207550

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Menaquinone (Vitamin K2) Biosynthesis: Localization and Characterization of the menA Gene from Escherichia coli. by Suvarna K, Stevenson D, Meganathan R, Hudspeth ME.; 1998 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107237

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Menaquinone (vitamin K2) biosynthesis: nucleotide sequence and expression of the menB gene from Escherichia coli. by Sharma V, Suvarna K, Meganathan R, Hudspeth ME.; 1992 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=206321

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Menaquinone (vitamin K2) biosynthesis: overexpression, purification, and characterization of a new isochorismate synthase from Escherichia coli. by Daruwala R, Bhattacharyya DK, Kwon O, Meganathan R.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=179089

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Menaquinone (vitamin K2) biosynthesis: overexpression, purification, and properties of o-succinylbenzoyl-coenzyme A synthetase from Escherichia coli. by Kwon O, Bhattacharyya DK, Meganathan R.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=178575

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Propeptide and glutamate-containing substrates bound to the vitamin K-dependent carboxylase convert its vitamin K epoxidase function from an inactive to an active state. by Sugiura I, Furie B, Walsh CT, Furie BC.; 1997 Aug 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23034

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Role of vitamin K2 in the organization and function of Staphylococcus aureua membranes. by Goldenbaum PE, Keyser PD, White DC.; 1975 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=245950

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Vitamin K policies and midwifery practice: questionnaire survey. by Ansell P, Roman E, Fear NT, Renfrew MJ.; 2001 May 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31591

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Vitamin K2 (menaquinone) biosynthesis in Escherichia coli: evidence for the presence of an essential histidine residue in o-succinylbenzoyl coenzyme A synthetase. by Bhattacharyya DK, Kwon O, Meganathan R.; 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=179509

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Vitamin K-dependent carboxylation of the carboxylase. by Berkner KL, Pudota BN.; 1998 Jan 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18443

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

A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin. Author(s): Watson HG, Baglin T, Laidlaw SL, Makris M, Preston FE. Source: British Journal of Haematology. 2001 October; 115(1): 145-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11722425&dopt=Abstract

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A patient with anaphylactoid hypersensitivity to intravenous cyclosporine and subcutaneous phytonadione (vitamin K(1)). Author(s): Riegert-Johnson DL, Kumar S, Volcheck GW. Source: Bone Marrow Transplantation. 2001 December; 28(12): 1176-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11803365&dopt=Abstract

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A rebuttal: vitamin K antagonists and cancer survival. Author(s): Zacharski LR, Henderson WG. Source: Thrombosis and Haemostasis. 2002 July; 88(1): 173-4; Author Reply 175. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12152670&dopt=Abstract

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A study of Vitamin K status in children on prolonged antibiotic therapy. Author(s): Bhat RV, Deshmukh CT. Source: Indian Pediatrics. 2003 January; 40(1): 36-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554916&dopt=Abstract

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PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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A survey of oral vitamin K use by anticoagulation clinics. Author(s): Libby EN, Garcia DA. Source: Archives of Internal Medicine. 2002 September 9; 162(16): 1893-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12196089&dopt=Abstract

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A vitamin K antagonist rapidly reverses a blue toe syndrome in a patient with lupus anticoagulant and antiprothrombin antibodies. Author(s): De Cuypere E, Peerlinck K, Verhaeghe R, Vanrusselt M, Arnout J, Vermylen J. Source: Acta Clin Belg. 2002 March-April; 57(2): 74-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12152242&dopt=Abstract

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Abrupt versus gradual withdrawal of vitamin K antagonist treatment in patients with venous thromboembolic disease: assessment of hypercoagulability and clinical outcome. Author(s): de Groot MR, Njo TL, van Marwijk Kooy M, Buller HR. Source: Clin Lab. 2000; 46(11-12): 575-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11109505&dopt=Abstract

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Accuracy of phylloquinone (vitamin K-1) data in 2 nutrient databases as determined by direct laboratory analysis of diets. Author(s): McKeown NM, Rasmussen HM, Charnley JM, Wood RJ, Booth SL. Source: Journal of the American Dietetic Association. 2000 October; 100(10): 1201-4. Erratum In: J Am Diet Assoc. 2001 February; 101(2): 180. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11043708&dopt=Abstract

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Active Crohn disease with maternal vitamin K deficiency and fetal subdural hematoma. Author(s): Hirose M, Akiyama M, Takakura K, Noda Y. Source: Obstetrics and Gynecology. 2001 November; 98(5 Pt 2): 919-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11704203&dopt=Abstract

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Administration of Vitamin K to newborns: implications and recommendations. Author(s): McMillan DD. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 1996 February 1; 154(3): 347-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8564904&dopt=Abstract

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Amino acids responsible for reduced affinities of vitamin K-dependent propeptides for the carboxylase. Author(s): Stanley TB, Humphries J, High KA, Stafford DW. Source: Biochemistry. 1999 November 23; 38(47): 15681-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10569955&dopt=Abstract

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Anaphylactoid reactions to vitamin K. Author(s): Fiore LD, Scola MA, Cantillon CE, Brophy MT. Source: Journal of Thrombosis and Thrombolysis. 2001 April; 11(2): 175-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11406734&dopt=Abstract

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Anaphylaxis after low dose intravenous vitamin K. Author(s): Wjasow C, McNamara R. Source: The Journal of Emergency Medicine. 2003 February; 24(2): 169-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12609647&dopt=Abstract

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Antithrombotic efficacy of the vitamin K antagonist fluindione in a human Ex vivo model of arterial thrombosis : effect of anticoagulation level and combination therapy with aspirin. Author(s): Bossavy JP, Sakariassen KS, Thalamas C, Boneu B, Cadroy Y. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 1999 September; 19(9): 226975. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10479672&dopt=Abstract

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Apoptosis provoked by the oxidative stress inducer menadione (Vitamin K(3)) is mediated by the Fas/Fas ligand system. Author(s): Caricchio R, Kovalenko D, Kaufmann WK, Cohen PL. Source: Clinical Immunology (Orlando, Fla.). 1999 October; 93(1): 65-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10497012&dopt=Abstract

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Are breast-fed infants vitamin K deficient? Author(s): Greer FR. Source: Advances in Experimental Medicine and Biology. 2001; 501: 391-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11787707&dopt=Abstract

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Aspiration pneumonia in association with oral vitamin K. Author(s): Bhandari V, Tin NO, Ahmed SR. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 2002 November; 87(3): F232. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12391003&dopt=Abstract

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Assessment of dietary phylloquinone intake and vitamin K status in postmenopausal women. Author(s): Booth SL, Sokoll LJ, O'Brien ME, Tucker K, Dawson-Hughes B, Sadowski JA. Source: European Journal of Clinical Nutrition. 1995 November; 49(11): 832-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8557021&dopt=Abstract

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Assessment of vitamin K status in human subjects administered “minidose” warfarin. Author(s): Bach AU, Anderson SA, Foley AL, Williams EC, Suttie JW. Source: The American Journal of Clinical Nutrition. 1996 December; 64(6): 894-902. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8942414&dopt=Abstract

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Association of diffuse alveolar haemorrhage with acquired vitamin K deficiency. Author(s): Drent M, Wessels S, Jacobs JA, Thijssen H. Source: Respiration; International Review of Thoracic Diseases. 2000; 67(6): 697. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11124658&dopt=Abstract

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Babies and vitamin K. Author(s): Enoch JH. Source: Midwifery Today Int Midwife. 2000 Winter; (56): 42-5, 64. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11984902&dopt=Abstract

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Beta-hydroxyaspartic acid in vitamin K-dependent proteins. Author(s): Fernlund P, Stenflo J. Source: The Journal of Biological Chemistry. 1983 October 25; 258(20): 12509-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6630196&dopt=Abstract

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Beta-lactam antibiotics and vitamin K. Author(s): Del Favero A, Agnelli G, Parise P. Source: Annals of Internal Medicine. 1992 June 15; 116(12 Pt 1): 1034; Author Reply 10345. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1586098&dopt=Abstract

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Beta-lactam antibiotics and vitamin K. Author(s): Bettinger C. Source: Annals of Internal Medicine. 1992 June 15; 116(12 Pt 1): 1035. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1497729&dopt=Abstract

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Binder's syndrome due to prenatal vitamin K deficiency: a theory of pathogenesis. Author(s): Howe AM, Webster WS, Lipson AH, Halliday JL, Sheffield LJ. Source: Aust Dent J. 1992 December; 37(6): 453-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1476496&dopt=Abstract

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Binding and inhibition of Cdc25 phosphatases by vitamin K analogues. Author(s): Kar S, Lefterov IM, Wang M, Lazo JS, Scott CN, Wilcox CS, Carr BI. Source: Biochemistry. 2003 September 9; 42(35): 10490-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12950176&dopt=Abstract

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Binding of anticoagulant vitamin K-dependent protein S to platelet-derived microparticles. Author(s): Dahlback B, Wiedmer T, Sims PJ. Source: Biochemistry. 1992 December 29; 31(51): 12769-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1463747&dopt=Abstract

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Binding site for C4b-binding protein in vitamin K-dependent protein S fully contained in carboxy-terminal laminin-G-type repeats. A study using recombinant factor IX-protein S chimeras and surface plasmon resonance. Author(s): He X, Shen L, Malmborg AC, Smith KJ, Dahlback B, Linse S. Source: Biochemistry. 1997 March 25; 36(12): 3745-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9132028&dopt=Abstract

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Binding site for vitamin K-dependent protein S on complement C4b-binding protein. Author(s): Suzuki K, Nishioka J. Source: The Journal of Biological Chemistry. 1988 November 15; 263(32): 17034-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2460456&dopt=Abstract

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Biochemical vitamin K deficiency in early infancy: diagnostic limitation of conventional coagulation tests. Author(s): Widdershoven J, Kollee L, van Munster P, Bosman AM, Monnens L. Source: Helv Paediatr Acta. 1986 August; 41(3): 195-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3759482&dopt=Abstract

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Biospecific interactions of Vitamin K-dependent factors with phospholipid-like polystyrene derivatives. Part I: Factor II. Author(s): Migonney V, Menard V, Jozefowicz M. Source: Biomaterials. 1996 April; 17(8): 823-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8730967&dopt=Abstract

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Biospecific interactions of vitamin K-dependent factors with phospholipid-like polystyrene derivatives. Part II: factor IX. Author(s): Migonney V, Souirti A, Jozefowicz M. Source: Biomaterials. 1997 August; 18(16): 1077-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9247344&dopt=Abstract

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Bleeding secondary to vitamin K deficiency in patients receiving parenteral cephem antibiotics. Author(s): Shimada K, Matsuda T, Inamatsu T, Urayama K. Source: The Journal of Antimicrobial Chemotherapy. 1984 September; 14 Suppl B: 32530. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6389475&dopt=Abstract

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Body weight and response to vitamin K administration. Author(s): Reinfried P, Su M, Howland MA, Nelson L. Source: The American Journal of Medicine. 2002 February 1; 112(2): 158-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11835960&dopt=Abstract

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Bone health of adult hemodialysis patients is related to vitamin K status. Author(s): Kohlmeier M, Saupe J, Shearer MJ, Schaefer K, Asmus G. Source: Kidney International. 1997 April; 51(4): 1218-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9083289&dopt=Abstract

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Bone markers during a 6-month space flight: effects of vitamin K supplementation. Author(s): Vermeer C, Wolf J, Craciun AM, Knapen MH. Source: J Gravit Physiol. 1998 October; 5(2): 65-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11541904&dopt=Abstract

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Bone mineral density in patients given oral vitamin K antagonists. Author(s): Lafforgue P, Daver L, Monties JR, Chagnaud C, de Boissezon MC, Acquaviva PC. Source: Rev Rhum Engl Ed. 1997 April; 64(4): 249-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9178397&dopt=Abstract

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Boning up on vitamin K. Author(s): Compston JE. Source: Gut. 2001 April; 48(4): 448. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11247882&dopt=Abstract

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Breastmilk, PCBs, dioxins and vitamin K deficiency: discussion paper. Author(s): Koppe JG, Pluim E, Olie K. Source: Journal of the Royal Society of Medicine. 1989 July; 82(7): 416-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2511307&dopt=Abstract

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Bulimia nervosa complicated by deficiency of vitamin K-dependent coagulation factors. Author(s): Niiya K, Kitagawa T, Fujishita M, Yoshimoto S, Kobayashi M, Kubonishi I, Taguchi H, Miyoshi I. Source: Jama : the Journal of the American Medical Association. 1983 August 12; 250(6): 792-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6576178&dopt=Abstract

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Calciphylaxis associated with cholangiocarcinoma treated with low-molecular-weight heparin and vitamin K. Author(s): Riegert-Johnson DL, Kaur JS, Pfeifer EA. Source: Mayo Clinic Proceedings. 2001 July; 76(7): 749-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11444409&dopt=Abstract

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Can 3 oral 2 mg doses of vitamin K effectively prevent late vitamin K deficiency bleeding? Author(s): von Kries R, Hachmeister A, Gobel U. Source: European Journal of Pediatrics. 1999 December; 158 Suppl 3: S183-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10650866&dopt=Abstract

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Carboxylase overexpression effects full carboxylation but poor release and secretion of factor IX: implications for the release of vitamin K-dependent proteins. Author(s): Hallgren KW, Hommema EL, McNally BA, Berkner KL. Source: Biochemistry. 2002 December 17; 41(50): 15045-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12475254&dopt=Abstract

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Carboxylation of osteocalcin may be related to bone quality: a possible mechanism of bone fracture prevention by vitamin K. Author(s): Sugiyama T, Kawai S. Source: Journal of Bone and Mineral Metabolism. 2001; 19(3): 146-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11368299&dopt=Abstract

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Catching up with vitamin K. Author(s): Tyler S. Source: Midwives. 1996 October; 109(1305): 273. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8949138&dopt=Abstract

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Cerebral hemorrhage associated with vitamin K deficiency in congenital tuberculosis treated with isoniazid and rifampin. Author(s): Kobayashi K, Haruta T, Maeda H, Kubota M, Nishio T. Source: The Pediatric Infectious Disease Journal. 2002 November; 21(11): 1088-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458578&dopt=Abstract

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Characterization of the EGF-like module pair 3-4 from vitamin K-dependent protein S using NMR spectroscopy reveals dynamics on three separate time scales and extensive effects from calcium binding. Author(s): Muranyi A, Evenas J, Stenberg Y, Stenflo J, Drakenberg T. Source: Biochemistry. 2000 December 26; 39(51): 15742-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11123899&dopt=Abstract

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Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health. Author(s): Shearer MJ, Bach A, Kohlmeier M. Source: The Journal of Nutrition. 1996 April; 126(4 Suppl): 1181S-6S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8642453&dopt=Abstract

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Childhood leukaemia and intramuscular vitamin K: findings from a case-control study. Author(s): Ansell P, Bull D, Roman E. Source: Bmj (Clinical Research Ed.). 1996 July 27; 313(7051): 204-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8696197&dopt=Abstract

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Combination of 22-oxa-1,25-dihydroxyvitamin D(3), a vitamin D(3) derivative, with vitamin K(2) (VK2) synergistically enhances cell differentiation but suppresses VK2inducing apoptosis in HL-60 cells. Author(s): Funato K, Miyazawa K, Yaguchi M, Gotoh A, Ohyashiki K. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 August; 16(8): 1519-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12145693&dopt=Abstract

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Commonly overlooked sources of vitamin K. Author(s): Johnson SR, Ernst ME, Graber MA. Source: The Annals of Pharmacotherapy. 2003 February; 37(2): 302. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12549966&dopt=Abstract

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Comparison of biochemical indexes for assessing vitamin K nutritional status in a healthy adult population. Author(s): Sokoll LJ, Sadowski JA. Source: The American Journal of Clinical Nutrition. 1996 April; 63(4): 566-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8599321&dopt=Abstract

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Concomitant treatment with nonsteroidal anti-inflammatory drugs and vitamin K antagonists: critical appraisal of the recommendations issued by the French Agency for Healthcare Product Safety. Author(s): Bannwarth B. Source: Joint, Bone, Spine : Revue Du Rhumatisme. 2001 December; 68(6): 451-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11808978&dopt=Abstract

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Congenital combined deficiencies of all vitamin K-dependent coagulation factors. Author(s): Mousallem M, Spronk HM, Sacy R, Hakime N, Soute BA. Source: Thrombosis and Haemostasis. 2001 November; 86(5): 1334-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11816728&dopt=Abstract

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Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex. Author(s): Oldenburg J, von Brederlow B, Fregin A, Rost S, Wolz W, Eberl W, Eber S, Lenz E, Schwaab R, Brackmann HH, Effenberger W, Harbrecht U, Schurgers LJ, Vermeer C, Muller CR. Source: Thrombosis and Haemostasis. 2000 December; 84(6): 937-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11154138&dopt=Abstract

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Congenital deficiency of vitamin K dependent coagulation factors--its rarity and need for an international registry. Author(s): Ghosh K, Shetty S, Mohanty D. Source: Thrombosis and Haemostasis. 2001 October; 86(4): 1131. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11686345&dopt=Abstract

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Congenital deficiency of vitamin K-dependent coagulation factors--a vitamin-K dependency state? Author(s): Goraya JS. Source: Thrombosis and Haemostasis. 2001 September; 86(3): 932. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11583331&dopt=Abstract

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Controversies surrounding the administration of vitamin K to newborns: a review. Author(s): Brousson MA, Klein MC. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 1996 February 1; 154(3): 307-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8564900&dopt=Abstract

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Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication. Author(s): Yasaka M, Sakata T, Minematsu K, Naritomi H. Source: Thrombosis Research. 2002 October 1; 108(1): 25-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12586128&dopt=Abstract

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Critical role of extracellular signal-regulated kinase (ERK) phosphorylation in novel vitamin K analog-induced cell death. Author(s): Osada S, Carr BI. Source: Japanese Journal of Cancer Research : Gann. 2000 December; 91(12): 1250-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11123423&dopt=Abstract

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Decreased circulating levels of vitamin K and 25-hydroxyvitamin D in osteopenic elderly men. Author(s): Tamatani M, Morimoto S, Nakajima M, Fukuo K, Onishi T, Kitano S, Niinobu T, Ogihara T. Source: Metabolism: Clinical and Experimental. 1998 February; 47(2): 195-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9472970&dopt=Abstract

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Decreased renal vitamin K-dependent gamma-glutamyl carboxylase activity in calcium oxalate calculi patients. Author(s): Chen J, Liu J, Zhang Y, Ye Z, Wang S. Source: Chinese Medical Journal. 2003 April; 116(4): 569-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875724&dopt=Abstract

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Deficient dietary vitamin K intake among elderly nursing home residents in Hong Kong. Author(s): Tse SL, Chan TY, Wu DM, Cheung AY, Kwok TC. Source: Asia Pacific Journal of Clinical Nutrition. 2002; 11(1): 62-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11892723&dopt=Abstract

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Detection of a novel plasma serine protease during purification of vitamin Kdependent coagulation factors. Author(s): Hunfeld A, Etscheid M, Konig H, Seitz R, Dodt J. Source: Febs Letters. 1999 August 6; 456(2): 290-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10456326&dopt=Abstract

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Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations. Author(s): Schurgers LJ, Vermeer C. Source: Haemostasis. 2000 November-December; 30(6): 298-307. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11356998&dopt=Abstract

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Determination of vitamin K compounds in plasma or serum by high-performance liquid chromatography using postcolumn chemical reduction and fluorimetric detection. Author(s): Davidson KW, Sadowski JA. Source: Methods Enzymol. 1997; 282: 408-21. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9330305&dopt=Abstract

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Determination of vitamin K in foods: a review. Author(s): Parrish DB. Source: Critical Reviews in Food Science and Nutrition. 1980; 13(4): 337-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7002471&dopt=Abstract

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Determination of vitamin K in milk and infant formulas by liquid chromatography: collaborative study. Author(s): Indyk HE, Woollard DC. Source: J Aoac Int. 2000 January-February; 83(1): 121-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10693013&dopt=Abstract

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Development of a self-assessment instrument to determine daily intake and variability of dietary vitamin K. Author(s): Couris RR, Tataronis GR, Booth SL, Dallal GE, Blumberg JB, Dwyer JT. Source: Journal of the American College of Nutrition. 2000 November-December; 19(6): 801-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11194535&dopt=Abstract

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Developmental changes of vitamin K epoxidase and reductase activities involved in the vitamin K cycle in human liver. Author(s): Itoh S, Onishi S. Source: Early Human Development. 2000 January; 57(1): 15-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10690708&dopt=Abstract

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Diagnostic value of protein induced by vitamin K absence (PIVKAII) and hepatomaspecific band of serum gamma-glutamyl transferase (GGTII) as hepatocellular carcinoma markers complementary to alpha-fetoprotein. Author(s): Cui R, He J, Zhang F, Wang B, Ding H, Shen H, Li Y, Chen X. Source: British Journal of Cancer. 2003 June 16; 88(12): 1878-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799630&dopt=Abstract

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Diarrhoea, vitamin K, and warfarin. Author(s): Black JA. Source: Lancet. 1994 November 12; 344(8933): 1373. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7968060&dopt=Abstract

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Dietary and nondietary determinants of vitamin K biochemical measures in men and women. Author(s): McKeown NM, Jacques PF, Gundberg CM, Peterson JW, Tucker KL, Kiel DP, Wilson PW, Booth SL. Source: The Journal of Nutrition. 2002 June; 132(6): 1329-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12042454&dopt=Abstract

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Dietary intake and adequacy of vitamin K. Author(s): Booth SL, Suttie JW. Source: The Journal of Nutrition. 1998 May; 128(5): 785-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9566982&dopt=Abstract

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Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Author(s): Trumbo P, Yates AA, Schlicker S, Poos M. Source: Journal of the American Dietetic Association. 2001 March; 101(3): 294-301. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11269606&dopt=Abstract

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Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Author(s): Booth SL, Tucker KL, Chen H, Hannan MT, Gagnon DR, Cupples LA, Wilson PW, Ordovas J, Schaefer EJ, Dawson-Hughes B, Kiel DP. Source: The American Journal of Clinical Nutrition. 2000 May; 71(5): 1201-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10799384&dopt=Abstract

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Differences in reactivity to vitamin K administration of the vitamin K-dependent procoagulant factors, protein C and S, and osteocalcin. Author(s): Shirakawa Y, Shirahata A, Fukuda M. Source: Seminars in Thrombosis and Hemostasis. 2000; 26(1): 119-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10805293&dopt=Abstract

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Differential effects of warfarin on the intracellular processing of vitamin Kdependent proteins. Author(s): Wu W, Bancroft JD, Suttie JW. Source: Thrombosis and Haemostasis. 1996 July; 76(1): 46-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8819250&dopt=Abstract

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Direct demonstration that the vitamin K-dependent bone Gla protein is incompletely gamma-carboxylated in humans. Author(s): Cairns JR, Price PA. Source: Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research. 1994 December; 9(12): 1989-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7872066&dopt=Abstract

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Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism. Author(s): Hutten BA, Prins MH. Source: Cochrane Database Syst Rev. 2000; (3): Cd001367. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10908494&dopt=Abstract

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Early versus delayed introduction of oral vitamin K antagonists in combination with low-molecular-weight heparin in the treatment of deep vein thrombosis. a randomized clinical trial. The ANTENOX Study Group. Author(s): Leroyer C, Bressollette L, Oger E, Mansourati J, Cheze-Le Rest C, Nonent M, Buchmuller A, Tardy B, Decousus H, Parent F, Simonneau G, Juste K, Ill P, Abgrall JF, Clavier J, Mottier D. Source: Haemostasis. 1998 March-April; 28(2): 70-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10087431&dopt=Abstract

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Effect of a reduced vitamin K supplementation on prothrombin time in prematures and high-risk neonates. Author(s): Rossi R, Albrecht O, Pollmann H, Jorch G, Harms E. Source: Acta Paediatrica (Oslo, Norway : 1992). 1996 June; 85(6): 747-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8816216&dopt=Abstract

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Effect of Ca2+ on the structure of vitamin K-dependent coagulation factors. Author(s): Sunnerhagen M, Drakenberg T, Forsen S, Stenflo J. Source: Haemostasis. 1996; 26 Suppl 1: 45-53. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8904173&dopt=Abstract

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Effect of continuous combined therapy with vitamin K(2) and vitamin D(3) on bone mineral density and coagulofibrinolysis function in postmenopausal women. Author(s): Ushiroyama T, Ikeda A, Ueki M. Source: Maturitas. 2002 March 25; 41(3): 211-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11886767&dopt=Abstract

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Effect of food composition on vitamin K absorption in human volunteers. Author(s): Gijsbers BL, Jie KS, Vermeer C. Source: The British Journal of Nutrition. 1996 August; 76(2): 223-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8813897&dopt=Abstract

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Effect of oral water soluble vitamin K on PIVKA-II levels in newborns. Author(s): Sharma RK, Marwaha N, Kumar P, Narang A. Source: Indian Pediatrics. 1995 August; 32(8): 863-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8635828&dopt=Abstract

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Effect of vitamin K and/or D on undercarboxylated and intact osteocalcin in osteoporotic patients with vertebral or hip fractures. Author(s): Takahashi M, Naitou K, Ohishi T, Kushida K, Miura M. Source: Clinical Endocrinology. 2001 February; 54(2): 219-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11207637&dopt=Abstract

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Effect of vitamin K on oral anticoagulation. Author(s): Booth S, Mayer J. Source: Postgraduate Medicine. 1995 December; 98(6): 27-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7501579&dopt=Abstract

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Effects of a hydrogenated form of vitamin K on bone formation and resorption. Author(s): Booth SL, Lichtenstein AH, O'Brien-Morse M, McKeown NM, Wood RJ, Saltzman E, Gundberg CM. Source: The American Journal of Clinical Nutrition. 2001 December; 74(6): 783-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11722960&dopt=Abstract

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Effects of oral and intramuscular vitamin K prophylaxis on PIVKA-II assay parameters in breastfed infants in Turkey. Author(s): Ulusahin N, Arsan S, Ertogan F. Source: Turk J Pediatr. 1996 July-September; 38(3): 295-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8827897&dopt=Abstract

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Effects of oral vitamin K on S- and R-warfarin pharmacokinetics and pharmacodynamics: enhanced safety of warfarin as a CYP2C9 probe. Author(s): Kim JS, Nafziger AN, Gaedigk A, Dickmann LJ, Rettie AE, Bertino JS Jr. Source: Journal of Clinical Pharmacology. 2001 July; 41(7): 715-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11452703&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10594627&dopt=Abstract

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Effects of vitamin K on bone mass and bone metabolism. Author(s): Vermeer C, Gijsbers BL, Craciun AM, Groenen-van Dooren MM, Knapen MH. Source: The Journal of Nutrition. 1996 April; 126(4 Suppl): 1187S-91S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8642454&dopt=Abstract

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Effects of vitamin K on calcium and bone metabolism. Author(s): Zittermann A. Source: Current Opinion in Clinical Nutrition and Metabolic Care. 2001 November; 4(6): 483-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11706280&dopt=Abstract

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Efficacy of intravenous vitamin K in a case of massive warfarin overdosage. Author(s): Kitchens CS. Source: Thrombosis and Haemostasis. 2001 August; 86(2): 719-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11522034&dopt=Abstract

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EGF-like module pair 3-4 in vitamin K-dependent protein S: modulation of calcium affinity of module 4 by module 3, and interaction with factor X. Author(s): Stenberg Y, Muranyi A, Steen C, Thulin E, Drakenberg T, Stenflo J. Source: Journal of Molecular Biology. 1999 October 29; 293(3): 653-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10543957&dopt=Abstract

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Electroimmunoassay of factor IX in patients with liver damage and vitamin K unresponsive coagulation disorder. Author(s): Girolami A, Burul A, Cappellato G, Dal Bo Zanon R. Source: Folia Haematol Int Mag Klin Morphol Blutforsch. 1979; 106(1): 65-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=88391&dopt=Abstract

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Emerging scientific evidence. Vitamin K and bone metabolism: effects of vitamins on behaviour and cognition. Author(s): Rambeck WA, Stahelin HB. Source: Bibl Nutr Dieta. 2001; (55): 206-8. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11125580&dopt=Abstract

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Evaluation of very low-dose subcutaneous vitamin K during postoperative warfarin therapy. Author(s): Possidente CJ, Howe JG, Cushman M. Source: Pharmacotherapy. 2001 March; 21(3): 295-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11253854&dopt=Abstract

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Expression and characterization of recombinant vitamin K-dependent gammaglutamyl carboxylase from an invertebrate, Conus textile. Author(s): Czerwiec E, Begley GS, Bronstein M, Stenflo J, Taylor K, Furie BC, Furie B. Source: European Journal of Biochemistry / Febs. 2002 December; 269(24): 6162-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12473112&dopt=Abstract

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Factor II (prothrombin) coagulant activity in immunoreactive protein: detection of vitamin K deficiency and liver disease in patients with cystic fibrosis. Author(s): Corrigan JJ Jr, Taussig LM, Beckerman R, Wagener JS. Source: The Journal of Pediatrics. 1981 August; 99(2): 254-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7252687&dopt=Abstract

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Factor II antigen in liver disease and warfarin-induced vitamin K deficiency: correlation with coagulant activity using Echis venom. Author(s): Corrigan JJ Jr, Earnest DL. Source: American Journal of Hematology. 1980; 8(3): 249-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6774611&dopt=Abstract

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Factor V assays in patients on coumarin therapy, or with vitamin K deficiency. Author(s): Macheta AT, Craig S, Fisher AH, Taberner DA. Source: Clinical and Laboratory Haematology. 1987; 9(4): 429. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3442978&dopt=Abstract

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Factor V: a prototype pro-cofactor for vitamin K-dependent enzyme complexes in blood clotting. Author(s): Jenny RJ, Mann KG. Source: Baillieres Clin Haematol. 1989 October; 2(4): 919-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2513010&dopt=Abstract

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Factor VIII lability, protein C and other vitamin K-dependent proteins. Author(s): Takahashi H, Hanano M, Tatewaki W, Shibata A. Source: Thrombosis Research. 1986 September 1; 43(5): 561-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3092397&dopt=Abstract

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Fatal intracranial hemorrhage in a normal infant secondary to vitamin K deficiency. Author(s): Lane PA, Hathaway WE, Githens JH, Krugman RD, Rosenberg DA. Source: Pediatrics. 1983 October; 72(4): 562-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6889070&dopt=Abstract

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Fatal late vitamin K-deficiency bleeding after oral vitamin K prophylaxis secondary to unrecognized bile duct paucity. Author(s): Humpl T, Bruhl K, Brzezinska R, Hafner G, Coerdt W, Shearer MJ. Source: Journal of Pediatric Gastroenterology and Nutrition. 1999 November; 29(5): 5947. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10554130&dopt=Abstract

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Fibroblast studies documenting a case of peroxisomal 2-methylacyl-CoA racemase deficiency: possible link between racemase deficiency and malabsorption and vitamin K deficiency. Author(s): Van Veldhoven PP, Meyhi E, Squires RH, Fransen M, Fournier B, Brys V, Bennett MJ, Mannaerts GP. Source: European Journal of Clinical Investigation. 2001 August; 31(8): 714-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11473573&dopt=Abstract

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Food sources and dietary intakes of vitamin K-1 (phylloquinone) in the American diet: data from the FDA Total Diet Study. Author(s): Booth SL, Pennington JA, Sadowski JA. Source: Journal of the American Dietetic Association. 1996 February; 96(2): 149-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8557941&dopt=Abstract

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For how long should the treatment with vitamin K antagonists be maintained? Author(s): Schulman S. Source: Haemostasis. 1999 December; 29 Suppl S1: 89-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10629413&dopt=Abstract

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Further evaluation of an automated amidolytic factor X assay in monitoring antivitamin K treatment. Author(s): van Wijk EM, Kahle LH, Jeletich A, ten Cate JW. Source: Scand J Haematol. 1982 August; 29(2): 105-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6813960&dopt=Abstract

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Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Author(s): Vermeer C. Source: The Biochemical Journal. 1990 March 15; 266(3): 625-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2183788&dopt=Abstract

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Gamma-carboxyglutamic acid: identification and distribution in vitamin Kdependent proteins. Author(s): Nelsestuen GL, Zytkovicz TH, Howard JB. Source: Mayo Clinic Proceedings. 1974 December; 49(12): 941-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4444341&dopt=Abstract

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Gastrointestinal bleeding due to vitamin K deficiency in patients on parenteral cefamandole. Author(s): Hooper CA, Haney BB, Stone HH. Source: Lancet. 1980 January 5; 1(8158): 39-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6101371&dopt=Abstract

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Gender differences in hepatic phylloquinone and menaquinones in the vitamin Kdeficient and -supplemented rat. Author(s): Huber AM, Davidson KW, O'Brien-Morse ME, Sadowski JA. Source: Biochimica Et Biophysica Acta. 1999 January 4; 1426(1): 43-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9878685&dopt=Abstract

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Generalized pseudoxanthoma elasticum with deficiency of vitamin K-dependent clotting factors. Author(s): Rongioletti F, Bertamino R, Rebora A. Source: Journal of the American Academy of Dermatology. 1989 November; 21(5 Pt 2): 1150-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2808851&dopt=Abstract

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Genes for human vitamin K-dependent plasma proteins C and S are located on chromosomes 2 and 3, respectively. Author(s): Long GL, Marshall A, Gardner JC, Naylor SL. Source: Somatic Cell and Molecular Genetics. 1988 January; 14(1): 93-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2829367&dopt=Abstract

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Genetic regulation of plasma levels of vitamin K-dependent proteins involved in hematostatis: results from the GAIT Project. Genetic Analysis of Idiopathic Thrombophilia. Author(s): Souto JC, Almasy L, Blangero J, Stone W, Borrell M, Urrutia T, Mateo J, Fontcuberta J. Source: Thrombosis and Haemostasis. 2001 January; 85(1): 88-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11204594&dopt=Abstract

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Giving vitamin K at birth. Approach to giving vitamin K should be reconsidered. Author(s): Lessof N. Source: Bmj (Clinical Research Ed.). 1996 November 2; 313(7065): 1147. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8916720&dopt=Abstract

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Giving vitamin K at birth. Paediatricians should return to policies of parenteral prophylaxis. Author(s): Miranda J, Guemes I. Source: Bmj (Clinical Research Ed.). 1996 November 2; 313(7065): 1147. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8916721&dopt=Abstract

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Giving vitamin K to newborn babies in the SCBU. Author(s): Stewart N. Source: Midwives. 1994 November; 107(1282): 418-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7621111&dopt=Abstract

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Giving vitamin K to newborn infants: a therapeutic dilemma. Author(s): Henderson-Smart DJ. Source: The Medical Journal of Australia. 1996 October 21; 165(8): 414-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8913240&dopt=Abstract

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Glutamyl substrate-induced exposure of a free cysteine residue in the vitamin Kdependent gamma-glutamyl carboxylase is critical for vitamin K epoxidation. Author(s): Bouchard BA, Furie B, Furie BC. Source: Biochemistry. 1999 July 20; 38(29): 9517-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10413529&dopt=Abstract

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Growth control and gene expression in a new hepatocellular carcinoma cell line, Hep40: inhibitory actions of vitamin K. Author(s): Bouzahzah B, Nishikawa Y, Simon D, Carr BI. Source: Journal of Cellular Physiology. 1995 December; 165(3): 459-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7593224&dopt=Abstract

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Growth inhibition of hepatoma cells induced by vitamin K and its analogs. Author(s): Nishikawa Y, Carr BI, Wang M, Kar S, Finn F, Dowd P, Zheng ZB, Kerns J, Naganathan S. Source: The Journal of Biological Chemistry. 1995 November 24; 270(47): 28304-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7499329&dopt=Abstract

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Haemorrhage responsive to vitamin K in a 6-week-old infant. Author(s): Minford AM, Eden OB. Source: Archives of Disease in Childhood. 1979 April; 54(4): 310-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=453915&dopt=Abstract

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Haemorrhagic disease and vitamin K. Author(s): Priestley BL. Source: Archives of Disease in Childhood. 1987 September; 62(9): 979. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3674956&dopt=Abstract

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Haemorrhagic disease and vitamin K. Author(s): Tripp JH, McNinch AW. Source: Archives of Disease in Childhood. 1987 May; 62(5): 436-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3606174&dopt=Abstract

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Half-life time and control frequency of vitamin K-dependent Coagulation factors. Theoretical considerations on the place of factor VII in the control of oral anticoagulation therapy. Author(s): van Dam-Mieras MC, Hemker HC. Source: Haemostasis. 1983; 13(3): 201-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6350124&dopt=Abstract

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Hazards of small amounts of heparin in a patient with subclinical vitamin K deficiency. Author(s): Shah MC, Schwarz KB. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 1989 May-June; 13(3): 324-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2503646&dopt=Abstract

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Hemolytic uremic syndrome complicated by vitamin K deficiency. Author(s): Silliman CC, Ford DM, Lane PA. Source: Am J Pediatr Hematol Oncol. 1991 Summer; 13(2): 176-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2069228&dopt=Abstract

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Hemorrhagic disease in a newborn due to inadequate vitamin K prophylaxis: case report. Author(s): Su CT, Hung FC, Huang CB. Source: Changgeng Yi Xue Za Zhi. 2000 May; 23(5): 309-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10916233&dopt=Abstract

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Hemorrhagic disease in an infant fed on a vitamin K-deficient soya formula. Author(s): Pellegrino M, Sacco M, D'Altilia MR, Meleleo D, De Anseris AG. Source: Journal of Pediatric Gastroenterology and Nutrition. 1996 November; 23(4): 4134. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8956177&dopt=Abstract

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Hereditary deficiency of all vitamin K-dependent procoagulants and anticoagulants. Author(s): Brenner B, Tavori S, Zivelin A, Keller CB, Suttie JW, Tatarsky I, Seligsohn U. Source: British Journal of Haematology. 1990 August; 75(4): 537-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2145029&dopt=Abstract

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Hereditary deficiency of vitamin K-dependent coagulation factors with skeletal abnormalities. Author(s): Boneh A, Bar-Ziv J. Source: American Journal of Medical Genetics. 1996 October 28; 65(3): 241-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9240751&dopt=Abstract

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Hereditary deficiency of vitamin K-dependent coagulation factors. Author(s): Brenner B. Source: Thrombosis and Haemostasis. 2000 December; 84(6): 935-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11154137&dopt=Abstract

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High affinity binding of human vitamin K-dependent protein S to a truncated recombinant beta-chain of C4b-binding protein expressed in Escherichia coli. Author(s): Hardig Y, Rezaie A, Dahlback B. Source: The Journal of Biological Chemistry. 1993 February 15; 268(5): 3033-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8428978&dopt=Abstract

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High affinity interaction between C4b-binding protein and vitamin K-dependent protein S in the presence of calcium. Suggestion of a third component in blood regulating the interaction. Author(s): Dahlback B, Frohm B, Nelsestuen G. Source: The Journal of Biological Chemistry. 1990 September 25; 265(27): 16082-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2144524&dopt=Abstract

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High-performance liquid chromatographic assay of vitamin K in human serum. Author(s): Lefevere MF, De Leenheer AP, Claeys AE. Source: Journal of Chromatography. 1979 December 30; 186: 749-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=546941&dopt=Abstract

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Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16. Author(s): Fregin A, Rost S, Wolz W, Krebsova A, Muller CR, Oldenburg J. Source: Blood. 2002 November 1; 100(9): 3229-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12384421&dopt=Abstract

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How important is vitamin K at birth? Author(s): Tolbert N. Source: The Birth Gazette. 1994 Winter; 11(1): 13-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7881310&dopt=Abstract

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Human genes for factor IX and other vitamin K dependent blood proteins. Author(s): Kurachi K, Chen SH. Source: Advances in Experimental Medicine and Biology. 1987; 214: 67-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3661296&dopt=Abstract

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Hyperparathyroidism and infantile hypophosphatasia: effect of prednisone and vitamin K therapy. Author(s): Wolfish NM, Heick H. Source: The Journal of Pediatrics. 1979 December; 95(6): 1079-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=501490&dopt=Abstract

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Hypersensitivity reactions to parenteral vitamin K. Author(s): Chung JY, Ramos-Caro FA, Beers B, Ford MJ, Flowers FP. Source: Cutis; Cutaneous Medicine for the Practitioner. 1999 January; 63(1): 33-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9951592&dopt=Abstract

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Hypoprothrombinemia associated with interleukin-2 therapy: correction with vitamin K. Author(s): Birchfield GR, Rodgers GM, Girodias KW, Ward JH, Samlowski WE. Source: Journal of Immunotherapy (Hagerstown, Md. : 1997). 1992 January; 11(1): 71-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1734951&dopt=Abstract

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Identification of sequences within the gamma-carboxylase that represent a novel contact site with vitamin K-dependent proteins and that are required for activity. Author(s): Pudota BN, Hommema EL, Hallgren KW, McNally BA, Lee S, Berkner KL. Source: The Journal of Biological Chemistry. 2001 December 14; 276(50): 46878-86. Epub 2001 October 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11591726&dopt=Abstract

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Identification of the phospholipid binding site in the vitamin K-dependent blood coagulation protein factor IX. Author(s): Freedman SJ, Blostein MD, Baleja JD, Jacobs M, Furie BC, Furie B. Source: The Journal of Biological Chemistry. 1996 July 5; 271(27): 16227-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8663165&dopt=Abstract

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Identification of the vitamin K-dependent carboxylase active site: Cys-99 and Cys-450 are required for both epoxidation and carboxylation. Author(s): Pudota BN, Miyagi M, Hallgren KW, West KA, Crabb JW, Misono KS, Berkner KL. Source: Proceedings of the National Academy of Sciences of the United States of America. 2000 November 21; 97(24): 13033-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11087858&dopt=Abstract

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Immunohistochemical study of protein induced by vitamin K absence or antagonist II in hepatocellular carcinoma. Author(s): Ajisaka H, Shimizu K, Miwa K. Source: Journal of Surgical Oncology. 2003 October; 84(2): 89-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14502782&dopt=Abstract

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Immunohistologic study on the expressions of alpha-fetoprotein and protein induced by vitamin K absence or antagonist II in surgically resected small hepatocellular carcinoma. Author(s): Fujioka M, Nakashima Y, Nakashima O, Kojiro M. Source: Hepatology (Baltimore, Md.). 2001 December; 34(6): 1128-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11732002&dopt=Abstract

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Improved bone metabolism in female elite athletes after vitamin K supplementation. Author(s): Craciun AM, Wolf J, Knapen MH, Brouns F, Vermeer C. Source: International Journal of Sports Medicine. 1998 October; 19(7): 479-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9839845&dopt=Abstract

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Improved functional endpoints for use in vitamin K assessment: important implications for bone disease. Author(s): Rucker RB. Source: The American Journal of Clinical Nutrition. 1997 March; 65(3): 883-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9062544&dopt=Abstract

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Improvement of vitamin K status of breastfeeding infants with maternal supplement of vitamin K2 (MK40). Author(s): Nishiguchi T, Yamashita M, Maeda M, Matsuyama K, Kobayashi T, Kanayama N, Terao T. Source: Seminars in Thrombosis and Hemostasis. 2002 December; 28(6): 533-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12536346&dopt=Abstract

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Improving the vitamin K status of breastfeeding infants with maternal vitamin K supplements. Author(s): Greer FR, Marshall SP, Foley AL, Suttie JW. Source: Pediatrics. 1997 January; 99(1): 88-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8989344&dopt=Abstract

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Influence of body weight on response to subcutaneous vitamin K administration in over-anticoagulated patients. Author(s): Kelly KC, Raj G, Weideman RA. Source: The American Journal of Medicine. 2001 June 1; 110(8): 623-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11382370&dopt=Abstract

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Inherited deficiency of multiple vitamin K-dependent coagulation factors and coagulation inhibitors presenting as hemorrhagic diathesis, mental retardation, and growth retardation. Author(s): Ghosh K, Shetty S, Mohanty D. Source: American Journal of Hematology. 1996 May; 52(1): 67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8638624&dopt=Abstract

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Inhibitory effects of combined treatment with vitamin K and D on bone loss of ovariectomized rats: a microradiographic study. Author(s): Kamezawa K. Source: Fukuoka Igaku Zasshi. 1999 March; 90(3): 71-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10339927&dopt=Abstract

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Interaction between vitamin K nutriture and bacterial overgrowth in hypochlorhydria induced by omeprazole. Author(s): Paiva SA, Sepe TE, Booth SL, Camilo ME, O'Brien ME, Davidson KW, Sadowski JA, Russell RM. Source: The American Journal of Clinical Nutrition. 1998 September; 68(3): 699-704. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9734750&dopt=Abstract

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Intestinal absorption of mixed micellar phylloquinone (vitamin K1) is unreliable in infants with conjugated hyperbilirubinaemia: implications for oral prophylaxis of vitamin K deficiency bleeding. Author(s): Pereira SP, Shearer MJ, Williams R, Mieli-Vergani G. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 2003 March; 88(2): F113-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598499&dopt=Abstract

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Intracranial haemorrhage due to vitamin K deficiency following gastroenteritis in an infant. Author(s): Manji KP, Azzopardi D. Source: Journal of Tropical Pediatrics. 1999 April; 45(2): 105-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10341505&dopt=Abstract

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Intracranial hemorrhage associated with vitamin K deficiency in a breastfed infant after intramuscular vitamin K prophylaxis at birth. follow-up at 18 months. Author(s): Latini G, Quartulli L, De Mitri B, Del Vecchio A, Vecchio C. Source: Acta Paediatrica (Oslo, Norway : 1992). 2000 July; 89(7): 878-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10943974&dopt=Abstract

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Intracranial hemorrhage in an infant owing to vitamin K deficiency despite prophylaxis. Author(s): Suzuki K, Fukushima T, Meguro K, Aoki T, Kamezaki T, Saitoh H, Enomoto T, Nose T. Source: Child's Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery. 1999 July; 15(6-7): 292-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10461777&dopt=Abstract

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Intravesical haemorrhage: a rare late manifestation of vitamin K deficiency inverted question markletterI. Author(s): Gurakan B, Yilmaz G, Ozbek N. Source: Journal of Paediatrics and Child Health. 2000 June; 36(3): 290. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10960343&dopt=Abstract

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Ireland lacks consensus on neonatal vitamin K prophylaxis. Author(s): Philip RK, Gul R, Dunworth M, Keane N. Source: Bmj (Clinical Research Ed.). 2001 November 3; 323(7320): 1068. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11691771&dopt=Abstract

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Is vitamin K deficiency a risk factor for osteoporosis in Crohn's disease? Author(s): Szulc P, Meunier PJ. Source: Lancet. 2001 June 23; 357(9273): 1995-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11438129&dopt=Abstract

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Kinetic aspects of the interaction of blood clotting enzymes. 3. Demonstration of an inhibitor of prothrombin conversion in vitamin K deficiency. Author(s): Hemker HC, Veltkamp JJ, Loeliger EA. Source: Thromb Diath Haemorrh. 1968 July 31; 19(3): 346-63. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4179187&dopt=Abstract

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Kinetic aspects of the interaction of blood-clotting enzymes. VI. Localization of the site of blood-coagulation inhibition by the protein induced by vitamin K absence (PIVKA). Author(s): Hemker HC, Muller AD. Source: Thromb Diath Haemorrh. 1968 November 15; 20(1): 78-87. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5708900&dopt=Abstract

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Known vitamin K intake and management of poorly controlled oral anticoagulant therapy. Author(s): Marongiu F, Sorano GG, Conti M, Mameli G, Biondi G, Licheri D, Balastrieri A. Source: Lancet. 1992 August 29; 340(8818): 545-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1354291&dopt=Abstract

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L-asparaginase treatment reduces the anticoagulant potential of the protein C system without affecting vitamin K-dependent carboxylation. Author(s): Vigano'D'Angelo S, Gugliotta L, Mattioli Belmonte M, Cascione ML, Pattarini E, D'Angelo A. Source: Thrombosis Research. 1990 September 15; 59(6): 985-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2148229&dopt=Abstract

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Late form of vitamin K deficiency bleeding in Germany. Author(s): Sutor AH, Dagres N, Niederhoff H. Source: Klinische Padiatrie. 1995 May-June; 207(3): 89-97. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7623433&dopt=Abstract

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Late haemothorax after oral vitamin K. Author(s): Motz R. Source: N Z Med J. 1992 November 11; 105(945): 459. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1436866&dopt=Abstract

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Late hemorrhagic disease of newborn: a case with increased vitamin K requirement. Author(s): von Kries R, Funda J, Shearer M, Gobel U. Source: Acta Paediatrica (Oslo, Norway : 1992). 1992 September; 81(9): 728-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1421921&dopt=Abstract

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Late neonatal vitamin K deficiency associated with subclinical liver dysfunction in human milk-fed infants. Author(s): Matsuda I, Nishiyama S, Motohara K, Endo F, Ogata T, Futagoishi Y. Source: The Journal of Pediatrics. 1989 April; 114(4 Pt 1): 602-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2926571&dopt=Abstract

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Latent vitamin K deficiency in healthy infants. Author(s): von Kries R, Maase B, Becker A, Gobel U. Source: Lancet. 1985 December 21-28; 2(8469-70): 1421-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2867412&dopt=Abstract

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Letter: Vitamin K and hemorrhage in the newborn. Author(s): Ward TF, McSheffrey JB. Source: Can Med Assoc J. 1976 July 17; 115(2): 109, 111, 115. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1277072&dopt=Abstract

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Levels of vitamin K, immunoreactive prothrombin, des-gamma-carboxy prothrombin and gamma-glutamyl carboxylase activity in hepatocellular carcinoma tissue. Author(s): Yamagata H, Nakanishi T, Furukawa M, Okuda H, Obata H. Source: Journal of Gastroenterology and Hepatology. 1995 January-February; 10(1): 8-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7620113&dopt=Abstract

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Levels of vitamin K-dependent procoagulant and anticoagulant proteins in overanticoagulated patients. Author(s): Penning-van Beest FJ, Gomez Garcia EB, van der Meer FJ, van Meegen E, Rosendaal FR, Stricker BH. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. 2002 December; 13(8): 733-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12441913&dopt=Abstract

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Liver function in patients with vitamin K deficiency in infancy. Author(s): Lin MT, Tsao LY, Shen MC. Source: Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1994 November-December; 35(6): 514-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7831984&dopt=Abstract

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Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Author(s): Bruno GR, Howland MA, McMeeking A, Hoffman RS. Source: Annals of Emergency Medicine. 2000 September; 36(3): 262-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10969235&dopt=Abstract

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Low circulating vitamin K levels and fractured femur. Author(s): Klenerman L. Source: Lancet. 1984 October 27; 2(8409): 979. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6149365&dopt=Abstract

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Low circulating vitamin K levels and fractured femur. Author(s): Mitchell JR. Source: Lancet. 1984 September 1; 2(8401): 516. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6147568&dopt=Abstract

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Low dose oral vitamin K to reverse acenocoumarol-induced coagulopathy: a randomized controlled trial. Author(s): Ageno W, Crowther M, Steidl L, Ultori C, Mera V, Dentali F, Squizzato A, Marchesi C, Venco A. Source: Thrombosis and Haemostasis. 2002 July; 88(1): 48-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12152676&dopt=Abstract

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Low dose vitamin K for excessively anticoagulated prosthetic valve patients. Author(s): Perry DJ, Kimball DB Jr. Source: Military Medicine. 1982 October; 147(10): 836-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6817166&dopt=Abstract

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Low serum and bone vitamin K status in patients with longstanding Crohn's disease: another pathogenetic factor of osteoporosis in Crohn's disease? Author(s): Schoon EJ, Muller MC, Vermeer C, Schurgers LJ, Brummer RJ, Stockbrugger RW. Source: Gut. 2001 April; 48(4): 473-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11247890&dopt=Abstract

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Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin. Author(s): Crowther MA, Donovan D, Harrison L, McGinnis J, Ginsberg J. Source: Thrombosis and Haemostasis. 1998 June; 79(6): 1116-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9657434&dopt=Abstract

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Management of osteoporosis: is there a role for vitamin K? Author(s): Weber P. Source: Int J Vitam Nutr Res. 1997; 67(5): 350-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9350477&dopt=Abstract

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Mandating vitamin K prophylaxis for newborns in New York State. Author(s): Tulchinsky TH, Patton MM, Randolph LA, Meyer MR, Linden JV. Source: American Journal of Public Health. 1993 August; 83(8): 1166-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8342729&dopt=Abstract

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Manipulation of the membrane binding site of vitamin K-dependent proteins: enhanced biological function of human factor VII. Author(s): Shah AM, Kisiel W, Foster DC, Nelsestuen GL. Source: Proceedings of the National Academy of Sciences of the United States of America. 1998 April 14; 95(8): 4229-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9539719&dopt=Abstract

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Measurement of immunoreactive prothrombin, des-gamma-carboxy prothrombin, and vitamin K in human liver tissues: overproduction of immunoreactive prothrombin in hepatocellular carcinoma. Author(s): Ono M, Ohta H, Ohhira M, Sekiya C, Namiki M. Source: The American Journal of Gastroenterology. 1990 September; 85(9): 1149-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1697141&dopt=Abstract

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Mechanism of action of vitamin K: synthesis of gamma-carboxyglutamic acid. Author(s): Suttie JW. Source: Crc Crit Rev Biochem. 1980; 8(2): 191-223. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6772376&dopt=Abstract

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Mechanism of cyanide inhibition of the blood-clotting, vitamin K-dependent carboxylase. Author(s): Dowd P, Ham SW. Source: Proceedings of the National Academy of Sciences of the United States of America. 1991 December 1; 88(23): 10583-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1961725&dopt=Abstract

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Mechanism of novel vitamin K analog induced growth inhibition in human hepatoma cell line. Author(s): Osada S, Carr BI. Source: Journal of Hepatology. 2001 May; 34(5): 676-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11434613&dopt=Abstract

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Mechanism of the abnormal vitamin K-dependent gamma-carboxylation process in human hepatocellular carcinomas. Author(s): Huisse MG, Leclercq M, Belghiti J, Flejou JF, Suttie JW, Bezeaud A, Stafford DW, Guillin MC. Source: Cancer. 1994 September 1; 74(5): 1533-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7520347&dopt=Abstract

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Mechanisms of vitamin K antagonism. Author(s): Bovill EG, Malhotra OP, Mann KG. Source: Baillieres Clin Haematol. 1990 July; 3(3): 555-81. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2271783&dopt=Abstract

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Membrane-dependent reactions in blood coagulation: role of the vitamin Kdependent enzyme complexes. Author(s): Kalafatis M, Swords NA, Rand MD, Mann KG. Source: Biochimica Et Biophysica Acta. 1994 November 29; 1227(3): 113-29. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7986819&dopt=Abstract

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Molecular analysis of the gene for vitamin K dependent protein S and its pseudogene. Cloning and partial gene organization. Author(s): Edenbrandt CM, Lundwall A, Wydro R, Stenflo J. Source: Biochemistry. 1990 August 28; 29(34): 7861-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2148112&dopt=Abstract

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Molecular basis of gamma-carboxylation. Role of the propeptide in the vitamin Kdependent proteins. Author(s): Furie B, Furie BC. Source: Annals of the New York Academy of Sciences. 1991; 614: 1-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2024877&dopt=Abstract

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Molecular basis of vitamin K-dependent gamma-carboxylation. Author(s): Furie B, Furie BC. Source: Blood. 1990 May 1; 75(9): 1753-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2184900&dopt=Abstract

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Monitoring therapy with vitamin K antagonists in patients with lupus anticoagulant: effect on different tests for INR determination. Author(s): Bijsterveld NR, Middeldorp S, Berends F, Buller HR. Source: Journal of Thrombosis and Thrombolysis. 2000 April; 9(3): 263-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10728026&dopt=Abstract

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Monoclonal antibody-based enzyme-linked immunosorbent assays (ELISA) for the measurement of vitamin K-dependent protein S: the effect of antibody immunoreactivity on plasma protein S antigen determinations. Author(s): D'Angelo SV, Tombesi S, Marcovina S, Albertini A, Della Valle P, D'Angelo A. Source: Thrombosis and Haemostasis. 1992 June 1; 67(6): 631-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1387263&dopt=Abstract

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More on vitamin K. Author(s): Seddon F. Source: Midwifery Today Childbirth Educ. 1997 Summer; (42): 9, 67. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9429420&dopt=Abstract

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More on vitamin K. Author(s): Donley J. Source: Midwifery Today Childbirth Educ. 1997 Summer; (42): 9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9429419&dopt=Abstract

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More on vitamin K. Author(s): Edmunds J. Source: Midwifery Today Childbirth Educ. 1997 Summer; (42): 8-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9429418&dopt=Abstract

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Multi-site-specificity of the vitamin K-dependent carboxylase: in vitro carboxylation of des-gamma-carboxylated bone Gla protein and Des-gamma-carboxylated pro bone Gla protein. Author(s): Benton ME, Price PA, Suttie JW. Source: Biochemistry. 1995 July 25; 34(29): 9541-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7626624&dopt=Abstract

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Mutations which introduce free cysteine residues in the Gla-domain of vitamin K dependent proteins result in the formation of complexes with alpha 1-microglobulin. Author(s): Wojcik EG, Simioni P, d Berg M, Girolami A, Bertina RM. Source: Thrombosis and Haemostasis. 1996 January; 75(1): 70-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8713782&dopt=Abstract

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Neonatal vitamin K administration and childhood cancer in the north of England: retrospective case-control study. Author(s): Parker L, Cole M, Craft AW, Hey EN. Source: Bmj (Clinical Research Ed.). 1998 January 17; 316(7126): 189-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9468683&dopt=Abstract

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Neonatal vitamin K administration and in vivo somatic mutation. Author(s): Pizer B, Boyse J, Hunt L, Mott M. Source: Mutation Research. 1995 August; 347(3-4): 135-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7565904&dopt=Abstract

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Neonatal vitamin K prophylaxis and childhood cancer. Author(s): Dubey AP. Source: Indian Pediatrics. 1998 July; 35(7): 691-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10216687&dopt=Abstract

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Neonatal vitamin K prophylaxis in Denmark: three years' experience with oral administration during the first three months of life compared with one oral administration at birth. Author(s): Hansen KN, Ebbesen F. Source: Acta Paediatrica (Oslo, Norway : 1992). 1996 October; 85(10): 1137-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8922069&dopt=Abstract

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Neonatal vitamin K prophylaxis in the British Isles: current practice and trends. Author(s): Barton JS, Tripp JH, McNinch AW. Source: Bmj (Clinical Research Ed.). 1995 March 11; 310(6980): 632-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7703751&dopt=Abstract

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Neonatal vitamin K prophylaxis. Report of Scientific and Standardization Subcommittee on Perinatal Haemostasis. Author(s): von Kries R, Hanawa Y. Source: Thrombosis and Haemostasis. 1993 March 1; 69(3): 293-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8470054&dopt=Abstract

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Neonatal vitamin K prophylaxis: the Gordian knot still awaits untying. Author(s): von Kries R. Source: Bmj (Clinical Research Ed.). 1998 January 17; 316(7126): 161-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9468666&dopt=Abstract

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Neonatal vitamin K. Author(s): von Kries R. Source: Bmj (Clinical Research Ed.). 1991 November 2; 303(6810): 1083-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1747572&dopt=Abstract

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Neonatology--then and now. Vitamin K (1961). Author(s): Walker CH. Source: Archives of Disease in Childhood. 1989 October; 64(10): 1526. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2684037&dopt=Abstract

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New Food and Drug Administration requirements for inclusion of vitamin K in adult parenteral multivitamins. Author(s): Helphingstine CJ, Bistrian BR. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 2003 May-June; 27(3): 220-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757117&dopt=Abstract

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New insights on vitamin K. Author(s): Hathaway WE. Source: Hematology/Oncology Clinics of North America. 1987 September; 1(3): 367-79. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3329179&dopt=Abstract

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New method for the rapid detection of vitamin k deficiency. Author(s): Bertina RM, van der Marel-van Nieuwkoop W, Dubbeldam J, BoekhoutMussert RJ, Veltkamp JJ. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 1980 July 17; 105(1): 93-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7398088&dopt=Abstract

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New Zealand hospital records insufficient for vitamin K study. Author(s): Dockerty JD, Broadbent R, McNoe B. Source: N Z Med J. 1995 May 10; 108(999): 169-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7753513&dopt=Abstract

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Non-vitamin K-dependent clotting factors during oral anticoagulant treatment. Author(s): van Wersch JW. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. 1992 December; 3(6): 727-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1489894&dopt=Abstract

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Novel effects of diets enriched with corn oil or with an olive oil/sunflower oil mixture on vitamin K metabolism and vitamin K-dependent proteins in young men. Author(s): Schurgers LJ, Shearer MJ, Soute BA, Elmadfa I, Harvey J, Wagner KH, Tomasch R, Vermeer C. Source: Journal of Lipid Research. 2002 June; 43(6): 878-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032162&dopt=Abstract

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Novel mutation in the gamma-glutamyl carboxylase gene resulting in congenital combined deficiency of all vitamin K-dependent blood coagulation factors. Author(s): Spronk HM, Farah RA, Buchanan GR, Vermeer C, Soute BA. Source: Blood. 2000 November 15; 96(10): 3650-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11071668&dopt=Abstract

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Novel type of very high affinity calcium-binding sites in beta-hydroxyasparaginecontaining epidermal growth factor-like domains in vitamin K-dependent protein S. Author(s): Dahlback B, Hildebrand B, Linse S. Source: The Journal of Biological Chemistry. 1990 October 25; 265(30): 18481-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2145284&dopt=Abstract

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Novel vitamin K-dependent pathways regulating cell survival. Author(s): Saxena SP, Israels ED, Israels LG. Source: Apoptosis : an International Journal on Programmed Cell Death. 2001 FebruaryApril; 6(1-2): 57-68. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11321042&dopt=Abstract

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Nutritional sources of vitamin K. Author(s): Lipsky JJ. Source: Mayo Clinic Proceedings. 1994 May; 69(5): 462-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8170198&dopt=Abstract

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Observations on vitamin K deficiency in the fetus and newborn: has nature made a mistake? Author(s): Israels LG, Israels ED. Source: Seminars in Thrombosis and Hemostasis. 1995; 21(4): 357-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8747698&dopt=Abstract

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Olestra affects serum concentrations of alpha-tocopherol and carotenoids but not vitamin D or vitamin K status in free-living subjects. Author(s): Koonsvitsky BP, Berry DA, Jones MB, Lin PY, Cooper DA, Jones DY, Jackson JE. Source: The Journal of Nutrition. 1997 August; 127(8 Suppl): 1636S-1645S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9237960&dopt=Abstract

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Oral anticoagulation reduces activated protein C less than protein C and other vitamin K-dependent clotting factors. Author(s): Simmelink MJ, de Groot PG, Derksen RH, Fernandez JA, Griffin JH. Source: Blood. 2002 December 1; 100(12): 4232-3. Epub 2002 August 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393585&dopt=Abstract

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Oral mixed micellar vitamin K for prevention of late vitamin K deficiency bleeding. Author(s): von Kries R, Hachmeister A, Gobel U. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 2003 March; 88(2): F109-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598498&dopt=Abstract

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Oral vitamin K for warfarin-associated coagulopathy. Author(s): Weideman R, Patel AP. Source: Annals of Internal Medicine. 2003 April 1; 138(7): 610; Author Reply 611. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667043&dopt=Abstract

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Oral vitamin K for warfarin-associated coagulopathy. Author(s): Ringstrom E, Long H. Source: Annals of Internal Medicine. 2003 April 1; 138(7): 610-1; Author Reply 611. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667042&dopt=Abstract

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Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial. Author(s): Crowther MA, Douketis JD, Schnurr T, Steidl L, Mera V, Ultori C, Venco A, Ageno W. Source: Annals of Internal Medicine. 2002 August 20; 137(4): 251-4. Summary for Patients In: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12186515&dopt=Abstract

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Oral vitamin K prophylaxis for newborn infants: safe enough? Author(s): Baenziger O, Braegger CP, Fanconi S. Source: Lancet. 1996 November 23; 348(9039): 1456. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8937308&dopt=Abstract

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Osteoporosis and vitamin K intake. Author(s): Olson RE. Source: The American Journal of Clinical Nutrition. 2000 May; 71(5): 1031-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10799363&dopt=Abstract

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Oxygen free radical generating mechanisms in the colon: do the semiquinones of vitamin K play a role in the aetiology of colon cancer? Author(s): Valko M, Morris H, Mazur M, Rapta P, Bilton RF. Source: Biochimica Et Biophysica Acta. 2001 August 15; 1527(3): 161-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11479033&dopt=Abstract

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Platelet-induced thrombin generation time II (PITT II). A modified global coagulation test to monitor prophylactic anticoagulation with vitamin K antagonists? Author(s): Radziwon P, Boczkowska-Radziwon B, Schenk JF, Wojtukiewicz MZ, Kloczko J, Giedrojc J, Breddin HK. Source: Thrombosis Research. 1999 October 1; 96(1): 77-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10554088&dopt=Abstract

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Potential effect of vitamin K on microgravity-induced bone loss. Author(s): Wolf J, Vermeer C. Source: J Gravit Physiol. 1996 September; 3(2): 29-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11540271&dopt=Abstract

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Prenatal exposure to phenytoin, facial development, and a possible role for vitamin K. Author(s): Howe AM, Lipson AH, Sheffield LJ, Haan EA, Halliday JL, Jenson F, David DJ, Webster WS. Source: American Journal of Medical Genetics. 1995 September 11; 58(3): 238-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8533825&dopt=Abstract

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Prevalence of vitamin K deficiency in cystic fibrosis. Author(s): Rashid M, Durie P, Andrew M, Kalnins D, Shin J, Corey M, Tullis E, Pencharz PB. Source: The American Journal of Clinical Nutrition. 1999 September; 70(3): 378-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10479200&dopt=Abstract

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Prevention of subclinical vitamin K deficiency based on PIVKA-II levels: oral versus intramuscular route. Author(s): Bakhshi S, Deorari AK, Roy S, Paul VK, Singh M. Source: Indian Pediatrics. 1996 December; 33(12): 1040-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9141807&dopt=Abstract

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Processive post-translational modification. Vitamin K-dependent carboxylation of a peptide substrate. Author(s): Morris DP, Stevens RD, Wright DJ, Stafford DW. Source: The Journal of Biological Chemistry. 1995 December 22; 270(51): 30491-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8530480&dopt=Abstract

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Prophylactic vitamin K for vitamin K deficiency bleeding in neonates. Author(s): Puckett RM, Offringa M. Source: Cochrane Database Syst Rev. 2000; (4): Cd002776. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11034761&dopt=Abstract

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Prophylactic vitamin K--should midwives be involved in its administration? Author(s): Hodgson H. Source: Midwives. 1996 February; 109(1297): 30. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8998619&dopt=Abstract

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Prophylaxis of neonatal vitamin K deficiency bleeding in premature infants. Author(s): Josty TL, Matthes JW. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 2001 May; 84(3): F218. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11351987&dopt=Abstract

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Protein Z, a vitamin K-dependent protein in patients with renal failure. Author(s): Malyszko J, Skrzydlewska E, Malyszko JS, Mysliwiec M. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 January; 1(1): 195-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871562&dopt=Abstract

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Quantitation of vitamin K in human milk. Author(s): Canfield LM, Hopkinson JM, Lima AF, Martin GS, Sugimoto K, Burr J, Clark L, McGee DL. Source: Lipids. 1990 July; 25(7): 406-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2395420&dopt=Abstract

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Rapid development of vitamin K deficiency in an adolescent boy receiving total parenteral nutrition following bone marrow transplantation. Author(s): Carlin A, Walker WA. Source: Nutrition Reviews. 1991 June; 49(6): 179-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1904566&dopt=Abstract

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Recommending particular treatment options: the vitamin K experience. Author(s): Coates J. Source: N Z Med J. 2001 May 11; 114(1131): 215. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11421437&dopt=Abstract

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Relationship between acute insulin response and vitamin K intake in healthy young male volunteers. Author(s): Sakamoto N, Nishiike T, Iguchi H, Sakamoto K. Source: Diabetes Nutr Metab. 1999 February; 12(1): 37-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10517305&dopt=Abstract

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Relationship between international normalized ratio values, vitamin K-dependent clotting factor levels and in vivo prothrombin activation during the early and steady phases of oral anticoagulant treatment. Author(s): D'Angelo A, Della Valle P, Crippa L, Fattorini A, Pattarini E, Vigano D'Angelo S. Source: Haematologica. 2002 October; 87(10): 1074-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368163&dopt=Abstract

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Response of vitamin K status to different intakes and sources of phylloquinone-rich foods: comparison of younger and older adults. Author(s): Booth SL, O'Brien-Morse ME, Dallal GE, Davidson KW, Gundberg CM. Source: The American Journal of Clinical Nutrition. 1999 September; 70(3): 368-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10479199&dopt=Abstract

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Reversible metabolism of vitamin K-vitamin K epoxide: modeling considerations and limitations. Author(s): Hallak HO, Wedlund PJ. Source: Journal of Pharmacokinetics and Biopharmaceutics. 1992 February; 20(1): 1-18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1588501&dopt=Abstract

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Review of conformation-specific affinity purification methods for plasma vitamin Kdependent proteins. Author(s): Yan SB. Source: Journal of Molecular Recognition : Jmr. 1996 May-June; 9(3): 211-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8938593&dopt=Abstract

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Role of the propeptide and gamma-glutamic acid domain of factor IX for in vitro carboxylation by the vitamin K-dependent carboxylase. Author(s): Stanley TB, Wu SM, Houben RJ, Mutucumarana VP, Stafford DW. Source: Biochemistry. 1998 September 22; 37(38): 13262-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9748333&dopt=Abstract

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Role of vitamin K and Gla proteins in the pathophysiology of osteoporosis and vascular calcification. Author(s): Shearer MJ. Source: Current Opinion in Clinical Nutrition and Metabolic Care. 2000 November; 3(6): 433-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11085828&dopt=Abstract

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Role of vitamin K and vitamin K-dependent proteins in vascular calcification. Author(s): Schurgers LJ, Dissel PE, Spronk HM, Soute BA, Dhore CR, Cleutjens JP, Vermeer C. Source: Zeitschrift Fur Kardiologie. 2001; 90 Suppl 3: 57-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11374034&dopt=Abstract

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Seaweed, vitamin K, and warfarin. Author(s): Bartle WR, Madorin P, Ferland G. Source: American Journal of Health-System Pharmacy : Ajhp : Official Journal of the American Society of Health-System Pharmacists. 2001 December 1; 58(23): 2300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11763808&dopt=Abstract

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Separation of human vitamin K-dependent coagulation proteins using hydrophobic interaction chromatography. Author(s): Husi H, Walkinshaw MD. Source: J Chromatogr B Biomed Sci Appl. 1999 December 24; 736(1-2): 77-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10676986&dopt=Abstract

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Severe vitamin K deficiency induced by occult celiac disease BR96-026. Author(s): Avery RA, Duncan WE, Alving BM. Source: American Journal of Hematology. 1996 September; 53(1): 55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8813108&dopt=Abstract

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Short-term effect of vitamin K administration on prednisolone-induced loss of bone mineral density in patients with chronic glomerulonephritis. Author(s): Yonemura K, Kimura M, Miyaji T, Hishida A. Source: Calcified Tissue International. 2000 February; 66(2): 123-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10652960&dopt=Abstract

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Silent infection of Giardia lamblia causing bleeding through vitamin K malabsorption. Author(s): Takahashi M, Katayama Y, Takada H, Hirakawa J, Kuwayama H, Yamaji H, Ogura K, Meda S, Omata M. Source: Journal of Gastroenterology and Hepatology. 2001 October; 16(10): 1171-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11686849&dopt=Abstract

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Six years' experience of prophylactic oral vitamin K. Author(s): Wariyar U, Hilton S, Pagan J, Tin W, Hey E. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 2000 January; 82(1): F64-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10634845&dopt=Abstract

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Small doses of recombinant factor VIIa in acquired deficiencies of vitamin K dependent factors. Author(s): Muleo G, Santoro R, Iannaccaro PG, Papaleo P, Leo F, Zappala D, Elia L. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. 1999 December; 10(8): 521-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10636464&dopt=Abstract

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Studies on coagulation in newborn infants: liver maturation and vitamin K procoagulant-inhibitor relations. Author(s): Suzuki S. Source: Journal of Perinatal Medicine. 1979; 7(4): 229-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=480106&dopt=Abstract

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Studies on the interaction between vitamin K-dependent protein S and complement regulator C4b-binding protein: localization of binding sites and identification of a possible function of the complex. Author(s): Webb JH. Source: Scand J Clin Lab Invest Suppl. 2002; 237: 19-28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12570163&dopt=Abstract

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Synthesis and anticancer evaluation of vitamin K(3) analogues. Author(s): Chen C, Liu YZ, Shia KS, Tseng HY. Source: Bioorganic & Medicinal Chemistry Letters. 2002 October 7; 12(19): 2729-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12217364&dopt=Abstract

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The anticancer effects of vitamin K. Author(s): Lamson DW, Plaza SM. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2003 August; 8(3): 303-18. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12946240&dopt=Abstract

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The effect of combined antenatal vitamin K and phenobarbital therapy on umbilical blood coagulation studies in infants less than 34 weeks' gestation. Author(s): Thorp JA, Caspers DR, Cohen GR, Zucker ML, Strope BD, McKenzie DR. Source: Obstetrics and Gynecology. 1995 December; 86(6): 982-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7501353&dopt=Abstract

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The effects of topical vitamin K on bruising after laser treatment. Author(s): Shah NS, Lazarus MC, Bugdodel R, Hsia SL, He J, Duncan R, Baumann L. Source: Journal of the American Academy of Dermatology. 2002 August; 47(2): 241-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12140470&dopt=Abstract

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The incidence of recurrent venous thromboembolism after treatment with vitamin K antagonists in relation to time since first event: a meta-analysis. Author(s): van Dongen CJ, Vink R, Hutten BA, Buller HR, Prins MH. Source: Archives of Internal Medicine. 2003 June 9; 163(11): 1285-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796064&dopt=Abstract

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The role of vitamin K in biological calcification. Author(s): Adams AB. Source: J Nebr Dent Assoc. 1979 Autumn; 56(1): 13-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=297129&dopt=Abstract

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The use of vitamin K for reversal of over-warfarinization in children. Author(s): Ann Intern Med. 2002 Aug 20;137(4):I39 Source: British Journal of Haematology. 2002 September; 118(3): 924. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12186539

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Transport of vitamin K to bone in humans. Author(s): Kohlmeier M, Salomon A, Saupe J, Shearer MJ. Source: The Journal of Nutrition. 1996 April; 126(4 Suppl): 1192S-6S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8642455&dopt=Abstract

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Treating all babies with vitamin K: an “unnatural” policy? Author(s): Slattery J. Source: British Journal of Obstetrics and Gynaecology. 1996 May; 103(5): 400-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8624309&dopt=Abstract

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Treating all babies with vitamin K: an 'unnatural' policy? Author(s): Grant JM. Source: British Journal of Obstetrics and Gynaecology. 1996 May; 103(5): Xxii. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8624307&dopt=Abstract

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Treatment with vitamin K antagonists: frequency of indications and appropriateness of continuation. Author(s): van Der Heijden JF, Remkes MG, Buller HR, Vermeulen M. Source: Pathophysiology of Haemostasis and Thrombosis. 2002 May-June; 32(3): 111-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372923&dopt=Abstract

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Undercarboxylated osteocalcin and development of a method to determine vitamin K status. Author(s): Sokoll LJ, O'Brien ME, Camilo ME, Sadowski JA. Source: Clinical Chemistry. 1995 August; 41(8 Pt 1): 1121-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7628086&dopt=Abstract

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Unexpected vitamin K deficiency in hospitalized patients. Author(s): Pineo GF, Gallus AS, Hirsh J. Source: Can Med Assoc J. 1973 November 3; 109(9): 880-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4750303&dopt=Abstract

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Unsuspected source of vitamin K in patients treated with anticoagulants: a case report. Author(s): Oren B, Shvartzman P. Source: Family Practice. 1989 June; 6(2): 151-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2663579&dopt=Abstract

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Upper limits of vitamin A in infant formulas, with some comments on vitamin K. Author(s): Olson JA. Source: The Journal of Nutrition. 1989 December; 119(12 Suppl): 1820-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2614529&dopt=Abstract

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Use of phospholipid bilayers and monolayers in binding studies of vitamin Kdependent blood coagulation proteins. Author(s): Castellino FJ, Ellison EH. Source: Methods in Molecular Biology (Clifton, N.J.). 2002; 199: 233-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12094573&dopt=Abstract

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Usefulness of determining a protein induced by vitamin K absence in detection of hepatocellular carcinoma. Author(s): Cui R, Wang B, Ding H, Shen H, Li Y, Chen X. Source: Chinese Medical Journal. 2002 January; 115(1): 42-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11930656&dopt=Abstract

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Vitamin K and blood clotting. Author(s): Fawns HT. Source: Nurs Times. 1978 October 26; 74(43): 1764-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=250782&dopt=Abstract

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Vitamin K and childhood cancer: a population based case-control study in Lower Saxony, Germany. Author(s): von Kries R, Gobel U, Hachmeister A, Kaletsch U, Michaelis J. Source: Bmj (Clinical Research Ed.). 1996 July 27; 313(7051): 199-203. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8696195&dopt=Abstract

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Vitamin K at birth. Author(s): Zipursky A. Source: Bmj (Clinical Research Ed.). 1996 July 27; 313(7051): 179-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8696177&dopt=Abstract

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Vitamin K prophylaxis to prevent neonatal vitamin K deficient intracranial haemorrhage in Shizuoka prefecture. Author(s): Nishiguchi T, Saga K, Sumimoto K, Okada K, Terao T. Source: British Journal of Obstetrics and Gynaecology. 1996 November; 103(11): 1078-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8916992&dopt=Abstract

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Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study. Author(s): Jie KG, Bots ML, Vermeer C, Witteman JC, Grobbee DE. Source: Calcified Tissue International. 1996 November; 59(5): 352-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8849401&dopt=Abstract

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Vitamin K status in human tissues: tissue-specific accumulation of phylloquinone and menaquinone-4. Author(s): Thijssen HH, Drittij-Reijnders MJ. Source: The British Journal of Nutrition. 1996 January; 75(1): 121-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8785182&dopt=Abstract

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Vitamin K: friend or foe. Author(s): Hodgson H. Source: Nurs Times. 1996 July 10-16; 92(28): 60. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8718087&dopt=Abstract

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Vitamin K: is it necessary? Author(s): Enoch J. Source: Midwifery Today Childbirth Educ. 1996 Winter; (40): 28-30. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9016062&dopt=Abstract

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Vitamin K-dependent carboxylase: mRNA distribution and effects of vitamin Kdeficiency and warfarin treatment. Author(s): Liu Y, Nelson AN, Lipsky JJ. Source: Biochemical and Biophysical Research Communications. 1996 July 16; 224(2): 549-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8702425&dopt=Abstract

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Vitamin K-dependent coagulopathy in a child receiving anticonvulsant therapy. Author(s): Tam DA Jr, Myer EC. Source: Journal of Child Neurology. 1996 May; 11(3): 244-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8734031&dopt=Abstract

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Warfarin and the biochemistry of the vitamin K dependent proteins. Author(s): Bovill EG, Mann KG. Source: Advances in Experimental Medicine and Biology. 1987; 214: 17-46. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3310538&dopt=Abstract

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Warfarin and vitamin K. Author(s): Suttie JW. Source: Clin Cardiol. 1990 April; 13(4 Suppl 6): Vi16-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2191810&dopt=Abstract

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Warfarin antagonism of natto and increase in serum vitamin K by intake of natto. Author(s): Kudo T. Source: Artery. 1990; 17(4): 189-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2360879&dopt=Abstract

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Warfarin dosage and vitamin K in Osmolite. Author(s): Lader E, Yang L, Clarke A. Source: Annals of Internal Medicine. 1980 August; 93(2): 373-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7406391&dopt=Abstract

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Warfarin poisoning and vitamin K antagonism in rat and human liver. Design of a system in vitro that mimics the situation in vivo. Author(s): Wallin R, Martin LF. Source: The Biochemical Journal. 1987 January 15; 241(2): 389-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3593198&dopt=Abstract

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Watch for severe reactions to vitamin K. Author(s): Porterfield LM. Source: Rn. 1993 November; 56(11): 87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8235332&dopt=Abstract

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Weekly oral vitamin K prophylaxis in Denmark. Author(s): Hansen KN, Minousis M, Ebbesen F. Source: Acta Paediatrica (Oslo, Norway : 1992). 2003 July; 92(7): 802-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12892158&dopt=Abstract

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What happens to vitamin K(1) in serum after bone fracture? Author(s): Cham BE, Smith JL, Colquhoun DM. Source: Clinical Chemistry. 1999 December; 45(12): 2261-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10585362&dopt=Abstract

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Which vitamin K preparation for the newborn? Author(s): Floyd L. Source: Pract Midwife. 1998 July-August; 1(7-8): 67-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10392158&dopt=Abstract

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

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

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

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

The effect of diet on blood Vitamin K status and urinary mineral excretion assessed by a food questionnaire. Author(s): Department of Hygiene, Hyogo College of Medicine (Japan) Source: Sakamoto, N. Nishiike, T. Iguchi, H. Sakamoto, K. Nutrition-and-Health (United Kingdom). (1999). volume 13(1) page 1-10.

Additional consumer oriented references include: •

An update on vitamin K: contribution of MAFF-funded research. Source: Hughes, J. Buttriss, J. BNF-nutr-bull. London : The British Nutrition Foundation. June 2000. volume 25 (2) page 125-134. 0141-9684

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Megavitamin E supplementation and vitamin K-dependent carboxylation. Source: Himms Hagen, Jean. Nutr-Rev. Washington, D.C. : Nutrition Foundation. Sept 1983. volume 41 (9) page 268-270. 0029-6643

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Rapid development of vitamin K deficiency in an adolescent boy receiving total parenteral nutrition following bone marrow transplantation. Author(s): Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Boston. Source: Carlin, A Walker, W A Nutr-Revolume 1991 June; 49(6): 179-83 0029-6643

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Role of pyridoxal-5'-phosphate in vitamin K-dependent carboxylation. Source: Nutrition-reviews (USA). (July 1985). volume 43(7) page 218-219. pyridoxine vitamin k enzymes protein metabolism chemicophysical properties 0029-6643

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Skeletal functions of vitamin K-dependent proteins: not just for clotting anymore. Author(s): Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA. Source: Booth, S L Nutr-Revolume 1997 July; 55(7): 282-4 0029-6643

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The vitamin K-dependent proteins: an update. Author(s): Universite de Montreal, Department of Nutrition, Quebec, Canada. Source: Ferland, G Nutr-Revolume 1998 August; 56(8): 223-30 0029-6643

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Vitamin K and antibiotics. Source: Chandra, R.K. Nutr-M-D. Van Nuys, Calif. : PM, Inc. December 1990. volume 16 (12) page 4-5. 0732-0167

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Vitamin K hydroperoxide: An Intermediate in glutamate carboxylation? Source: Nutrition-reviews (USA). (August 1984). volume 42(8) page 290-292. vitamin k enzymes glutamic acid 0029-6643

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Vitamin K-dependent proteins in the developing and aging nervous system. Author(s): Harvard Medical School, New England Regional Primate Research Center, Southborough, MA 01772-9102, USA. Source: Tsaioun, K I Nutr-Revolume 1999 August; 57(8): 231-40 0029-6643

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

Developmental expression of vitamin K-dependent gamma-carboxylase activity in zebrafish embryos: effect of warfarin. Author(s): Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. Source: Hanumanthaiah, R Thankavel, B Day, K Gregory, M Jagadeeswaran, P BloodCells-Mol-Dis. 2001 Nov-December; 27(6): 992-9 1079-9796

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Expression and characterization of recombinant vitamin K-dependent gammaglutamyl carboxylase from an invertebrate, Conus textile. Author(s): Marine Biological Laboratory, Woods Hole, MA, USA. Source: Czerwiec, E Begley, G S Bronstein, M Stenflo, J Taylor, K Furie, B C Furie, B EurJ-Biochem. 2002 December; 269(24): 6162-72 0014-2956

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Maintenance of trabecular structure and bone volume by vitamin K(2) in mature rats with long-term tail suspension. Author(s): Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Japan. Source: Iwasaki, Y Yamato, H Murayama, H Sato, M Takahashi, T Ezawa, I Kurokawa, K Fukagawa, M J-Bone-Miner-Metab. 2002; 20(4): 216-22 0914-8779

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Oral vitamin K reversed warfarin-associated coagulopathy faster than subcutaneous vitamin K. Author(s): Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada. Source: Laupacis, A ACP-J-Club. 2003 Jan-February; 138(1): 10 1056-8751

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Treatment for patients with postmenopausal osteoporosis who have been placed on HRT and show a decrease in bone mineral density: effects of concomitant administration of vitamin K(2). Author(s): Department of Obstetrics and Gynecology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. Source: Hidaka, T Hasegawa, T Fujimura, M Sakai, M Saito, S J-Bone-Miner-Metab. 2002; 20(4): 235-9 0914-8779

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Use of phospholipid bilayers and monolayers in binding studies of vitamin Kdependent blood coagulation proteins. Author(s): Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. Source: Castellino, F J Ellison, E H Methods-Mol-Biol. 2002; 199: 233-43 1064-3745

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 vitamin K; 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 Vitamin E Alternative names: Alpha-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Vitamin K Source: Healthnotes, Inc.; www.healthnotes.com

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Vitamin K Alternative names: Menadione Source: Integrative Medicine Communications; www.drkoop.com Vitamin K Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin K Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10068,00.html •

Minerals Alpha-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Beta-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Chromium Source: Integrative Medicine Communications; www.drkoop.com Copper Source: Integrative Medicine Communications; www.drkoop.com D-alpha-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Delta-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Gabapentin Source: Healthnotes, Inc.; www.healthnotes.com Gamma-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Iodine Source: Integrative Medicine Communications; www.drkoop.com Iron Alternative names: Ferrous Sulfate Source: Integrative Medicine Communications; www.drkoop.com Manganese Source: Integrative Medicine Communications; www.drkoop.com

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Vitamin A (Retinol) Source: Integrative Medicine Communications; www.drkoop.com Zinc Source: Integrative Medicine Communications; www.drkoop.com •

Food and Diet Broccoli Source: Healthnotes, Inc.; www.healthnotes.com Brussels Sprouts Source: Healthnotes, Inc.; www.healthnotes.com Brussels Sprouts Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,12,00.html Cabbage Source: Healthnotes, Inc.; www.healthnotes.com Chives Source: Healthnotes, Inc.; www.healthnotes.com Collards Source: Healthnotes, Inc.; www.healthnotes.com Endive Source: Healthnotes, Inc.; www.healthnotes.com Ferrous Sulfate Source: Integrative Medicine Communications; www.drkoop.com Iceberg Lettuce Source: Healthnotes, Inc.; www.healthnotes.com Kale Source: Healthnotes, Inc.; www.healthnotes.com Scallions Source: Healthnotes, Inc.; www.healthnotes.com Spinach Source: Healthnotes, Inc.; www.healthnotes.com Spinach Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,35,00.html

Nutrition

Turnips Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. ALTERNATIVE MEDICINE AND VITAMIN K Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to vitamin K. At the conclusion of this chapter, we will provide additional sources.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to vitamin K and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “vitamin K” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to vitamin K: •

“Resistance” to warfarin due to unrecognized vitamin K supplementation. Author(s): O'Reilly RA, Rytand DA. Source: The New England Journal of Medicine. 1980 July 17; 303(3): 160-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7383081&dopt=Abstract

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A conserved epitope on several human vitamin K-dependent proteins. Location of the antigenic site and influence of metal ions on antibody binding. Author(s): Church WR, Messier T, Howard PR, Amiral J, Meyer D, Mann KG. Source: The Journal of Biological Chemistry. 1988 May 5; 263(13): 6259-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2452160&dopt=Abstract

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A microsomal endopeptidase from liver with substrate specificity for processing proproteins such as the vitamin K-dependent proteins of plasma. Author(s): Kawabata S, Davie EW.

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Source: The Journal of Biological Chemistry. 1992 May 25; 267(15): 10331-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1316898&dopt=Abstract •

Binary/ternary combined effects of vitamin K3 with other antitumor agents in nasopharyngeal carcinoma CG1 cells. Author(s): Liao WC, Wu FY, Wu CW. Source: International Journal of Oncology. 2000 August; 17(2): 323-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10891542&dopt=Abstract

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Binding of anticoagulant vitamin K-dependent protein S to platelet-derived microparticles. Author(s): Dahlback B, Wiedmer T, Sims PJ. Source: Biochemistry. 1992 December 29; 31(51): 12769-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1463747&dopt=Abstract

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Biosynthesis of o-succinylbenzoic acid. II: Properties of o-succinylbenzoic acid synthase, an enzyme involved in vitamin K2 biosynthesis. Author(s): Weische A, Garvert W, Leistner E. Source: Archives of Biochemistry and Biophysics. 1987 July; 256(1): 223-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3300553&dopt=Abstract

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Bone markers during a 6-month space flight: effects of vitamin K supplementation. Author(s): Vermeer C, Wolf J, Craciun AM, Knapen MH. Source: J Gravit Physiol. 1998 October; 5(2): 65-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11541904&dopt=Abstract

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Calcium, vitamin D and vitamin K in the prevention of fractures due to osteoporosis. Author(s): Meunier PJ. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. 1999; 9 Suppl 2: S48-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10525726&dopt=Abstract

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Can prenatal vitamin K1 (phylloquinone) supplementation replace prophylaxis at birth? Author(s): Anai T, Hirota Y, Yoshimatsu J, Oga M, Miyakawa I. Source: Obstetrics and Gynecology. 1993 February; 81(2): 251-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8423960&dopt=Abstract

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Carboxylation of osteocalcin in post-menopausal osteoporotic women following vitamin K and D supplementation. Author(s): Douglas AS, Robins SP, Hutchison JD, Porter RW, Stewart A, Reid DM.

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Source: Bone. 1995 July; 17(1): 15-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7577153&dopt=Abstract •

Cell growth inhibition by a novel vitamin K is associated with induction of protein tyrosine phosphorylation. Author(s): Ni R, Nishikawa Y, Carr BI. Source: The Journal of Biological Chemistry. 1998 April 17; 273(16): 9906-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9545333&dopt=Abstract

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Comparative effects of vitamin K and vitamin D supplementation on prevention of osteopenia in calcium-deficient young rats. Author(s): Iwamoto J, Yeh JK, Takeda T, Ichimura S, Sato Y. Source: Bone. 2003 October; 33(4): 557-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14555259&dopt=Abstract

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Congenital deficiency of vitamin K-dependent coagulation factors and protein C. Author(s): Vicente V, Maia R, Alberca I, Tamagnini GP, Lopez Borrasca A. Source: Thrombosis and Haemostasis. 1984 July 29; 51(3): 343-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6548583&dopt=Abstract

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Corn oil-induced decrease in arterial thrombosis tendency may be related to altered plasma vitamin K transport. Author(s): Schurgers LJ, Vermeer C. Source: Journal of Lipid Research. 2001 July; 42(7): 1120-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11441140&dopt=Abstract

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Covalent modification of the solubilized rat liver vitamin K-dependent carboxylase with pyridoxal-5'-phosphate. Author(s): Kappel WK, Olson RE. Source: Archives of Biochemistry and Biophysics. 1984 December; 235(2): 521-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6440487&dopt=Abstract

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Determination of vitamin K1 in emulsified nutritional supplements by solid-phase extraction and high-performance liquid chromatography with postcolumn reduction on a platinum catalyst and fluorescence detection. Author(s): Iwase H. Source: J Chromatogr A. 2000 June 9; 881(1-2): 261-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10905710&dopt=Abstract

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Dietary modification of potential vitamin K supply from enteric bacterial menaquinones in rats. Author(s): Mathers JC, Fernandez F, Hill MJ, McCarthy PT, Shearer MJ, Oxley A.

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Source: The British Journal of Nutrition. 1990 May; 63(3): 639-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2383538&dopt=Abstract •

Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Author(s): Booth SL, Tucker KL, Chen H, Hannan MT, Gagnon DR, Cupples LA, Wilson PW, Ordovas J, Schaefer EJ, Dawson-Hughes B, Kiel DP. Source: The American Journal of Clinical Nutrition. 2000 May; 71(5): 1201-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10799384&dopt=Abstract

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Diets enriched in (n-3) fatty acids affect rat coagulation factors dependent on vitamin K. Author(s): Andriamampandry M, Freund M, Wiesel ML, Rhinn S, Ravanat C, Cazenave JP, Leray C, Gachet C. Source: Comptes Rendus De L'academie Des Sciences. Serie Iii, Sciences De La Vie. 1998 May; 321(5): 415-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9766191&dopt=Abstract

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Discrimination of normal and abnormal prothrombin and protein C in plasma using a calcium ion-inhibited monoclonal antibody to a common epitope on several vitamin K-dependent proteins. Author(s): Church WR, Bhushan FH, Mann KG, Bovill EG. Source: Blood. 1989 November 15; 74(7): 2418-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2804372&dopt=Abstract

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Effect of a reduced vitamin K supplementation on prothrombin time in prematures and high-risk neonates. Author(s): Rossi R, Albrecht O, Pollmann H, Jorch G, Harms E. Source: Acta Paediatrica (Oslo, Norway : 1992). 1996 June; 85(6): 747-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8816216&dopt=Abstract

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Effect of vitamin K1 supplementation on vitamin K status in cystic fibrosis patients. Author(s): Beker LT, Ahrens RA, Fink RJ, O'Brien ME, Davidson KW, Sokoll LJ, Sadowski JA. Source: Journal of Pediatric Gastroenterology and Nutrition. 1997 May; 24(5): 512-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9161943&dopt=Abstract

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Effect of vitamin K2 (menaquinone-7) in fermented soybean (natto) on bone loss in ovariectomized rats. Author(s): Yamaguchi M, Taguchi H, Gao YH, Igarashi A, Tsukamoto Y. Source: Journal of Bone and Mineral Metabolism. 1999; 17(1): 23-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10084398&dopt=Abstract

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Effect of vitamin K2 on osteoblast apoptosis: vitamin K2 inhibits apoptotic cell death of human osteoblasts induced by Fas, proteasome inhibitor, etoposide, and staurosporine. Author(s): Urayama S, Kawakami A, Nakashima T, Tsuboi M, Yamasaki S, Hida A, Ichinose Y, Nakamura H, Ejima E, Aoyagi T, Nakamura T, Migita K, Kawabe Y, Eguchi K. Source: The Journal of Laboratory and Clinical Medicine. 2000 September; 136(3): 181-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10985496&dopt=Abstract

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Effects of chronic beta-carotene supplementation on vitamin K status in adults. Author(s): Canfield LM, Corrigan JJ Jr, Plezia PM, Jeter M, Sayers S, Alberts DS. Source: Nutrition and Cancer. 1990; 13(4): 263-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2189123&dopt=Abstract

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Effects of sodium ascorbate (vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) treatment on human tumor cell growth in vitro. II. Synergism with combined chemotherapy action. Author(s): De Loecker W, Janssens J, Bonte J, Taper HS. Source: Anticancer Res. 1993 January-February; 13(1): 103-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8476199&dopt=Abstract

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High affinity interaction between C4b-binding protein and vitamin K-dependent protein S in the presence of calcium. Suggestion of a third component in blood regulating the interaction. Author(s): Dahlback B, Frohm B, Nelsestuen G. Source: The Journal of Biological Chemistry. 1990 September 25; 265(27): 16082-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2144524&dopt=Abstract

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Improved bone metabolism in female elite athletes after vitamin K supplementation. Author(s): Craciun AM, Wolf J, Knapen MH, Brouns F, Vermeer C. Source: International Journal of Sports Medicine. 1998 October; 19(7): 479-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9839845&dopt=Abstract

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Improvement of vitamin K status of breastfeeding infants with maternal supplement of vitamin K2 (MK40). Author(s): Nishiguchi T, Yamashita M, Maeda M, Matsuyama K, Kobayashi T, Kanayama N, Terao T. Source: Seminars in Thrombosis and Hemostasis. 2002 December; 28(6): 533-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12536346&dopt=Abstract

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Intake of fermented soybean (natto) increases circulating vitamin K2 (menaquinone7) and gamma-carboxylated osteocalcin concentration in normal individuals. Author(s): Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M.

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Source: Journal of Bone and Mineral Metabolism. 2000; 18(4): 216-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10874601&dopt=Abstract •

Is vitamin K1 supplementation necessary in long-term parenteral nutrition? Author(s): Chambrier C, Leclercq M, Saudin F, Vignal B, Bryssine S, Guillaumont M, Bouletreau P. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 1998 March-April; 22(2): 87-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9527965&dopt=Abstract

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Isolation and sequence of the vitamin K-dependent matrix Gla protein from the calcified cartilage of the soupfin shark. Author(s): Rice JS, Williamson MK, Price PA. Source: Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research. 1994 April; 9(4): 567-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8030445&dopt=Abstract

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Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk. Author(s): Kaneki M, Hedges SJ, Hosoi T, Fujiwara S, Lyons A, Crean SJ, Ishida N, Nakagawa M, Takechi M, Sano Y, Mizuno Y, Hoshino S, Miyao M, Inoue S, Horiki K, Shiraki M, Ouchi Y, Orimo H. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2001 April; 17(4): 315-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11369171&dopt=Abstract

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Lapachol inhibition of vitamin K epoxide reductase and vitamin K quinone reductase. Author(s): Preusch PC, Suttie JW. Source: Archives of Biochemistry and Biophysics. 1984 November 1; 234(2): 405-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6497379&dopt=Abstract

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Long-chain n-3 fatty acids specifically affect rat coagulation factors dependent on vitamin K: relation to peroxidative stress. Author(s): Leray C, Wiesel ML, Freund M, Cazenave JP, Gachet C. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2001 March; 21(3): 459-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11231929&dopt=Abstract

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Monoclonal antibodies to human vitamin K-dependent protein S. Author(s): Litwiller RD, Jenny RJ, Katzmann JA, Miller RS, Mann KG. Source: Blood. 1986 June; 67(6): 1583-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2939895&dopt=Abstract

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No effect of vitamin K1 supplementation on biochemical bone markers in haemodialysis patients. Author(s): Reichel H. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 1999 January; 14(1): 249-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10052531&dopt=Abstract

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Non-competitive inhibition of angiotensin II and PGE2 on guinea-pig ileum with streptomycin, vitamin K3 and rutin. Author(s): Altinkurt O, Abacioglu N. Source: Arzneimittel-Forschung. 1980; 30(4): 610-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7190400&dopt=Abstract

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Novel effect of vitamin K(1) (phylloquinone) and vitamin K(2) (menaquinone) on promoting nerve growth factor-mediated neurite outgrowth from PC12D cells. Author(s): Tsang CK, Kamei Y. Source: Neuroscience Letters. 2002 April 19; 323(1): 9-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11911978&dopt=Abstract

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Novel type of very high affinity calcium-binding sites in beta-hydroxyasparaginecontaining epidermal growth factor-like domains in vitamin K-dependent protein S. Author(s): Dahlback B, Hildebrand B, Linse S. Source: The Journal of Biological Chemistry. 1990 October 25; 265(30): 18481-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2145284&dopt=Abstract

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Oral supplementation of vitamin K for pregnant women and effects on levels of plasma vitamin K and PIVKA-II in the neonate. Author(s): Motohara K, Takagi S, Endo F, Kiyota Y, Matsuda I. Source: Journal of Pediatric Gastroenterology and Nutrition. 1990 July; 11(1): 32-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2388129&dopt=Abstract

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Oxidative stress, disturbance of energy balance, and death of ascites tumour cells under menadione (vitamin K3) action. Author(s): Gabai VL, Seilanov AS, Makarova YuM, Mosin AF. Source: Biomed Sci. 1990 April; 1(4): 407-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2133060&dopt=Abstract

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Plant stanol esters and vitamin K. Author(s): Nguyen TT, Dale LC. Source: Mayo Clinic Proceedings. 1999 June; 74(6): 642-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10377943&dopt=Abstract

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Potentiation of vitamin K antagonists by high-dose intravenous methylprednisolone. Author(s): Costedoat-Chalumeau N, Amoura Z, Aymard G, Sevin O, Wechsler B, Cacoub P, Du LT, Diquet B, Ankri A, Piette JC. Source: Annals of Internal Medicine. 2000 April 18; 132(8): 631-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10766681&dopt=Abstract

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Prolonged intake of fermented soybean (natto) diets containing vitamin K2 (menaquinone-7) prevents bone loss in ovariectomized rats. Author(s): Yamaguchi M, Kakuda H, Gao YH, Tsukamoto Y. Source: Journal of Bone and Mineral Metabolism. 2000; 18(2): 71-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10701161&dopt=Abstract

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Prolonged nonoliguric acute renal failure associated with high-dose vitamin K administration in a renal transplant recipient. Author(s): Chung YC, Huang MT, Chang CN, Lee PH, Lee CS, Huang TW. Source: Transplantation Proceedings. 1994 August; 26(4): 2129-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8066694&dopt=Abstract

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Properties and biosynthesis of a vitamin K-dependent calcium binding protein in bone. Author(s): Lian JB, Hauschka PV, Gallop PM. Source: Fed Proc. 1978 October; 37(12): 2615-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=700171&dopt=Abstract

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Protein S, a new vitamin K-dependent protein from bovine plasma. Author(s): Stenflo J, Jonsson M. Source: Febs Letters. 1979 May 15; 101(2): 377-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=109318&dopt=Abstract

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Relationship of milk intake and vitamin K supplementation to vitamin K status in newborns. Author(s): Motohara K, Matsukane I, Endo F, Kiyota Y, Matsuda I. Source: Pediatrics. 1989 July; 84(1): 90-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2740181&dopt=Abstract

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Remission of abdominal colic during enteroscopy by injecting vitamin K3 into Zusanli acupoint. Author(s): Cheng Q. Source: J Tradit Chin Med. 2000 December; 20(4): 271-2. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11263280&dopt=Abstract

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Similarities and differences between the effects of ipriflavone and vitamin K on bone resorption and formation in vitro. Author(s): Notoya K, Yoshida K, Shirakawa Y, Taketomi S, Tsuda M. Source: Bone. 1995 April; 16(4 Suppl): 349S-353S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7626324&dopt=Abstract

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Studies on immunological assay of vitamin K dependent factors. II. Comparison of four immunoassay methods with functional activity of protein C in human plasma. Author(s): Mikami S, Tuddenham EG. Source: British Journal of Haematology. 1986 January; 62(1): 183-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3753650&dopt=Abstract

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Supplementation of vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. Author(s): Cornelissen M, Steegers-Theunissen R, Kollee L, Eskes T, Motohara K, Monnens L. Source: American Journal of Obstetrics and Gynecology. 1993 March; 168(3 Pt 1): 884-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8456897&dopt=Abstract

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Surreptitious ingestion of a long-acting vitamin K antagonist/rodenticide, brodifacoum: clinical and metabolic studies of three cases. Author(s): Weitzel JN, Sadowski JA, Furie BC, Moroose R, Kim H, Mount ME, Murphy MJ, Furie B. Source: Blood. 1990 December 15; 76(12): 2555-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2265249&dopt=Abstract

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The anticancer effects of vitamin K. Author(s): Lamson DW, Plaza SM. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2003 August; 8(3): 303-18. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12946240&dopt=Abstract

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The early history of vitamin K. Author(s): Almquist HJ. Source: The American Journal of Clinical Nutrition. 1975 June; 28(6): 656-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=805522&dopt=Abstract

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The effect of formula versus breast feeding and exogenous vitamin K1 supplementation on circulating levels of vitamin K1 and vitamin K-dependent clotting factors in newborns. Author(s): Hogenbirk K, Peters M, Bouman P, Sturk A, Buller HA.

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Source: European Journal of Pediatrics. 1993 January; 152(1): 72-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8444211&dopt=Abstract •

The effect of vitamin K and D supplementation on ovariectomy-induced bone loss. Author(s): Matsunaga S, Ito H, Sakou T. Source: Calcified Tissue International. 1999 October; 65(4): 285-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10485979&dopt=Abstract

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The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Author(s): Knapen MH, Hamulyak K, Vermeer C. Source: Annals of Internal Medicine. 1989 December 15; 111(12): 1001-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2556952&dopt=Abstract

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The identification of the vitamin K-dependent bone protein osteocalcin as one of the gamma-carboxyglutamic acid containing proteins present in calcified atherosclerotic plaque and mineralized heart valves. Author(s): Levy RJ, Gundberg C, Scheinman R. Source: Atherosclerosis. 1983 January; 46(1): 49-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6601488&dopt=Abstract

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The pharmacokinetics and lipoprotein fraction distribution of intramuscular vs. oral vitamin K1 supplementation in women of childbearing age: effects on hemostasis. Author(s): Hagstrom JN, Bovill EG, Soll RF, Davidson KW, Sadowski JA. Source: Thrombosis and Haemostasis. 1995 December; 74(6): 1486-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8772225&dopt=Abstract

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Vitamin D(3) and vitamin K(1) supplementation of Dutch postmenopausal women with normal and low bone mineral densities: effects on serum 25-hydroxyvitamin D and carboxylated osteocalcin. Author(s): Schaafsma A, Muskiet FA, Storm H, Hofstede GJ, Pakan I, Van der Veer E. Source: European Journal of Clinical Nutrition. 2000 August; 54(8): 626-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10951511&dopt=Abstract

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Vitamin K and tissue mineralization. Author(s): Vermeer C, Thijssen HH, Hamulyak K. Source: Bibl Nutr Dieta. 2001; (55): 159-70. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11125573&dopt=Abstract

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Vitamin K deficiency. Author(s): Hathaway WE.

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Source: Southeast Asian J Trop Med Public Health. 1993; 24 Suppl 1: 5-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7886607&dopt=Abstract •

Vitamin K in preterm breastmilk with maternal supplementation. Author(s): Bolisetty S, Gupta JM, Graham GG, Salonikas C, Naidoo D. Source: Acta Paediatrica (Oslo, Norway : 1992). 1998 September; 87(9): 960-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9764891&dopt=Abstract

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Vitamin K intake and bone mineral density in women and men. Author(s): Booth SL, Broe KE, Gagnon DR, Tucker KL, Hannan MT, McLean RR, Dawson-Hughes B, Wilson PW, Cupples LA, Kiel DP. Source: The American Journal of Clinical Nutrition. 2003 February; 77(2): 512-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12540415&dopt=Abstract

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Vitamin K prophylaxis in high-dose chemotherapy. Author(s): Elston TN, Dudley JM, Shearer MJ, Schey SA. Source: Lancet. 1995 May 13; 345(8959): 1245. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7739334&dopt=Abstract

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Vitamin K replacement in osteoporosis associated with cirrhosis: another reason to “eat your vegetables”? Author(s): Lipkin EW, Kowdley KV. Source: The American Journal of Gastroenterology. 2002 April; 97(4): 786-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12003410&dopt=Abstract

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Vitamin K status and parenteral nutrition; the effect of Intralipid on plasma vitamin K1 levels. Author(s): Drittij-Reijnders MJ, Sels JP, Rouflart M, Thijssen HH. Source: European Journal of Clinical Nutrition. 1994 July; 48(7): 525-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7956996&dopt=Abstract

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Vitamin K supplementation does not affect ovariectomy-induced bone loss in rats. Author(s): Binkley N, Krueger D, Engelke J, Crenshaw T, Suttie J. Source: Bone. 2002 June; 30(6): 897-900. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052460&dopt=Abstract

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Vitamin K supplementation during prophylactic use of cefoperazone in urologic surgery. Author(s): Rockoff SD, Blumenfrucht MJ, Irwin RJ Jr, Eng RH. Source: Infection. 1992 May-June; 20(3): 146-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1644490&dopt=Abstract

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Vitamin K supplementation in cystic fibrosis. Author(s): van Hoorn JH, Hendriks JJ, Vermeer C, Forget PP. Source: Archives of Disease in Childhood. 2003 November; 88(11): 974-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14612359&dopt=Abstract

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Vitamin K supplementation in patients on continuous ambulatory peritoneal dialysis. Author(s): Vychytil A, Druml W. Source: Lancet. 1998 June 6; 351(9117): 1734-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9734914&dopt=Abstract

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Vitamin K supplementation reduces serum concentrations of under-gammacarboxylated osteocalcin in healthy young and elderly adults. Author(s): Binkley NC, Krueger DC, Engelke JA, Foley AL, Suttie JW. Source: The American Journal of Clinical Nutrition. 2000 December; 72(6): 1523-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11101481&dopt=Abstract

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Vitamin K therapy in severe liver disease. Author(s): Mehta R, Reilly JJ, Olson RE. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 1991 May-June; 15(3): 350-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1865555&dopt=Abstract

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Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Author(s): Braam LA, Knapen MH, Geusens P, Brouns F, Hamulyak K, Gerichhausen MJ, Vermeer C. Source: Calcified Tissue International. 2003 July; 73(1): 21-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506950&dopt=Abstract

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Vitamin K-deficiency bleeding in neonates. Author(s): Kelly D. Source: Journal of Pediatric Gastroenterology and Nutrition. 1999 November; 29(5): 532. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10554118&dopt=Abstract

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Vitamin K-dependent and vitamin K-independent hypocoagulant effects of dietary fish oil in rats. Author(s): Nieuwenhuys CM, Feijge MA, Vermeer C, Hennissen AH, Beguin S, Heemskerk JW. Source: Thrombosis Research. 2001 October 15; 104(2): 137-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11672757&dopt=Abstract

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Vitamin K-dependent carboxylase. Solubilization and properties. Author(s): Esmon CT, Suttie JW.

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Source: The Journal of Biological Chemistry. 1976 October 25; 251(20): 6238-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=977568&dopt=Abstract •

Warfarin antagonism of natto and increase in serum vitamin K by intake of natto. Author(s): Kudo T. Source: Artery. 1990; 17(4): 189-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2360879&dopt=Abstract

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

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

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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

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

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

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

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

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

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

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

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

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

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

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

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

General Overview Amenorrhea Source: Integrative Medicine Communications; www.drkoop.com Bleeding Source: Integrative Medicine Communications; www.drkoop.com

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Body Odor Source: Integrative Medicine Communications; www.drkoop.com Bone Cancer Source: Integrative Medicine Communications; www.drkoop.com Bone Loss Source: Integrative Medicine Communications; www.drkoop.com Bone Marrow Disorders Source: Integrative Medicine Communications; www.drkoop.com Cancer Source: Integrative Medicine Communications; www.drkoop.com Celiac Disease Source: Healthnotes, Inc.; www.healthnotes.com Chronic Myelogenous Leukemia Source: Integrative Medicine Communications; www.drkoop.com Cirrhosis Source: Integrative Medicine Communications; www.drkoop.com Cystic Fibrosis Source: Healthnotes, Inc.; www.healthnotes.com Fecal Odor Source: Integrative Medicine Communications; www.drkoop.com Hemophilia Source: Integrative Medicine Communications; www.drkoop.com Hyperparathyroidism Source: Integrative Medicine Communications; www.drkoop.com Hypoparathyroidism Source: Integrative Medicine Communications; www.drkoop.com Kidney Stones Source: Integrative Medicine Communications; www.drkoop.com Liver Cancer Source: Integrative Medicine Communications; www.drkoop.com Liver Disease Source: Integrative Medicine Communications; www.drkoop.com Menopause Source: Integrative Medicine Communications; www.drkoop.com

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Menstrual Disorders Source: Integrative Medicine Communications; www.drkoop.com Morning Sickness Source: Healthnotes, Inc.; www.healthnotes.com Myelofibrosis Source: Integrative Medicine Communications; www.drkoop.com Myeloproliferative Disorders Source: Integrative Medicine Communications; www.drkoop.com Nausea Source: Prima Communications, Inc.www.personalhealthzone.com Osteoporosis Source: Healthnotes, Inc.; www.healthnotes.com Osteoporosis Source: Integrative Medicine Communications; www.drkoop.com Osteoporosis Source: Prima Communications, Inc.www.personalhealthzone.com Phenylketonuria Source: Healthnotes, Inc.; www.healthnotes.com Polycythemia Vera Source: Integrative Medicine Communications; www.drkoop.com Scleroderma Source: Integrative Medicine Communications; www.drkoop.com Thrombocytosis Source: Integrative Medicine Communications; www.drkoop.com Urinary Odor Source: Integrative Medicine Communications; www.drkoop.com Wounds Source: Integrative Medicine Communications; www.drkoop.com •

Herbs and Supplements Alfalfa Alternative names: Medicago sativa Source: Healthnotes, Inc.; www.healthnotes.com Aminoglycoside Antibiotics Source: Healthnotes, Inc.; www.healthnotes.com

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Aminoglycosides Source: Integrative Medicine Communications; www.drkoop.com Amoxicillin Source: Healthnotes, Inc.; www.healthnotes.com Ampicillin Source: Healthnotes, Inc.; www.healthnotes.com Antibiotic Combination: Sulfa Drugs Source: Integrative Medicine Communications; www.drkoop.com Antibiotics Source: Healthnotes, Inc.; www.healthnotes.com Antibiotics (general) Source: Prima Communications, Inc.www.personalhealthzone.com Anticonvulsants Source: Healthnotes, Inc.; www.healthnotes.com Antituberculosis Agents Source: Integrative Medicine Communications; www.drkoop.com Azithromycin Source: Healthnotes, Inc.; www.healthnotes.com Bile Acid Sequestrant Drugs Source: Prima Communications, Inc.www.personalhealthzone.com Bile Acid Sequestrants Source: Healthnotes, Inc.; www.healthnotes.com Bile Acid Sequestrants Source: Integrative Medicine Communications; www.drkoop.com Bone-Building Formula Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,838,00.html Camellia Sinensis Alternative names: Green Tea Source: Integrative Medicine Communications; www.drkoop.com Cephalosporins Source: Healthnotes, Inc.; www.healthnotes.com Cephalosporins Source: Integrative Medicine Communications; www.drkoop.com

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Cephalosporins Source: Prima Communications, Inc.www.personalhealthzone.com Chlorhexidine Source: Healthnotes, Inc.; www.healthnotes.com Ciprofloxacin Source: Healthnotes, Inc.; www.healthnotes.com Clarithromycin Source: Healthnotes, Inc.; www.healthnotes.com Clindamycin Oral Source: Healthnotes, Inc.; www.healthnotes.com Clindamycin Topical Source: Healthnotes, Inc.; www.healthnotes.com Colestipol Source: Healthnotes, Inc.; www.healthnotes.com Cycloserine Source: Healthnotes, Inc.; www.healthnotes.com Dapsone Source: Healthnotes, Inc.; www.healthnotes.com Dicloxacillin Source: Healthnotes, Inc.; www.healthnotes.com Doxycycline Source: Healthnotes, Inc.; www.healthnotes.com Erythromycin Source: Healthnotes, Inc.; www.healthnotes.com Gentamicin Source: Healthnotes, Inc.; www.healthnotes.com Green Tea Alternative names: Camellia sinensis Source: Integrative Medicine Communications; www.drkoop.com Green Tea Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10032,00.html Isoniazid Source: Healthnotes, Inc.; www.healthnotes.com

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L. Acidophilus Source: Integrative Medicine Communications; www.drkoop.com Lactobacillus Acidophilus Source: Integrative Medicine Communications; www.drkoop.com Levofloxacin Source: Healthnotes, Inc.; www.healthnotes.com Loracarbef Source: Healthnotes, Inc.; www.healthnotes.com Lubricant Laxatives Source: Integrative Medicine Communications; www.drkoop.com Macrolides Source: Healthnotes, Inc.; www.healthnotes.com Macrolides Source: Integrative Medicine Communications; www.drkoop.com Menadione Alternative names: Vitamin K Source: Integrative Medicine Communications; www.drkoop.com Menaphthone Alternative names: Vitamin K Source: Integrative Medicine Communications; www.drkoop.com Menaquinone Alternative names: Vitamin K Source: Integrative Medicine Communications; www.drkoop.com Minocycline Source: Healthnotes, Inc.; www.healthnotes.com Neomycin Source: Healthnotes, Inc.; www.healthnotes.com Nitrofurantoin Source: Healthnotes, Inc.; www.healthnotes.com Ofloxacin Source: Healthnotes, Inc.; www.healthnotes.com Oral Corticosteroids Source: Healthnotes, Inc.; www.healthnotes.com Penicillin Derivatives Source: Integrative Medicine Communications; www.drkoop.com

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Penicillin V Source: Healthnotes, Inc.; www.healthnotes.com Penicillins Source: Healthnotes, Inc.; www.healthnotes.com Phenobarbital Source: Healthnotes, Inc.; www.healthnotes.com Phenobarbital Alternative names: Bellatal, Solfoton Source: Prima Communications, Inc.www.personalhealthzone.com Phenytoin Alternative names: Dilantin Infatab, Dilantin-125 Oral Suspension Source: Prima Communications, Inc.www.personalhealthzone.com Phylloquinone Alternative names: Vitamin K Source: Integrative Medicine Communications; www.drkoop.com Primidone Alternative names: Mysoline Source: Prima Communications, Inc.www.personalhealthzone.com Quinolones Source: Healthnotes, Inc.; www.healthnotes.com Quinolones Source: Integrative Medicine Communications; www.drkoop.com Sulfamethoxazole Source: Healthnotes, Inc.; www.healthnotes.com Sulfasalazine Source: Healthnotes, Inc.; www.healthnotes.com Sulfonamides Source: Healthnotes, Inc.; www.healthnotes.com Tetracycline Source: Healthnotes, Inc.; www.healthnotes.com Tetracycline Derivatives Source: Integrative Medicine Communications; www.drkoop.com Tetracyclines Source: Healthnotes, Inc.; www.healthnotes.com Tobramycin Source: Healthnotes, Inc.; www.healthnotes.com

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Trimethoprim Source: Healthnotes, Inc.; www.healthnotes.com Trimethoprim/Sulfamethoxazole Source: Healthnotes, Inc.; www.healthnotes.com Valproic Acid Source: Healthnotes, Inc.; www.healthnotes.com Warfarin Source: Healthnotes, Inc.; www.healthnotes.com Warfarin Alternative names: Coumadin Source: Prima Communications, Inc.www.personalhealthzone.com

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

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

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

Antagonism between Vitamin K1 and Coumarin Anticoagulants Evidence in Vitro Studies That the Anticoagulant Effect Depends on Inhibition of Vitamin K Uptake by Birnbaum, Henry; AdvDeg from McGill University (Canada), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK07255

•

Characterization of the Putative Vitamin K-Dependent Carboxylase Internal Propeptide Sequence by Lin, Pen-jen; PhD from The University of North Carolina at Chapel Hill, 2003, 61 pages http://wwwlib.umi.com/dissertations/fullcit/3086561

•

Vitamin K(1) and Plasma Clotting Factor Formation: an in Vitro System for the Study of Intra-Cellular Localization and Release by Dworkind, Jack; PhD from McGill University (Canada), 1973 http://wwwlib.umi.com/dissertations/fullcit/NK18198

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

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

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

Vitamin K and Bone Turnover in Postmenopausal Women Condition(s): Osteoporosis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Eisai Medical Research Inc Purpose - Excerpt: This one year study of the K vitamers phylloquinone (K1) and menatetranone (MK4) will study supplementation effects on bone turnover and bone density. Women at least 5 years postmenopause with normal bone density who do not use estrogen therapy or the following medications may be eligible: alendronate (Fosamax) risedronate (Actonel) pamidronate (Aredia) etidronate (Didronel) zoledronate (Zometa) teriparatide (Forteo) raloxifene (Evista) tamoxifene warfarin (Coumadin) anti-seizure medications prednisone oral steroids Eligible subjects will take calcuim and vitamin D (Citracal) twice a day for the first two months and through-out the study. After the first two months, subjects are randomized to the K1, MK4 or placebo groups. Return visits occur at 1, 3, 6 and 12 months. Fasting blood and urine is collected at each visit and bone density is performed at 3 study visits. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00062595

8

These are listed at www.ClinicalTrials.gov.

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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 “vitamin K” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

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

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

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

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

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

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

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

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

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

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

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

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

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

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•

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

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

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CHAPTER 6. PATENTS ON VITAMIN K 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 “vitamin K” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on vitamin K, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Vitamin K By performing a patent search focusing on vitamin K, 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 will tell you how to obtain this information later in the chapter. The following is an 9Adapted

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

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example of the type of information that you can expect to obtain from a patent search on vitamin K: •

1,4,4.sub.a derivative(s)

5,8,9.sub.a

-hexahydro-1.alpha.,4.alpha.-methanoan-thraquinone

Inventor(s): Hamamura; Kimio (Chiba Prefecture, JP), Konishi; Masayuki (Ibaraki Prefecture, JP), Seki; Chiaki (Aichi Prefecture, JP) Assignee(s): Eisai Chemical Co., Ltd. (Ibaraki Prefecture, JP) Patent Number: 5,608,092 Date filed: January 5, 1995 Abstract: The present invention relates to intermediates useful for the preparation of vitamin K derivatives. Excerpt(s): The present invention relates to new industrial processes for the preparation of vitamin K derivatives, which play an important role in the vital body as hematostatic vitamins, and intermediates useful for the preparation thereof. Naphthoquinone derivatives, which are vitamin K derivatives, have heretofore been prepared by reacting 2-methyl-1,4-naphthoquinone (menadione) or the like with an allyl halide derivative by the Friedel-Crafts reaction. Besides, Japanese Patent Application Laid-Open (KOKAI) No. 56935/1985 discloses a process for preparing a naphthoquinone derivative by forming 1,4,4.sub.alpha.,9.sub.a -tetrahydro-9.sub.a.alpha.-methyl-1.alpha.,4.alpha.methanoanthraquinone from 2-methyl-1,4-naphthoquinone and cyclopentadiene, reacting this product with an allyl halide derivative into a 1,4,4.sub.a.alpha.,9.sub.a tetrahydro-9.sub.a.alpha.-methyl-4.sub.a.alpha.-alkenyl-1.alpha.,4.alpha.methanoanthraquinone, and then refluxing the thus-obtained product under heat in a toluene solvent to conduct a Retro Dieis-Alder reaction. Web site: http://www.delphion.com/details?pn=US05608092__ •

Agent for acting upon bone formation disturbances containing alkaline citrates, lactates and/or malates Inventor(s): Dietl; Hans (Bad Aibling, DE) Assignee(s): Orthomol Pharmazeutische Vertriebs GmbH (Langenfeld, DE) Patent Number: 5,985,335 Date filed: November 28, 1997 Abstract: The invention relates to an agent for the prophylaxis and/or therapy of conditions associated with a disorder of bone formation. It contains alkali metal citrates and/or alkali metal lactates and/or alkali metal malates, optionally together with one or more active substances selected from vitamin K, calcium salts and vitamin D. The agent preferably contains potassium citrates and/or sodium citrates or potassium lactates and/or sodium lactates and serves for the prophylaxis and/or therapy of osteoclasis, in particular osteoporosis or osteomalacia. Excerpt(s): The invention relates to an agent for the prophylaxis and/or therapy of conditions associated with a disorder of bone formation. Disorders of bone metabolism, in particular in the form of the occurrence of osteoporosis, are widespread in Western industrial countries. Osteoporosis is a disease which is characterised by disorders of

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osteogenesis and also by intensified osteoclasis. In the case of a disorder of osteogenesis, reduced synthesis of the bone proteins, eg. collagen, elastin, osteocalcin, occurs. There may also be reduced incorporation of calcium and phosphate. Such a diminution of synthesis and/or of incorporation results in osteoporosis or, in some cases, a more intense osteoporosis. Vitamins D and K, for example, are important for protein synthesis and for the incorporation of calcium and phosphate. In the case of osteoclasis, besides calcium, phosphate is also excreted in increased amounts, and in addition the bone proteins decrease. Consequently osteoporosis constitutes a multi-factor phenomenon, with the catabolism of bone mass and the reduction in bone density in the foreground. In this connection the annual rate of catabolism amounts to 1% to 2%; but it may rise to a multiple of this value and becomes dramatic with regard to osteoporosis if it exceeds 3% to 4%. In the case of osteoclasis, calcium, above all, is removed from the bone, which as a result can easily become brittle. Another disease involving a disorder of bone formation is osteomalacia, which is characterised by deficient incorporation of minerals into the normally or exuberantly formed albumin basic skeleton. This results in broad uncalcified osteoid seams and, accompanied by a general increase in the elastic osteoid substance, greater softness of the bones and a tendency for them to become distorted. Web site: http://www.delphion.com/details?pn=US05985335__ •

Aqueous solution containing fat-soluble vitamin K Inventor(s): Ida; Katsumi (Saitama, JP), Ikeuchi; Takayuki (Kounan, JP), Kayano; Masanori (Saitama, JP) Assignee(s): Eisai Co., Ltd. (Tokyo, JP) Patent Number: 5,021,570 Date filed: July 7, 1989 Abstract: An aqueous solution containing fat-soluble vitamin K is prepared by adding vegetable oil(s), gycerol fatty acid ester(s) or sorbitan fatty acid ester(s) in an amount of 0.004 to 5% by weight, based on the whole aqueous solution, to an aqueous solution containing menatetrenone (vitamin K.sub.2) or phytonadione (vitamin K.sub.1) and hydrogenated lecithin. Excerpt(s): This invention relates to an aqueous solution containing fat-soluble vitamin K, which solution contains specified stabilizer(s) and thus remains stable for a prolonged period of time. Vitamin Ks are substances which have activity on blood coagulation and electron transport systems and they have been widely employed clinically. Recently it is desired to provide them in the form of an aqueous solution. A known method for dissolving fat-soluble vitamins in water comprises using nonionic surfactants such as HCO-60 (mfd. by Nikko Chemical K.K.). However this process requires the use of a large amount of the surfactant HCO-60, which sometimes causes the liberation of histamine-like substances when the obtained preparation is to be used as an injection. Furthermore, such a preparation would sometimes cause disorders in the digestive tract and thus induce some undesirable side effects, such as diarrhea, when internally administered. Web site: http://www.delphion.com/details?pn=US05021570__

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Complete nutritional milk compositions and products Inventor(s): Kamarei; A. Reza (Princeton, NJ) Assignee(s): Princeton Nutrition, L.L.C. (Princeton, NY) Patent Number: 6,030,650 Date filed: May 4, 1999 Abstract: Complete nutritional milk compositions and products such as unflavored and flavored milks, yogurts, ice creams and frozen yogurts can be prepared through pasteurization, ultra-pasteurization or sterilization processes. By varying the choice and quantity of nutritional and functional ingredients, compositions which include a milk comprise, per service size: from about 0.1% to about 20% of the daily value of Sodium, Potassium, vitamin A, and vitamin C; from about 0.1% to about 40% of the daily value of Calcium; from about 0.1% to about 20% of the daily value of iron; from about 0.1% to about 30% of the daily value of vitamin D; from about 0.1% to about 20% of the daily value of vitamin E, vitamin K and Thiamine; form about 0.1% to about 30% of the daily value of Riboflavin; from about 0.1% to about 20% of the daily value of Niacin, vitamin B6, Folate, vitamin B12, Biotin, and Pantothenic acid; from about 0.1% to about 30% of the daily value of Phosphorus; and from about 0.1% to about 20% of the daily value of Iodine, Magnesium, Zinc, Selenium, Copper, Manganese, Chromium, Molybdenum, and Chloride; wherein the percent daily value (D.V.) is based on a 2,000 calorie diet. Excerpt(s): This invention relates to the field of complete nutritional compositions and products and more particularly to complete nutritional milk compositions and products which are prepared using pasteurization, ultra-pasteurization or sterilization processes. This invention further relates to the preparation of complete nutritional unflavored or flavored milks, ice creams and yogurts. Nutrition is one of the cornerstones of health, well-being, and the prevention of numerous chromic diseases. Nutritional products play an important role in these areas and attempts to provide readily available and convenient nutritional products to the general public has been a major focus in recent years. To remain healthy one must receive essential nutrients which are indispensable to human nutrition. Essential nutrients include both macronutrients, such as fats, carbohydrates and proteins, and micronutrients, such as vitamins and minerals (including trace elements and electrolytes). Table 1 shows a list of essential macronutrients and micronutrients and corresponding percent daily value (D.V.) of these essential nutrients based on a 2,000 calorie diet as currently specified by governmental regulations, 21 C.F.R. 101.9, 1998. Electrolytes include sodium, potassium and chloride. Nutritionally compete and balanced foods are important for ensuring that the public receives all essential nutrients. The public should not be encouraged to receive incomplete or imbalanced nutrition with food or liquids that are perceived or marketed to have nutritional benefits. Consumption of nutritionally incomplete foods or liquids that do not contain all the essential nutrients as listed in Table 1 will not necessarily provide complete nutritional well-being. Furthermore, a nutritionally imbalanced product can result in over consumption or under consumption of essential nutrients because some nutrients are presented in very high concentrations while other nutrients are presented in very low concentrations. A balance of essential nutrients, especially micronutrients, is often recommended for optimal nutritional well-being. Web site: http://www.delphion.com/details?pn=US06030650__

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Composition containing diosgenin Inventor(s): Clayton; Paul Rodney (London, GB) Assignee(s): The Boots Company PLC (Nottingham, GB) Patent Number: 5,968,917 Date filed: July 13, 1998 Abstract: Method of treating osteoporosis according to the present invention comprises the administration to a subject in need thereof a therapeutically effective amount of diosgenin, a therapeutically effective amount of vitamin K and a therapeutically effective amount of vitamin D. Excerpt(s): The present invention relates to the prevention and treatment of osteoporosis and to compositions for use in such prevention or treatment. Compositions for the prevention and treatment of osteoporosis according to the present invention comprise a therapeutically effective amount of diosgenin, a therapeutically effective amount of vitamin K and a therapeutically effective amount of vitamin D. Optionally the composition also contains a therapeutically effective amount of vitamin B6 and/or vitamin A. Method of preventing or treating osteoporosis according to the present invention comprises the administration to a subject in need thereof a therapeutically effective amount of diosgenin, a therapeutically effective amount of vitamin K and a therapeutically effective amount of vitamin D. Optionally the method of the present invention also comprises the administration of a therapeutically effective amount of vitamin B6 and/or vitamin A. The diosgenin, vitamin K, vitamin D and optional vitamins B6 and A may be administered simultaneously or sequentially. For simultaneous administration the components may be combined into a single dosage form or may be formulated into several dosage forms which are intended to be taken at the same time. Web site: http://www.delphion.com/details?pn=US05968917__

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Daily vitamin and mineral supplement for women Inventor(s): Sultenfuss; Sherry (102 Harbor View La., Largo, FL 34640) Assignee(s): none reported Patent Number: 5,514,382 Date filed: October 17, 1994 Abstract: A daily vitamin and mineral supplement for women comprising vitamin A, beta-carotene, niacin, riboflavin, pantothenic acid, pyridoxine, cyanocobalamin, biotin, para-aminobenzoic acid, inositol, choline, vitamin C, vitamin D, vitamin E, vitamin K, boron, calcium, chromium, copper, iodine, iron, magnesium, manganese, molybdenum, selenium, zinc and bioflavonoid. For women up to 40 years of age, iron is included. For women over 40 years of age, iron is optionally included. Excerpt(s): The present invention relates to a daily vitamin and mineral supplement for women and more particularly pertains to providing the necessary nutrients for allowing women to maintain their present health and positively influence their future health with a daily vitamin and mineral supplement. The use of vitamin and mineral supplements for women is known in the prior art. More specifically, vitamin and mineral supplements for women heretofore devised and utilized for the purpose of providing necessary daily nutrients are known to consist basically of familiar, expected and

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obvious structural configurations, notwithstanding the myriad of designs encompassed by the crowded prior art which have been developed for the fulfillment of countless objectives and requirements. While prior art supplements fulfill their respective, particular objective and requirements, the aforementioned patents do not describe a daily vitamin and mineral supplement for women that is specifically formulated to provide the necessary nutrients for allowing a women to maintain her present health and positively influence her future health. In this respect, the daily vitamin and mineral supplement for women according to the present invention substantially departs from the conventional concepts and designs of the prior art, and in doing so provides an apparatus primarily developed for the purpose of providing the necessary nutrients for allowing women to maintain their present health and positively influence their future health. Web site: http://www.delphion.com/details?pn=US05514382__ •

Derivatives based upon pyrido-menadione adducts and use thereof as feed premixes Inventor(s): Bruschi; Enrico (Genoa, IT) Assignee(s): Heterochemical Corporation (Valley Stream, NY) Patent Number: 4,808,602 Date filed: February 9, 1987 Abstract: Novel adducts of menadione with pyridine derivatives, said compounds having vitamin B.sub.6 activity and vitamin K activity, and being useful in animal feed premix and animal feed compositions. Excerpt(s): The present invention relates to novel adducts of menadione with a derivative of pyridine such as pyridoxine, pyridoxal or pyridoxamine, which adduct has vitamin B.sub.6 activity and vitamin K activity, and is useful in animal feed premix and compositions. It has long been known that among the vitamin K active substances (VKAS) menadione sodium bisulfite (MSB), the adduct of of sodium bisulfite and menadione (2-methyl-1,4-naphthoquinone) provides better vitamin K (antihemorrhagic) activity on an equal weight basis than menadione itself. Menadione is one of the first synthetic analogues of the natural vitamin K's of vegetable or animal origin. This quality has been partially explained on the basis of the high water solubility of the adduct (menadione is oil soluble) and the consequently easier and more effective absorption into the organism receiving this form of VKAS. Web site: http://www.delphion.com/details?pn=US04808602__

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Dietary food enhancement agent Inventor(s): Bangs; William E. (Philadelphia, PA), Khoo; Chor San Heng (Mt. Laurel, NJ), Ko; Sandy (Abington, PA) Assignee(s): Campbell Soup Company (Camden, NJ) Patent Number: 6,039,978 Date filed: September 20, 1996 Abstract: The invention is a dietary food enhancement agent for fortifying food products. The agent includes a premixed combination of Vitamin A, Vitamin B.sub.1, Vitamin B.sub.2, Vitamin B.sub.6, Vitamin B.sub.12, Vitamin C, Vitamin D, Vitamin E,

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Vitamin K, Biotin, Calcium, Copper, Folic Acid, Iodine, Iron, Magnesium, Manganese, Pantothenic Acid, Phosphorus, and Zinc. Further, calcium may be supplied by a combination of calcium citrate and dicalcium phosphate, the phosphorus is supplied by a combination of dicalcium phosphate and magnesium phosphate, and the magnesium is supplied by magnesium phosphate. Excerpt(s): This invention relates generally to therapeutic systems and methods for dietary health management, i.e., the prevention, treatment, or reduction of risk factors associated with diet-responsive conditions, or a combination thereof In particular, it relates to systems providing a choice of prepackaged, easy to prepare, and good tasting, therapeutic meals which are intended to improve the health and quality of life of patients utilizing the system. Further, it relates to the fortification of meals and food products for use with such a system. As confirmed by clinical trials, the systems and methods disclosed herein achieve improvements in quantifiable indicators of dietresponsive conditions, improved quality of life, and a high degree of compliance. People have become increasingly aware of the importance of a proper diet for health maintenance and disease prevention and treatment. Unfortunately, because numerous different and often conflicting dietary guidelines are presented in such complex manners, it is often very difficult for a person attempting to follow a diet for health and disease management (hereinafter a "patient") to understand and fully and effectively implement a healthy diet. For example, a diet which maximizes health and disease management concerns might control the intake of simple sugars, cholesterol, and different quantities and types of fat, as well as calories, while also attempting to optimize levels of macro- and micronutrients, e.g., protein, carbohydrates, and fat, and vitamins and minerals, and to provide adequate dietary fiber. As suggested above, however, the problem of planning and maintaining a healthful diet goes beyond the usual health concerns and exists with respect to special diet situations, including those associated with diet-responsive conditions, such as cardiovascular disease (hypertension and hyperlipidemia), diabetes and cancer. Diet planning assistance available to patients has been of limited value and often fails to satisfy long term compliance. Much additional planning has been left in the hands of patients who usually lack sufficient knowledge in the field of nutrition to fully and properly implement an adequate diet plan as part of a system or method for health management. More specifically, prior approaches to the planning and maintenance of a patient's diet have supplied the patient with general food and beverage categories to be consumed or avoided: for example, meat, eggs, and fish; fruits and vegetables; breads and cereals; and dairy products. Such approaches generally fail to achieve their desired goal, however, because patients do not consume general food and beverage categories; instead, they consume complex meals composed of specific foods and beverages. Even within these broad categories, specific foods and beverages are so diverse that it is often difficult for patients to convert the broad categories into meals, i.e., to plan actual diets, while still maintaining adequate consumption of protein, carbohydrates, fat, sugars, cholesterol, fiber and other macro- and micronutrients meeting the dietary guidelines. Web site: http://www.delphion.com/details?pn=US06039978__

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External ophthalmic preparation containing vitamin D Inventor(s): Kita; Kiyoshi (4-4-7-502 Honmachi, Shibuya-ku, Tokyo 151, JP) Assignee(s): none reported Patent Number: 6,162,801 Date filed: February 12, 1998 Abstract: An ophthalmic composition, containing ergocalciferol or cholecalciferol, i.e., an inactive vitamin D, as the active ingredient, for treating and conditioning damaged tissue of the region of the eye. An ophthalmic composition for preventing and treating disturbed metabolism in eye tissues, such as "dry eye", including a vitamin D or an active vitamin D as the active ingredient. An ophthalmic composition or a dermatological composition for protecting the skin or eyes from harmful ultraviolet radiation including a vitamin D or a vitamin K as the active ingredient. The ophthalmic composition normalizes the transparency or refraction of the eyeballs when administered to the region of the eye, and contributes to the amendment, healing or prevention of symptoms due to disturbed metabolism in eye tissue. The dermatological composition protects the skin and scalp from harmful ultraviolet radiation. It is possible to supply vitamin D to the skin by applying the vitamin D-containing dermatological composition via a cosmetic. Excerpt(s): This invention relates to ophthalmic or dermatological compositions for external use, and more specifically, to such external medicines when used for the purpose of mediating healing of injured ocular tissue or treating ophthalmic diseases with ophthalmic compositions containing vitamin D (ergocalciferol or cholecalciferol), or for the purpose of protecting ocular tissue or skin from harmful ultraviolet rays with ophthalmic or dermatological compositions containing vitamin D or vitamin K. Vitamin D2, which is refined from vitamin D1 containing other isomers and is highly antirachitic, and vitamin D3, which was researched after vitamin D2, are often used today for the treatment of patients suffering from rickets, osteomalacia, osteoporosis, osteatis fibrosa, osteosclerosis and other bone diseases, malignant tumors such as breast and colon cancers, and skin diseases such as psoriasis. In general, the term "vitamin D" by itself is used to refer to highly antirachitic vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). In general, the ultraviolet (UV) light absorption spectra of vitamin D and active vitamin D have absorption maxima near 265 nm, with molar absorption coefficients of about 18,000. Their UV light absorption bands are in the 240-290 nm range. For example, ergocalciferol, 25-monohydroxyvitamin D2, 1alpha,25dihydroxyvitamin D2, 24,25-dihydroxyvitamin D2 and others have UV light absorption spectra with maxima near 265 nm, and molar absorption coefficients of about 18,900. In addition to these vitamins, provitamin D and previtamin D also have similar UV light absorption spectra. The provitamins D ergosterol and 7-dehydrocholesterol have respective molar absorption coefficients of 11,000 and 10,920, and UV light absorption spectra with maxima at 271, 281 and 293 nm. The previtamins D pre-ergocalciferol and pre-cholecalciferol both have molar absorption coefficients of 9,000 and UV light absorption spectra with absorption maxima at 260 nm. Web site: http://www.delphion.com/details?pn=US06162801__

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High yield production of active Factor IX Inventor(s): Kaufman; Randal J. (Boston, MA), Shoemaker; Charles B. (Belmont, MA), Wasley; Louise C. (West Roxbury, MA) Assignee(s): Genetics Institute, Inc. (Cambridge, MA) Patent Number: 4,770,999 Date filed: May 5, 1986 Abstract: High yields of active Factor IX are produced by culturing a CHO cell line transfected with chromosomally-integrated Factor IX cDNA in medium to which vitamin K is added. Excerpt(s): This invention relates generally to the cloning and expression in high yield of Factor IX, and more particularly, to the production of biologically-active Factor IX by means of culturing mammalian cells into media containing vitamin K which Factor IX cDNA has been chromosomally-integrated. The plasma glycoprotein, Factor IX, plays a critical role in the blood-clotting process. Normally synthesized in the liver, Factor IX requires vitamin K activity for the.gamma.-carboxylation of its 12 amino-terminal glutamic acid residues. A deficiency of Factor IX in the body characterizes a type of hemophilia (type B). Treatment of this disease is presently limited to intravenous tranfusion of human plasma protein concentrates of Factor IX. However, in addition to the practical disadvantages of time and expense, transfusion of blood concentrates involves the risk of transmission of viral hepatitis, acquired immune deficiency syndrome or thromboembolic diseases to the recipient. An alternative method of producing Factor IX, other than extraction from human plasma, is therefore highly desirable. The application of recombinant DNA techniques to the production of Factor IX has elicited considerable information about the protein. The cDNA coding for human Factor IX has been isolated, characterized, and cloned into expression vectors. See, e.g., K. H. Choo et al, "Molecular Cloning of the Gene for Human Anti-hemophilic Factor IX', Nature, Vol. 299: 178-180 (September 1982) and K. Kurachi et al, "Isolation and Characterization of a cDNA Coding for Human Factor IX," Proc. Natl. Acad. Sci. U.S.A., Vol. 79: 6461-65 (November 1982). Web site: http://www.delphion.com/details?pn=US04770999__

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Immunoassay for vitamin K-dependent bone protein Inventor(s): Nishimoto; Satoru K. (Bristol, CT), Price; Paul A. (San Diego, CA) Assignee(s): The Regents of the University of California (Berkeley, CA) Patent Number: 4,410,506 Date filed: March 24, 1981 Abstract: Immunoassay and compositions therefore for detection of human vitamin Kdependent bone protein. Heterologous labeled vitamin K-dependent protein or antigenic fragment thereof is employed with antibodies to the protein in an assay for the protein in various physiological fluids for bone extracts. The assay may be used in the diagnosis of bone diseases, by itself or in conjunction with an alkaline phosphatase assay. Excerpt(s): The assessment of bone metabolism and bone disease remains a difficult problem in clinical medicine. The measurements of alkaline phosphatase in blood and hydroxyproline in urine have been the most widely used biochemical tests for this

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purpose. Although these measurements are of considerable clinical value, each has its limitations. Alkaline phosphatase is not a specific reflection of bone function, because its concentration in blood is also contributed to by the liver, gastrointestinal tract, placenta, certain tumors, and perhaps other sources. Hydroxyproline is similarly not specific for bone because it can be influenced by diet and nonosseous as well as osseous collagen. It would therefore be of substantial value to have an assay which could be used in the specific diagnosis of bone related diseases, either independently or as a confirmation of other diagnostic factors. An abstract of a paper by Price et al. was published in June, 1979, for the meeting of the American Society For Bone And Mineral Research. Price and Nishimoto, Proc. Natl. Acad. Sci. USA 77, 2234-2238 (1980) and Price et al., J. Clin. Invest. 66, 878-883 (1980) both describe the subject invention. The references cited in the aforementioned references should also be noted. Web site: http://www.delphion.com/details?pn=US04410506__ •

Immunoassay means and methods useful in human native prothrombin and human abnormal prothorombin determinations Inventor(s): Blanchard; Rita A. (Newton, MA), Furie; Barbara C. (Wellesley, MA), Furie; Bruce E. (Wellesley, MA) Assignee(s): New England Medical Center Hospitals, Inc. (Boston, MA) Patent Number: 4,769,320 Date filed: October 15, 1984 Abstract: Antibodies which form immune complexes with human native prothrombin only, in the presence of mixtures of human native prothrombin and human abnormal prothrombin as well as antibodies which form antibody antigen complexes with human abnormal prothrombin in the presence of such mixtures have been obtained. Immunoassay techniques are used for qualitative and quantitative determinations of these antigens in human plasma or serum. Unique methods of obtaining the antibodies are described including obtaining antibodies to native prothrombin by dissociation of antigen antibody complexes formed in the presence of calcium ions with a material having a greater affinity constant for binding with calcium ions than does prothrombin. Dissociation of the complex in this manner yields human native prothrombin antibodies which are specific and non-reactive with human abnormal prothrombin. A process is described in which assays are applied to the sensitive detection of vitamin K deficiency and various forms of liver disease including hepatocellular carcinoma, and to monitoring of anticoagulant therapy with sodium warfarin. The invention described herein was made in the course of working under a grant from the Department of Health and Human Services. Excerpt(s): Prothrombin is a vitamin K dependent plasma protein involved in the final stages of blood coagulation as has been well-known for some time. It has a molecular weight of about 72,000 and contains about 12% carbohydrate. Prothrombin is a calciumbinding protein that undergoes a conformational transition in the presence of calcium as is known. The proteolytic activation of prothrombin to thrombin is a critical step in normal hemostasis. Prothrombin is synthesized in the liver where a prothrombin precursor undergoes post-translational modification to yield the functional form of prothrombin which is known as "native prothrombin" and contains.gamma.carboxyglutamic acid. In the presence of vitamin K antagonists, such as sodium warfarin also known as Coumadin, a trademarked product of Endo Laboratories division of DuPont Corp. of Wilmington, Del., or in the absence of vitamin K, the

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prothrombin activity in the blood may be significantly diminished. This can be measured indirectly by the prothrombin time, a one-stage coagulation assay, or by direct measurement of prothrombin coagulant activity using prothrombin deficient substrate plasma. Severe liver disease may also be associated with low plasma prothrombin activity. Thus impaired synthesis of protein (liver disease), inadequate supplies of vitamin K (vitamin K deficiency) or drugs that inhibit the action of vitamin K (sodium warfarin) lead to diminished plasma prothrombin activity in humans and other mammals. Coumadin is the trade name for warfarin. When Coumadin is used as an oral anticoagulant as is widely done in the therapy or prevention of thrombotic disease, it lowers the activity of vitamin K dependent blood coagulation proteins such as prothrombin. The appropriate Coumadin dose is established by monitoring the prothrombin time. The prothrombin time is maintained at one and a half to two and a half times that obtained with normal plasma. In 1968 an altered from of prothrombin known as "abnormal prothrombin" and "human abnormal prothrombin" as opposed to human native prothrombin was discovered in the plasma of human patients treated with sodium warfarin. Abnormal prothrombin has low prothrombin activity but cross reacts with many prothrombin antisera. Abnormal prothrombin from bovine blood was first isolated in 1972. Such abnormal prothrombin was found to have about 3% of the coagulant activity of an equivalent amount of native prothrombin. Otherwise, the molecular weight, carbohydrate composition and amino acid composition of the acid hydrolysate were substantially identical within experimental error. In the early 70's it was discovered that bovine abnormal prothrombin unlike prothrombin does not bind to barium salts and does not bind to calcium ions. It was subsequently shown that the functional differences between abnormal and native prothrombin relate to the structural differences between these proteins and full prothrombin function requires intact calcium binding sites. In the mid-70's it was discovered that a theretofore unknown amino acid.gamma.-carboxyglutamic acid occurred in bovine prothrombin and was lacking in abnormal bovine prothrombin. This amino acid seemed to be required for the full expression of prothrombin coagulant activity. Abnormal prothrombin is known to have no coagulant activity, does not bind metal ions and does not contain.gamma.carboxyglutamic acid. Other researchers have theorized that prothrombin is synthesized in the liver in a precursor form containing glutamic acid instead of.gamma.carboxyglutamic acid. A carboxylation process in the liver modifies glutamic acid to form.gamma.-carboxyglutamic acid. This enzyme system requires vitamin K and is inhibited by vitamin K antagonists. Web site: http://www.delphion.com/details?pn=US04769320__ •

In vivo treatment of mycobacterial infections with 6-cyclo octylamino-5,8-quinoline quinone Inventor(s): Gangadharam; Pattisapu R. J. (Denver, CO) Assignee(s): National Jewish Center for Immunology and Respiratory Medicine (Denver, CO) Patent Number: 4,963,565 Date filed: July 30, 1986 Abstract: 6-cyclo-octylamino-5,8-quinoline quinone, a Vitamin K analogue, shows surprising efficacy as an in vivo therapeutic agent for treatment of tuberculosis and leprosy. Mycobacteria species, intracellulare, tuberculosis, and leprae are inhibited following administration of the compound in any form.

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Excerpt(s): This invention relates to the field of treatment of bacterial infections, and diseases caused thereby. Specifically, mycobacterial infections caused by Mycobacterium tuberculosis and related organisms are treated. Various diseases are caused by infections by foreign bacteria. An exhaustive list of such diseases and their causative agents is not possible, but one such example is tuberculosis, caused by Mycobacterium tuberculosis. Mycobacterium intracellulare is another pathogen causing disease in humans, more so in immune compromised individuals and those with Acquired Immune Deficiency Syndrome (AIDS). Current research in the field has focused on compounds which are bactericidal and non-toxic to treat diseases caused by these organisms. Of special significance is the fact that at present no specific drugs are available to treat disease caused by M. intracellulare group of organisms. The rifamycin family of antibiotics has received particular attention in this regard. For example, U.S. Pat. No. 4,086,344, discloses N,15-Didehydro-15-deoxo-3,15-epi (methano alkyl amino) rifamycins, in quinone or hydroquinone form. These compounds are only used in in vitro tests, however. While results which show biocidal activity in vitro can be applied for the development of, e.g., cleaning solutions, disinfectants, and so forth, in vitro efficacy is no guarantee that the subject compound will work in vivo. Web site: http://www.delphion.com/details?pn=US04963565__ •

Method for the isolation and purification of vitamin K-dependent proteins Inventor(s): Dorner; Friedrich (Vienna, AT), Fischer; Bernhard (Vienna, AT), Mitterer; Artur (Orth/Donau, AT) Assignee(s): Immuno Aktiengesellschaft (Vienna, AT) Patent Number: 5,633,350 Date filed: February 27, 1995 Abstract: A method for the separation of vitamin K-dependent proteins from nonvitamin K-dependent accompanying proteins is described wherein the method is characterized in that at least anion exchange chromatography and optionally affinity chromatography is carried out as well. The method is suitable especially for the purification of Factor II, VII, IX, X as well as Protein S, Protein C and Protein Z. With the aid of the method according to the invention a vitamin K-dependent protein is obtained which is present at a purity of 95%. Excerpt(s): Aside from the naturally occurring proteins, it is possible today, with the aid of gene technology methods, to produce mammalian proteins by recombinant techniques, especially human proteins. For this purpose, host cells transformed or transfected with foreign DNA are cultured, wherein in the case of eucaryotic host cells the recombinantly produced protein is released in soluble form into the cell culture medium (R. G. Werner and W. Berthold, Arzneim.-Forsch. Drug Res. 38, 422-428 (1988)). However, since the host cells also release other proteins into the cell culture medium in addition to the desired recombinantly produced protein, it is necessary to enrich and/or isolate the desired protein in one or more purification steps. Concerning this, methods are needed which effectively and selectively permit the isolation of recombinant proteins from the cell culture medium. As a rule, physical and chemical properties of the proteins are used for the purification of recombinant proteins. Such properties are the size of the proteins, the natural charge of the surface, their hydrophilicity or solubility. Additional purification methods concern the binding with other molecules, such as for example antibodies. The same applies for the purification of proteins from natural sources. Here as well, based on the physical and chemical properties of a protein, a

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separation of the same occurs from the remaining accompanying proteins. Vitamin Kdependent proteins were purified so far according to such methods as protein precipitation, ion exchange chromatography and gel filtration M. Bertina and J. J. Veltkamp, Haemostasis and Thrombosis, (Ed. A. L. Bloom and D. P. Thomas, Churchill Livingstone, New York, 1987, 116-130). B. Dahlb ack (Biochem. J. 209, 837-846 (1983)) describes a purification method for Protein S (PS). After a barium citrate precipitation, PS is isolated on DEAE-Sephacel. J. Malm et al., (Eur. J. Biochem. 187, 737-743 (1990)) purified recombinant PS (rPS) by affinity chromatography on a monoclonal antibody. Factor IX (FaIX) was isolated by B. Osterud and R. Flengsrud (Biochem. J. 145, 469-474 (1975)) by barium sulfate precipitation and ion exchange chromatography on cellulose. Monoclonal antibodies were used by H. C. Kim et al., (Sem. Hematol. 28(3) Suppl. 6, 1519 (1991) for the purification of FaIX. Web site: http://www.delphion.com/details?pn=US05633350__ •

Method for the purification of vitamin K-dependent proteins Inventor(s): Yan; S. Betty (Indianapolis, IN) Assignee(s): Eli Lilly and Company (Indianapolis, IN) Patent Number: 4,981,952 Date filed: August 16, 1989 Abstract: The recovery of vitamin K-dependent proteins produced by transformed microorganisms can be effected from the cell culture medium utilizing the changes in the protein which occur in the presence of divalent cations. The present process uses divalent cations to alter the binding affinity of the proteins and thereby selectively elute the proteins away from contaminants in the culture medium using standard chromatography. Excerpt(s): A large number of human and other mammalian proteins, including, for example, human growth hormone, human protein C and clotting Factor VII, have been produced in host cells by transfecting these cells with DNA encoding these proteins and growing the recombinant cells under conditions favorable for the expression of the protein. Grinnell et al. describe the expression of recombinant human protein C (HPC) by human kidney cells in Biotechnology, 5:1189-1192 (1987). The proteins are secreted by the cells into the cell culture medium, and must be separated from the culture medium and the other components, such as cell waste products, cell debris and proteins or other material, which also has collected in the medium. In addition, the biological activity of the protein must be preserved, so the recovery conditions must be mild enough to preserve the biological activity of the protein, but, at the same time, thorough enough to effectively separate the protein from contaminants in the medium. Purity is often an important consideration, especially for pharmaceutical applications. Recovery of proteins in biologically active form from cell culture medium presents a number of problems. For example, the desired protein must be separated from other closely related proteins in the cell culture medium, such as homologous, biologically inactive proteins, which may be associated with the protein. The recovery process should yield the biologically active form of the protein with a high level of purity. Jones et al. describe a method for recovering refractile proteins (non-exported proteins which form insoluble protein granules within the host cell) from the cytoplasm of a host cell in U.S. Pat. No. 4,512,922. Related patents describing denaturing-refolding protein recovery systems include U.S. Pat. Nos. 4,599,197; 4,518,526; and 4,511,503.

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Web site: http://www.delphion.com/details?pn=US04981952__ •

Method of determination of pivka Inventor(s): Iwasaki; Yoshihiro (Tokyo, JP), Naraki; Toru (Chiba, JP), Watanabe; Keisuke (Ibaraki, JP) Assignee(s): Eisai Co., Ltd. (Tokyo, JP) Patent Number: 5,516,640 Date filed: April 18, 1994 Abstract: To provide a simple immunochemical assay of a PIVKA of every kind (PIVKA-VII, -IX, -X, -C, -S or -Z: protein induced by vitamin K absence) corresponding to a vitamin K-dependent protein. It has been confirmed that a PIVKA of every kind can be determined according to the double antibody sandwich method wherein use is made of a solid-supported anti-PIVKA-II monoclonal antibody. There is also disclosed a reagent for determination of a PIVKA of every kind according to the above-mentioned method. Excerpt(s): The present invention relates to The immunochemical assay of a PIVKA of every kind present in an organic specimen and a reagent therefor, which are utilized in the medical field. Vitamin K-dependent plasma proteins present in organisms include prothrombin, factor VII, factor IX, factor X, protein C, protein S, and protein Z. According to biosynthesis mechanisms of these proteins, a precursor protein is carboxylated at the.gamma.-positions of about 10 glutamic acid residues thereof in the presence of vitamin K and a carboxylase to be converted into an active-form normal protein, which manifests the physiological action thereof. These glutamic acid residues are present in the N-terminal region, which is referred to as the "Glaregion." In a state of physiological or clinical deficiency of vitamin K or in a state of suppressed action of vitamin K through administration of a vitamin K antagonist, proteins with incomplete carboxylation of those glutamic acid residues are formed. The clinical usefulness of the determination of PIVKA is that PIVKA is produced in blood as a result of the abovementioned incomplete.gamma.-carboxylation in a state of vitamin K deficiency or suppression. Thus, the determination of PIVKA as a marker of the state of vitamin K deficiency or suppression is of clinical importance. It has recently been found out that various PIVKAs are produced in blood as a result of hepatocellular carcinoma. Since PIVKA-II is very often produced in patients with hepatocellular carcinoma who are negative for.alpha.-fetoprotein, which has been believed to be a good marker for hepatocellular carcinoma, it is recognized that clinical usefulness of PIVKA-II is equal to that of.alpha.-fetoprotein. The following publications (1) to (4) report on the relationship between various PIVKAs and vitamin K and hepatocellular carcinoma. Web site: http://www.delphion.com/details?pn=US05516640__

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Method of treating blood vessel disorders of the skin using vitamin K Inventor(s): Elson; Melvin L. (Nashville, TN) Assignee(s): Mayapple Holdings, LLC (Burns, TN) Patent Number: 5,510,391 Date filed: October 22, 1993

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Abstract: A vitamin K mixture is used in a topical application for the treatment of blood vessel disorders of the skin which include, but are not limited to, actinic and iatrogenic purpura, lentigines and other vascular problems of the skin and subcutaneous tissue. The formulation of the mixture includes a number of the following substances: vitamin K, 95% ethyl alcohol SD40, isopropyl alcohol 99%, benzyl alcohol, lecithin granules, isopropyl palmitate NF, propyl paraben, methyl paraben, Pluronic F-127 NF, Dowicil 200 and preserved water. The concentrations of the substituent compounds vary in the different formulations of the vitamin K cream. Excerpt(s): Treatment of vascular problems of the skin and subcutaneous tissue is a major area of dermatological therapy given the increasingly large aging population. A number of dermatological conditions which involve blood vessel disorders of the skin and skin disorders caused by photoaging include actinic and iatrogenic purpura, lentigines, telangiectasias of the face, spider angiomas, spider veins of the face, spider veins of the legs as well as other vascular problems of the skin and subcutaneous tissue. There is currently no treatment for actinic or iatrogenic purpura and the only treatment for spider veins is surgical. Thus, treatments for these various blood vessel disorders of the skin are clearly limited at best. The present invention relates to a new composition and method of treating blood vessel disorders of the skin using vitamin K. I have discovered that disorders of the skin which respond to treatment by use of vitamin K include but are not limited to actinic and iatrogenic purpura, lentigines, telangiectasias of the face, spider angiomas, spider veins of the face, spider veins of the legs and other vascular problems of the skin and subcutaneous tissue. Vitamin K is necessary for the production via the liver of active prothrombin (Factor II), proconvertin (Factor VII), plasma thromboplastin component (Factor IX) and Stuart Factor X. Vitamin K is found in the form of vitamin K-1 (produced by green leafy vegetables) and vitamin K-2 (produced by gastrointestinal bacteria). In addition, vitamin K analogs have been synthesized and currently include vitamins K-3, K-4, K-5, K-6 and K-7. Naturally occurring in many foods, especially green leafy vegetables, the minimum daily requirement for vitamin K-1 has not been established. Most data accumulated regarding hypovitaminosis K is in the newborn. Guillamoont, Sann et al reported in the Journal of Pediatric Gastroenterology and Nutrition that hepatic phylloquinone storage at birth was poor (<1 microgram) and that the newborn infant might be in a situation of potential deficiency and prophylactic administration of the vitamin would be essential in neonatal surgical situations to prevent excessive bleeding. This deficiency in the new born period is due to two factors--the only sources are green leafy vegetables (for vitamin K1) and synthesis (of vitamin K2) by gastrointestinal bacteria, which are not yet established in the newborn. Web site: http://www.delphion.com/details?pn=US05510391__ •

Method of treating ulcerative colitis Inventor(s): Bennet; Justin D. (4803 Hart Dr., San Diego, CA 92116) Assignee(s): none reported Patent Number: 4,617,317 Date filed: October 31, 1984 Abstract: A method of treating and/or preventing ulcerative colitis in humans by daily administering of between 1-6 grams of biological antagonists of Vitamin K generated either in vivo or in vitro by oxidation of tocopherols.

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Excerpt(s): Ulcerative colitis is a chronic, inflammatory disease associated with inflammation of the mucosa of the colon, often starting in the distal portion of the colon, and most frequently affecting individuals ranging in age from 14-40. The most common symptoms are bloody diarrhea accompanied by severe cramps and high fever. Hemorrhage, perforation of the colon, and peripheral arthritis are potential complications. At present neither the cause nor an effective non-surgical method of treating the disease are known. Depending on whether the stage of the disease is classified as mild, moderate, moderately severe, or severe, the strategies for treating it differ. For mild attacks treatment is focused on controlling diarrhea usually with diphenoxylate. Moderate and moderately severe forms of the disease are treated with antibiotics, generally sulfasalazine and/or with corticosteroids respectively. Severe attacks of the disease require hospitalization, drug therapy and in extreme situations colectomy if there is massive hemorrhaging or perforation of the colon. The only known cure for severe ulcerative colitis is complete proctocolectomy, but unfortunately, the patient pays a high price as ileostomy is necessary. While the cause of ulcerative colitis is unknown several lines of evidence suggest that one or more metabolic by-products secreted by bacteria endogenous to the gut may be responsible. The theory that bacteria are involved has its roots in epidemiological studies which have linked colon cancer to ulcerative colitis. For example, work by Greenstein et al in Gastroenterology, Vol. 77, p. 290 (1979), shows that a high percentage of patients that suffer from ulcerative colitis subsequently develop colon cancer. Because of the association of colon cancer and ulcerative colitis it is probable that both diseases are caused by the same or similar bacterial metabolic by-products. As discussed by Hill in Cancer, Vol. 36, p. 2387 (1975), colon cancer is thought to be due to metabolic conversion of bile acids into carcinogens by bacteria as the bile acids pass through the colon. The link between bile acids and colon cancer is supported by the observation that the risk of developing colon cancer is greater in people that ingest large amounts of fats. Excessive fat, as discussed by Howell in J. Chronic Dis., Vol. 28, p. 67 (1975), stimulates the production and subsequent secretion of bile acids into the gut. The chemical reactions necessary to carry out the conversion of bile acids into potential carcinogens are known, and have been described by Hill in Cancer, Vol. 36, p. 2387 (1975), and Goddard et al in J. Med. Microbiol., Vol. 8, p. 429 (1975). These reactions require an electron acceptor, and as noted by Goddard et al in J. Med. Microbiol., Vol. 8, p. 429 (1975), the likely candidate in the colon is Vitamin K. Thus, it should be possible to prevent both ulcerative colitis and colon cancer by administering to patients drugs that antagonize the effects of Vitamin K. Web site: http://www.delphion.com/details?pn=US04617317__ •

Methods for producing hybrid phospholipid-binding proteins Inventor(s): Foster; Donald C. (Seattle, WA) Assignee(s): ZymoGenetics, Inc. (Seattle, WA) Patent Number: 5,225,537 Date filed: December 29, 1989 Abstract: Methods are disclosed for producing hybrid phospholipid-binding proteins from eukaryotic cells. DNA constructs comprising a transcriptional promoter, at least one signal sequence and a hybrid phospholipid-binding protein coding sequence comprising at least one lipocortin lipid-binding domain joined to a gla-domainless, vitamin K-dependent protein and a transcriptional terminator are also disclosed.

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Excerpt(s): The present invention relates to the production of proteins in general, and more specifically, to the production of hybrid phospholipid-binding proteins and to DNA sequences encoding these proteins. Vitamin K is a cofactor of the microsomal enzymes that perform post-translational conversion of glutamyl residues (glu) to.gamma.-carboxyglutamyl residues (gla) in domains of certain proteins. These proteins, termed vitamin K-dependent proteins, contain domains that have been identified to contain gla residues, termed gla domains. The.gamma.-carboxylation of glu residues in the gla domains of vitamin K-dependent proteins is required for the biological function of these proteins. The gla residues bind calcium ions and are believed to be responsible for the interaction between vitamin K-dependent proteins and phospholipids, which is required for the biological activity of such proteins. Vitamin K-dependent proteins, which include prothrombin, factor VII, factor IX, factor X, protein C, protein S, bone gla protein, bone matrix protein, protein Z and pulmonary surfactant-associated proteins, play roles in the regulation and promotion of blood coagulation, skeletal growth and lung development. Prothrombin, factor VII, factor IX, and factor X, for example, play important roles in clot formation. The formation of a fibrin clot is the result of a "cascade" of protein activations that involves a number of blood proteins. These proteins, termed "coagulation factors," are generally proenzymes or zymogens, enzymatically inactive proteins that are converted to proteolytic enzymes by the action of an activator, itself an activated clotting factor. Coagulation factors which have undergone such conversion are generally referred to as "activated factors," and are designated by the addition of a lower case "a" (e.g., VIIa). Activation of proenzyme forms is generally accelerated in the presence of acidic phospholipids and Ca.sup.2+ ions. It is believed that in the presence of Ca.sup.2+ ions the activating enzyme and proenzyme form a complex with each other and with acidic phospholipids in the cell membrane (for review, see Jackson and Nemerson, Ann. Rev. Biochem. 49:765-811, 1980). Web site: http://www.delphion.com/details?pn=US05225537__ •

Modified protein C Inventor(s): Smirnov; Mikhail D. (Oklahoma City, OK), Esmon; Charles T. (Oklahoma City, OK) Assignee(s): Oklahoma Medical Research Foundation (Oklahoma City, OK) Patent Number: 5,837,843 Date filed: November 8, 1996 Abstract: Modified Protein C molecules have been made which substitute the gamma carboxylglutamic acid (Gla) region of another Vitamin K dependent protein, most preferably prothrombin, for the native region of the Protein C. The modified or chimeric protein C has advantages over the wild-type protein C since it is less sensitive to inhibition by natural inhibitors of protein C (which would otherwise decrease the ability of the protein C to act as an anticoagulant) and which does not need the same cofactors or same amounts of cofactors, and can therefore be effective in patients with lowered levels of the cofactors such as protein S or the lipids present in activated platelets such as phosphatidyl ethanolamine (PE). Excerpt(s): The present invention is generally in the area of a modified protein C having enhanced anticoagulant activity. Protein C plays a major role in the regulation of blood coagulation. Patients deficient in protein C usually exhibit life threatening thromboticcomplications in infancy (Seligsohn et al., (1984) N. Engl. J. Med. 310, 559-562; Esmon,

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(1992) Trends Cardiovasc. Med. 2, 214-220) that are corrected by protein C administration (Dreyfus et al., (1991) N. Engl. J. Med. 325, 1565-1568). In addition, activated protein C (APC) can prevent the lethal effects of E. coli in baboon models of gram negative sepsis (Taylor et al., (1987) J. Clin. Invest. 79; U.S. Pat. No. 5,009,889 to Taylor and Esmon) and preliminary clinical results suggest that protein C is effective in treating certain forms of human septic shock (Gerson et al., (1993) Pediatrics 91, 418422). These results suggest that protein C may both control coagulation and influence inflammation. Indeed, inhibition of protein S, an important component of the protein C pathway, exacerbates the response of primates to sublethal levels of E. coli and augments the appearance of TNF in the circulation (Taylor et al., (1991) Blood 78, 357363). The mechanisms involved in controlling the inflammatory response remain unknown. Protein C is activated when thrombin, the terminal enzyme of the coagulation system, binds to an endothelial cell surface protein, thrombomodulin (Esmon, (1989) J. Biol. Chem. 264, 4743-4746; Dittman and Majerus, (1990) Blood 75, 329-336; Dittman, (1991) Trends Cardiovasc. Med. 1, 331-336). In cell culture, thrombomodulin transcription is blocked by exposure of endothelial cells to tumor necrosis factor (TNF) (Conway and Rosenberg, (1988) Mol. Cell. Biol. 8, 5588-5592) and thrombomodulin activity and antigen are subsequently internalized and degraded (Lentz et al., (1991) Blood 77, 543-550, Moore, K. L., et.al., (1989) Blood 73, 159-165). In addition, C4bBP, a regulatory protein of the complement system, binds protein S to form a complex that is functionally inactive in supporting APC anticoagulant activity in vitro (Dahlback, (1986) J. Biol. Chem. 261, 12022-12027) and in vivo (Taylor, et al., 1991). Furthermore, C4bBP behaves as an acute phase reactant (Dahlback, (1991) Thromb. Haemostas. 66, 49-61). Thus, proteins of this pathway not only appear to regulate inflammation, but they also interact with components that regulate inflammation, and they themselves are subject to down regulation by inflammatory mediators. Web site: http://www.delphion.com/details?pn=US05837843__ •

Multi-vitamin and mineral supplement Inventor(s): Cooper; Kenneth H. (Dallas, TX), Grundy; Scott Montgomery (Dallas, TX), Jialal; Ishwarlal (Dallas, TX), Selhub; Jacob (Brookline, MA), Willett; Walter Churchill (Cambridge, MA) Assignee(s): Cooper Concepts, Inc. (Dallas, TX) Patent Number: 6,299,896 Date filed: April 13, 2000 Abstract: This invention is directed to a multi-vitamin and mineral supplement tailored to men and post-menopausal women, pre-menopausal women, and athletes which supplies the right amount of the right micronutrients at the right time to assure adequate intake of micronutrients needed for disease prevention and protection against nutritional losses and deficiencies due to lifestyle factors and common inadequate dietary patterns. The multi-vitamin and mineral supplement is comprised of vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, vitamin B1, vitamin B2, niacinamide, vitamin B6, vitamin B12, biotin, pantothenic acid, iron, iodine, magnesium, zinc, selenium, copper, chromium, potassium, choline, lycopene, and co-enzyme Q-10. Excerpt(s): This invention relates to multi-vitamin and mineral supplements. In particular, this invention relates to multi-vitamin and mineral supplements for improving health by insuring adequate intake of micronutrients needed for disease prevention and protection against nutritional losses and deficiencies due to such factors

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as lifestyle patterns and common inadequate dietary patterns. More particularly, this invention related to multi-vitamin and mineral supplements for men and postmenopausal women. Vitamin and mineral preparations are commonly administered to treat specific medical conditions or as general nutritional supplements. Micronutrients are elements or compounds which are present in foods in small or trace amounts and includes vitamins, minerals, or other elements, and compounds found in foods for which a Recommended Daily Allowance (RDA) has not yet been determined. The macronutrients consist of carbohydrates, fats, and proteins which supply nutrients and calories. Some elements such as calcium, sodium, potassium, chloride, and phosphorus are consumed in relatively large amounts, while many such as iron, iodine, and zinc are consumed in small amounts. Vitamins such as B12 and folic acid and the minerals cooper, selenium, and chromium are consumed in very small or trace amounts. In as much as the human body does not synthesize many compounds which are essential to the human body, these specific vitamins and minerals can be obtained from only two sources: food and supplements. The primary source of all nutrients is food. However, the majority of people do not meet the RDA of the foods containing these essential compounds and elements. Thus vitamin and mineral supplementation has become a recognized method of meeting accepted medical and health standards. An international panel of diet and cancer experts announced in London on Sep. 30, 1997, that as many as 30 to 40 percent of all cancer cases worldwide--3 to 4 million a year--could be avoided if people ate a healthy diet and got enough exercise. USA Today, Oct. 1, 1997. However, for some nutrients, the amounts proposed as being healthy apparently cannot be provided by a reasonable quantity and variety of natural foods. Thus nutrient supplements may be important for health promotion and prevention of chronic diseases. Journal of the American Medical Association, May 7, 1997. Web site: http://www.delphion.com/details?pn=US06299896__ •

Plant growth regulation Inventor(s): Iino; Yasuo (Iwaki, JP), Saito; Yoshinori (Iwaki, JP) Assignee(s): Tomoe Kagaku Kogyo Kabushiki Kaisha (Fukushima, JP) Patent Number: 4,764,201 Date filed: March 18, 1985 Abstract: Certain water-soluble derivatives of vitamin K compounds have been found to regulate the growth of plants. The present invention relates to a method for plant growth regulation with such water-soluble derivatives of vitamin K compounds and plant growth regulating compositions comprising the same. Excerpt(s): The present invention relates to the use of certain water-soluble derivatives of vitamin K compounds. More particularly, the invention relates to a method for plant growth regulation with such water-soluble derivatives of vitamin K compounds and plant growth regulating compositions comprising the same. It is highly profitable from the economical point of view to hasten the harvesttime or to enhance the yield of plants by accelerating the growth of the plants. We have conducted intensive investigations to develop plant growth regulating compositions from among drugs, food additives, feed additives and the like which have been evaluated as innoxious. As a result, we have unexpectedly found that, by applying water-soluble derivatives of vitamin K compounds to cereals such as rice plants, a variety of garden plants such as fruit vegetables, leaf vegetables, and root vegetables, flowers and ornamental plants, and fruit trees, the growth of the shoots or tops and/or roots of the plants is notably

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accelerated as compared with that in the case where no such compounds are applied. On the basis of this finding, we have arrived at the present invention. Web site: http://www.delphion.com/details?pn=US04764201__ •

Plasma protein concentrates of reduced thrombogenicity and their use in clinical replacement therapy Inventor(s): Behre; H. Evan (Alexandria, VA), Kosow; David P. (Derwood, MD), Menache-Aronson; Doris (Bethesda, MD), Orthner; Carolyn L. (Rockville, MD) Assignee(s): American National Red Cross (Washington, DC) Patent Number: 4,447,416 Date filed: April 28, 1982 Abstract: Plasma concentrates of vitamin-K dependent clotting factors of reduced thrombogenic potential useful for clinical replacement therapy in deficiency diseases of these clotting factors are provided. Preferably, concentrates substantially devoid of zymogens extraneous to the deficient factor are employed. Excerpt(s): Plasma contains a variety of proteins which have specific biologic functions, some known and well defined for a given protein, some still to be determined. Any plasma protein deficiency occurring either as a congenital disease or as an acquired state associated with a pathologic condition may indicate the need for replacement therapy. Because of technologic advances in the collection, storage and fractionation of plasma, a single unit of blood can now supply many concentrated, purified proteins for different therapeutic uses. For example, plasma was formerly the mainstay of hemophilia A and hemophilia B therapy; it is now used only when no other source of Factor VIII or Factor IX (the respective deficient factors) is available. It is currently considered poor practice to use unfractionated materials except in an emergency, because of the difficulty of achieving adequate and sustained therapeutic levels of the deficient materials without inducing circulatory overload. With the introduction of new techniques for protein purification and the recognition of congenital or acquired pathological states associated with specific protein deficiency, a number of plasma derivatives or concentrated fractions have been made available for the treatment of specific plasma protein deficiencies. Prothrombin complex concentrates are clinically employed in current replacement therapy for patients with deficiencies of the vitamin K-dependent clotting Factors II, VII, IX and X. These concentrates, also referred to as Factor IX concentrates, Factor IX complex concentrates, and PPSB (prothrombin, proconvetin, Stuart factor, and antihemophilic B factor), have demonstrated efficacy in the treatment of hemophilia B (Christmas disease) by alleviating hemorrhagic episodes and preventing post-surgical complications. The efficacy of these Factor IX concentrates for replacement therapy in deficiencies of prothrombin (Factor II), Factor VII, and Factor X is also generally accepted, although the incidence of congenital deficiency of these factors is much rarer, and fewer data are available. Factor IX complex concentrates have, however, been implicated as a cause of thromboembolic complications and disseminated intravascular coagulation (DIC), particularly in patients with acquired deficiencies of the vitamin Kdependent clotting factors, especially those with liver disease. In patients with hemophilia B, thrombohemorrhagic complications occasionally result from infusions of conventional Factor IX complex concentrates. The reaction to these concentrates may be quite severe, with manifestations including superficial vein thrombosis, deep vein thrombosis, pulmonary embolism, and myocardial infarction. Fatalities believed to be directly attributable to commercial Factor IX complex concentrates have been

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documented. It is accordingly highly desirable to provide concentrated plasma protein fractions useful for replacement therapy in congenital or acquired deficiencies of vitamin K-dependent clotting factors but which have little or no thrombogenic potential. From a practical standpoint, it is particularly desirable to provide a Factor IX concentrate devoid of thrombogenic agents but retaining clinical activity for the control of hemorrhage in hemophilia B patients, owing to the relatively more common incidence of this deficiency disease. Web site: http://www.delphion.com/details?pn=US04447416__ •

Process for extraction and concentration of liposoluble vitamins and provitamins, growth factors and animal and vegetable hormones from residues and by-products of industrialized animal and vegetable products Inventor(s): Rohr; Rodolfo (Campinas, BR), Trujillo-Quijano; Jose Anibal (Campinas, BR) Assignee(s): Resitec Industria Quimica LTDA (Duane de Caxias, BR) Patent Number: 6,344,573 Date filed: September 25, 2000 Abstract: A process for the extraction and concentration of unsaponifiable substances, containing liposoluble vitamins and provitamins, growth factors and animal and vegetable hormones, from residues of the industrialization of animal or vegetable products. This process does not require the use of solvents. Its main goal is to obtain the separation of these "valuable products", by means of distillation/evaporation at high vacuum, and the production of fatty acids and other high quality organic acids, once the recovery of the unsaponifiable fraction of residues from the industrialization of animal or vegetable products, is of great commercial interest. This is due to the fact that the "valuable products", have in many cases, vitamin activity, such as: tocopherols, sterols, carotenoids, vitamin A, vitamin K, vitamin D, while other products present cholesterol reducing properties, such as: sterols, tocotrienols, esqualene, etc; or even, anti-oxidant properties like: tocopherols, tocotrienols; as well as anti-carcinogenic properties such as: tocotrienols, sterols, lycopene, and alpha-carotene. Some other products are used as a structure for chemical-synthesis, like for example: sterols for hormone synthesis, vitamin D synthesis; and other products which have nutraceutic properties, apart from the commercial interest in some products, the cosmetic formulas of which present emulsifying properties, emulsion stabilizers and/or viscosity modifiers like for example sterols. Excerpt(s): The invention stated herewith, is a new process for the extraction and concentration of unsaponifiable substances, containing liposoluble vitamins and provitamins, growth factors and animal and vegetable hormones, called from this point out as "valuable products", obtained from animal or vegetable products, or even from the residues of the industrialization of these same products, without the need for solvents. The objective here is the extraction and concentration of the "valuable products", by means of high vacuum distillation/evaporation, also producing fatty acids and other high quality organic acids, by hydrolyzing the residues obtained from distillation/evaporation. The novelty of this new invention process lies in the fact that while the processes used nowadays, to separate and concentrate "valuable products", use solvents, taking advantage of the difference of solubility between unsaponifiable substances and their soap matrix, this new process uses, by means of high vacuum distillation/evaporation, the difference of volatility between volatile unsaponifiables and fatty acid, rosin acid and other practically non-volatile organic acid soaps, under the

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same conditions. The solvents available at present are not sufficiently selective to obtain, though the current process, a reasonable separation between the unsaponifiable components and the fatty acids, the rosin acid soaps, etc. Due to this, many times it is necessary to use more than one solvent, which in turn complicates and increases tremendously the cost of recovery and recycling of the same. Web site: http://www.delphion.com/details?pn=US06344573__ •

Process for producing 2-methyl-1,4-benzoquinone Inventor(s): Kobayashi; Masayuki (Kawaguchi, JP), Nakatu; Eiko (Utsunomiya, JP), Onodera; Kenji (Ohmiya, JP) Assignee(s): Chuo Chemical Co., Inc. (Tokyo, JP) Patent Number: 5,932,753 Date filed: February 9, 1998 Abstract: A process for producing 2-methyl-1,4-benzoquinone at a high conversion, a high selectivity and at a low cost by oxidizing m-cresol with oxygen at a low partial pressure in the presence of at least one copper (I) halide catalyst and a mixed solvent of ketone and acetonitrile. The 2-methyl-1,4-benzoquinone is useful as an intermediate compound to produce vitamin K. Excerpt(s): The present invention relates to an improved process for producing 2methyl-1,4-benzoquinone. More particularly, the present invention relates to a process for industrially advantageously producing 2-methyl-1,4-benzoquinone useful as an intermediate compound for producing Vitamin K by oxidizing m-cresol with molecular oxygen with a high conversion and a high selectivity at a low cost for facilities for the production. Vitamin K is known as an antihemorrhagic vitamin and includes various types, such as vitamin K.sub.1 (phytonadione), vitamin K.sub.2 (menatetorenone), vitamin K.sub.3 (menadione), and vitamin K.sub.3 sodium hydrogensulfite (menadione sodium hydrogensulfite). Among these vitamins, menadione sodium hydrogensulfite is used in a large amount as an additive to feed. These types of Vitamin K are prepared by using 2-methyl-1,4-naphthoquinone as the starting material (vitamin K.sub.3 is 2methyl-1,4-naphthoquinone itself). 2-Methyl-1,4-naphthoquinone has heretofore been industrially produced by oxidation of 2-methylnaphthalene with chromic anhydride. However, this process has a problem in that 6-methyl-1,4-naphthoquinone which is an isomer of 2-methyl-1,4-naphthoquinone is formed at the same time, and efficient separation of 6-methyl-1,4-naphthoquinone is difficult. Therefore, the yield is as low as 20 to 50%. Web site: http://www.delphion.com/details?pn=US05932753__

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Process for purifying blood clotting factors Inventor(s): Feldman; Peter A. (Oxford, GB2) Assignee(s): National Blood Authority (Hertfordshire, GB2) Patent Number: 5,445,958 Date filed: February 23, 1993 Abstract: A method for at least partially separating vitamin K-dependent blood clotting factors from a mixture containing at least one such factor, e.g. a prothrombin complex

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concentrate, which comprises adsorption of said mixture on to a chelate of a polyvalent metal immobilized on an inert support, e.g. Cu.sup.2 + -primed Chelating Sepharose, followed by elution to yield one or more fractions enriched in respect of one of said factors. Excerpt(s): This invention concerns an improved method for the purification or enrichment of vitamin K-dependent blood clotting factors in fractions containing such factors. The subscript "a" means that the enzyme is in the activated form. Further significant plasma proteins, which may be considered to fall within the general category of blood clotting factors, include Protein C and Protein S. Protein C is an inactive zymogen of the proteolytic enzyme Activated Protein C (APC,PC.sub.a), Unlike the above-mentioned clotting factors, APC has an anticoagulant effect which functions through the proteolysis of Factor V and Factor VIII which are thus inactivated. Activation of Protein C appears to be by a feedback process involving thrombin and an endothelial-bound protein, thrombomodulin, which both function during the coagulation process. The activity of APC is then enhanced by the presence of Protein S, which seems to act as a cofactor. Web site: http://www.delphion.com/details?pn=US05445958__ •

Process for the manufacture of a high-purity activated factor VII concentrate essentially free of vitamin K-dependent factors and factors VIIIC and VIIICAg Inventor(s): Dazey; Bernard (Bordeaux, FR), Enfedaque-Morer; Sylvia (Bordeaux, FR), Hamsany; Mohamed (Bordeaux, FR) Assignee(s): Association d'Aquitaine pour le Developpement de la Transfusion Sanguine (Bordeaux, FR) Patent Number: 5,344,918 Date filed: December 10, 1992 Abstract: The invention relates to a process for the manufacture of a high-purity activated factor VII concentrate.This process comprises the use of a plasma free of cryoprecipitate, preferably of human origin, as well as at least one purification step involving chromatography at least once on an ion exchange resin, and a factor VII activation step, wherein the first stage is direct activation of the factor VII in the crude supernatant of plasma free of cryoprecipitate, without the addition of exogenous proteins.By virtue of the invention, the high-purity activated factor VII is essentially free of vitamin K-dependent factors and factors VIIIC and VIIICAg and has a factor VIIa/factor VII ratio greater than 5 with a specific activity of the activated factor VII greater than 200 IU/mg of proteins. Excerpt(s): The present invention relates essentially to the process for the manufacture of a high-purity activated factor VII concentrate essentially free of vitamin K-dependent factors and factors VIIIC and VIIICAg, and to the product obtained by this process. The clotting factor responsible for reestablishing hemostasis in hemophiliacs who have circulating antibodies is known to be activated factor VII. This is present in the composition of activated prothrombin concentrates such as, for example, FEIBA.RTM. or AUTOPLEX.RTM. Various documents, such as WO-A-89/12097, WO-A-83/00016, EPA-0 225 160, U.S. Pat. No. 4,637,932 and FR-A-2 622 108, have demonstrated the effective role of factor VIIa. In particular, the document EP-B1-0 225 160 demonstrates the efficacy of factor VIIa in reestablishing normal hemostasis in the case of hemorrhagic disorders not caused by factor VIII deficiencies or by inhibitors.

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Web site: http://www.delphion.com/details?pn=US05344918__ •

Refrigeration-shelf-stable ultra-pasteurized or pasteurized infant formula Inventor(s): Kamarei; A. Reza (Princeton, NJ) Assignee(s): Princeton Nutrition, L.L.C. (Princeton, NY) Patent Number: 6,039,985 Date filed: May 4, 1999 Abstract: Refrigeration-shelf-stable ready-to-feed and concentrated infant formulas prepared through an ultra-pasteurization and/or pasteurization process, comprise per five fluid ounces from about 1.8 to about 6.3 grams of protein; from about 3.3 to about 15.9 grams of fat; from about 300 mg to about 3000 mg of linoleic acid; from about 250 to about 900 IU of Vitamin A; from about 40 to about 180 IU of Vitamin D; from about 0.7 to about 9 IU of Vitamin E; from about 4 to about 24 mcg of Vitamin K; from about 40 to about 300 mcg of Thiamine (Vitamin B1); from about 60 to about 450 mcg of Riboflavin (Vitamin B2); from about 35 to about 180 mcg of Vitamin B6; from about 0.15 to about 0.9 mcg of Vitamin B12; from about 250 to about 3150 mcg of Niacin; from about 4 to about 48 mcg of Folic Acid (Folacin); from about 300 to about 1500 mcg of Pantothenic Acid; from about 1.5 to about 13.2 mcg of Biotin; from about 8 to about 36 mg of Vitamin C (Ascorbic Acid); from about 7 to about 48 mg of Choline; from about 4 to about 18 mg of Inositol; from about 60 to about 234 mg of Calcium; from about 30 to about 159 mg of Phosphorus; from about 6 to about 24 mg of Magnesium; from about 0.15 to about 5.4 mg of Iron; from about 0.5 to about 3 mg of Zinc; from about 5 to about 45 mcg of Manganese; from about 60 to about 270 mcg of Copper; from about 5 to about 75 mcg of Iodine; from about 20 to about 81 mg of Sodium; from about 80 to about 324 mg of Potassium; and from about 55 to about 195 mg of Chloride; wherein the total caloric content is from about 80 kilocalories to about 300 kilocalories per five fluid ounces. Excerpt(s): This invention relates to refrigeration-shelf-stable ready-to-feed and concentrated infant formulas and products, as defined by the U.S. Code of Federal Regulations, which are prepared using pasteurization or ultra-pasteurization processes. Infant formula is used as a supplement to or substitute for breast milk when a mother cannot or does not want to breast feed her infant. Ideally, the composition of the infant formula would be exactly the same as the composition of human milk. Nonetheless, because infant formulas are typically made with cow milk (and sometimes soy protein), on a molecular level, these formulas are not the same as human milk. Nonetheless, infant formulas are designed to mimic the formulation of human milk as much as possible. Furthermore, infant formulas should contain nutrients as listed by the U.S. Code of Federal Regulations, 21 CFR 107.100, 1998, as presented in Table 1. The resultant infant formulas can be called "humanized milk", "simulated human milk", "simulated mother milk", "simulated breast milk" and "infant nutritional formula". An infant formula which contains all the essential macronutrients and micronutrients, have heretofore been available only in shelf-stable sterilized products. Sterilized products are generally sold in hermetically sealed containers such as cans and are intended to have a long room temperature shelf-life. Table 2 lists several commercially available shelfstable sterilized infant formulas. Such formulas require expensive processing steps which must be carefully controlled to properly remove microorganisms and bacterial enzymes. As will be discussed further herein, sterilization processes, due to the severity of the heat treatment can cause undesirable physical, chemical, enzymatic and microbial changes which deleteriously affect the final product.

Patents 135

Web site: http://www.delphion.com/details?pn=US06039985__ •

Region-specific determinants for vitamin K dependent bone protein Inventor(s): Catherwood; Bayard D. (San Diego, CA), Deftos; Leonard J. (Del Mar, CA) Assignee(s): The Regents of the University of California (Berkeley, CA) Patent Number: 4,438,208 Date filed: May 27, 1982 Abstract: Novel oligopeptide used as reagents or in the preparation of reagents in relation to gamma-carboxyglutamic acid-containing protein of bone. Particularly, labeled oligopeptides and antibodies prepared from immunogen conjugates are disclosed for use in immunoassays. Excerpt(s): As increasing knowledge is obtained concerning vitamin K dependent bone protein, referred to hereinafter as bone Gla protein (BGP) or.gamma.-carboxyglutamic acid containing protein, assays will be required having an enhanced sensitivity and specificity. That is, where antibodies are employed, it will be necessary that the antibodies be specific for the protein of interest and in particular defined regions of protein, having substantially different binding affinities between the protein of interest and regions thereof, and other proteins. The greater the binding affinity, all other things being equal, the greater the sensitivity of the assay. An abstract of a paper by Price, et al., was published in June, 1979, for the meeting of the American Society for Bone and Mineral Research. Price and Nishimoto, Proc. Natl. Acad. Sci. USA 77: 2234-2238 (1980) and Price, et al., J. Clin. Invest. 66: 878-883 (1980) both describe a radioimmunoassay utilizing antibodies and labels derived from the intact BGP molecule. Deftos, et al., Calcif. Tissue Int., 34: 121-124 (1982) describes the clinical measurement of changes in BGP during treatment of bone disease. The references cited in the aforementioned references should also be noted. Copending application Ser. No. 246,972 suggests the use of fragments of BGP of at least 20 amino acids as reagents in immunoassays for BGP. Small oligopeptides are provided capable of being employed as haptens for the preparation of highly specific antibodies for BGP. Particularly, the oligopeptides are of from about 10 to 16 amino acids and have the same or substantially the same amino acid sequence as the naturally occurring BGP. These are employed for the preparation of antibodies, and for use as labelled reagents in sensitive immunoassays. Web site: http://www.delphion.com/details?pn=US04438208__

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Soluble thrombomodulin-based coagulation-inhibiting proteins

one-stage

assay

for

vitamin-K

dependent

Inventor(s): Matschiner; John T. (4015 Swanson Hall, University of Nebraska Medical Center, 600 S. 42nd St., Omaha, NE 68198-8090) Assignee(s): none reported Patent Number: 5,525,478 Date filed: June 7, 1995 Abstract: The present invention provides a novel one-stage assay which uses soluble thrombomodulin for directly determining the functional status in plasma of the vitamin K-dependent coagulation-inhibiting proteins, protein C and protein S. The method

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comprises combining a blood plasma test sample and a coagulation-activating substance in a calcium-free solution, then adding soluble thrombomodulin and calcium ions to initiate a coagulation reaction, measuring the time required for the test plasma sample to clot, comparing the measured clot time to that of standard control plasma samples, including protein C- and protein S-deficient plasma controls, and then using the compared clot time values for determining the functional status of protein C and protein S in the individual from whom the test plasma sample was taken. The functional status of the vitamin K-dependent coagulation-inhibiting proteins is used to determine the risk of thrombosis in the host individual. Excerpt(s): The present invention relates to a novel one-stage blood coagulation assay which incorporates soluble thrombomodulin for the rapid and direct in vitro determination of the functional status of vitamin K-dependent coagulation-inhibiting proteins in a plasma sample. In particular, the functional status of protein C and protein S are reliably and sensitively determined with this assay, without separation from the plasma sample in which they are contained. In addition, the present invention relates to novel molecular complexes produced in the aforementioned one-stage blood coagulation assay. The capacity of blood to clot and stop flowing from a wound is dependent on the proper functional interaction of a large number of factors and cofactors in the blood coagulation cascade. The ability of clinical laboratories to reliably and conveniently assay for these factors and cofactors in plasma samples from donor patients can be critical in monitoring individuals for whom either inappropriate coagulation episodes (such as occurs, for example, in disseminated intravascular coagulation disease) or inappropriate failure of blood to clot (such as occurs, for example, in hemophilia) is a daily life-threatening problem. The physiologic basis for these clinically important coagulation problems can be exceedingly complex to diagnose. In most cases, however, diagnosis can be made by detecting either quantitative or functional changes in certain of the biological factors and cofactors which activate or regulate the coagulation process. A number of diagnostic assays have been developed which reliably measure many of the regulatory proteins involved in the coagulation cascade (see, for example, the textbooks by R. Hoffman et al., Hematology: Basic Principles and Practice, New York: Churchill Livingston Inc., 1991; and by C. Kjeldsberg et al., Practical Diagnosis of Hematologic Disorders, Chicago: American Society of Clinical Pathologists Press, 1989). These include such routine coagulation assays as the activated partial thromboplastin time (APTT) assay, the prothrombin time (PT) assay, and the thrombin clotting time (TCT) assay. In spite of extensive research, none of these assays directly measure, in a one-stage assay, the functional status in plasma of the vitamin K-dependent coagulation-inhibiting proteins, protein C and protein S. Because protein C and protein S are both essential in the normal regulatory process of down-regulating the blood coagulation cascade, the lack of any one-stage assay which directly determines both of their functional activities remains a serious deficiency in the art. Web site: http://www.delphion.com/details?pn=US05525478__

Patents 137

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Syntheses based on 2-hydroxyacetophenone Inventor(s): Aslam; Mohammad (Corpus Christi, TX), Brown, II; Charles H. (North Kingstown, RI), Fitzhenry; Sharon R. (Foxboro, MA), McDonough; Joseph A. (West Greenwich, RI), Uwaydah; Ibrahim M. (Corpus Christi, TX) Assignee(s): Hoechst Celanese Corporation (Somerville, NJ) Patent Number: 5,696,274 Date filed: May 22, 1996 Abstract: The present invention provides processes which are flexible, cost effective, and commercially viable methods of manufacturing or producing products from 2hydroxyacetophenone (2-HAP).Of particular interest of the available products are 4hydroxycoumarin, warfarin-alkali salt, preferably warfarin sodium and warfarin-alkali salt-isopropyl alcohol (2-propanol) complex, more preferably warfarin-sodiumisopropyl alcohol complex.As is known, these compounds are useful as vitamin K dependent anticoagulants in the treatment of humans and animals. In different doses, they are also useful as rodenticide.The inventive process involves contacting 2-HAP, carbonate ester and effective base followed by treatment with an unsaturated ketone and phase transfer catalyst to ultimately yield product. Excerpt(s): This is a NON-PROVISIONAL PATENT APPLICATION, said application claiming the benefit under 35 U.S.C.sctn.119(e) of a Provisional Patent Application, Application Number 60/009,416, filed on Dec. 28, 1995, and said APPLICATION being executed as a Non-Provisional application for filing under 35 USC 111(a) and 1.53(b)(1) concurrently herewith. This invention relates to compounds which may be synthesized from 2-Hydroxyacetophenone in commercially feasible and cost-effective fashion. In the commercial production of various organic compounds it is useful to have flexible systems which can be tailored to production needs at any given time. In production of pharmaceutical materials it is highly desirable to have systems and production protocols which provide clean manufacturing and do not provide multiple transfers and cleaning steps during which contaminants may be introduced. As the background demonstrates numerous others have provided means or syntheses, usually including multiple steps, for reaching a single compound at a single endpoint. Web site: http://www.delphion.com/details?pn=US05696274__

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Ultrapurification of factor IX and other vitamin K-dependent proteins Inventor(s): Zimmerman; Theodore S. (La Jolla, CA) Assignee(s): Scripps Clinic & Research Foundation (La Jolla, CA) Patent Number: 5,055,557 Date filed: November 23, 1988 Abstract: A method of recovering active, highly purified and concentrated vitamin Kdependent proteins from plasma, concentrate or mixtures of proteins produced by recombinant DNA technology using an immuno adsorbent comprising a monoclonal antibody. Excerpt(s): This invention relates generally to a method of separating and purifying Factor IX and other vitamin K-dependent proteins including Factor II, Factor VII, Factor X, prothrombin, Protein C, and Protein S. More specifically, high purity protein is separated by a chromatographic adsorption and concentration technique from plasma

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or concentrate. Blood coagulation factors play a vital role in the normal coagulation mechanism. For instance, patients with a deficiency of Factor IX exhibit severe bleeding problems ("Hemophilia B"). It would be desirable to be able to isolate substantial quantities of Factor IX and other vitamin K-dependent proteins for therapeutic administration, as well as for scientific study, and several processes directed to this objective have been described in the literature. The process of the present invention surpasses these processes in providing a combination of high yield of the desired protein with high purity, and particularly with relatively low contamination by other clotting factors. In addition, the prior art processes require a large number of steps each of which is time-consuming and introduces losses of protein into the overall process. One such process is that of S. P. Bajaj, et al., "A Simplified Procedure for Purification of Human Prothrombin, Factor IX and Factor X", in Preparative Biochemistry, 11 (4), 397412 (1981). This process subjects pooled plasma to adsorption onto and elution from barium citrate, ammonium sulfate fractionation, DEAE-Sephadex chromatography, and heparin-agarose chromatography in a sodium citrate buffer at pH 7.5, to separate prothrombin, Factor X, and Factor IX. The reported yield of Factor IX was about 35%, at a specific activity of 80-220 units/mg. Another process is that of J. P. Miletich, et al., "Purification of Human Coagulation Factors II, IX, and X Using Sulfated Dextran Beads", in Methods in Enzymology, Vol. 80, pp. 221-228. Fresh frozen plasma is thawed, and subjected to a sequence of precipitation with barium citrate, resuspension in Tris-HCl with diisopropylfluorophosphate, precipitation with ammonium sulfate, chromatography on De-52 cellulose, and application of selected pooled fractions to sulfated dextran beads. Following concentration, the fraction containing the Factor IX is said to be contaminated with as much as 1 wt. % of Factor X. B. Osterud, et al. in "Human Blood Coagulation Factor IX", J. Biological Chemistry, Vol. 253, No. 17, pp. 5946-5951 ( 1978), describe the purification of Factor IX by a sequence of adsorption onto and elution from barium sulfate, DEAE-cellulose batch chromatography, polyacrylamide gel electrophoresis, and heparin-agarose affinity chromatography. The Factor IX activity was said to be 207 units/mg, though the yield of Factor IX was not started. Web site: http://www.delphion.com/details?pn=US05055557__ •

Vitamin K adduct, particularly suitable as vitamin supplement for feeds Inventor(s): Bonati; Stefano (Milan, IT), Monteleone; Francesco (Cassina De'Pecchi, IT) Assignee(s): Luigi Stoppani S.p.A. (Milan, IT) Patent Number: 6,488,924 Date filed: June 12, 2000 Abstract: A vitamin K adduct, particularly suitable as vitamin supplement for feeds, constitued by menadione bisulfite bonded with an appropriate ion-exchange resin and exceptionally stabilized thereby. The adduct can be used as an antihemorrhagic additive for farm animal feeds. The high thermal stability of the vitamin adduct allows to use it in modern technologies for producing feeds in extruded form. Excerpt(s): The present invention relates to a vitamin K adduct, particularly suitable as a vitamin supplement for feeds. In particular, the present invention relates to a highly stable form of vitamin K, to its production process and to its use as vitamin supplement for feeds for farm animals. Menadione (2-methyl-1,4-naphthoquinone) is a vitamin derivative (K.sub.3) in the form of a yellow crystalline powder which is poorly soluble in water and has a high antihemorrhagic activity.

Patents 139

Web site: http://www.delphion.com/details?pn=US06488924__ •

Vitamin K-dependent carboxylase Inventor(s): Stafford; Darrel W. (Carrboro, NC), Wu; Sheue-Mei (Carrboro, NC) Assignee(s): The University of North Carolina at Chapel Hill (Chapel Hill, NC) Patent Number: 5,268,275 Date filed: September 9, 1991 Abstract: Isolated DNA encoding a vitamin K dependent carboxylase is disclosed. The carboxylase is selected from the group consisting of: (a) isolated DNA which encodes bovine or human vitamin K dependent carboxylase; (b) isolated DNA which hybridizes to isolated DNA of (a) above and which encodes a vitamin K dependent carboxylase; and (c) isolated DNA differing from the isolated DNAs of (a) and (b) above in nucleotide sequence due to the degeneracy of the genetic code, and which encodes a vitamin K dependent carboxylase. Also disclosed are vectors and host cells containing the aforesaid DNA, methods of using the same, and purified protein coded for by the aforesaid DNA. Excerpt(s): This invention relates to DNA sequences encoding enzymes, known as the vitamin K dependent carboxylases, which carry out the.gamma.-carboxylation of glutamic acid residues in vitamin K dependent proteins such as Factor VII, Factor IX, Factor X, Protein C, Protein S, and Prothrombin. A number of blood coagulation proteins require a post-translational, vitamin K-dependent modification for biological activity. In 1974, Stenflo et al., Nelsestuen et al. and Magnusson et al. reported that the prototype of these vitamin K-dependent proteins, prothrombin, contained the modified amino acid,.gamma.-carboxyglutamic acid (Gla). See J. Stenflo et al., Proc. Natl. Acad. Sci. USA 71:2730-2733 (1974); G. Nelsestuen et al., J. Biol. Chem. 249:6347-6350 (1974); S. Magnusson et al. FEBS Lett. 44:189-193. (1974). Prothrombin from animals treated with the vitamin K antagonist warfarin lacked this Gla modification. It was inferred from these observations that the blood-clotting activity of the vitamin K-dependent proteins required.gamma.-carboxylation of specific glutamic acid residues. Shortly thereafter, Esmon et al. demonstrated an enzyme activity, vitamin K-dependent carboxylase (hereafter called carboxylase), capable of making this Gla modification. See C. Esmon et al., J. Biol. Chem. 250:4744-4748 (1975). After cDNA sequences were obtained for several of the vitamin K-dependent proteins, Pan and Price compared the deduced amino-acid sequences and suggested that the propeptide consensus sequence preceding the amino terminus of the vitamin K-dependent protein was a recognition site for the carboxylase See L. Pan and P. Price, Proc. Natl. Acad. Sci. USA 82:6109-6113 (1985). This suggestion was confirmed by Knobloch and Suttie, who demonstrated the importance of the propeptide in carboxylation by showing that the synthetic propeptide sequence of human factor X stimulated the activity of the carboxylase for a small substrate (Boc-GluGlu-Leu-OMe) in vitro. J. Knobloch and J. Suttie, J. Biol. Chem. 262:16157-16163 (1987). Jorgensen extended this observation by showing that factor IX with its propeptide deleted was not carboxylated. M. Jorgensen et al., Cell 48:185-191 (1987). Web site: http://www.delphion.com/details?pn=US05268275__

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Vitamin/mineral-enriched cyanoacrylate cosmetic Inventor(s): Papay; Kristy L. (Orange, CA) Assignee(s): Pacer Technology (Rancho Cucamonga, CA) Patent Number: 5,866,106 Date filed: February 3, 1997 Abstract: A nail tip adhesive is made by the process of mixing cyanoacrylate and a vitamin fortifier in a proportion by weight in the range of 0.0001% to 0.1% vitamin-tocyanoacrylate, wherein the shelf life of the cyanoacrylate is at least not substantially shortened by adding such vitamin. Such vitamin fortifier comprises at least one of vitamin A, vitamin D-3, vitamin E, vitamin K, vitamin B-1, vitamin B-2, vitamin B-6, vitamin B-12, vitamin C, niacinamide, folic acid, panthothenic acid, and biotin. Excerpt(s): The invention relates generally to cosmetics and adhesives, and more particularly to adhesive compounds that include vitamins, minerals, and other lotions and nutrients generally regarded as beneficial to humans. Cyanoacrylates, or more specifically ethyl a cyanoacrylates, are variously referred to as EACA, Instant Magic, Krazy Glue, Miracle Glue, Nail Glue, Super Glue, etc. Such are conventionally used for adhesives, aircraft and automobile industry, cosmetics (nail mending kits), electronic industry (circuit boards), leather finish resins, medicine (binding of tissue, sealing of wounds, ileostomy appliances), meat slaughter (carcass sealing), paint vehicles (water emulsion), paper and textile coatings, perfume, rubber, and textile and paper coatings. Vitamins play varied roles in preventing certain diseases, such as cancer. Small quantities can be sufficient to maintain a good health. An adequate intake of minerals is also essential to remain healthy. More than sixty different minerals contribute to the overall health of the human body. Among them, twenty-two are considered to be essential. Minerals, and many trace elements have been recently proposed as miracle solutions to health problems created by modern life. External sources of vitamins and minerals are required, because our bodies do not produce all that are required. The most common source is the food we take in. Web site: http://www.delphion.com/details?pn=US05866106__

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

10

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

Patents 141

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Composition for increasing bone density Inventor(s): Forusz, Samuel L.; (Thousand Oaks, CA), Liu, Hanlan; (New City, NY), Muatine, Rose M.; (Sylmar, CA) Correspondence: Blakely Sokoloff Taylor & Zafman; 12400 Wilshire Boulevard, Seventh Floor; Los Angeles; CA; 90025; US Patent Application Number: 20020172724 Date filed: October 25, 2001 Abstract: A composition and a method for administering an improved supplement to prevent bone density loss. The composition combines a calcium compound with inulin, and optionally magnesium, Vitamin D.sub.3, Vitamin K, Vitamin C, and may combine a soy isoflavone, all in a dietary acceptable form in a beverage, a beverage preparation, a paste, a bar, or a cookie. Excerpt(s): The application is a Continuation co-pending Application Ser. No. 09/365,156, filed Jul. 30, 1999 by applicants, Samuel L. Forusz, Hanlan Liu, and Rose M. Muatine, entitled "Composition for Increasing Bone Density". The invention relates to nutritional supplements and more particularly to a composition and method for reducing the risks associated with bone density loss, e.g., the risks of osteoporosis. Osteoporosis is a debilitating disease affecting as many as one in three women after menopause. The disease affects the skeletal structure making the skeletal structure weak and frail. Calcium and magnesium supplementation is seen as one way to protect against osteoporosis. Men also experience a loss in bone density with age. Accordingly, health care practitioners increasingly encourage calcium and magnesium supplementation for men and women of all ages. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Enhanced gamma-carboxylation of recombinant vitamin K-dependent clotting factors Inventor(s): Camire, Rodney M.; (Voorhees, NJ), High, Katherine A.; (Merion, PA), Larson, Peter J.; (Oakland, CA), Stafford, Darrel W.; (Canboro, NC) Correspondence: Intellectual Property Group; Pillsbury Winthrop Llp; 11682 EI Camino Real, #200; San Diego; CA; 92130; US Patent Application Number: 20030220247 Date filed: January 22, 2003 Abstract: The invention relates to methods of optimizing gamma carboxylation of a vitamin K-dependent protein, methods of generating fully gamma carboxylated vitamin K-dependent protein, and compositions comprising chimeric nucleic acids and proteins for use in treatment of vitamin K-dependent disease states. Excerpt(s): Biologically active human blood clotting Factor X is fully gamma carboxylated. Factor X, a vitamin K-dependent two-chain glycoprotein, is a substrate for both the extrinsic (tissue factor/FVIIa) and intrinsic (FVIIIa/FIXa) tenase complexes thus linking these two pathways (Kalafatis et al.,1994, Biochem. Biophys. Acta 1227:113). The activated form of Factor X (FXa) is the serine protease component of the enzymatic complex termed prothrombinase, the only known physiological activator of prothrombin. Prothrombinase assembles through reversible interactions between FXa and the cofactor factor Va (FVa) on an appropriate membrane (i.e., platelet) surface in the presence of Ca.sup.2+ ions (Mann et al., 990, Blood 76: 1). While FXa catalyzes

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prothrombin activation, the macromolecular interactions which stabilize prothrombinase lead to a substantial enhancement in catalytic efficiency (Mann et al.,1988, Ann. Rev. Biochem. 57:915), indicating that assembly of this complex is an important requisite for rapid and localized thrombin generation. Because Factor X/FXa occupies a central position in the coagulation pathway, there is considerable interest in its therapeutic modulation (Hauptmann et al.,1999, Thromb. Res. 93:203), highlighting the need to better understand structural determinants on Factor X/FXa important to its function. While extensive progress has been made in delineating structural determinants important for function on thrombin, FIXa, FVIIa, and activated protein C (APC), less is known about FXa. One explanation is the limited number of naturally occurring FXa mutations to study. Another reason is the difficulty in producing (as compared to other vitamin K-dependent proteins) functional recombinant Factor X/FXa (rFXa). As with all vitamin K-dependent proteins, the biosynthesis of Factor X is complex, involving several co- and post-translational modifications (Kaufman R J, 1998, Thromb. Haemost. 79:1068). Efficient processing and release of mature two-chain Factor X into the circulation requires, 1) removal of the signal sequence, 2) formation of disulfide bonds, 3) modification of amino-terminal glutamic acid residues to.gamma.-carboxyglutamic acid, 4) modification of one aspartic acid in the first epidermal growth factor (EGF) domain to.beta.-hydroxyaspartic acid, 5) addition of N- and O-linked oligosaccharides to the activation peptide, 6) removal of an internal tripeptide to yield two chain Factor X, and 7) removal of the propeptide just prior to secretion (for review see Kaufman R J, 1998, Thromb. Haemost. 79:1068). While some of these modifications do not appear essential for Factor X function, the removal of the signal sequence, propeptide, internal tripeptide, and full.gamma.-carboxylation are all steps which are important requisites for the production of biologically active Factor X/FXa. Expression of rFactor X is heterogeneous with respect to removal of the internal tripeptide, propeptide cleavage, and y-carboxylation. Expression of rFactor X/FXa in CHO and COS-1 cells appears less efficient than HEK 293 cells with respect to these modifications (Messier et al., 1991, Gene 99:291; Wolf et al., 1991, J. Biol. Chem. 266:13726; Rudolph et al., 1997, Protein Expression and Purification 10:373; Sinha et al., 1994, Thromb. Res. 75:427; Larson et al., 1998, Biochemistry 37:5029). Some of these inefficient modifications can be overcome by expressing rFactor X in HEK 293 cells, cotransfecting with PACE/furin, and modifying the Factor X propeptide at position -2 (Thr.fwdarw.Arg; henceforth referred to as native rwtFactor X). However, inefficient.gamma.-carboxylation still remains a major problem (Rudolph et al., 1997, Protein Expression and Purification 10:373; Larson et al., 1998, Biochemistry 37:5029). For example, it has been discovered that on average only 32% of the rFactor X produced by HEK 293 cells is fully.gamma.-carboxylated while the remaining material exhibits no.gamma.-carboxylation (Larson et al., 1998, Biochemistry 37:5029). While separation of uncarboxylated and fully.gamma.-carboxylated rFactor X can be readily accomplished, the resulting protein yields are less than desirable. This heterogeneity in.gamma.-carboxylation can be overcome completely by expressing Gladomainless rFactor X (Rezaie et al., 1993, J Biol. Chem. 268:8176); however, this is a less than satisfactory solution for studies involving macromolecular complex assembly of Factor X/FXa which requires a membrane surface. Thus, an ideal expression system would direct high-level protein production (>2-5.mu.g rFactor X/106 cells/24 hour) while still allowing for efficient execution of post-translational modifications essential to Factor X/FXa function. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 143

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High molecular weight derivatives of vitamin k-dependent polypeptides Inventor(s): Nelsestuen, Gary L.; (St. Paul, MN) Correspondence: Fish & Richardson; Suite 3300; 60 South Sixth Street; Minneapolis; MN; 55402; US Patent Application Number: 20030211094 Date filed: December 30, 2002 Abstract: Modifications of vitamin K-dependent polypeptides that lead to enhanced protein function on a weight or molar basis and/or increase of protein lifetime in the circulation are described. Both objectives are important for using vitamin K-dependent polypeptides for pro- and anti-coagulation therapies, as well as for other uses in the circulation. Excerpt(s): This invention relates to high molecular weight derivatives of vitamin Kdependent polypeptides, and more particularly to dimerized vitamin K-dependent polypeptides and vitamin K-dependent polypeptides that are linked to PEG polymers. Vitamin K-dependent proteins contain 9 to 13 gamma-carboxyglutamic acid residues (Gla) in their amino terminal 45 residues. The Gla residues are produced by enzymes in the liver that utilize vitamin K to carboxylate the side chains of glutamic acid residues in protein precursors. Vitamin K-dependent proteins are involved in a number of biological processes, of which the most well described is blood coagulation (reviewed in Nelsestuen (2000) Vitam. Horm. 58:355-389). Vitamin K-dependent proteins include protein Z, protein S, prothrombin (factor II), factor X, factor IX, protein C, factor VII, Gas6, and matrix GLA protein. Factors VII, IX, X and II function in procoagulation processes while protein C, protein S and protein Z serve in anticoagulation roles. Gas6 is a growth arrest hormone encoded by growth arrest-specific gene 6 (gas6) and is related to protein S. See, Maiifioletti et al. (1993) Mol. Cell. Biol. 13:4976-4985. Matrix GLA protein normally is found in bone and is critical to prevention of calcification of soft tissues in the circulation. Luo et al. (1997) Nature 386:78-81. The regulation of blood coagulation is a process that presents a number of leading health problems, including both the failure to form blood clots as well as thrombosis, the formation of unwanted blood clots. Agents that prevent unwanted clots are used in many situations and a variety of agents are available. Unfortunately, most current therapies have undesirable side effects. Orally administered anticoagulants such as Warfarin act by inhibiting the action of vitamin K in the liver, thereby preventing complete carboxylation of glutamic acid residues in the vitamin K-dependent proteins, resulting in a lowered concentration of active proteins in the circulatory system and reduced ability to form clots. Warfarin therapy is complicated by the competitive nature of the drug with its target. Fluctuations of dietary vitamin K can result in an over-dose or unider-dose of Warfarin. Fluctuations in coagulation activity are an undesirable outcome of this therapy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method for preventing and treating alzheimer's disease and brain damage associated with cardiov ascular disease and head injury Inventor(s): Allison, Anthony Clifford; (Belmont, CA) Correspondence: Barbara J. Luther Chartered; 18124 Wedge Parkway, #516; Reno; NV; 89511; US Patent Application Number: 20020016372 Date filed: June 11, 2001 Abstract: A method for preventing and treating AD is supplementation with vitamin K so that the concentration of the vitamin in the circulation is sufficient for its functions outside the liver. Vitamin K supplementation will also be useful to reduce brain damage associated with cardiovascular disease and injury. Vitamin K can be administered orally, subcutaneously, intramuscularly or intravenously. The vitamin K can be phylloquinone, menaquinones of varying chain lengths, or menadione. Preferred forms of the vitamin are all-trans menadione and menaquinone-4. These are formulated so as to ensure efficient absorption from the gastrointestinal tract and rapid bioavailability in the brain following administration. Excerpt(s): This application claims the benefit of the priority of U.S. Provisional Application No. 60/222,143, filed Jul. 31, 2000. The present invention relates to a method of medical treatment. More specifically the method provides for preventing the development of Alzheimer's disease (AD) in predisposed persons and for treatment of patients with dementias suggestive of AD. The treatment will also limit brain damage associated with cardiovascular disease and head injury. Alzheimer's disease (AD) is a type of dementia accompanied by characteristic pathological changes. The brains of patients with AD show extracellular deposits of.beta.-amyloid protein, often associated with altered neurons or dendrites. Most cases also show within neurons neurofibrillary tangles composed of paired helical filaments containing a highly phosphorylated form of the tau protein of microtubules. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Modified vitamin K-dependent polypeptides Inventor(s): Nelsestuen, Gary L.; (St. Paul, MN) Correspondence: Mark S. Ellinger, PH.D.; Fish & Richardson P.C., P.A.; Suite 3300; 60 South Sixth Street; Minneapolis; MN; 55402; US Patent Application Number: 20010018414 Date filed: March 12, 2001 Abstract: The invention provides vitamin k-dependent polypeptides with enhanced membrane binding affinity. These polypeptides can be used to modulate clot formation in mammals. Methods of modulating clot formation in mammals are also described. Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 08/955,636, filed on Oct. 23, 1997. Vitamin K-dependent proteins contain 9 to 13 gamma-carboxyglutamic acid residues (Gla) in their amino terminal 45 residues. The Gla residues are produced by enzymes in the liver that utilize vitamin K to carboxylate the side chains of glutamic acid residues in protein precursors. Vitamin K-dependent proteins are involved in a number of biological processes, of which the most well-described is blood coagulation (reviewed in Furie, B. and Furie, B. C., 1988, Cell, 53:505-518). Vitamin K-dependent

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proteins include protein Z, protein S, prothrombin, factor X, factor IX, protein C, factor VII and Gas6. The latter protein functions in cell growth regulation. Matsubara et al., 1996, Dev. Biol., 180:499-510. The Gla residues are needed for proper calcium binding and membrane interaction by these proteins. The membrane contact site of factor X is thought to reside within amino acid residues 1-37. Evans and Nelsestuen, 1996, Protein Science 5:suppl. 1, 163 Abs. Although the Gla-containing regions of the plasma proteins show a high degree of sequence homology, they have at least a 1000-fold range in membrane affinity. McDonald, J. F. et al., 1997, Biochemistry, 36:5120-5137. Factor VII functions in the initial stage of blood clotting and may be a key element in forming blood clots. The inactive precursor, or zymogen, has low enzyme activity that is greatly increased by proteolytic cleavage to form factor VIIa. This activation can be catalyzed by factor Xa as well as by VIIa-tissue factor, an integral membrane protein found in a number of cell types. Fiore, M. M., et al., 1994, J. Biol. Chem., 269:143-149. Activation by VIIa-tissue factor is referred to as autoactivation. It is implicated in both the activation (formation of factor VIIa from factor VII) and the subsequent activity of factor VIIa. The most important pathway for activation in vivo is not known. Factor VIIa can activate blood clotting factors IX and X. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Multi-vitamin and hormone replacement supplement Inventor(s): Fox, Dorothy Jean; (Chesapeake, VA), Schloss, Caroline Maxine; (Knotts Island, NC) Correspondence: Kimberly A Chasteen; Williams Mullen Clark & Dobbins; One Iod Oyster Point Road; Suite 210; Newport News; VA; 23602 Patent Application Number: 20030096018 Date filed: September 23, 2002 Abstract: A supplement is disclosed for use by naturally or surgically menopausal women. The supplement includes: Estrogen, Selenium, Zinc, Chromium, Calcium, Copper, Phosphorus, Magnesium, Molybdenum, Iodine, Beta Carotene, Ascorbic Acid, Vitamin D, Vitamin E, Vitamin K, Thiamin, Riboflavin, Vitamin B6, Vitamin B12, Folic Acid, Iron, Pantothenic Acid, and Biotin. The supplement provides hormone replacement therapy along with nutritional supplements. Excerpt(s): The present invention relates generally to a pharmaceutical supplement for menopausal women and more specifically to a pharmaceutical supplement which combines the hormone estrogen with daily supplemental vitamins to treat menopausal women and women who have undergone complete hysterectomies as more fully set forth in the below specifications, drawings and claims. It is well known that estrogen is critical to a woman's health in that it helps to protect the cardiovascular system, helps protect against bone loss and aids mental sharpness. At menopause or subsequent to a complete hysterectomy, the estrogen levels decline significantly thus, the protective aspects of estrogen are significantly reduced for these women. Because heart disease is a major cause of death in women, this creates an increased risk for menopausal and posthysterectomy women. Further, loss of the protection against bone loss can lead to osteoporosis, another major problem for these women. The impairment of cognitive abilities can be another side effect of the significant estrogen loss suffered in menopause or post-hysterectomy. Additional side effects have been linked to reduced estrogen levels such as urinary incontinence and weight gain. Many women are treated with hormone replacement therapy to help reduce these symptoms. The treatment generally

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consists of supplemental estrogen. This reduces the problems noted above, heart disease, bone loss, loss of cognitive ability, urinary incontinence, weight gain, as well as other well-known symptoms such as hot flashes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Nutritional composition made from conventional foods for mixing onsite in a blender and treating patients with hepatic disorders Inventor(s): Muszynska, Julia; (Staten Island, NY) Correspondence: Julia Muszynska; 108 Center Street; Staten Island; NY; 10306; US Patent Application Number: 20020119181 Date filed: February 26, 2001 Abstract: A nutritional composition made from conventional food mixed on-site in a blender and treating patients with hepatic disorders. The composition includes a vitamin A enriched conventional food, a vitamin D enriched conventional food, a vitamin E enriched conventional food, a vitamin K enriched conventional food, a vitamin C enriched conventional food, a thiamine enriched conventional food, a riboflavin enriched conventional food, a niacin enriched conventional food; a pyridoxine enriched conventional food, a folic acid enriched conventional food, a pantothenic acid enriched conventional food, a vitamin B12 enriched conventional food, a biotin enriched conventional food, a choline enriched conventional food, a sodium enriched conventional food, a potassium enriched conventional food, a chlorine enriched conventional food, a calcium enriched conventional food, a phosphorus enriched conventional food, a magnesium enriched conventional food, a copper enriched conventional food, an Iodine enriched conventional food, a manganese enriched conventional food, and a zinc enriched conventional food. Excerpt(s): The present invention relates to a nutritional composition. More particularly, the present invention relates to a nutritional composition made from conventional foods for mixing onsite in a blender and treating patients with hepatic disorders. The liver, and its proper functioning, is of utmost importance to the survival of a patient. Because it is responsible for the metabolism of nearly all nutrients, and is the primary site for the inactivation of numerous toxins, the liver is one of the most important organs of the body. For example, the liver accounts for approximately 20% of the body's basal metabolism. The liver extracts a majority of the amino acids, carbohydrates, lipids, vitamins, and minerals from portal circulation. These nutrients, extracted by the liver, are used as substrates or cofactors in all metabolic processes carried out in the liver. Synthesis of plasma proteins and bile secretion are additionally important processes carried out by the liver. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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PROCESS FOR PREPARING AGENTS CONTAINING VIRUS-INACTIVATED VITAMIN K- DEPENDENT PLASMA COMPONENTS AS WELL AS PROTEIN C AND PROTEIN S BY MEMBRANE CHROMATOGRAPHY Inventor(s): JOSIC, DJURO; (VIENNA, AT), STRANCAR, ALES; (AJDOVSINA, SI) Correspondence: Jacobson Price Holman & Stern; 400 7th ST NW; Suite 600; Washington; DC; 20004 Patent Application Number: 20020045240 Date filed: August 29, 1996 Abstract: Disclosed is a process for preparing agents containing virus-inactivated vitamin K-dependent plasma components as well as protein C, protein S, factors II, VII, IX and/or X as well as combinations thereof, such as, for example, PPSB preparations, wherein a source containing these components is subjected to appropriate separation procedures, especially by using membrane-chromatographic methods. Excerpt(s): The subject matter of the present invention is a process for preparing agents containing virus-inactivated vitamin K-dependent plasma components as well as protein C and protein S from a source containing these components. Vitamin Kdependent plasma components such as protein C, protein S, the factors II, VII, IX and X are constituents which are contained in blood plasma and play an important role in the pathophysiology of the blood clotting cascade. These factors are employed as medicaments in the therapy of patients exhibiting symptoms caused by a respective deficiency in these factors. Now, blood plasma is not available in any desired amount as a source for a commercial recovery of the factors. Thus, for both ethical and economic reasons it must be the goal of any fractionation and isolation of these vitamin Kdependent plasma components as well as protein C and protein S to ensure a yield as high as possible of each factor alone by itself, on the one hand, and at the same time to also allow an isolation of each of the other factors, on the other hand. It is the object of the invention to provide a process capable of reaching said goal. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Skin treatments containing nano-sized vitamin K Inventor(s): Marchal, Alfred; (Waterloo, BE) Correspondence: Hillary W. Hawkins; Williams Mullen; 1021 East Cary Street; Richmond; VA; 23219; US Patent Application Number: 20030170187 Date filed: March 3, 2003 Abstract: This invention relates to skin treatments containing nano-sized vitamin K. Specifically, the invention relates to a skin treatment containing nano-sized vitamin K for the use in improving the aesthetic aspects of the skin. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/361,234 filed in the United States Patent Office on Mar. 1, 2002. The use of vitamin K for various skin care treatments is known in the art. U.S. Pat. No. 5,510,391 describes a method for treating blood vessel disorders of the skin using non-nano-sized ("conventional") vitamin K. Such disorders include actinic and iatrogenic purpura, lentigines, telangiectasias of the face, spider angiomas and spider veins of the face. The present invention describes a more effective and efficient way to use vitamin K in

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treating the skin. The use of nano-sized vitamin K provides for enhanced penetration through the skin, and therefore, the current treatment has a much quicker response time. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Vitamin K and essential fatty acids Inventor(s): Horrobin, David Frederick; (Stirling, GB) Correspondence: Jacobson Holman; Professional Limited Liability Company; 400 Seventh Street, N.W.; Washington; DC; 20004; US Patent Application Number: 20020025983 Date filed: July 5, 2001 Abstract: Nutritional and pharmaceutical formulations comprising in combination vitamin K and a source of at least one essential fatty acid (EFA) as the essential ingredients, and foodstuff containing EFA(s) and an artificially elevated quantity of vitamin K are provided for the treatment or prevention of a variety of diseases or conditions. Excerpt(s): Vitamin K is a general name for a group of compounds all with similar biological activity. They all contain the 2-methyl-1,4-naphthoqui- none nucleus with a lipophilic side chain at position 3. The three best known members are phylloquinone (vitamin K1) which is the only type of vitamin K found in plants. Vitamin K2, the menaquinones, consists of a family of compounds with variable length isoprenyl side chains. Vitamin K3, menadione, is a pro-vitamin which can be converted to vitamin K2 by animals. Menadione and the menaquinones may occasionally have toxic effects in high doses whereas phylloquinone seems to be safe even in massive overdose. Phylloquinone is therefore the preferred form of the vitamin for human use. Vitamin K compounds are widely distributed in foods. Among animal foods, eggs, butter and liver are good sources and contain amounts of from about 2 to about 50.mu.g/100 g of the food. Green vegetables are also good sources and may contain from 30 to as much as 800.mu.g/100 g of the food. Spinach, kale, sprouts and broccoli are good sources. Vegetable oils, and products made from vegetable oils such as margarines and salad dressings, can also be good sources, containing from 10 to 300.mu.g of vitamin K per 100 g of oil. Olive oil and soy oil are particularly rich in vitamin K. Some vitamin K is also made from gut bacteria although this is difficult to quantitate and may be very variable. The US Recommended Daily Allowance (RDA) for vitamin K starts at 10.mu.g/day for infants and rises to 65.mu.g/day in women and 80.mu.g/day in men. There is, however, evidence that vitamin K from some foods may be relatively poorly absorbed and there have been suggestions that these RDAs for ordinary foods may be somewhat low (BLMG Gijsbers et al, Effect of food composition on vitamin K absorption in human volunteers, Br J Nutrition 1996; 76:223-229). 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 vitamin K, 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,

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and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “vitamin K” (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 vitamin K. You can also use this procedure to view pending patent applications concerning vitamin K. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “vitamin K” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “vitamin K” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “vitamin K” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

Current Advances in Vitamin K Research: Proceedings of the 17th Steenbock Symposium Held June 21st Through June 25th, 1987, at the University of wisc by John W. Suttie (Editor); ISBN: 0444012990; http://www.amazon.com/exec/obidos/ASIN/0444012990/icongroupinterna

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DRI Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, vanadi: Um, and Zinc by National Academy Press (2002); ISBN: 0309072794; http://www.amazon.com/exec/obidos/ASIN/0309072794/icongroupinterna

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Prothrombin and Other Vitamin K Proteins by W.H., Dr. Seegers, D.A., Dr. Waltz (Editor) (1986); ISBN: 084936308X; http://www.amazon.com/exec/obidos/ASIN/084936308X/icongroupinterna

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Vitamin K and Vitamin K-Dependent Proteins: Analytical, Physiological, and Clinical Aspects by Martin J. Shearer, M.J. Seghatchian (Editor); ISBN: 084936423X; http://www.amazon.com/exec/obidos/ASIN/084936423X/icongroupinterna

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Vitamin K metabolism and vitamin K-dependent proteins : [proceedings of the 8th Steenbock Symposium held at the University of Wisconsin--Madison, June 10-13, 1979]; ISBN: 0839115407; http://www.amazon.com/exec/obidos/ASIN/0839115407/icongroupinterna

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Vitamin K-Dependent Biological Processes by Maria B. Donati (Editor) (1986); ISBN: 3805542704; http://www.amazon.com/exec/obidos/ASIN/3805542704/icongroupinterna

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Vitamin K-Dependent Proteins and Their Metabolic Roles by Hidehiko Saito, J.W. Suttie (Editor); ISBN: 0444015663; http://www.amazon.com/exec/obidos/ASIN/0444015663/icongroupinterna

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

Contribution to the study of bone healing with reference to the action of certain therapeutic agents, especially vitamin K. Author: Said, A. H.; Year: 1960; Ghent, State University of Ghent, School of Veterinary Medicine, Clinic for Large Animals, 1960

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DRI, dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc: a report of the Panel on Micronutrients. [et al.]. Author: Institute of Medicine (U.S.). Panel on Micronutrients.; Year: 1962; Washington, D.C.: National Academy Press, c2001; ISBN: 0309072905 http://www.amazon.com/exec/obidos/ASIN/0309072905/icongroupinterna

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Factor X and its behaviour in anti-vitamin K treatment and other deficiency states Author: Wijk, Eduard Marie van.; Year: 2000; Amsterdam: Rodopi, 1981

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Pharmacological aspects of vitamin K1; a clinical and experimental study in man, by J. van der Meer, H. C. Hemker [and] E. A. Loeliger. Author: Meer, Jan van der.; Year: 1978; Stuttgart, New York, Schattauer, 1968

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Vitamin K [by] Hugh R. Butt [and] Albert M. Snell. Author: Butt, Hugh R.,; Year: 1993; Philadelphia, Saunders, 1941

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Vitamin K in infancy: international symposium, Basel, Switzerland, 7-8 October 1994 Author: Sutor, A. H. (Anton H.); Year: 1958; Stuttgart; New York: Schattauer; Basel: Editiones Roche, c1995; ISBN: 3794516117

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

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Vitamin K; annotated bibliography. Author: Merck; co., inc.; Year: 1995; Rahway, N. J., Merck; co. inc., c1941

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Vitamin K; annotated bibliography. Author: Merck; co., inc.; Year: 1995; Rahway, N. J., New York [etc.] Merck; co. inc.; Montreal and Toronto, Merck; co. ltd. [c1940]

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

Differential Diagnosis of Scleroderma-like Disorders Source: in Clements, P.J.; Furst, D.E., Eds. Systemic Sclerosis. Baltimore, MD: Williams and Wilkins. 1996. p. 99-120. Contact: Available from Williams and Wilkins, Special Sales Department. (800) 358-3583. Summary: This chapter for health professionals focuses on the differential diagnosis of scleroderma-like disorders. These disorders include scleredema, scleredema associated with paraproteinemia or myeloma, scleromyxedema, scleroderma-like lesions in endocrine disorders, Werner's syndrome, progeria, sclerodermiform neonatal progeria, restrictive dermopathy, sclerodermiform chronic graft-versus-host disease, and scleroderma-like changes of porphyria cutanea tarda. Other disorders include scleroderma-like lesions in phenylketonuria, congenital fascial dystrophy, sclerodermalike changes induced by bleomycin, scleroderma-like plaques after vitamin K injection, progressive facial hemiatrophy, fibroblastic rheumatism, localized lipoatrophies, lichen sclerosus et atrophicus, sclerodermiform variety of acrodermatitis chronica atrophicans, and atrophoderma Pasini- pierini. Most of these disorders are discussed in terms of their clinical features, pathology and pathophysiology, differential diagnosis, and treatment. 115 references and 10 figures.

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Pediatric Liver Disease Source: in Friedman, L.S. and Keeffe, E.B., eds. Handbook of Liver Disease. Philadelphia, PA: Churchill-Livingstone. 1998. p. 315-325. Contact: Available from W.B. Saunders Company. Book Order Fulfillment Department, 6277 Sea Harbor Drive, Orlando, FL 32887-4430. (800) 545-2522. Fax (800) 874-6418. Email: [email protected]. PRICE: $73.00 plus shipping and handling. ISBN: 0443055203. Summary: This chapter on pediatric liver disease is from a comprehensive handbook in outline format that offers easy access to information on the full range of liver disorders and covers symptoms, signs, differential diagnoses, and treatments. The authors note that acquired liver diseases seen in adults are rare in children. Congenital or metabolic disorders are more common There is physiologic immaturity of the liver during the perinatal period, and significant maturational changes in hepatic metabolic processes

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occur during childhood; these affect the presentation of and reaction to exposure to viruses and toxins. Liver disease may present as hyperbilirubinemia, hepatomegaly, liver cell failure, cirrhosis (liver scarring), cystic disease of the liver, portal hypertension, or systemic disease from secondary effects of liver disease. These secondary effects may be life threatening and include metabolic derangement such as hypoglycemia, coagulopathy secondary to low levels of vitamin K dependent clotting factors resulting in intracranial hemorrhage in the infant, persistent toxic exposure, as may be seen in diseases such as galactosemia or frustosemia, sepsis as a cause of liver disease or as a result of secondary immunodeficiency from malnutrition, or portal hypertension with potential gastrointestinal bleeding. 2 figures. 5 references. •

Oral Manifestations of Systemic Diseases Source: in Eisen, D. and Lynch, D.P. Mouth: Diagnosis and Treatment. St. Louis, MO: Mosby, Inc. 1998. p. 212-236. Contact: Available from Harcourt Health Sciences. Book Order Fulfillment Department, 11830 Westline Industrial Drive, St. Louis, MO 63146-9988. Website: www.mosby.com. PRICE: $79.95 plus shipping and handling. ISBN: 0815131054. Summary: This chapter on the oral manifestations of systemic diseases is from a textbook on the mouth that offers information to primary care physicians and to many specialists in medicine and dentistry. The chapter covers six areas: gastrointestinal diseases, cutaneous diseases, hematologic (blood) diseases, nutritional disorders, connective tissue disorders, and multisystem diseases. Specific conditions discussed include Crohn's disease, ulcerative colitis and pyostomatitis vegetans, hepatitis and other liver disease, psoriasis, pityriasis rosea, acanthosis nigricans, iron deficiency anemia, pernicious anemia, thalassemias, hemolytic disease of the newborn, polycythemia vera, thrombocytopenia, neutropenia, leukemia, multiple myeloma, Langerhans cell histiocytosis, riboflavin (vitamin B12) deficiency, niacin deficiency, folic acid deficiency, pyridoxine deficiency, vitamin C deficiency, vitamin K deficiency, zinc deficiency, Sjogren's syndrome, Melkersson Rosenthal syndrome, Wegener's granulomatosis, lethal midline granuloma, and amyloidosis. For each condition, the authors describe symptoms, identification, complications, and treatment. The chapter is illustrated with numerous full color photographs of the conditions under discussion. 29 figures. 2 tables. 84 references.

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Vitamins and Minerals Source: in Warshaw, H.S. and Webb, R. Diabetes Food and Nutrition Bible: A Complete Guide to Planning, Shopping, Cooking, and Eating. Alexandria, VA: American Diabetes Association. 2001. p. 7-14. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $18.95 plus shipping and handling. ISBN: 158040037. Summary: This chapter on vitamins and minerals is from a book that offers a complete food and nutrition resource for people with diabetes. The book brings readers up to date on meal planning, carbohydrate counting, vitamins, minerals, and the best ways to prepare healthy delicious meals. In this chapter, the authors emphasize that vitamins are essential to the proper functioning of the body and they must be eaten in sufficient quantities to maintain health. The authors describe Recommended Dietary Allowances (RDAs) and several new categories of recommendations being developed under the

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heading of Dietary Reference Intakes (DRIs): Recommended Dietary Allowance, Adequate Intake (AI), Estimated Average Requirement (EAR), and Tolerable Upper Intake Level (UL). The authors then discuss water soluble vitamins, including vitamin B1 (thiamin), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), folate or folic acid, vitamin B12 (cobalamin), vitamin C, and biotin. The chapter then addresses the fat-soluble vitamins, including vitamin A, vitamin D, vitamin E, and vitamin K; and minerals, including calcium, iron, phosphorus, iodine, magnesium, zinc, selenium, copper, fluoride, and chromium. For each vitamin or mineral, the authors note good food sources for obtaining that nutrient. •

Nutritional Disease Source: in Miller, R.L., et al. General and Oral Pathology for the Dental Hygienist. St. Louis, MO: Mosby-Year Book, Inc. 1995. p. 291-308. Contact: Available from Mosby-Year Book, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146-9934. (800) 426-4545 or (314) 872-8370; Fax (800) 535-9935 or (314) 4321380; E-mail: [email protected]; http://www.mosby.com. PRICE: $43.00 plus shipping and handling. ISBN: 0801670241. Stock Number 07024. Summary: This chapter, from a textbook on pathology for dental hygiene students, discusses nutritional disease. Topics covered include the role of diet and genetics in the development of obesity; the significant sequelae of obesity; beriberi; the oral and systemic signs and symptoms of vitamin B complex deficiency; the relationship of vitamin C with the common cold and with cancer; vitamin C deficiency and hypervitaminosis C; the function of vitamin K; chronic vitamin A deficiency and its possible role in several oral lesions; iron deficiency anemia, its etiology and clinical manifestations; Plummer-Vinson syndrome and its relationship to oral cancer; calcium regulation and the causes of hypercalcemia; the role of nutrition in periodontal disease and dental caries; and common mineral deficiencies and their clinical signs and symptoms. The chapter includes a list of learning objectives; illustrative case studies; and recommended readings. 7 figures. 2 tables.

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

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

Drugs which interact with vitamin K antagonists [slide] Source: Health Sciences, McMaster University; produced by Audio Visual Services, McMaster University; Year: 1976; Format: Slide; Hamilton, Ont.: The University, 1976

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

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

Children with cystic fibrosis may benefit from vitamin K supplementation Source: Reuters Industry Breifing Date: December 05, 2003

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Anaphylaxis risk with IV vitamin K low, comparable to that of penicillin Source: Reuters Medical News Date: November 18, 2002

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Vitamin K prevents bone loss in women with cirrhosis Source: Reuters Medical News Date: May 27, 2002

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Vitamin K deficiency common in infants with diarrhea Source: Reuters Medical News Date: April 30, 2001

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Vitamin K reduces blood-clotting time in patients on warfarin Source: Reuters Medical News Date: November 03, 2000

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High vitamin K intake reduces risk of hip fractures in the elderly Source: Reuters Medical News Date: May 04, 2000

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Low vitamin K dose reverses excessive anticoagulation Source: Reuters Medical News Date: August 18, 1999

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Low vitamin K intake increases risk of hip fracture in women Source: Reuters Medical News Date: January 21, 1999

•

Evidence Linking Childhood Leukaemia And Vitamin K Injections Still Inconclusive Source: Reuters Medical News Date: January 16, 1998

•

Cancer Risk From Vitamin K Injections? Source: Reuters Health eLine Date: January 16, 1998

•

Medicis To Market Advanced Polymer's Vitamin K Product Source: Reuters Medical News Date: November 13, 1997

•

Oral Vitamin K1 For Excessive Anticoagulation: Still Important But Use Has Waned Source: Reuters Medical News Date: June 16, 1997

•

Maternal Supplements Increase Vitamin K Levels in Breastfed Infants Source: Reuters Medical News Date: January 16, 1997

•

Vitamin K Injections For Newborns Are Safe Source: Reuters Health eLine Date: July 29, 1996

•

No Association Found Between Vitamin K And Pediatric Cancer Source: Reuters Medical News Date: July 26, 1996

•

Antenatal Vitamin K Does Not Improve Umbilical Blood Prothrombin Times In Preterm Infants Source: Reuters Medical News Date: December 19, 1995

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•

Antenatal Vitamin K and Phenobarbital Do Not Prevent Intracranial Hemorrhage In Preemies Source: Reuters Medical News Date: July 03, 1995

•

Oral Vitamin K Doses Need To Be Radically Increased For Newborns Source: Reuters Medical News Date: April 28, 1995 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 “vitamin K” (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 “vitamin K” (or synonyms). If you know the name of a company that is relevant to vitamin K, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/.

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

Boning Up on Bone Health Source: University of California, Berkeley, Wellness Letter. 16(12):5. September 2000. Contact: Health Letter Associates. P.O. Box 412, Prince Street Station, New York, NY 10012-0007. Summary: Strong bones are dependent on more than just the mineral calcium. Depending on many factors, including testosterone in men and estrogen in women, calcium is laid down in bone and released from it. Weight-bearing exercise such as walking synergizes with nutrients and hormones to build up bone tissue. Lack of activity robs the body of bone mass. The article reviews the other nutrients besides calcium that are necessary for bone health: vitamin C, vitamin K, vitamin D, magnesium, potassium, zinc, copper, manganese, and boron. These nutrients can be found in diets rich in fruits, whole grains, vegetables, low-fat and non-fat dairy products, and fortified cereals. The author also recommends a daily multivitamin and mineral supplement for most people.

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

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CHAPTER 10. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for vitamin K. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with vitamin K. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The

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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to vitamin K: Vitamin K •

Systemic - U.S. Brands: AquaMEPHYTON; Mephyton http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202599.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee. If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

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APPENDICES

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

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

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/

12

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

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•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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

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

•

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

•

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

•

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

•

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

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

13

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 14 See http://www.nlm.nih.gov/databases/databases.html.

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•

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

•

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

The NLM Gateway15 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.16 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “vitamin K” (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 9064 74 923 10 0 10071

HSTAT17 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.18 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.19 Simply search by “vitamin K” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

15

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

16

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 17 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 18 19

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

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

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Coffee Break: Tutorials for Biologists20 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.21 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.22 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

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

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

•

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

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

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

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 22 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 23 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “vitamin K” (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 vitamin K: •

Vitamin K-dependent Clotting Factors, Combined Deficiency Of, 1 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?277450

•

Vitamin K-dependent Clotting Factors, Combined Deficiency Of, 2 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?607473 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, 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,

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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

•

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

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

24

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

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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 vitamin K 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 vitamin K. 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 vitamin K. 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 “vitamin K”:

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•

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Other guides 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 Vitamin and Mineral Supplements http://www.nlm.nih.gov/medlineplus/vitaminandmineralsupplements.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 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 vitamin K. 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

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Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to vitamin K. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with vitamin K. 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 vitamin K. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “vitamin K” (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 “vitamin K”. 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 “vitamin K” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months.

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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 “vitamin K” (or a synonym) into the search box, and click “Submit Query.”

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

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

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

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

26

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

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

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

•

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

•

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

•

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

•

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

•

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

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

27

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

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•

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

•

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

•

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

•

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

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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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

185

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

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

•

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

•

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

•

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

•

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

•

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

•

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

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

Basic Guidelines for Vitamin K Vitamin K Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002407.htm

•

Nutrition for Vitamin K Balanced diet Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002449.htm Vitamins Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002399.htm

•

Background Topics for Vitamin K Food guide pyramid Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002093.htm

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

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

•

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

•

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

•

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

187

VITAMIN K DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 2-Propanol: An isomer of 1-propanol. It is a colorless liquid having disinfectant properties. It is used in the manufacture of acetone and its derivatives and as a solvent. Topically, it is used as an antiseptic. [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] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Acanthosis Nigricans: A circumscribed melanosis consisting of a brown-pigmented, velvety verrucosity or fine papillomatosis appearing in the axillae and other body folds. It occurs in association with endocrine disorders, underlying malignancy, administration of certain drugs, or as in inherited disorder. [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] Acetone: A colorless liquid used as a solvent and an antiseptic. It is one of the ketone bodies produced during ketoacidosis. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acrodermatitis: Inflammation involving the skin of the extremities, especially the hands and feet. Several forms are known, some idiopathic and some hereditary. The infantile form is called Gianotti-Crosti syndrome. [NIH] Acrylonitrile: A highly poisonous compound used widely in the manufacture of plastics, adhesives and synthetic rubber. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH]

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Adhesives: Substances that cause the adherence of two surfaces. They include glues (properly collagen-derived adhesives), mucilages, sticky pastes, gums, resins, or latex. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] 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] Aerobic Metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, oxidative metabolism, or cell respiration. [NIH] Aerobic Respiration: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as oxidative metabolism, cell respiration, or aerobic metabolism. [NIH] Aetiology: Study of the causes of disease. [EU] 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] Affinity Chromatography: In affinity chromatography, a ligand attached to a column binds specifically to the molecule to be purified. [NIH] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Agarose: A polysaccharide complex, free of nitrogen and prepared from agar-agar which is produced by certain seaweeds (red algae). It dissolves in warm water to form a viscid solution. [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] 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

Dictionary 189

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] Alendronate: A nonhormonal medication for the treatment of postmenopausal osteoporosis in women. This drug builds healthy bone, restoring some of the bone loss as a result of osteoporosis. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1. [NIH] 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-fetoprotein: AFP. A protein normally produced by a developing fetus. AFP levels are usually undetectable in the blood of healthy nonpregnant adults. An elevated level of AFP suggests the presence of either a primary liver cancer or germ cell tumor. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alveolar Process: The thickest and spongiest part of the maxilla and mandible hollowed out into deep cavities for the teeth. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a conserved sequence which can be represented by a consensus sequence. [NIH]

Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (-

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COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [NIH] Ammonium Sulfate: Sulfuric acid diammonium salt. It is used in fractionation of proteins. [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] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] 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] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]

Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] 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] Angioid Streaks: Small breaks in the elastin-filled tissue of the retina. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans.

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Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antiallergic: Counteracting allergy or allergic conditions. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]

Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] 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] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] 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] Aorta: The main trunk of the systemic arteries. [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 12-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 12-hydroperoxyarachidonate (12-HPETE) which is itself rapidly converted by a peroxidase to 12-hydroxy-5,8,10,14-eicosatetraenoate (12-HETE). The 12-hydroperoxides are preferentially formed in platelets. EC 1.13.11.31. [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] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [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] Asparaginase: A hydrolase enzyme that converts L-asparagine and water to L-aspartate and NH3. EC 3.5.1.1. [NIH] Aspartate: A synthetic amino acid. [NIH] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH]

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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] Aspiration: The act of inhaling. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astigmatism: A condition in which the surface of the cornea is not spherical; causes a blurred image to be received at the retina. [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] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [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] Atropine: A toxic alkaloid, originally from Atropa belladonna, but found in other plants, mainly Solanaceae. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH] Aztreonam: A monocyclic beta-lactam antibiotic originally isolated from Chromobacterium violaceum. It is resistant to beta-lactamases and is used in gram-negative infections, especially of the meninges, bladder, and kidneys. It may cause a superinfection with grampositive organisms. [NIH] Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [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 Infections: Infections by bacteria, general or unspecified. [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

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or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Barium: An element of the alkaline earth group of metals. It has an atomic symbol Ba, atomic number 56, and atomic weight 138. All of its acid-soluble salts are poisonous. [NIH] Barium Sulfate: Sulfuric acid, barium salt (1:1). A compound used as an x-ray contrast medium that occurs in nature as the mineral barite. It is also used in various manufacturing applications and mixed into heavy concrete to serve as a radiation shield. [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] Basal Metabolism: Heat production, or its measurement, of an organism at the lowest level of cell chemistry in an inactive, awake, fasting state. It may be determined directly by means of a calorimeter or indirectly by calculating the heat production from an analysis of the end products of oxidation within the organism or from the amount of oxygen utilized. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Benzyl Alcohol: A colorless liquid with a sharp burning taste and slight odor. It is used as a local anesthetic and to reduce pain associated with lidocaine injection. Also, it is used in the manufacture of other benzyl compounds, as a pharmaceutic aid, and in perfumery and flavoring. [NIH] Beta-Lactamases: Enzymes found in many bacteria which catalyze the hydrolysis of the amide bond in the beta-lactam ring. Well known antibiotics destroyed by these enzymes are penicillins and cephalosporins. EC 3.5.2.6. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH]

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Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological Factors: Compounds made by living organisms that contribute to or influence a phenomenon or process. They have biological or physiological activities. [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] Biomolecular: A scientific field at the interface between advanced computing and biotechnology. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotic: Pertaining to living organisms in their ecological rather than their physiological relations. [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] 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] Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in

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an insoluble fibrin clot. [NIH] Blood Coagulation Disorders: Hemorrhagic and thrombotic disorders that occur as a consequence of abnormalities in blood coagulation due to a variety of factors sych as coagulation protein disorders, blood platelet disorders, blood protein disorders or nutritional conditions. [NIH] Blood Coagulation Factors: Endogenous substances, usually proteins, that are involved in the blood coagulation process. [NIH] Blood Coagulation Tests: Laboratory tests for evaluating the individual's clotting mechanism. [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] Blood Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH] Blood-Borne Pathogens: Infectious organisms in the blood, of which the predominant medical interest is their contamination of blood-soiled linens, towels, gowns, bandages, other items from individuals in risk categories, needles and other sharp objects, and medical and dental waste, all of which health workers are exposed to. This concept is differentiated from the clinical conditions of bacteremia, viremia, and fungemia where the organism is present in the blood of a patient as the result of a natural infectious process. [NIH] Blue Toe Syndrome: Blue sclera associated with osteogenesis imperfecta. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Regions: Anatomical areas of the body. [NIH] Bone Density: The amount of mineral per square centimeter of bone. This is the definition used in clinical practice. Actual bone density would be expressed in grams per milliliter. It is most frequently measured by photon absorptiometry or x-ray computed tomography. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone Remodeling: The continuous turnover of bone matrix and mineral that involves first, an increase in resorption (osteoclastic activity) and later, reactive bone formation (osteoblastic activity). The process of bone remodeling takes place in the adult skeleton at

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discrete foci. The process ensures the mechanical integrity of the skeleton throughout life and plays an important role in calcium homeostasis. An imbalance in the regulation of bone remodeling's two contrasting events, bone resorption and bone formation, results in many of the metabolic bone diseases, such as osteoporosis. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [NIH] Boron: A trace element with the atomic symbol B, atomic number 5, and atomic weight 10.81. Boron-10, an isotope of boron, is used as a neutron absorber in boron neutron capture therapy. [NIH] Boron Neutron Capture Therapy: A technique for the treatment of neoplasms, especially gliomas and melanomas in which boron-10, an isotope, is introduced into the target cells followed by irradiation with thermal neutrons. [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] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Breast Feeding: The nursing of an infant at the mother's breast. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchial: Pertaining to one or more bronchi. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal

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functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium Chloride: A salt used to replenish calcium levels, as an acid-producing diuretic, and as an antidote for magnesium poisoning. [NIH] Calcium Oxalate: The calcium salt of oxalic acid, occurring in the urine as crystals and in certain calculi. [NIH] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [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] Calorimeter: Measures the amounts of heat absorbed or given off by a solid, a liquid, or a gas. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary Fragility: The lack of resistance, or susceptibility, of capillaries to damage or disruption under conditions of increased stress. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboxy: Cannabinoid. [NIH] Carboxy-terminal: The end of any polypeptide or protein that bears a free carboxyl group. [NIH]

Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] 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] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH]

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Carotenoids: Substance found in yellow and orange fruits and vegetables and in dark green, leafy vegetables. May reduce the risk of developing cancer. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction. [NIH] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] Cathode: An electrode, usually an incandescent filament of tungsten, which emits electrons in an X-ray tube. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caustic: An escharotic or corrosive agent. Called also cauterant. [EU] Cefamandole: Semisynthetic wide-spectrum cephalosporin with prolonged action, probably due to beta-lactamase resistance. It is used also as the nafate. [NIH] Cefoperazone: Semisynthetic broad-spectrum cephalosporin with a tetrazolyl moiety that is resistant to beta-lactamase. It has been proposed especially against Pseudomonas infections. [NIH]

Cefotetan: A semisynthetic cephamycin antibiotic that is administered intravenously or intramuscularly. The drug is highly resistant to a broad spectrum of beta-lactamases and is active against a wide range of both aerobic and anaerobic gram-positive and gram-negative microorganisms. It has a high rate of efficacy in many types of infections and to date no severe side effects have been noted. [NIH] Cefoxitin: Semisynthetic cephamycin antibiotic resistant to beta-lactamase. [NIH] Celiac Disease: A disease characterized by intestinal malabsorption and precipitated by gluten-containing foods. The intestinal mucosa shows loss of villous structure. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing

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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] Cellobiose: A disaccharide consisting of two glucose units in beta (1-4) glycosidic linkage. Obtained from the partial hydrolysis of cellulose. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] 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] 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] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Chlorine: A greenish-yellow, diatomic gas that is a member of the halogen family of elements. It has the atomic symbol Cl, atomic number 17, and atomic weight 70.906. It is a powerful irritant that can cause fatal pulmonary edema. Chlorine is used in manufacturing, as a reagent in synthetic chemistry, for water purification, and in the production of chlorinated lime, which is used in fabric bleaching. [NIH]

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Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholecalciferol: An antirachitic oil-soluble vitamin. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Cholera Toxin: The enterotoxin from Vibrio cholerae. It is a protein that consists of two major components, the heavy (H) or A peptide and the light (L) or B peptide or choleragenoid. The B peptide anchors the protein to intestinal epithelial cells, while the A peptide, enters the cytoplasm, and activates adenylate cyclase, and production of cAMP. Increased levels of cAMP are thought to modulate release of fluid and electrolytes from intestinal crypt cells. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] 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] 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] Chromic: Catgut sterilized and impregnated with chromium trioxide. [NIH] Chromium: A trace element that plays a role in glucose metabolism. It has the atomic symbol Cr, atomic number 24, and atomic weight 52. According to the Fourth Annual Report on Carcinogens (NTP85-002,1985), chromium and some of its compounds have been listed as known carcinogens. [NIH] 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] Circulatory system: The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system. [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] 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]

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Cleave: A double-stranded cut in DNA with a restriction endonuclease. [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] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cod Liver Oil: Oil obtained from fresh livers of the cod family, Gadidae. It is a source of vitamins A and D. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Colectomy: An operation to remove the colon. An open colectomy is the removal of the colon through a surgical incision made in the wall of the abdomen. Laparoscopic-assisted colectomy uses a thin, lighted tube attached to a video camera. It allows the surgeon to remove the colon without a large incision. [NIH] Colic: Paroxysms of pain. This condition usually occurs in the abdominal region but may occur in other body regions as well. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease

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inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Concretion: Minute, hard, yellow masses found in the palpebral conjunctivae of elderly people or following chronic conjunctivitis, composed of the products of cellular degeneration retained in the depressions and tubular recesses in the conjunctiva. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH]

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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 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] 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] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved sequences. [NIH] Consolidation: The healing process of a bone fracture. [NIH] 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] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Corn Oil: Oil from corn or corn plant. [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

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results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Coumarin: A fluorescent dye. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Crystallization: The formation of crystals; conversion to a crystalline form. [EU] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyanide: An extremely toxic class of compounds that can be lethal on inhaling of ingesting in minute quantities. [NIH] Cyanoacrylates: A group of compounds having the general formula CH2=C(CN)-COOR; it polymerizes on contact with moisture; used as tissue adhesive; higher homologs have hemostatic and antibacterial properties. [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] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

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] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Dairy Products: Raw and processed or manufactured milk and milk-derived products. These are usually from cows (bovine) but are also from goats, sheep, reindeer, and water buffalo. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, 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] Decubitus: An act of lying down; also the position assumed in lying down. [EU] Decubitus Ulcer: An ulceration caused by prolonged pressure in patients permitted to lie too still for a long period of time. The bony prominences of the body are the most frequently affected sites. The ulcer is caused by ischemia of the underlying structures of the skin, fat, and muscles as a result of the sustained and constant pressure. [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] 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] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [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]

Dental Waste: Any waste product generated by a dental office, surgery, clinic, or laboratory including amalgams, saliva, and rinse water. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the

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cell membrane potential to become positive with respect to the potential outside the cell. [EU] 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] 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] 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] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] 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] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastolic: Of or pertaining to the diastole. [EU] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Dietary Fiber: The remnants of plant cell walls that are resistant to digestion by the alimentary enzymes of man. It comprises various polysaccharides and lignins. [NIH] Dietitian: An expert in nutrition who helps people plan what and how much food to eat. [NIH]

Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] 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]

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Diosgenin: (25R)-Spirost-5-en-3-beta-ol. A steroid sapogenin which is isolated from various plants. Can be converted to ecdysone, pregnenolone, and progesterone. Synonym: nitogenin. [NIH] Dioxins: Chlorinated hydrocarbons containing heteroatoms that are present as contaminants of herbicides. Dioxins are carcinogenic, teratogenic, and mutagenic. They have been banned from use by the FDA. [NIH] Diphenoxylate: A meperidine congener used as an antidiarrheal, usually in combination with atropine. At high doses, it acts like morphine. Its unesterified metabolite difenoxin has similar properties and is used similarly. It has little or no analgesic activity. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diuresis: Increased excretion of urine. [EU] Diuretic: A drug that increases the production of urine. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended

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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] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Ellagic Acid: A fused four ring compound occurring free or combined in galls. Isolated from the kino of Eucalyptus maculata Hook and E. Hemipholia F. Muell. Activates Factor XII of the blood clotting system which also causes kinin release; used in research and as a dye. [NIH]

Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [NIH] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [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

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embryoge). [NIH] 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] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [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] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Enteral Nutrition: Nutritional support given via the alimentary canal or any route connected to the gastrointestinal system (i.e., the enteral route). This includes oral feeding, sip feeding, and tube feeding using nasogastric, gastrostomy, and jejunostomy tubes. [NIH] Enteric bacteria: Single-celled microorganisms that lack chlorophyll. Some bacteria are capable of causing human, animal, or plant diseases; others are essential in pollution control because they break down organic matter in the air and in the water. [NIH] Enterobactin: An iron-binding cyclic trimer of 2,3-dihydroxy-N-benzoyl-L-serine. It is produced by E. coli and other enteric bacteria. [NIH] Enteroscopy: An examination of the small intestine with an endoscope. The endoscope is inserted through the mouth and stomach into the small intestine. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Enzyme-Linked Immunosorbent Assay: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is

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proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local 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] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythropoiesis: The production of erythrocytes. [EU] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethanolamine: A viscous, hygroscopic amino alcohol with an ammoniacal odor. It is widely distributed in biological tissue and is a component of lecithin. It is used as a surfactant, fluorimetric reagent, and to remove CO2 and H2S from natural gas and other gases. [NIH] Etidronate: A drug that belongs to the family of drugs called bisphosphonates. Bisphosphonates are used as treatment for hypercalcemia (abnormally high levels of calcium in the blood) and for cancer that has spread to the bone (bone metastases). [NIH] Etoposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase

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of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] 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] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Expectorant: 1. Promoting the ejection, by spitting, of mucus or other fluids from the lungs and trachea. 2. An agent that promotes the ejection of mucus or exudate from the lungs, bronchi, and trachea; sometimes extended to all remedies that quiet cough (antitussives). [EU]

Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [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] Extraction: The process or act of pulling or drawing out. [EU] Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. [EU] F Factor: A plasmid whose presence in the cell, either extrachromosomal or integrated into the bacterial chromosome, determines the "sex" of the bacterium, host chromosome mobilization, transfer via conjugation of genetic material, and the formation of sex pili. [NIH] Facial: Of or pertaining to the face. [EU] Facial Hemiatrophy: A syndrome characterized by slowly progressive unilateral atrophy of facial subcutaneous fat, muscle tissue, skin, cartilage, and bone. The condition typically progresses over a period of 2-10 years and then stabilizes. [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] Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Neck Fractures: Fractures of the short, constricted portion of the thigh bone between the femur head and the trochanters. It excludes intertrochanteric fractures which are hip fractures. [NIH] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place

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in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Fetal Development: Morphologic and physiologic growth and development of the mammalian embryo or fetus. [NIH] Fetoprotein: Transabdominal aspiration of fluid from the amniotic sac with a view to detecting increases of alpha-fetoprotein in maternal blood during pregnancy, as this is an important indicator of open neural tube defects in the fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [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] 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]

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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] 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 (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 Coloring Agents: Natural or synthetic dyes used as coloring agents in processed foods. [NIH] Food Preservatives: Substances capable of inhibiting, retarding or arresting the process of fermentation, acidification or other deterioration of foods. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Fungemia: The presence of fungi circulating in the blood. Opportunistic fungal sepsis is seen most often in immunosuppressed patients with severe neutropenia or in postoperative patients with intravenous catheters and usually follows prolonged antibiotic therapy. [NIH] Galactosemia: Buildup of galactose in the blood. Caused by lack of one of the enzymes needed to break down galactose into glucose. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastroenteritis: An acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhoea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Called also enterogastritis. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastrostomy: Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression. [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]

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Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] 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] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [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] 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] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

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

Gluten: The protein of wheat and other grains which gives to the dough its tough elastic character. [EU] Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions

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are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [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] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Goats: Any of numerous agile, hollow-horned ruminants of the genus Capra, closely related to the sheep. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [NIH] 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] Haematoma: A localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel. [EU] Haemodialysis: The removal of certain elements from the blood by virtue of the difference in the rates of their diffusion through a semipermeable membrane, e.g., by means of a haemodialyzer. [EU] Haemorrhage: The escape of blood from the vessels; bleeding. Small haemorrhages are

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classified according to size as petechiae (very small), purpura (up to 1 cm), and ecchymoses (larger). The massive accumulation of blood within a tissue is called a haematoma. [EU] Hallucinogen: A hallucination-producing drug, a category of drugs producing this effect. The user of a hallucinogenic drug is almost invariably aware that what he is seeing are hallucinations. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Health Promotion: Encouraging consumer behaviors most likely to optimize health potentials (physical and psychosocial) through health information, preventive programs, and access to medical care. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart Valves: Flaps of tissue that prevent regurgitation of blood from the ventricles to the atria or from the pulmonary arteries or aorta to the ventricles. [NIH] Hematoma: An extravasation of blood localized in an organ, space, or tissue. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhagic Disorders: Spontaneous or near spontaneous bleeding caused by a defect in clotting mechanisms (blood coagulation disorders) or another abnormality causing a structural flaw in the blood vessels (vascular hemostatic disorders). [NIH] Hemorrhaging: A copious discharge of blood from the blood vessels. [NIH]

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Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis A: Hepatitis caused by hepatovirus. It can be transmitted through fecal contamination of food or water. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hepatoma: A liver tumor. [NIH] Hepatomegaly: Enlargement of the liver. [NIH] Hepatovirus: A genus of Picornaviridae causing infectious hepatitis naturally in humans and experimentally in other primates. It is transmitted through fecal contamination of food or water. [NIH] Herbicides: Pesticides used to destroy unwanted vegetation, especially various types of weeds, grasses, and woody plants. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Hip Fractures: Fractures of the femur head, the femur neck, the trochanters, or the inter- or subtrochanteric region. Excludes fractures of the acetabulum and fractures of the femoral shaft below the subtrochanteric region. For the fractures of the femur neck the specific term femoral neck fractures is available. [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH]

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Histiocytosis: General term for the abnormal appearance of histiocytes in the blood. Based on the pathological features of the cells involved rather than on clinical findings, the histiocytic diseases are subdivided into three groups: Langerhans cell histiocytosis, nonLangerhans cell histiocytosis, and malignant histiocytic disorders. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [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] Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Hospital Records: Compilations of data on hospital activities and programs; excludes patient medical records. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Human growth hormone: A protein hormone, secreted by the anterior lobe of the pituitary, which promotes growth of the whole body by stimulating protein synthesis. The human gene has already been cloned and successfully expressed in bacteria. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [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] 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] 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]

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Vitamin K

Hygienic: Pertaining to hygiene, or conducive to health. [EU] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperopia: Farsightedness; ability to see distant objects more clearly than close objects; may be corrected with glasses or contact lenses. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypervitaminosis: A condition due to ingestion of an excess of one or more vitamins; called also supervitaminosis. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypovitaminosis: A condition due to a deficiency of one or more essential vitamins. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hysterectomy: Excision of the uterus. [NIH] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Ice Cream: A frozen dairy food made from cream or butterfat, milk, sugar, and flavorings. Frozen custard and French-type ice creams also contain eggs. [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] Ileostomy: Surgical creation of an external opening into the ileum for fecal diversion or drainage. Loop or tube procedures are most often employed. [NIH] Ileum: The lower end of the small intestine. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immaturity: The state or quality of being unripe or not fully developed. [EU] Immune Complex Diseases: Group of diseases mediated by the deposition of large soluble complexes of antigen and antibody with resultant damage to tissue. Besides serum sickness and the arthus reaction, evidence supports a pathogenic role for immune complexes in many other systemic immunologic diseases including glomerulonephritis, systemic lupus erythematosus and polyarteritis nodosa. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity:

Nonsusceptibility

to

the

invasive

or

pathogenic

effects

of

foreign

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microorganisms or to the toxic effect of antigenic substances. [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] Immunogen: A substance that is capable of causing antibody formation. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] 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 Nutrition: Nutrition of children from birth to 2 years of age. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH]

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Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] 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] 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] Intermediate Filaments: Cytoplasmic filaments intermediate in diameter (about 10 nanometers) between the microfilaments and the microtubules. They may be composed of any of a number of different proteins and form a ring around the cell nucleus. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] International Normalized Ratio: System established by the World Health Organization and the International Committee on Thrombosis and Hemostasis for monitoring and reporting blood coagulation tests. Under this system, results are standardized using the International Sensitivity Index for the particular test reagent/instrument combination used. [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] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravascular: Within a vessel or vessels. [EU] 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] Involuntary: Reaction occurring without intention or volition. [NIH]

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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] Ion Exchange: Reversible chemical reaction between a solid, often an ION exchange resin, and a fluid whereby ions may be exchanged from one substance to another. This technique is used in water purification, in research, and in industry. [NIH] 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] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoelectric: Separation of amphoteric substances, dissolved in water, based on their isoelectric behavior. The amphoteric substances are a mixture of proteins to be separated and of auxiliary "carrier ampholytes". [NIH] Isoelectric Focusing: Electrophoresis in which a pH gradient is established in a gel medium and proteins migrate until they reach the site (or focus) at which the pH is equal to their isoelectric point. [NIH] Isoelectric Point: The pH in solutions of proteins and related compounds at which the dipolar ions are at a maximum. [NIH] Isoniazid: Antibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis. [NIH] Isopropyl: A gene mutation inducer. [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]

Jejunostomy: Surgical formation of an opening through the abdominal wall into the jejunum, usually for enteral hyperalimentation. [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] Keratolytic: An agent that promotes keratolysis. [EU] Ketamine: A cyclohexanone derivative used for induction of anesthesia. Its mechanism of action is not well understood, but ketamine can block NMDA receptors (receptors, NMethyl-D-Aspartate) and may interact with sigma receptors. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lactates: Salts or esters of lactic acid containing the general formula CH3CHOHCOOR. [NIH] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH]

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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] Lenses: Pieces of glass or other transparent materials used for magnification or increased visual acuity. [NIH] Leprosy: A chronic granulomatous infection caused by Mycobacterium leprae. The granulomatous lesions are manifested in the skin, the mucous membranes, and the peripheral nerves. Two polar or principal types are lepromatous and tuberculoid. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] 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] Leukocytosis: A transient increase in the number of leukocytes in a body fluid. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Lidocaine: A local anesthetic and cardiac depressant used as an antiarrhythmia agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine. [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] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] 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]

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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] 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]

Liver Extracts: Extracts of liver tissue containing uncharacterized specific factors with specific activities; a soluble thermostable fraction of mammalian liver is used in the treatment of pernicious anemia. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view and on which the outline of the object may be traced. [NIH] Lumen: The cavity or channel within a tube or tubular organ. [EU] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lycopene: A red pigment found in tomatoes and some fruits. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [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] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH]

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Macronutrients: Nutrients in the diet that are the key sources of energy, namely protein, fat, and carbohydrates. [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] Maculopapular: Both macular and papular, as an eruption consisting of both macules and papules; sometimes erroneously used to designate a papule that is only slightly elevated. [EU]

Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Maternal Exposure: Exposure of the female parent, human or animal, 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 that may affect offspring. It includes pre-conception maternal exposure. [NIH] 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]

Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] 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] 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

Dictionary 227

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] Melanosis: Disorders of increased melanin pigmentation that develop without preceding inflammatory disease. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Meperidine: 1-Methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester. A narcotic analgesic that can be used for the relief of most types of moderate to severe pain, including postoperative pain and the pain of labor. Prolonged use may lead to dependence of the morphine type; withdrawal symptoms appear more rapidly than with morphine and are of shorter duration. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Metoclopramide: A dopamine D2 antagonist that is used as an antiemetic. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH]

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Microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. [NIH] Microgram: A unit of mass (weight) of the metric system, being one-millionth of a gram (106 gm.) or one one-thousandth of a milligram (10-3 mg.). [EU] 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 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] Microtubule-Associated Proteins: High molecular weight proteins found in the microtubules of the cytoskeletal system. Under certain conditions they are required for tubulin assembly into the microtubules and stabilize the assembled microtubules. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Midwifery: The practice of assisting women in childbirth. [NIH] Milligram: A measure of weight. A milligram is approximately 450,000-times smaller than a pound and 28,000-times smaller than an ounce. [NIH] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Mineralization: The action of mineralizing; the state of being mineralized. [EU] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [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] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH]

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Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] 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] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] 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] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [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] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [NIH]

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Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] 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] Nasogastric: The process of passing a small, flexible plastic tube through the nose or mouth into the stomach or small intestine. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neocortex: The largest portion of the cerebral cortex. It is composed of neurons arranged in six layers. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU]

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Neural tube defects: These defects include problems stemming from fetal development of the spinal cord, spine, brain, and skull, and include birth defects such as spina bifida, anencephaly, and encephalocele. Neural tube defects occur early in pregnancy at about 4 to 6 weeks, usually before a woman knows she is pregnant. Many babies with neural tube defects have difficulty walking and with bladder and bowel control. [NIH] Neurofibrillary Tangles: Abnormal structures located in various parts of the brain and composed of dense arrays of paired helical filaments (neurofilaments and microtubules). These double helical stacks of transverse subunits are twisted into left-handed ribbon-like filaments that likely incorporate the following proteins: (1) the intermediate filaments: medium- and high-molecular-weight neurofilaments; (2) the microtubule-associated proteins map-2 and tau; (3) actin; and (4) ubiquitin. As one of the hallmarks of Alzheimer disease, the neurofibrillary tangles eventually occupy the whole of the cytoplasm in certain classes of cell in the neocortex, hippocampus, brain stem, and diencephalon. The number of these tangles, as seen in post mortem histology, correlates with the degree of dementia during life. Some studies suggest that tangle antigens leak into the systemic circulation both in the course of normal aging and in cases of Alzheimer disease. [NIH] Neurofilaments: Bundle of neuronal fibers. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] 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] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [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] Niacinamide: An important compound functioning as a component of the coenzyme NAD. Its primary significance is in the prevention and/or cure of blacktongue and pellagra. Most animals cannot manufacture this compound in amounts sufficient to prevent nutritional deficiency and it therefore must be supplemented through dietary intake. [NIH] Nickel: A trace element with the atomic symbol Ni, atomic number 28, and atomic weight 58.69. It is a cofactor of the enzyme urease. [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] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a

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mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] 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] Nutrition Assessment: Evaluation and measurement of nutritional variables in order to assess the level of nutrition or the nutritional status of the individual. Nutrition surveys may be used in making the assessment. [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] Occult: Obscure; concealed from observation, difficult to understand. [EU] Octreotide: A potent, long-acting somatostatin octapeptide analog which has a wide range of physiological actions. It inhibits growth hormone secretion, is effective in the treatment of hormone-secreting tumors from various organs, and has beneficial effects in the management of many pathological states including diabetes mellitus, orthostatic hypertension, hyperinsulinism, hypergastrinemia, and small bowel fistula. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] 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] Oligopeptides: Peptides composed of between two and twelve amino acids. [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] 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] Opacity: Degree of density (area most dense taken for reading). [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Ophthalmic: Pertaining to the eye. [EU] Oral Manifestations: Disorders of the mouth attendant upon non-oral disease or injury. [NIH]

Orf: A specific disease of sheep and goats caused by a pox-virus that is transmissible to man

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and characterized by vesiculation and ulceration of the lips. [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] Orthostatic: Pertaining to or caused by standing erect. [EU] 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] Ossification: The formation of bone or of a bony substance; the conversion of fibrous tissue or of cartilage into bone or a bony substance. [EU] Osteoblasts: Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. [NIH] Osteocalcin: Vitamin K-dependent calcium-binding protein synthesized by osteoblasts and found primarily in bone. Serum osteocalcin measurements provide a noninvasive specific marker of bone metabolism. The protein contains three residues of the amino acid gammacarboxyglutamic acid (GLA), which, in the presence of calcium, promotes binding to hydroxyapatite and subsequent accumulation in bone matrix. [NIH] Osteogenesis: The histogenesis of bone including ossification. It occurs continuously but particularly in the embryo and child and during fracture repair. [NIH] Osteogenesis Imperfecta: A collagen disorder resulting from defective biosynthesis of type I collagen and characterized by brittle, osteoporotic, and easily fractured bones. It may also present with blue sclerae, loose joints, and imperfect dentin formation. There are four major types, I-IV. [NIH] Osteomalacia: A condition marked by softening of the bones (due to impaired mineralization, with excess accumulation of osteoid), with pain, tenderness, muscular weakness, anorexia, and loss of weight, resulting from deficiency of vitamin D and calcium. [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] Osteosclerosis: An abnormal hardening or increased density of bone tissue. [NIH] Ovariectomy: The surgical removal of one or both ovaries. [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] Overdosage: 1. The administration of an excessive dose. 2. The condition resulting from an excessive dose. [EU] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxalic Acid: A strong dicarboxylic acid occurring in many plants and vegetables. It is produced in the body by metabolism of glyoxylic acid or ascorbic acid. It is not metabolized but excreted in the urine. It is used as an analytical reagent and general reducing agent. [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)

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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]

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] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pamidronate: A drug that belongs to the family of drugs called bisphosphonates. Pamidronate is used as treatment for abnormally high levels of calcium in the blood. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] 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] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parenteral Nutrition: The administering of nutrients for assimilation and utilization by a patient who cannot maintain adequate nutrition by enteral feeding alone. Nutrients are administered by a route other than the alimentary canal (e.g., intravenously, subcutaneously). [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Partial Thromboplastin Time: Test of the intrinsic (factors VIII, IX, XI, and XII) and common (fibrinogen, prothrombin, factors V and X) pathways of coagulation in which a mixture of plasma and phospholipid platelet substitute (e.g., crude cephalins, soybean phosphatides) is recalcified and the time required for the appearance of fibrin strands measured. Activation may be provided by contact with the glass tube or exposure to activators (e.g., ellagic acid, particulate silicates such as diatomaceous earth or kaolin) before addition of the calcium chloride. It is used as a screening test and to monitor heparin therapy. [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]

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Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pelvic: Pertaining to the pelvis. [EU] Penicillin: An antibiotic drug used to treat infection. [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] Perennial: Lasting through the year of for several years. [EU] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Peripheral Nerves: The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [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] Pernicious: Tending to a fatal issue. [EU] Pernicious anemia: A type of anemia (low red blood cell count) caused by the body's inability to absorb vitamin B12. [NIH] Petechiae: Pinpoint, unraised, round red spots under the skin caused by bleeding. [NIH] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is

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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] 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] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure; also, such effects on the actions of a particular drug or drugs. [EU] Pharmacogenetics: A branch of genetics which deals with the genetic components of variability in individual responses to and metabolism (biotransformation) of drugs. [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] Phencyclidine: A hallucinogen formerly used as a veterinary anesthetic, and briefly as a general anesthetic for humans. Phencyclidine is similar to ketamine in structure and in many of its effects. Like ketamine, it can produce a dissociative state. It exerts its pharmacological action through inhibition of NMDA receptors (receptors, N-methyl-Daspartate). As a drug of abuse, it is known as PCP and Angel Dust. [NIH] Phenobarbital: A barbituric acid derivative that acts as a nonselective central nervous system depressant. It promotes binding to inhibitory GABA subtype receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. [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] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not

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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] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] 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] Phytonadione: 2-Methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-1,4-naphthalenedione. A fat-soluble vitamin occurring naturally as the trans-isomer. It is used in the treatment of prothrombinemias. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Pityriasis: A name originally applied to a group of skin diseases characterized by the formation of fine, branny scales, but now used only with a modifier. [EU] Pityriasis Rosea: A mild exanthematous inflammation of unknown etiology. It is characterized by the presence of salmon-colored maculopapular lesions. The most striking feature is the arrangement of the lesions such that the long axis is parallel to the lines of cleavage. The eruptions are usually generalized, affecting chiefly the trunk, and the course is often self-limiting. [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] Plant Diseases: Diseases of plants. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a

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fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma Exchange: Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (PPF), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Transfusion: The transfer of blood platelets from a donor to a recipient or reinfusion to the donor. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]

Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [NIH] 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] 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] Polycythemia Vera: A myeloproliferative disorder of unknown etiology, characterized by abnormal proliferation of all hematopoietic bone marrow elements and an absolute increase in red cell mass and total blood volume, associated frequently with splenomegaly,

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leukocytosis, and thrombocythemia. Hematopoiesis is also reactive in extramedullary sites (liver and spleen). In time myelofibrosis occurs. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyvalent: Having more than one valence. [EU] Porphyria: A group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [NIH]

Porphyria Cutanea Tarda: A form of hepatic porphyria (porphyria, hepatic) characterized by photosensitivity resulting in bullae that rupture easily to form shallow ulcers. This condition occurs in two forms: a sporadic, nonfamilial form that begins in middle age and has normal amounts of uroporphyrinogen decarboxylase with diminished activity in the liver; and a familial form in which there is an autosomal dominant inherited deficiency of uroporphyrinogen decarboxylase in the liver and red blood cells. [NIH] Porphyria, Hepatic: Porphyria in which the liver is the site where excess formation of porphyrin or its precursors is found. Acute intermittent porphyria and porphyria cutanea tarda are types of hepatic porphyria. [NIH] Porphyrins: A group of compounds containing the porphin structure, four pyrrole rings connected by methine bridges in a cyclic configuration to which a variety of side chains are attached. The nature of the side chain is indicated by a prefix, as uroporphyrin, hematoporphyrin, etc. The porphyrins, in combination with iron, form the heme component in biologically significant compounds such as hemoglobin and myoglobin. [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] Postmenopause: The physiological period following the menopause, the permanent cessation of the menstrual life. Since in the United States the age of the menopause ranges between 48 and 55 years, generally conceived as middle age, the postmenopause often refers to women considerably older. [NIH] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Citrate: A powder that dissolves in water, which is administered orally, and is used as a diuretic, expectorant, systemic alkalizer, and electrolyte replenisher. [NIH]

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Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precipitation: The act or process of precipitating. [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] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Pregnenolone: Steroid hormone. [NIH] Prekallikrein: A plasma protein which is the precursor of kallikrein. Plasma that is deficient in prekallikrein has been found to be abnormal in thromboplastin formation, kinin generation, evolution of a permeability globulin, and plasmin formation. The absence of prekallikrein in plasma leads to Fletcher factor deficiency, a congenital disease. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] 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] Proctocolectomy: An operation to remove the colon and rectum. Also called coloproctectomy. [NIH] Proenzyme: 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] Progeria: An abnormal congenital condition characterized by premature aging in children, where all the changes of cell senescence occur. It is manifested by premature greying, hair loss, hearing loss, cataracts, arthritis,osteoporosis, diabetes mellitus, atrophy of subcutaneous fat, skeletal hypoplasia, and accelerated atherosclerosis. Many affected individuals develop malignant tumors, especially sarcomas. [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] 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] Prophylaxis: An attempt to prevent disease. [NIH]

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Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]

Prothrombin Time: Measurement of clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen, prothrombin, and factors V, VII, and X. It is used for monitoring anticoagulant therapy with coumarins. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pseudoxanthoma: A rare disease of the skin characterized by the appearance of elevated yellowish papules or plaques, particularly on the neck, chest an abdomen and infrequently on the eyelids. [NIH] Pseudoxanthoma Elasticum: A rare, progressive inherited disorder resulting from extensive basophilic degeneration of elastic tissue, usually presenting after puberty and involving the skin, eye, and cardiovascular system. Characteristic manifestations are small, circumscribed yellowish patches at sites of considerable movement of the skin, angioid streaks in the retina, and a tendency towards hemorrhage and arterial insufficiency. [NIH]

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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] 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 Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [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]

Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a 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.

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Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioimmunoassay: Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Nonimmunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. [NIH] Raloxifene: A second generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women. It has estrogen agonist effects on bone and cholesterol metabolism but behaves as a complete estrogen antagonist on mammary gland and uterine tissue. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU]

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Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Research Design: A plan for collecting and utilizing data so that desired information can be obtained with sufficient precision or so that an hypothesis can be tested properly. [NIH] Resected: Surgical removal of part of an organ. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] 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] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoids: Derivatives of vitamin A. Used clinically in the treatment of severe cystic acne, psoriasis, and other disorders of keratinization. Their possible use in the prophylaxis and treatment of cancer is being actively explored. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] 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] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rickets: A condition caused by deficiency of vitamin D, especially in infancy and childhood, with disturbance of normal ossification. The disease is marked by bending and distortion of the bones under muscular action, by the formation of nodular enlargements on the ends and sides of the bones, by delayed closure of the fontanelles, pain in the muscles, and sweating

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of the head. Vitamin D and sunlight together with an adequate diet are curative, provided that the parathyroid glands are functioning properly. [EU] Rifamycins: A group of antibiotics characterized by a chromophoric naphthohydroquinone group spanned by an aliphatic bridge not previously found in other known antibiotics. They have been isolated from fermentation broths of Streptomyces mediterranei. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [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] Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Rutin: 3-((6-O-(6-Deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranosyl)oxy)-2-(3,4dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one. Found in many plants, including buckwheat, tobacco, forsythia, hydrangea, pansies, etc. It has been used therapeutically to decrease capillary fragility. [NIH] Saline: A solution of salt and water. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] 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,

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excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [NIH] 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] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] 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] 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] Sharpness: The apparent blurring of the border between two adjacent areas of a radiograph having different optical densities. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as

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the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] 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 Care: Maintenance of the hygienic state of the skin under optimal conditions of cleanliness and comfort. Effective in skin care are proper washing, bathing, cleansing, and the use of soaps, detergents, oils, etc. In various disease states, therapeutic and protective solutions and ointments are useful. The care of the skin is particularly important in various occupations, in exposure to sunlight, in neonates, and in decubitus ulcer. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Soaps: Sodium or potassium salts of long chain fatty acids. These detergent substances are obtained by boiling natural oils or fats with caustic alkali. Sodium soaps are harder and are used as topical anti-infectives and vehicles in pills and liniments; potassium soaps are soft, used as vehicles for ointments and also as topical antimicrobials. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland,

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27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Lactate: The sodium salt of racemic or inactive lactic acid. It is a hygroscopic agent used intravenously as a systemic and urinary alkalizer. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] 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] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [NIH] Space Flight: Travel beyond the earth's atmosphere. [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] 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] 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] Splenomegaly: Enlargement of the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilizer: A device for maintaining constant X-ray tube voltage or current. [NIH] Staurosporine: A drug that belongs to the family of drugs called alkaloids. It is being studied in the treatment of cancer. [NIH]

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Steady state: Dynamic equilibrium. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Sterilization: The destroying of all forms of life, especially microorganisms, by heat, chemical, or other means. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

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] Streptomycin: O-2-Deoxy-2-(methylamino)-alpha-L-glucopyranosyl-(1-2)-O-5- deoxy-3-Cformyl-alpha-L-lyxofuranosyl-(1-4)-N,N'-bis(aminoiminomethyl)-D-streptamine. Antibiotic substance produced by the soil actinomycete Streptomyces griseus. It acts by inhibiting the initiation and elongation processes during protein synthesis. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] 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] Styrene: A colorless, toxic liquid with a strong aromatic odor. It is used to make rubbers, polymers and copolymers, and polystyrene plastics. [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]

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Vitamin K

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] Subtrochanteric: Below a trochanter. [NIH] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] 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] Superinfection: A frequent complication of drug therapy for microbial infection. It may result from opportunistic colonization following immunosuppression by the primary pathogen and can be influenced by the time interval between infections, microbial physiology, or host resistance. Experimental challenge and in vitro models are sometimes used in virulence and infectivity studies. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Surface Plasmon Resonance: A biosensing technique in which biomolecules capable of binding to specific analytes or ligands are first immobilized on one side of a metallic film. Light is then focused on the opposite side of the film to excite the surface plasmons, that is, the oscillations of free electrons propagating along the film's surface. The refractive index of light reflecting off this surface is measured. When the immobilized biomolecules are bound by their ligands, an alteration in surface plasmons on the opposite side of the film is created which is directly proportional to the change in bound, or adsorbed, mass. Binding is measured by changes in the refractive index. The technique is used to study biomolecular interactions, such as antigen-antibody binding. [NIH] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]

Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [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]

Dictionary 251

Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] 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-

Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thromboembolism: Obstruction of a vessel by a blood clot that has been transported from a distant site by the blood stream. [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]

Thromboplastin: Constituent composed of protein and phospholipid that is widely distributed in many tissues. It serves as a cofactor with factor VIIa to activate factor X in the extrinsic pathway of blood coagulation. [NIH] Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH]

252

Vitamin K

Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tin: A trace element that is required in bone formation. It has the atomic symbol Sn, atomic number 50, and atomic weight 118.71. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [NIH] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [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] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Translation: The process whereby the genetic information present in the linear sequence of

Dictionary 253

ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Trees: Woody, usually tall, perennial higher plants (Angiosperms, Gymnosperms, and some Pterophyta) having usually a main stem and numerous branches. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberculostatic: Inhibiting the growth of Mycobacterium tuberculosis. [EU] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquinone: A lipid-soluble benzoquinone which is involved in electron transport in mitochondrial preparations. The compound occurs in the majority of aerobic organisms, from bacteria to higher plants and animals. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Ultraviolet Rays: That portion of the electromagnetic spectrum immediately below the visible range and extending into the x-ray frequencies. The longer wavelengths (near-UV or biotic or vital rays) are necessary for the endogenous synthesis of vitamin D and are also called antirachitic rays; the shorter, ionizing wavelengths (far-UV or abiotic or extravital rays) are viricidal, bactericidal, mutagenic, and carcinogenic and are used as disinfectants. [NIH]

Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH]

254

Vitamin K

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]

Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uroporphyrinogen Decarboxylase: One of the enzymes active in heme biosynthesis. It catalyzes the decarboxylation of uroporphyrinogen III to coproporphyrinogen III by the conversion of four acetic acid groups to four methyl groups. EC 4.1.1.37. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [NIH]

Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vanadium: Vanadium. A metallic element with the atomic symbol V, atomic number 23, and atomic weight 50.94. It is used in the manufacture of vanadium steel. Prolonged exposure can lead to chronic intoxication caused by absorption usually via the lungs. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular Hemostatic Disorders: Alterations in the mechanical integrity or structure of the blood vessels leading to bleeding disorders. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venom: That produced by the poison glands of the mouth and injected by the fangs of poisonous snakes. [NIH] Venous: Of or pertaining to the veins. [EU] Venous Thrombosis: The formation or presence of a thrombus within a vein. [NIH] Ventricles: Fluid-filled cavities in the heart or brain. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vibrio: A genus of Vibrionaceae, made up of short, slightly curved, motile, gram-negative rods. Various species produce cholera and other gastrointestinal disorders as well as

Dictionary 255

abortion in sheep and cattle. [NIH] Vibrio cholerae: The etiologic agent of cholera. [NIH] Villous: Of a surface, covered with villi. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] Viremia: The presence of viruses in the blood. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] 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 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] Vitamin K: A substance that promotes the clotting of blood. [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] Warfarin: An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. [NIH] Weight Gain: Increase in body weight over existing weight. [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]

Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH]

256

Vitamin K

Zoledronate: A drug that belongs to the family of drugs called bisphosphonates. It is used to prevent bone fractures and reduce bone pain in people who have cancer that has spread to the bone. [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]

257

INDEX 2 2-Propanol, 137, 187 A Abdomen, 187, 197, 202, 222, 225, 234, 235, 241, 248, 249, 255 Abdominal, 92, 187, 202, 214, 223, 234, 235, 253 Abdominal Pain, 187, 214, 253 Acanthosis Nigricans, 154, 187 Acceptor, 126, 187, 224, 234, 252 Acetone, 187 Acetylcholine, 187, 201 Acrodermatitis, 153, 187 Acrylonitrile, 187, 245 Actin, 187, 231 Acute renal, 92, 187, 217 Adaptability, 187, 199, 200 Adduct, 116, 138, 187 Adenocarcinoma, 187, 218 Adenosine, 187, 197, 237 Adenylate Cyclase, 187, 201 Adhesives, 140, 187, 188 Adrenal Cortex, 188, 205, 240 Adrenal Glands, 188, 190 Adsorption, 133, 137, 188 Adsorptive, 188 Adverse Effect, 188, 247 Aerobic, 10, 188, 199, 228, 253 Aerobic Metabolism, 188 Aerobic Respiration, 10, 188 Aetiology, 67, 188 Affinity, 11, 13, 47, 53, 65, 69, 89, 91, 120, 122, 123, 135, 138, 144, 145, 188, 224, 247 Affinity Chromatography, 122, 123, 138, 188 Agar, 188, 237 Agarose, 138, 188 Agonist, 188, 208, 243 Albumin, 113, 188, 196, 238, 243, 246 Alendronate, 107, 189 Alertness, 189, 197 Algorithms, 189, 195 Alimentary, 189, 207, 210, 234 Alkaline, 28, 112, 119, 189, 194, 197, 236 Alkaline Phosphatase, 28, 119, 189 Alpha Particles, 189, 242 Alpha-fetoprotein, 43, 55, 189, 213

Alternative medicine, 85, 104, 161, 189, 203 Alveolar Process, 189, 244 Amine, 189, 218 Amino Acid Motifs, 189, 204 Amino Acid Sequence, 135, 189, 191, 204, 215 Amino-terminal, 119, 142, 190 Ammonium Sulfate, 138, 190 Amyloid, 144, 190 Amyloidosis, 154, 190 Anaerobic, 26, 31, 190, 199 Anaesthesia, 190, 221 Analgesic, 190, 208, 227, 229 Analog, 8, 41, 61, 190, 232 Analytes, 190, 250 Anaphylatoxins, 190, 203 Anatomical, 190, 196, 210, 221, 245 Androgens, 188, 190, 205 Anemia, 154, 155, 173, 190, 214, 225, 229, 235 Anesthesia, 190, 223 Angiogenesis, 21, 190 Angioid Streaks, 190, 241 Animal model, 16, 17, 30, 190 Anions, 189, 191, 223, 246 Anorexia, 191, 214, 233 Antagonism, 61, 75, 97, 105, 191, 197 Antiallergic, 191, 205 Antibacterial, 191, 205, 223, 248 Antibiotic, 33, 100, 191, 193, 197, 199, 214, 235, 248, 249 Antibodies, 16, 21, 23, 26, 34, 90, 119, 120, 122, 133, 135, 191, 217, 225, 229, 238 Antibody, 26, 62, 85, 88, 120, 123, 124, 137, 188, 191, 203, 210, 211, 217, 219, 220, 221, 226, 229, 242, 243, 248, 250 Anticonvulsant, 75, 93, 191 Antiemetic, 191, 227 Antigen, 48, 62, 120, 128, 188, 191, 203, 210, 219, 220, 221, 226, 243, 250 Antigen-Antibody Complex, 191, 203 Anti-infective, 191, 214, 223, 247 Anti-Infective Agents, 191, 214 Anti-inflammatory, 40, 191, 193, 205, 207, 215, 240 Anti-Inflammatory Agents, 191, 193, 205 Antineoplastic, 191, 195, 205, 238

258

Vitamin K

Antioxidant, 192, 234 Antiseptic, 187, 192 Aorta, 192, 217 Apolipoproteins, 192, 224 Apoptosis, 29, 35, 40, 65, 89, 192 Aqueous, 113, 192, 194, 205, 210 Arachidonate 12-Lipoxygenase, 192, 225 Arachidonate 15-Lipoxygenase, 192, 225 Arachidonate Lipoxygenases, 192, 225 Arterial, 16, 19, 35, 87, 192, 201, 220, 241, 250 Arteries, 16, 23, 192, 196, 204, 217, 225, 227, 230 Arterioles, 192, 196, 198 Ascites, 91, 192 Ascorbic Acid, 134, 145, 192, 219, 233 Asparaginase, 57, 192 Aspartate, 192, 223, 236 Aspartic, 142, 192, 193 Aspartic Acid, 142, 192, 193 Aspiration, 35, 193, 213 Aspirin, 35, 193 Assay, 21, 23, 46, 49, 53, 93, 119, 120, 121, 124, 135, 136, 193, 210, 221, 243 Astigmatism, 193, 243 Ataxia, 172, 173, 193, 251 Atrial, 193, 255 Atrial Fibrillation, 193, 255 Atrophy, 172, 173, 193, 212, 229, 240 Atropine, 193, 208 Autoimmune disease, 193, 238 Autosuggestion, 193, 220 Aztreonam, 31, 193 B Bacteremia, 193, 196 Bacterial Infections, 122, 193 Bactericidal, 122, 193, 211, 253 Bacteriophage, 193, 237, 252 Bacterium, 20, 193, 204, 212, 217 Barium, 121, 123, 138, 194 Barium Sulfate, 123, 138, 194 Basal Ganglia, 193, 194 Basal Ganglia Diseases, 193, 194 Basal Metabolism, 146, 194 Base, 14, 62, 135, 137, 194, 206, 212, 215, 223, 236, 238, 250 Base Sequence, 194, 215 Basement Membrane, 194, 212, 223 Benzyl Alcohol, 125, 194 Beta-Lactamases, 193, 194, 199 Beta-pleated, 190, 194

Bile, 48, 100, 126, 146, 194, 195, 214, 223, 225, 249 Bile Acids, 126, 194, 249 Bile Acids and Salts, 194 Biliary, 194, 198 Biliary Tract, 194, 198 Bilirubin, 189, 195, 220 Binding Sites, 14, 65, 71, 91, 121, 195 Bioavailability, 144, 195 Biochemical, 12, 13, 14, 16, 27, 37, 40, 43, 49, 75, 91, 119, 195, 213, 216, 236 Biological Factors, 136, 195 Biological therapy, 195, 216 Biomolecular, 195, 250 Biosynthesis, 8, 26, 28, 31, 32, 86, 92, 124, 142, 195, 233, 246, 254 Biotechnology, 30, 33, 123, 152, 161, 169, 171, 172, 173, 174, 195 Biotic, 195, 253 Biotin, 114, 115, 117, 128, 134, 140, 145, 146, 155, 195 Biotransformation, 195, 236 Bladder, 193, 195, 221, 231, 241, 254 Blastocyst, 195, 203, 237 Bleomycin, 153, 195 Blood Cell Count, 195, 235 Blood Coagulation Disorders, 196, 217 Blood Coagulation Factors, 65, 195, 196 Blood Coagulation Tests, 196, 222 Blood Platelets, 196, 226, 238, 251 Blood pressure, 196, 198, 220, 229, 248 Blood Proteins, 53, 127, 196 Blood Volume, 196, 238 Blood-Borne Pathogens, 15, 196 Blue Toe Syndrome, 34, 196 Body Fluids, 196, 209, 247 Body Regions, 196, 202 Bone Density, 18, 107, 113, 141, 196 Bone Marrow, 18, 33, 68, 78, 98, 196, 205, 216, 225, 226, 229, 238, 248, 249 Bone Marrow Cells, 18, 196, 226 Bone Marrow Transplantation, 33, 68, 78, 196 Bone Remodeling, 18, 196 Bone Resorption, 4, 30, 93, 197 Boron, 44, 115, 151, 152, 162, 197 Boron Neutron Capture Therapy, 197 Bowel, 3, 197, 207, 222, 231, 232, 235, 249, 253 Bowel Movement, 197, 207, 249 Bradykinin, 197, 238 Brain Stem, 197, 231

Index 259

Branch, 183, 197, 225, 234, 236, 248, 251 Breakdown, 197, 207, 214 Breast Feeding, 93, 197 Broad-spectrum, 197, 199 Bronchial, 197, 218 Buccal, 197, 225 C Caffeine, 12, 197, 242 Calcification, 16, 70, 72, 143, 197 Calcium Chloride, 198, 234 Calcium Oxalate, 42, 198 Calculi, 42, 198 Callus, 198, 209 Calorimeter, 194, 198 Capillary, 197, 198, 245, 254 Capillary Fragility, 198, 245 Capsules, 198, 208 Carbohydrate, 120, 154, 198, 205, 215, 216, 232, 239 Carbon Dioxide, 198, 206, 237, 244 Carboxy, 11, 37, 58, 60, 198 Carboxy-terminal, 37, 198 Carcinogen, 187, 198 Carcinogenic, 131, 198, 208, 222, 240, 249, 253 Carcinoma, 43, 51, 54, 55, 58, 60, 73, 86, 120, 124, 198, 201, 207, 218 Cardiac, 17, 193, 197, 198, 211, 224, 230, 249 Cardiovascular, 5, 14, 17, 117, 144, 145, 198, 241 Cardiovascular disease, 14, 17, 117, 144, 198 Cardiovascular System, 145, 198, 241 Carotene, 89, 115, 131, 145, 198 Carotenoids, 66, 131, 199 Carrier Proteins, 199, 238, 243 Case report, 52, 73, 199, 202 Case series, 199, 202 Catabolism, 113, 199, 254 Catalytic Domain, 11, 199 Cataracts, 199, 240 Cathode, 199, 209 Cations, 123, 199, 223 Cause of Death, 145, 199 Caustic, 199, 247 Cefamandole, 49, 199 Cefoperazone, 95, 199 Cefotetan, 31, 199 Cefoxitin, 31, 199 Celiac Disease, 70, 98, 199 Cell Cycle, 29, 199, 212

Cell Death, 41, 65, 89, 192, 199, 212, 230 Cell Differentiation, 40, 199, 247 Cell Division, 172, 193, 199, 200, 212, 216, 228, 237, 245 Cell membrane, 127, 199, 200, 206, 236 Cell proliferation, 200, 247 Cell Respiration, 188, 200, 228, 244 Cell Size, 200, 213 Cell Survival, 65, 200, 216 Cellobiose, 200 Cellulose, 123, 138, 200, 237 Central Nervous System, 187, 197, 200, 214, 215, 217, 229, 236 Centrifugation, 200, 228 Cerebellar, 193, 200, 243 Cerebral, 39, 193, 194, 197, 200, 204, 211, 230 Cerebrovascular, 194, 198, 200, 251 Cerebrum, 200, 253 Character, 200, 206, 215 Chemotactic Factors, 200, 203 Chemotherapy, 37, 89, 95, 200 Chimeras, 8, 24, 37, 200 Chlorine, 146, 200 Chlorophyll, 201, 210 Cholecalciferol, 118, 201 Cholera, 21, 201, 254, 255 Cholera Toxin, 21, 201 Cholesterol, 117, 131, 194, 201, 204, 224, 225, 243, 249 Cholesterol Esters, 201, 224 Choline, 115, 128, 134, 146, 201 Chromatin, 192, 201, 231 Chromic, 114, 132, 201 Chromium, 44, 81, 114, 115, 128, 129, 145, 151, 152, 155, 201 Chromosome, 26, 30, 53, 201, 204, 212, 217, 224, 245 Chronic Disease, 129, 201, 224 Chronic renal, 201, 238 Chylomicrons, 201, 224 Circulatory system, 143, 201 CIS, 7, 201 Clear cell carcinoma, 201, 207 Cleave, 8, 202 Clinical Medicine, 89, 119, 202, 240 Clinical study, 27, 202 Clinical trial, 5, 16, 45, 107, 108, 117, 169, 202, 205, 243 Cloning, 8, 31, 61, 119, 195, 202, 224 Cod Liver Oil, 202, 210 Codon, 202, 215

260

Vitamin K

Coenzyme, 32, 192, 202, 231 Cofactor, 13, 18, 22, 24, 28, 48, 127, 133, 141, 202, 231, 241, 251 Cognition, 47, 202 Colectomy, 126, 202 Colic, 92, 202 Colitis, 125, 126, 154, 202, 253 Collagen, 12, 22, 28, 113, 120, 188, 194, 202, 233, 240 Colloidal, 23, 189, 202, 209, 235, 246 Combination Therapy, 35, 202 Combinatorial, 8, 203 Complement, 37, 71, 128, 190, 203, 215, 238 Complementary and alternative medicine, 85, 104, 203 Complementary medicine, 85, 203 Computational Biology, 169, 171, 203 Conception, 203, 213, 226 Concomitant, 40, 79, 203 Concretion, 198, 203 Confusion, 203, 254 Conjugated, 56, 194, 204 Conjugation, 195, 204, 212 Connective Tissue, 154, 192, 196, 202, 204, 213, 214, 227, 235, 244, 249 Connective Tissue Cells, 204 Consciousness, 190, 204, 206, 208 Consensus Sequence, 8, 139, 189, 204 Conserved Sequence, 189, 204 Consolidation, 13, 204 Consumption, 114, 117, 204, 207, 214, 232, 244 Contamination, 138, 196, 204, 218 Contraindications, ii, 4, 204 Convulsions, 191, 204 Corn Oil, 65, 204 Coronary, 198, 204, 205, 227, 230 Coronary heart disease, 198, 204 Coronary Thrombosis, 205, 227, 230 Cortex, 188, 193, 205, 218, 230, 240, 243 Corticosteroid, 4, 205, 240 Cortisol, 189, 205 Cortisone, 205, 207, 240 Coumarin, 48, 105, 205 Creatinine, 28, 205 Crossing-over, 205, 243 Crystallization, 20, 205 Curative, 205, 231, 245, 251 Cutaneous, 54, 154, 205, 225, 237 Cyanide, 31, 61, 205 Cyanoacrylates, 140, 205

Cyclic, 20, 187, 197, 205, 210, 239 Cyclosporine, 33, 205 Cysteine, 22, 23, 51, 63, 205, 250 Cystine, 205 Cytokine, 7, 205 Cytoplasm, 123, 192, 200, 201, 205, 206, 216, 231, 244 Cytoskeleton, 206, 228 Cytotoxic, 206, 247 D Dairy Products, 117, 162, 206 Databases, Bibliographic, 169, 206 Decarboxylation, 206, 218, 254 Decidua, 206, 237 Decubitus, 206, 247 Decubitus Ulcer, 206, 247 Degenerative, 10, 206, 218 Dehydration, 201, 206 Deletion, 192, 206 Dementia, 144, 206, 231 Dendrites, 144, 206, 231 Density, 12, 18, 38, 44, 45, 70, 79, 88, 95, 107, 113, 141, 196, 200, 206, 213, 224, 225, 232, 233 Dental Caries, 155, 206 Dental Waste, 196, 206 Depolarization, 206, 247 DES, 58, 60, 62, 190, 207 Detergents, 207, 247 Developed Countries, 207, 214 Dexamethasone, 26, 207 Diabetes Mellitus, 207, 217, 222, 232, 240 Diagnostic procedure, 111, 161, 207 Dialyzer, 207, 217 Diarrhea, 113, 126, 160, 207 Diarrhoea, 43, 207, 214 Diastolic, 207, 220 Diathesis, 55, 207 Diencephalon, 207, 231 Dietary Fiber, 117, 207 Dietitian, 4, 207 Diffusion, 207, 216, 221 Digestion, 11, 189, 194, 197, 207, 222, 225, 249 Digestive system, 108, 207 Digestive tract, 113, 207, 247 Dihydrotestosterone, 207, 243 Dihydroxy, 26, 32, 207, 210, 245 Dilatation, 207, 240 Diosgenin, 115, 208 Dioxins, 38, 208 Diphenoxylate, 126, 208

Index 261

Diploid, 208, 237 Direct, iii, 6, 8, 30, 34, 44, 121, 133, 136, 142, 163, 202, 208, 225, 243 Disinfectant, 187, 208, 211 Dissociation, 24, 120, 188, 208 Dissociative Disorders, 208 Distal, 26, 126, 208, 241 Diuresis, 197, 208 Diuretic, 198, 208, 239 Dopamine, 208, 227, 236 Dosage Forms, 115, 208, 236 Drug Interactions, 164, 208 Drug Tolerance, 208, 252 Duct, 48, 138, 209, 245 Duodenum, 194, 209, 249 Dyes, 190, 209, 213, 214, 231, 236 Dysplasia, 173, 209 Dystrophy, 153, 172, 209, 230 E Effector, 187, 203, 209 Efficacy, 17, 33, 35, 47, 121, 122, 130, 133, 199, 209 Elastin, 16, 113, 190, 202, 209 Electrocoagulation, 202, 209 Electrolysis, 191, 199, 209 Electrolyte, 205, 209, 228, 239, 248 Electrons, 192, 194, 199, 209, 223, 234, 242, 250 Electrophoresis, 138, 209, 223 Ellagic Acid, 209, 234 Emboli, 209, 255 Embolism, 130, 209, 242, 255 Embolization, 209, 255 Embryo, 7, 30, 195, 200, 209, 213, 221, 233 Embryogenesis, 29, 209 Emulsion, 131, 140, 210 Enamel, 206, 210 Endemic, 201, 210, 248 Endoscope, 210 Endothelial cell, 9, 23, 128, 210, 251 Endotoxin, 210, 253 End-stage renal, 201, 210, 238 Energy balance, 91, 210 Enteral Nutrition, 4, 52, 64, 90, 96, 210 Enteric bacteria, 87, 210 Enterobactin, 31, 210 Enteroscopy, 92, 210 Environmental Exposure, 210, 232 Environmental Health, 168, 170, 210 Enzymatic, 7, 13, 18, 134, 141, 198, 199, 203, 206, 210, 213, 218 Enzyme Inhibitors, 210, 238

Enzyme-Linked Immunosorbent Assay, 62, 210 Epidemiological, 12, 15, 126, 211 Epidermal, 9, 24, 65, 91, 142, 211, 226 Epidermal Growth Factor, 9, 24, 65, 91, 142, 211 Epidermis, 211, 242 Epinephrine, 208, 211, 253 Epithelial, 26, 187, 201, 206, 211, 218, 223 Epithelial Cells, 201, 211, 218, 223 Epitope, 85, 88, 211 Erythrocytes, 190, 195, 196, 211, 243 Erythropoiesis, 5, 211 Esophagus, 207, 211, 249 Essential Tremor, 172, 211 Estrogen, 107, 145, 162, 211, 243, 246 Ethanol, 211, 213 Ethanolamine, 127, 211 Etidronate, 107, 211 Etoposide, 89, 211 Eukaryotic Cells, 126, 212, 233, 253 Excipients, 212, 214, 236 Excitation, 212, 213 Excitatory, 212, 215 Exhaustion, 191, 212 Exogenous, 21, 93, 133, 188, 195, 212, 241 Expectorant, 212, 239 Extensor, 212, 242 Extracellular, 41, 144, 190, 204, 212, 233, 247 Extracellular Matrix, 204, 212, 233 Extraction, 87, 119, 131, 212 Extravasation, 212, 217 F F Factor, 13, 18, 39, 133, 212 Facial, 67, 153, 212 Facial Hemiatrophy, 153, 212 Family Planning, 169, 212 Fatty acids, 88, 90, 131, 148, 189, 212, 216, 225, 247 Femoral, 12, 212, 218 Femoral Neck Fractures, 212, 218 Femur, 59, 212, 218 Fermentation, 10, 212, 214, 245 Fetal Development, 30, 213, 231 Fetoprotein, 43, 55, 124, 189, 213 Fetus, 29, 65, 189, 213, 237, 240, 254 Fibrin, 13, 24, 127, 196, 213, 234, 238, 251 Fibrinogen, 24, 213, 234, 238, 241, 251 Fibrinolysis, 4, 59, 65, 71, 213 Fibrinolytic, 13, 213

262

Vitamin K

Fibrosis, 47, 67, 88, 96, 98, 159, 173, 213, 245 Filtration, 123, 213 Fistula, 213, 232 Flavoring Agents, 213, 214, 236 Flow Cytometry, 18, 213 Fluorescence, 6, 13, 24, 25, 87, 213 Fluorescent Dyes, 213 Folate, 17, 114, 155, 213, 214 Fold, 8, 145, 213 Folic Acid, 5, 117, 129, 134, 140, 145, 146, 154, 155, 213, 214 Food Additives, 129, 214 Food Coloring Agents, 214 Food Preservatives, 214 Fractionation, 130, 138, 147, 190, 214 Fructose, 214, 216, 222 Fungemia, 196, 214 G Galactosemia, 154, 214 Gallbladder, 187, 194, 207, 214 Ganglia, 187, 193, 194, 214, 230 Gas, 198, 200, 207, 211, 214, 219, 231, 250 Gastric, 208, 211, 214, 218 Gastrin, 214, 219 Gastroenteritis, 56, 214 Gastrointestinal, 49, 120, 125, 144, 154, 197, 210, 211, 214, 248, 249, 254 Gastrointestinal tract, 120, 144, 211, 214, 248 Gastrostomy, 210, 214 Gene Expression, 17, 22, 31, 51, 173, 215 Genetic Code, 139, 215, 232 Genetic Engineering, 195, 202, 215 Genetics, 4, 10, 17, 24, 50, 52, 67, 119, 155, 204, 215, 236 Genotype, 19, 215, 236 Gestation, 71, 215, 235, 237 Gland, 188, 205, 215, 234, 237, 241, 243, 245, 249, 251, 252 Glomerular, 215, 222, 244 Glomeruli, 215 Glomerulonephritis, 70, 215, 220 Glucocorticoid, 207, 215, 240 Glucose, 172, 192, 200, 201, 207, 214, 215, 216, 217, 222 Glucuronic Acid, 215, 218 Glutamate, 22, 29, 32, 78, 215, 236 Glutamic Acid, 8, 11, 22, 69, 78, 119, 121, 124, 139, 142, 143, 144, 214, 215, 240 Glutathione Peroxidase, 215, 246 Gluten, 199, 215

Glycerol, 215, 216, 236 Glycerophospholipids, 215, 236 Glycine, 194, 216, 246 Glycoprotein, 119, 141, 213, 216, 223, 251, 253 Glycoside, 216, 219 Glycosidic, 200, 216, 232 Glycosylation, 22, 216 Goats, 206, 216, 232 Governing Board, 216, 240 Graft, 153, 216, 219 Graft-versus-host disease, 153, 216 Gram-negative, 193, 199, 216, 254 Gram-positive, 193, 199, 216 Granulocytes, 216, 224, 247, 255 Granuloma, 154, 216 Grasses, 214, 216, 218 Growth factors, 27, 131, 216 H Haematoma, 216, 217 Haemodialysis, 91, 216 Haemorrhage, 36, 51, 56, 57, 74, 216 Hallucinogen, 217, 236 Haploid, 217, 237 Haptens, 135, 188, 217, 243 Headache, 197, 217 Health Promotion, 129, 217 Heart attack, 198, 217 Heart Valves, 94, 217 Hematoma, 34, 217 Heme, 195, 217, 239, 254 Hemodialysis, 38, 207, 217 Hemoglobin, 190, 195, 211, 217, 239 Hemoglobinuria, 172, 217 Hemolytic, 52, 154, 217 Hemorrhage, 39, 48, 56, 58, 126, 131, 154, 161, 209, 217, 241, 242, 249 Hemorrhagic Disorders, 133, 217 Hemorrhaging, 126, 217 Hemostasis, 7, 9, 10, 13, 18, 20, 22, 25, 29, 44, 55, 65, 89, 94, 120, 133, 218, 222 Heparin, 4, 5, 14, 39, 45, 52, 138, 218, 234 Hepatic, 4, 29, 49, 125, 146, 153, 189, 218, 239 Hepatitis, 4, 119, 154, 218, 255 Hepatitis A, 154, 218 Hepatocellular, 43, 51, 54, 55, 58, 60, 61, 73, 120, 124, 218 Hepatocellular carcinoma, 43, 51, 54, 55, 58, 60, 61, 73, 120, 124, 218 Hepatocytes, 218 Hepatoma, 4, 43, 51, 61, 218

Index 263

Hepatomegaly, 154, 218 Hepatovirus, 218 Herbicides, 208, 218 Hereditary, 9, 52, 53, 187, 218, 244 Heredity, 214, 215, 218 Heterogeneity, 142, 188, 218 Hip Fractures, 45, 160, 212, 218 Hippocampus, 218, 231 Histamine, 113, 190, 218 Histidine, 32, 218 Histiocytosis, 154, 219 Histology, 219, 231 Homeostasis, 22, 197, 219 Homologous, 6, 123, 205, 219, 245, 250 Hormonal, 193, 205, 219, 255 Hormone Replacement Therapy, 145, 219 Horseradish Peroxidase, 210, 219 Hospital Records, 64, 219 Host, 122, 123, 136, 139, 193, 212, 216, 219, 250 Human growth hormone, 123, 219, 248 Hybrid, 16, 126, 127, 219 Hydrogen, 187, 189, 194, 198, 215, 219, 224, 229, 231, 233, 236, 241 Hydrolases, 21, 219, 235, 237 Hydrolysis, 192, 194, 195, 200, 219, 235, 236, 237, 239, 241, 253 Hydrophilic, 20, 207, 219 Hydrophobic, 9, 13, 70, 207, 215, 219, 224 Hydroxylysine, 202, 219 Hydroxyproline, 28, 119, 202, 219 Hygienic, 220, 247 Hyperbilirubinemia, 154, 220, 223 Hypercalcemia, 155, 211, 220 Hyperlipidemia, 117, 220 Hyperopia, 220, 243 Hypersensitivity, 33, 54, 220, 244 Hypertension, 117, 154, 198, 217, 220, 232 Hypervitaminosis, 155, 220 Hypoglycemia, 154, 220 Hypoplasia, 220, 240 Hypovitaminosis, 125, 220 Hypoxia, 21, 220, 251 Hysterectomy, 145, 220 I Iatrogenic, 125, 147, 220 Ice Cream, 114, 220 Id, 80, 97, 176, 182, 184, 220 Idiopathic, 50, 187, 220 Ileostomy, 126, 140, 220 Ileum, 91, 220 Imidazole, 195, 218, 220

Immaturity, 153, 220 Immune Complex Diseases, 191, 220, 238 Immune response, 191, 193, 205, 217, 220, 221, 249, 255 Immune system, 195, 220, 221, 225, 226, 255 Immunity, 220, 221 Immunoassay, 93, 119, 120, 210, 221 Immunodeficiency, 154, 172, 221 Immunogen, 135, 221 Immunogenic, 17, 221, 243 Immunoglobulin, 191, 221, 229 Immunologic, 200, 220, 221 Immunology, 9, 17, 35, 121, 188, 213, 219, 221 Immunosuppressive, 4, 215, 221 Impairment, 145, 193, 221, 227 In vitro, 6, 9, 10, 17, 21, 23, 29, 31, 62, 69, 75, 89, 93, 122, 125, 128, 136, 139, 221, 250 In vivo, 7, 8, 9, 10, 17, 20, 21, 22, 25, 30, 31, 63, 69, 75, 121, 122, 125, 128, 145, 218, 221 Incision, 202, 221 Incontinence, 145, 221 Indicative, 151, 221, 234, 254 Induction, 21, 87, 190, 221, 223 Infancy, 37, 59, 127, 152, 221, 244 Infant Nutrition, 134, 221 Infantile, 53, 187, 221 Infarction, 130, 205, 221, 227, 230, 255 Infection, 70, 95, 191, 195, 200, 214, 221, 224, 225, 235, 244, 249, 250, 255 Infiltration, 215, 221 Inflammation, 126, 128, 187, 189, 191, 193, 202, 213, 214, 218, 221, 237, 244, 253 Infusion, 4, 5, 16, 222, 252 Ingestion, 93, 220, 222, 238 Inhalation, 222, 238 Initiation, 13, 222, 249, 252 Inositol, 115, 134, 222 Insight, 28, 30, 222 Insulin, 5, 69, 222 Insulin-dependent diabetes mellitus, 222 Interleukin-2, 54, 222 Intermediate Filaments, 222, 231 Intermittent, 222, 235, 239 International Normalized Ratio, 66, 69, 222 Interstitial, 222, 244 Intestinal, 3, 26, 56, 198, 199, 201, 222, 226, 255

264

Vitamin K

Intestine, 194, 197, 209, 210, 219, 220, 222, 224, 230, 243, 247, 253 Intoxication, 222, 254, 255 Intracellular, 23, 44, 197, 221, 222, 239, 246, 247 Intramuscular, 40, 46, 56, 67, 94, 222, 234 Intravascular, 130, 136, 222 Intravenous, 4, 33, 35, 47, 92, 119, 214, 222, 234 Intrinsic, 6, 13, 141, 188, 194, 222, 234 Inulin, 141, 222 Involuntary, 194, 211, 222, 230 Iodine, 44, 81, 114, 115, 117, 128, 129, 134, 145, 146, 151, 152, 155, 223 Ion Exchange, 123, 133, 200, 223 Ionizing, 189, 210, 223, 226, 253 Ions, 85, 120, 121, 127, 136, 141, 194, 208, 209, 219, 223, 229, 241 Ischemia, 193, 206, 223 Isoelectric, 16, 223 Isoelectric Focusing, 16, 223 Isoelectric Point, 223 Isoniazid, 39, 101, 223 Isopropyl, 125, 137, 223 J Jaundice, 220, 223 Jejunostomy, 210, 223 K Kb, 168, 223 Keratolytic, 206, 223, 238 Ketamine, 15, 223, 236 Kidney Disease, 107, 108, 168, 173, 223 Kinetic, 6, 22, 57, 223 L Labile, 203, 223 Lactates, 112, 223 Laminin, 37, 194, 223 Large Intestine, 207, 222, 224, 243, 247 Lenses, 220, 224, 243 Leprosy, 121, 224 Lesion, 216, 224, 225 Lethal, 128, 154, 193, 205, 224 Leucocyte, 224 Leukaemia, 40, 160, 224 Leukemia, 40, 98, 154, 172, 224 Leukocytes, 195, 196, 200, 216, 224, 231, 253 Leukocytosis, 224, 239 Library Services, 182, 224 Lidocaine, 194, 224 Ligament, 224, 241 Ligands, 23, 224, 250

Ligase, 30, 224 Linkage, 23, 200, 224 Lipid, 4, 8, 29, 65, 87, 126, 192, 201, 215, 222, 224, 234, 253 Lipid Peroxidation, 224, 234 Lipophilic, 148, 224 Lipoprotein, 94, 216, 224, 225 Lipoxygenase, 29, 192, 225 Liver cancer, 189, 225 Liver Extracts, 146, 225 Lobe, 219, 225 Localization, 32, 57, 71, 105, 225 Localized, 20, 23, 27, 142, 153, 190, 206, 216, 217, 221, 223, 225, 237, 245 Locomotion, 225, 237 Loop, 9, 220, 225 Low-density lipoprotein, 224, 225 Lucida, 223, 225 Lumen, 23, 30, 225 Lupus, 34, 62, 220, 225 Lycopene, 128, 131, 225 Lymph, 201, 210, 225, 249 Lymphatic, 221, 225, 227, 248 Lymphatic system, 225, 248 Lymphocyte, 191, 225, 226 Lymphoid, 191, 224, 225 Lymphoma, 172, 225 M Macronutrients, 114, 129, 134, 226 Macrophage, 21, 226 Maculopapular, 226, 237 Malabsorption, 4, 48, 70, 172, 199, 226 Malignancy, 187, 226 Malignant, 118, 172, 187, 191, 219, 225, 226, 229, 230, 240 Malignant tumor, 118, 226, 229, 240 Malnutrition, 4, 154, 189, 193, 226, 229 Mammary, 226, 243 Mammogram, 197, 226, 228 Mandible, 189, 226, 244 Manifest, 3, 226 Maternal Exposure, 29, 226 Meat, 117, 140, 226 Mediate, 23, 26, 91, 208, 226 Mediator, 222, 226 Medical Records, 219, 226 MEDLINE, 169, 171, 173, 226 Megakaryocytes, 196, 226 Megaloblastic, 214, 226 Melanin, 226, 227, 236, 253 Melanocytes, 226, 227 Melanoma, 172, 197, 227

Index 265

Melanosis, 187, 227 Memory, 191, 206, 227 Meninges, 193, 200, 227 Menopause, 98, 141, 145, 227, 239 Menstruation, 206, 227 Mental Disorders, 109, 227 Mental Processes, 208, 227, 242 Mental Retardation, 55, 174, 227 Meperidine, 208, 227 Mercury, 213, 227 Mesenchymal, 26, 211, 227 Meta-Analysis, 72, 227 Metabolic disorder, 153, 227 Metabolite, 195, 208, 227 Methionine, 227, 250 Metoclopramide, 5, 227 MI, 186, 227 Microcalcifications, 197, 228 Microgram, 125, 228 Micronutrients, 114, 117, 128, 134, 152, 228 Microorganism, 202, 228, 234, 255 Micro-organism, 206, 228 Microscopy, 23, 194, 219, 228 Microsomal, 23, 85, 127, 228 Microtubule-Associated Proteins, 228, 231 Microtubules, 144, 222, 228, 231 Midwifery, 32, 36, 62, 74, 228 Milligram, 228 Milliliter, 196, 228 Mineralization, 10, 30, 94, 228, 233 Mineralocorticoids, 188, 205, 228 Mitochondria, 20, 228, 233 Mitosis, 192, 228 Mitotic, 211, 228 Mobilization, 212, 228 Modeling, 15, 69, 228 Modification, 8, 21, 22, 28, 29, 30, 68, 87, 120, 139, 142, 215, 228, 242 Modulator, 26, 229, 243, 246 Molecular Structure, 13, 229 Monitor, 5, 6, 21, 67, 205, 229, 232, 234 Monoclonal, 23, 62, 88, 90, 123, 124, 137, 229, 242 Monoclonal antibodies, 23, 90, 123, 229 Mononuclear, 216, 229, 253 Morphine, 208, 227, 229 Morphogenesis, 26, 229 Morphological, 209, 226, 229 Mucosa, 126, 199, 225, 229, 249 Mucus, 212, 229, 253 Multiple Myeloma, 154, 229 Muscle Fibers, 229

Muscular Atrophy, 172, 229 Muscular Dystrophies, 209, 229 Mutagenesis, 20, 22, 229 Mutagenic, 208, 229, 253 Mutagens, 229 Myelofibrosis, 99, 229, 239 Myeloma, 153, 154, 229, 230 Myocardial infarction, 130, 205, 227, 230, 255 Myocardium, 227, 230 Myopia, 230, 243 Myotonic Dystrophy, 172, 230 N Nasogastric, 210, 230 Nausea, 99, 191, 208, 214, 230, 254 NCI, 1, 108, 167, 201, 230 Necrosis, 128, 192, 221, 227, 230, 253 Need, 3, 11, 17, 41, 115, 127, 130, 131, 142, 153, 161, 162, 177, 188, 201, 230, 252 Neocortex, 230, 231 Neonatal, 7, 35, 56, 57, 58, 63, 64, 66, 68, 71, 74, 93, 125, 153, 230 Neoplasia, 172, 230 Neoplasm, 230, 253 Neoplastic, 225, 230 Nephropathy, 223, 230 Nerve, 91, 190, 193, 206, 226, 230, 239, 244, 245 Nerve Growth Factor, 91, 230 Nervous System, 56, 78, 172, 187, 197, 200, 214, 215, 217, 226, 229, 230, 231, 236, 248, 249 Neural, 190, 213, 230, 231 Neural tube defects, 213, 231 Neurofibrillary Tangles, 144, 231 Neurofilaments, 231 Neurologic, 15, 231 Neuronal, 231, 235 Neurons, 144, 206, 212, 214, 230, 231, 250 Neuropeptides, 14, 231 Neutrons, 189, 197, 231, 242 Neutropenia, 154, 214, 231 Neutrophils, 192, 216, 224, 231 Niacin, 114, 115, 134, 146, 154, 155, 231, 253 Niacinamide, 128, 140, 231 Nickel, 44, 151, 152, 231 Nitrogen, 188, 189, 190, 231, 253 Nuclear, 29, 194, 204, 209, 212, 230, 231 Nucleic acid, 141, 194, 215, 229, 231, 232, 242 Nucleotidases, 219, 232

266

Vitamin K

Nucleus, 148, 192, 193, 194, 201, 205, 212, 222, 229, 231, 232, 241, 243, 251 Nutrition Assessment, 4, 17, 232 Nutritional Status, 12, 40, 232 Nutritive Value, 214, 232 O Occult, 70, 232 Octreotide, 5, 232 Ocular, 118, 232 Ointments, 208, 232, 247 Oligopeptides, 135, 232 Oligosaccharides, 142, 232 Oncogene, 172, 232 Opacity, 199, 206, 232 Operon, 26, 232, 244 Ophthalmic, 118, 232 Oral Manifestations, 154, 232 Orf, 26, 232 Organelles, 200, 205, 226, 233 Orthostatic, 232, 233 Osmotic, 189, 233, 246 Ossification, 233, 244 Osteoblasts, 89, 233 Osteocalcin, 12, 18, 28, 39, 44, 45, 73, 86, 89, 94, 96, 113, 233 Osteogenesis, 113, 196, 233 Osteogenesis Imperfecta, 196, 233 Osteomalacia, 112, 113, 118, 233 Osteosclerosis, 118, 233 Ovariectomy, 18, 94, 95, 233 Ovaries, 233, 246 Overdosage, 47, 233 Overdose, 59, 148, 233 Ovum, 206, 215, 233, 240 Oxalic Acid, 198, 233 Oxidation, 7, 125, 132, 187, 192, 194, 195, 205, 215, 224, 233, 234 Oxidative Stress, 17, 35, 234 Oxygenation, 7, 25, 234 P Palliative, 234, 251 Pamidronate, 107, 234 Pancreas, 187, 195, 207, 222, 234, 248, 253 Pancreatic, 172, 234 Pancreatic cancer, 172, 234 Parathyroid, 234, 245 Parathyroid Glands, 234, 245 Parenteral, 4, 28, 37, 49, 50, 52, 54, 64, 68, 78, 90, 95, 96, 234 Parenteral Nutrition, 4, 68, 78, 90, 95, 234 Paroxysmal, 172, 234 Partial Thromboplastin Time, 136, 234

Pathogen, 122, 234, 250 Pathogenesis, 36, 234 Pathologic, 25, 130, 192, 204, 220, 234, 235, 242, 244 Pathologic Processes, 192, 235 Pathophysiology, 3, 7, 27, 70, 72, 147, 153, 235 Patient Education, 5, 180, 182, 186, 235 Pelvic, 235, 241 Penicillin, 102, 103, 159, 191, 235 Peptide, 8, 9, 14, 23, 27, 68, 142, 201, 219, 235, 239, 241 Peptide Hydrolases, 219, 235 Perennial, 235, 253 Perforation, 126, 235 Perfusion, 220, 235, 252 Perinatal, 63, 71, 153, 235 Periodontal disease, 155, 235 Peripheral Nerves, 224, 235 Peripheral stem cells, 216, 235 Peritoneal, 96, 192, 235 Peritoneal Cavity, 192, 235 Peritoneal Dialysis, 96, 235 Peritoneum, 235 Pernicious, 154, 225, 226, 235 Pernicious anemia, 154, 225, 235 Petechiae, 217, 235 Petrolatum, 210, 235 PH, 92, 196, 236 Pharmaceutic Aids, 214, 236 Pharmaceutical Preparations, 200, 211, 236 Pharmaceutical Solutions, 208, 236 Pharmacodynamics, 46, 236 Pharmacogenetics, 19, 236 Pharmacokinetic, 236 Pharmacologic, 6, 190, 236, 252 Phencyclidine, 15, 236 Phenobarbital, 71, 103, 161, 236 Phenolphthalein, 210, 236 Phenotype, 10, 22, 23, 236 Phenylalanine, 236, 253 Phospholipases, 236, 247 Phospholipids, 18, 19, 127, 212, 222, 224, 236 Phosphoric Monoester Hydrolases, 219, 237 Phosphorus, 114, 117, 129, 134, 145, 146, 155, 197, 234, 237 Phosphorylated, 10, 144, 202, 237 Phosphorylation, 10, 25, 41, 87, 237 Photocoagulation, 202, 237

Index 267

Photosensitivity, 237, 239 Physiologic, 136, 153, 188, 195, 213, 222, 227, 228, 237, 243, 244 Physiology, 6, 26, 51, 237, 250 Phytonadione, 33, 113, 132, 237 Pigment, 195, 225, 226, 227, 237 Pilot study, 28, 237 Pituitary Gland, 205, 237 Pityriasis, 154, 237 Pityriasis Rosea, 154, 237 Placenta, 120, 237, 240 Plant Diseases, 210, 237 Plants, 26, 129, 148, 193, 198, 201, 208, 215, 216, 218, 222, 233, 237, 245, 252, 253 Plaque, 17, 94, 237 Plasma cells, 191, 229, 230, 238 Plasma Exchange, 4, 238 Plasma protein, 13, 19, 50, 62, 119, 120, 124, 130, 133, 145, 146, 188, 238, 240, 241, 246 Plasmid, 212, 238 Plasmin, 238, 240 Platelet Activation, 238, 247 Platelet Transfusion, 4, 238 Platelets, 13, 22, 127, 192, 196, 226, 238, 251 Platinum, 87, 225, 238 Podophyllotoxin, 211, 238 Point Mutation, 17, 20, 238 Poisoning, 75, 198, 214, 222, 227, 230, 238 Polycystic, 173, 238 Polycythemia Vera, 99, 154, 238 Polymers, 143, 239, 241, 249 Polypeptide, 189, 190, 198, 202, 204, 211, 213, 238, 239, 240, 241, 248, 256 Polysaccharide, 188, 191, 200, 239 Polyvalent, 133, 239 Porphyria, 153, 239 Porphyria Cutanea Tarda, 153, 239 Porphyria, Hepatic, 239 Porphyrins, 239 Posterior, 193, 234, 239, 245 Postmenopausal, 4, 28, 35, 45, 79, 94, 96, 107, 189, 233, 239, 243 Postmenopause, 107, 239 Postoperative, 47, 214, 227, 239 Postsynaptic, 239, 247 Post-translational, 8, 22, 28, 30, 68, 120, 127, 139, 142, 239 Potassium, 112, 114, 128, 129, 134, 146, 162, 228, 239, 247 Potassium Citrate, 112, 239

Potentiation, 92, 240, 247 Practice Guidelines, 170, 240 Precipitation, 123, 138, 240 Precursor, 120, 124, 145, 201, 208, 209, 210, 236, 240, 241, 253, 255 Prednisolone, 70, 240 Prednisone, 53, 107, 240 Pregnenolone, 208, 240 Prekallikrein, 14, 240 Prenatal, 36, 67, 86, 209, 240 Probe, 46, 240 Proctocolectomy, 126, 240 Proenzyme, 127, 240 Progeria, 153, 240 Progesterone, 208, 240, 249 Progression, 191, 240 Progressive, 153, 199, 201, 206, 208, 212, 216, 229, 230, 238, 240, 241, 244, 253 Proline, 202, 219, 240 Promoter, 14, 22, 26, 126, 240 Prophylaxis, 28, 46, 48, 50, 52, 56, 57, 60, 63, 64, 66, 68, 74, 76, 86, 95, 112, 240, 244, 255 Proportional, 211, 241, 250 Prostate, 172, 241 Protease, 9, 13, 22, 42, 141, 202, 241 Protein Binding, 241, 252 Protein Conformation, 189, 241 Proteinuria, 229, 241 Proteolytic, 120, 127, 133, 145, 203, 213, 238, 241 Prothrombin Time, 45, 88, 121, 136, 160, 241 Protons, 189, 219, 223, 241, 242 Proximal, 208, 241 Pseudoxanthoma, 50, 241 Pseudoxanthoma Elasticum, 50, 241 Psoriasis, 118, 154, 242, 244 Psychology, 208, 242 Puberty, 241, 242 Public Policy, 169, 242 Publishing, 30, 242 Pulmonary, 127, 130, 196, 200, 204, 217, 242, 250, 255 Pulmonary Artery, 196, 242 Pulmonary Edema, 200, 242 Pulmonary Embolism, 130, 242, 255 Pulse, 229, 242 Purifying, 132, 137, 207, 242 Purines, 194, 242, 246 Purpura, 46, 125, 147, 217, 242 Pyridoxal, 78, 87, 116, 242

268

Vitamin K

Q Quality of Life, 19, 117, 242 R Race, 242, 248 Radiation, 118, 194, 210, 213, 214, 223, 226, 242, 243, 255 Radiation therapy, 214, 242 Radioactive, 29, 219, 229, 232, 242, 243 Radioimmunoassay, 135, 243 Raloxifene, 107, 243, 246 Randomized, 28, 45, 59, 66, 107, 209, 243 Randomized clinical trial, 45, 243 Reagent, 124, 200, 211, 222, 233, 243 Receptor, 9, 11, 23, 29, 191, 208, 236, 243, 246, 247 Recombinant, 6, 8, 11, 14, 17, 29, 37, 47, 53, 71, 79, 119, 122, 123, 137, 141, 142, 243 Recombinant Proteins, 7, 8, 11, 14, 29, 122, 243 Recombination, 6, 204, 243 Rectum, 197, 207, 214, 221, 224, 240, 241, 243 Red blood cells, 211, 217, 239, 243 Red Nucleus, 193, 243 Reductase, 23, 28, 41, 43, 90, 243 Refer, 1, 118, 197, 203, 225, 231, 243 Refraction, 118, 230, 243, 248 Regimen, 5, 209, 243 Regurgitation, 217, 243 Renal failure, 68, 92, 217, 238, 244 Repressor, 232, 244 Research Design, 15, 244 Resected, 55, 244 Resorption, 4, 18, 30, 46, 93, 196, 197, 244 Respiration, 10, 36, 188, 198, 200, 228, 229, 244 Retina, 190, 193, 230, 241, 244, 245 Retinoblastoma, 172, 244 Retinoids, 244, 255 Retinol, 46, 82, 244 Retrospective, 63, 244 Rheumatism, 153, 244 Rheumatoid, 3, 244 Rheumatoid arthritis, 3, 244 Riboflavin, 5, 114, 115, 134, 145, 146, 154, 155, 244 Ribose, 21, 187, 244 Ribosome, 244, 253 Rickets, 118, 244, 255 Rifamycins, 122, 245 Rigidity, 237, 245

Risk factor, 8, 16, 17, 19, 27, 28, 57, 117, 245 Rod, 193, 245 Rubber, 140, 187, 245 Rutin, 91, 245 S Saline, 238, 245 Salivary, 207, 234, 245, 249 Salivary glands, 207, 245 Schizoid, 245, 255 Schizophrenia, 245, 255 Schizotypal Personality Disorder, 245, 255 Sclera, 196, 245 Scleroderma, 99, 153, 245 Sclerosis, 153, 172, 173, 245, 253 Screening, 19, 202, 234, 245 Secretion, 26, 39, 126, 142, 146, 205, 211, 218, 222, 228, 229, 232, 245, 246 Secretory, 25, 245 Segregation, 243, 245 Seizures, 234, 245 Selective estrogen receptor modulator, 243, 246 Selenium, 114, 115, 128, 129, 145, 155, 246 Semen, 241, 246 Semisynthetic, 199, 211, 246 Senescence, 240, 246 Senile, 233, 246 Sensor, 10, 246 Sepsis, 128, 154, 214, 246 Septic, 128, 246 Sequence Homology, 145, 246 Serine, 9, 18, 42, 141, 210, 246, 253 Serologic, 221, 246 Serum Albumin, 196, 243, 246 Sex Characteristics, 190, 242, 246, 251 Sex Determination, 173, 246 Sharpness, 145, 246 Shock, 128, 246 Side effect, 113, 143, 145, 163, 188, 195, 199, 246, 252 Signal Transduction, 10, 222, 247 Signs and Symptoms, 155, 247 Silicon, 44, 151, 152, 247 Silicon Dioxide, 247 Skeletal, 3, 10, 14, 28, 52, 78, 127, 141, 190, 229, 240, 247 Skeleton, 113, 187, 196, 212, 247 Skin Care, 147, 247 Skull, 231, 247, 250 Small intestine, 201, 209, 210, 219, 220, 222, 230, 247, 253

Index 269

Smooth muscle, 190, 197, 204, 218, 229, 247, 249 Soaps, 131, 247 Social Environment, 242, 247 Sodium, 19, 89, 112, 114, 116, 120, 129, 132, 134, 137, 138, 146, 228, 247, 248 Sodium Lactate, 112, 248 Soft tissue, 143, 196, 247, 248 Solid tumor, 21, 190, 195, 248 Solvent, 112, 132, 187, 211, 215, 233, 236, 248 Soma, 248 Somatic, 50, 63, 209, 228, 248 Somatostatin, 232, 248 Space Flight, 38, 86, 248 Specialist, 177, 248 Species, 7, 20, 121, 204, 211, 214, 219, 228, 229, 242, 246, 248, 249, 253, 254, 255 Specificity, 18, 20, 30, 62, 85, 135, 188, 192, 248, 250, 252 Spectrum, 19, 197, 199, 248, 253 Sperm, 190, 201, 248, 253 Spinal cord, 197, 200, 201, 227, 230, 231, 235, 248 Spleen, 190, 225, 239, 248 Splenomegaly, 238, 248 Sporadic, 239, 244, 248 Stabilizer, 113, 248 Staurosporine, 89, 248 Steady state, 6, 21, 249 Steel, 249, 254 Sterilization, 114, 134, 249 Steroid, 194, 205, 208, 240, 249 Stimulant, 197, 218, 249 Stomach, 187, 207, 210, 211, 214, 219, 230, 235, 247, 248, 249 Stool, 221, 224, 249 Streptomycin, 91, 249 Stress, 17, 35, 90, 91, 198, 205, 214, 230, 234, 244, 245, 249 Stroke, 109, 168, 198, 249 Stromal, 196, 249 Stromal Cells, 196, 249 Styrene, 245, 249 Subacute, 221, 249 Subclinical, 52, 58, 67, 221, 245, 249 Subcutaneous, 33, 47, 55, 66, 79, 125, 212, 234, 240, 249 Submaxillary, 211, 249 Subspecies, 248, 249 Substance P, 227, 245, 249

Substrate, 7, 13, 14, 18, 21, 22, 24, 25, 51, 68, 85, 121, 139, 141, 199, 210, 219, 250 Substrate Specificity, 85, 250 Subtrochanteric, 218, 250 Suction, 213, 250 Sulfur, 20, 227, 250 Superinfection, 193, 250 Suppression, 124, 205, 250 Surface Plasmon Resonance, 37, 250 Surfactant, 113, 127, 211, 250 Symphysis, 241, 250 Symptomatic, 44, 250 Synaptic, 247, 250 Systemic, 3, 153, 154, 155, 164, 190, 192, 196, 211, 220, 221, 231, 239, 240, 242, 245, 248, 250, 255 Systemic disease, 154, 250 Systolic, 220, 250 T Telangiectasia, 173, 250 Temporal, 26, 29, 218, 250 Teratogen, 29, 250 Teratogenic, 208, 251 Terminator, 126, 202, 251 Testosterone, 162, 243, 251 Thalamic, 193, 251 Thalamic Diseases, 193, 251 Therapeutics, 7, 164, 251 Thermal, 138, 197, 208, 231, 251 Thiamine, 114, 134, 146, 251 Thigh, 212, 251 Threonine, 246, 251 Threshold, 220, 251 Thrombin, 6, 9, 11, 24, 67, 120, 128, 133, 136, 142, 213, 241, 251 Thrombocytes, 238, 251 Thrombocytopenia, 154, 251 Thromboembolism, 19, 20, 44, 72, 251 Thrombomodulin, 128, 133, 135, 136, 241, 251 Thromboplastin, 125, 136, 234, 240, 241, 251 Thrombus, 25, 205, 221, 251, 254 Thyroid, 223, 234, 251, 252, 253 Thyroxine, 189, 236, 252 Tin, 35, 71, 238, 252 Tissue Distribution, 40, 252 Tolerance, 5, 187, 208, 252 Tomography, 196, 252 Topical, 46, 72, 101, 125, 211, 236, 247, 252 Toxic, iv, 122, 148, 154, 193, 204, 205, 210, 216, 221, 226, 238, 246, 249, 252

270

Vitamin K

Toxicity, 208, 227, 252 Toxicokinetics, 252 Toxicology, 170, 252 Toxins, 146, 154, 191, 215, 221, 229, 252 Trace element, 114, 140, 197, 201, 231, 247, 252 Transcription Factors, 7, 14, 252 Transduction, 10, 222, 247, 252 Transfection, 195, 252 Transferases, 216, 252 Transfusion, 4, 119, 133, 238, 252 Translation, 22, 30, 252 Translational, 8, 22, 28, 30, 68, 120, 127, 139, 142, 239, 253 Trees, 129, 245, 253 Trypsin, 240, 253, 256 Tryptophan, 202, 253 Tuberculosis, 39, 121, 122, 204, 223, 225, 253 Tuberculostatic, 223, 253 Tuberous Sclerosis, 173, 253 Tubulin, 228, 253 Tumor Necrosis Factor, 128, 253 Tumour, 91, 253 Tyrosine, 29, 87, 208, 253 U Ubiquinone, 10, 253 Ubiquitin, 30, 231, 253 Ulceration, 206, 233, 253 Ulcerative colitis, 125, 126, 154, 253 Ultraviolet Rays, 118, 253 Unconscious, 220, 253 Urea, 254 Uremia, 5, 244, 254 Urethra, 241, 254 Urinary, 12, 28, 78, 94, 99, 145, 198, 221, 248, 254 Urine, 28, 107, 119, 195, 198, 205, 208, 211, 217, 221, 233, 241, 244, 254 Uroporphyrinogen Decarboxylase, 239, 254 Uterus, 206, 220, 227, 233, 240, 254 V Vaccines, 254, 255 Vagina, 207, 227, 254 Vanadium, 44, 152, 254

Vascular, 10, 17, 35, 70, 90, 125, 217, 221, 237, 251, 254 Vascular Hemostatic Disorders, 217, 254 Vasodilator, 197, 208, 218, 254 Vein, 45, 130, 222, 232, 254 Venom, 48, 254 Venous, 8, 19, 27, 34, 44, 72, 195, 241, 254, 255 Venous Thrombosis, 8, 27, 254, 255 Ventricles, 217, 254 Venules, 196, 198, 254 Vertebral, 45, 254 Vesicular, 228, 254 Veterinary Medicine, 15, 152, 169, 254 Vibrio, 201, 254, 255 Vibrio cholerae, 201, 255 Villous, 199, 255 Viral, 15, 119, 252, 255 Viral Hepatitis, 119, 255 Viremia, 196, 255 Virus, 4, 147, 193, 215, 232, 237, 252, 255 Viscera, 248, 255 Viscosity, 131, 255 Vitamin A, 115, 116, 128, 131, 132, 134, 138, 144, 145, 151, 222, 244, 255 Vitamin D, 14, 94, 116, 118, 134, 138, 141, 145, 245, 255 Vitro, 6, 9, 10, 17, 21, 23, 24, 29, 31, 62, 69, 75, 89, 93, 105, 122, 125, 128, 136, 139, 218, 221, 250, 255 Vivo, 7, 8, 9, 10, 17, 20, 21, 22, 23, 25, 30, 31, 35, 63, 69, 75, 121, 122, 125, 128, 145, 218, 221, 255 W Weight Gain, 145, 255 White blood cell, 191, 224, 225, 226, 229, 230, 231, 238, 255 Withdrawal, 34, 227, 255 Wound Healing, 5, 255 X Xenograft, 191, 255 X-ray, 20, 194, 196, 199, 213, 226, 232, 242, 248, 253, 255 Y Yeasts, 236, 255 Z Zoledronate, 107, 256 Zymogen, 13, 133, 145, 240, 241, 256

Index 271

272

Vitamin K

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

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

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

Hepatitis A Vaccine: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Foot and Mouth Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Butternut Squash: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

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

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

Premenstrual Dysphoric Disorder - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Anagrelide: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Peanut Allergy: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

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Marburg Virus: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

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

Vitamin B6 - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

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

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

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

Hepatitis A Vaccine: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Foot and Mouth Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Butternut Squash: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

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

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

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

Premenstrual Dysphoric Disorder - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Anagrelide: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Peanut Allergy: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Cauda Equina Syndrome - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Magnesium Citrate: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

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

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

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

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