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

FOLIC ACID A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

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

ii

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

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Folic Acid: 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: 0-597-83913-1 1. Folic Acid-Popular works. I. Title.

iii

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.

iv

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 folic acid. 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.

v

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.

vi

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

vii

Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON FOLIC ACID ............................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Folic Acid ...................................................................................... 5 E-Journals: PubMed Central ....................................................................................................... 59 The National Library of Medicine: PubMed ................................................................................ 61 CHAPTER 2. NUTRITION AND FOLIC ACID ................................................................................... 107 Overview.................................................................................................................................... 107 Finding Nutrition Studies on Folic Acid................................................................................... 107 Federal Resources on Nutrition ................................................................................................. 113 Additional Web Resources ......................................................................................................... 113 CHAPTER 3. ALTERNATIVE MEDICINE AND FOLIC ACID ............................................................. 121 Overview.................................................................................................................................... 121 National Center for Complementary and Alternative Medicine................................................ 121 Additional Web Resources ......................................................................................................... 134 General References ..................................................................................................................... 145 CHAPTER 4. DISSERTATIONS ON FOLIC ACID ............................................................................... 147 Overview.................................................................................................................................... 147 Dissertations on Folic Acid........................................................................................................ 147 Keeping Current ........................................................................................................................ 148 CHAPTER 5. CLINICAL TRIALS AND FOLIC ACID ......................................................................... 149 Overview.................................................................................................................................... 149 Recent Trials on Folic Acid........................................................................................................ 149 Keeping Current on Clinical Trials ........................................................................................... 151 CHAPTER 6. PATENTS ON FOLIC ACID.......................................................................................... 153 Overview.................................................................................................................................... 153 Patents on Folic Acid ................................................................................................................. 153 Patent Applications on Folic Acid ............................................................................................. 180 Keeping Current ........................................................................................................................ 208 CHAPTER 7. BOOKS ON FOLIC ACID ............................................................................................. 209 Overview.................................................................................................................................... 209 Book Summaries: Federal Agencies............................................................................................ 209 Book Summaries: Online Booksellers......................................................................................... 213 The National Library of Medicine Book Index ........................................................................... 215 Chapters on Folic Acid............................................................................................................... 216 CHAPTER 8. MULTIMEDIA ON FOLIC ACID .................................................................................. 225 Overview.................................................................................................................................... 225 Bibliography: Multimedia on Folic Acid.................................................................................... 225 CHAPTER 9. PERIODICALS AND NEWS ON FOLIC ACID ............................................................... 227 Overview.................................................................................................................................... 227 News Services and Press Releases.............................................................................................. 227 Newsletter Articles .................................................................................................................... 232 Academic Periodicals covering Folic Acid ................................................................................. 234 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 235 Overview.................................................................................................................................... 235 U.S. Pharmacopeia..................................................................................................................... 235 Commercial Databases ............................................................................................................... 236 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 239 Overview.................................................................................................................................... 239 NIH Guidelines.......................................................................................................................... 239

viii Contents

NIH Databases........................................................................................................................... 241 Other Commercial Databases..................................................................................................... 244 The Genome Project and Folic Acid ........................................................................................... 244 APPENDIX B. PATIENT RESOURCES ............................................................................................... 249 Overview.................................................................................................................................... 249 Patient Guideline Sources.......................................................................................................... 249 Finding Associations.................................................................................................................. 255 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 257 Overview.................................................................................................................................... 257 Preparation................................................................................................................................. 257 Finding a Local Medical Library................................................................................................ 257 Medical Libraries in the U.S. and Canada ................................................................................. 257 ONLINE GLOSSARIES................................................................................................................ 263 Online Dictionary Directories ................................................................................................... 265 FOLIC ACID DICTIONARY ....................................................................................................... 267 INDEX .............................................................................................................................................. 359

1

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 folic acid 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 folic acid, 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 folic acid, 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 folic acid. 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 folic acid, 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 folic acid. The Editors

1

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

3

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

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

Neuropathy and Folic Acid Source: Diabetes Forecast. 44(2): 46. February 1991. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Summary: Neuropathy is a serious complication of diabetes that also affects one's quality of life. This article reviews the different types of neuropathies and then discusses the role that folic acid (a B vitamin) may play in the treatment of neuropathies. By telling one person's story, the author shows how folic acid treatments may be effective in treating diabetic neuropathy. The author cautions that folic acid is still experimental and the evidence for its use in diabetic neuropathy has never been proven in a controlled scientific study.

4

Folic Acid

•

Dentist's Role: The Unnecessary Epidemic of Folic Acid-Preventable Birth Defects, Spina Bifida and Anencephaly Source: Virginia Dental Journal. 79(3): 24-25. July-September 2002. Contact: Available from Virginia Dental Association. 7525 Staples Mill Road, Richmond, VA 23228. (804) 261-1610 or, in Virginia, (800) 552-3886. Summary: This article familiarizes dentists and dental care professionals with folic acidpreventable birth defects, notably the neural tube defects (NTDs), spina bifida and anencephaly. Prevention of most NTDs is possible if all women in the perioconceptional period have high enough body content of folic acid (a B vitamin). The author reviews neural tube formation and prevention of NTDs, and the role of health care providers in reducing the risk of NTDs. The author notes that many women of childbearing age, who may not yet be pregnant, visit dentists on a regular basis for preventive dental exams. Thus, dentists are in a unique position to provide information about folic acid and the prevention of NTDs, as it is most effective if taken before and during early pregnancy. 7 references.

•

Memories are made of Folic Acid, B1, B3, NA, and ZN Source: Lifeline. 10(1): 3. Winter 1992. Contact: Available from Celiac Sprue Association/USA, Inc. P.O. Box 31700, Omaha, NE 68131. (402) 558-0600. Summary: This brief newsletter article explores the relationship between good nutrition and cognitive function, with an emphasis on the impact of celiac disease in this area. Topics include nutrition and memory; vitamins and intelligence; and research on these topics. The article concludes with a list of some common symptoms and the vitamins and minerals reported to be related. Symptoms listed include apathy, confusion, depression, dry eye, fatigue, insomnia, irritability, muscle problems, nervousness, night blindness, numbness of limbs, poor appetite, poor coordination, poor memory, rapid pulse, sensitivity to light, and sore tongue. 2 references.

•

Risks of Orofacial Clefts in Children Born to Women Using Multivitamins Containing Folic Acid Periconceptionally Source: Lancet. 346(8972): 393-396. August 12, 1995. Summary: Women are advised to take folic acid before they conceive as a precaution against neural-tube defects; however, the use of folic acid in preventing orofacial clefts is unknown. In this article, the authors report on a study that investigated whether a woman's periconceptional use of multivitamins containing folic acid was associated with a reduced risk of orofacial clefts. They derived data from a population-based casecontrol study of fetuses and liveborn infants with orofacial anomalies among a 19871989 cohort of births in California. They interviewed 731 eligible mothers who have infants with orofacial clefts and 734 mothers with non-malformed, control infants. The results showed a reduced risk of orofacial clefts if the mother had used multivitamins containing folic acid during the period from 1 month before through 2 months after conception. Maternal daily consumption of cereal containing folic acid was also associated with a reduced risk of orofacial clefts. The authors note that this association may not be attributable to folic acid specifically, but may be a consequence of other multivitamin supplement components or behaviors that are highly correlated with the use of multivitamins containing folic acid. 3 tables. 30 references. (AA-M).

Studies

5

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

Project Title: A RANDOMIZED, CONTROLLED TRIAL FOR HOMOCYSTEINE Principal Investigator & Institution: Bostom, Andrew G.; Associate Professor of Medicine; Rhode Island Hospital (Providence, Ri) Providence, Ri 02903 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JAN-2006 Summary: (Adapted from the application) This multicenter, randomized, double-blind controlled clinical trial has been designed to determine whether total homocysteine (tHcy)-lowering treatment with a standard multivitamin augmented by a high dose combination of folic acid, vitamin B12, and vitamin B6, versus treatment with a standard multivitamin devoid of these three B-vitamins, reduces the pooled rate of recurrent and de novo cardiovascular disease outcomes (i.e., pooled occurrence of nonfatal and fatal arteriosclerotic outcomes, including coronary heart, cerebrovascular, and peripheral vascular disease events= primary outcome), among clinically stable renal transplant recipients who have mild to moderately elevated tHcy levels. The basic eligibility criteria are age 35 to 75 years old, functioning renal allograft for greater than six-months with serum creatinine based creatinine clearance greater than 30 mL/min, and a screening random tHcy level greater than12 uM/L. Patients will be stratified based on the presence/absence of clinical CVD, and randomly assigned to treatment with a standard multivitamin containing a high dose combination of folic acid, vitamin B6, and vitamin B12, or an identical multivitamin devoid of these three micronutrients. Randomized patients will also undergo a methionine loading test. All patients will receive standard clinical management for traditional CVD risk factor reduction. The study is designed to recruit 4000 patients (2000 in each group) over a two-year period for 83% power to detect a 25% treatment effect. Follow-up continues until occurrence of de novo or recurrent non-fatal CVD, or death, or a maximum of four-years. Data analysis will be performed on the basis of original randomization (intention to treat) using the log-rank test of difference in survival-without-endpoint curves. In the current era of cereal grain flour fortified with physiologic amounts of folic acid, RTRs comprise a patient population particularly well-suited to test the tenable hypothesis that tHcylowering treatment will reduce CVD outcomes, given: a) their persistent excess

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).

6

Folic Acid

prevalence of mild hyperhomocysteinemia post-fortification, in contrast, for example, to coronary heart disease patients with normal renal function; b) the demonstrated capability of B-vitamin treatment regimens featuring supraphysiologic amounts of folic acid to successfully "normalize" tHcy levels in RTRs. Furthermore, overall "conditions" in the RTR population (i.e., renal impairment, mild to moderate hyperhomocysteinemia which can be normalized by supraphysiologic dose B-vitamin supplements, and high CVD event rates) are representative of the larger population of patients with chronic renal insufficiency, who are not yet dialysis-dependent. Accordingly, findings from the proposed trial are very likely to be generalizable to the much more sizable population of patients with renal insufficiency progressing to end-stage renal disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AGING OF BRAIN--EFFECTS OF PERINATAL NUTRITION Principal Investigator & Institution: Blusztajn, Jan K.; Professor; Pathology and Lab Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 01-MAR-1991; Project End 31-MAR-2004 Summary: The overall goal of the proposed studies is to determine the mechanisms by which the availability of choline and folic acid during the prenatal period modifies brain structure and function in development, adulthood and old age. Our major premise is that the development of the brain during critical periods in embryogenesis is sensitive to changes in maternal diet, and specifically, is influenced by changes in the intake of choline and folic acid. We found that rats treated with choline during specific perinatal periods inhibited improved memory function which lasted throughout their lifespan, i.e. supplementation with choline in development prevented age-related deterioration in learning and memory. Moreover, variations in maternal choline intake during the second half of pregnancy caused biochemical, structural, and electrophysiological changes in the brains of the offspring. We also found that memory performance in rats was improved by prenatal supplementation with folic acid. The proposed studies will be conducted using a unified experimental design common to all projects. Dr. Blusztajn will determine the molecular mechanisms involved in the brain reorganization that is governed by choline and folate availability by studying signal transduction pathways and developmental patterns of gene expression in brain. Dr. Swartzwelder will measure synaptic function and plasticity (long-term potentiation in hippocampus of rats exposed to varying levels of choline or folate in utero. Dr. Meck will examine age-related changes in conditioned stimulus processing (attention) as a function of the prenatal availability of choline and folate. Dr. Williams will determine if supplementation with folate in early development leads to life long changes in spatial memory, brain anatomy, and neurochemistry, as has been documented for choline supplementation, and will investigate whether choline supplementation with folate in early development leads to lifelong changes in spatial memory, brain anatomy, and neurochemistry, as has been documented for choline supplementation, and will investigate whether choline supplementation either prenatal or across the lifespan ameliorates behavioral, anatomical, and biochemical deficits seen in mice lacking the gene for apolipoprotein Ea molecular involved in the transport of phosphatidylcholine within brain. Dr. Zeisel will study metabolic interrelationships between folate and choline in order to determine if they share a common mechanism of action on brain organization. He will determine the effects of choline and folate on patterns of fetal brain cell division and apoptosis, and will investigate the mechanism by which choline deficiency causes apoptosis. Dr. Kowall will provide neuroanatomy core services for the five projects. The ultimate goal

Studies

7

of our studies is to related our results to age-related changes in memory in humans, and to develop perinatal nutritional strategies which will benefit people. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIVIRAL MICRODIALYSIS

DRUG

KINETICS

IN

VITREOUS

USING

Principal Investigator & Institution: Mitra, Ashim K.; Professor and Chairman; Pharmaceutical Sciences; University of Missouri Kansas City Kansas City, Mo 64110 Timing: Fiscal Year 2003; Project Start 01-APR-1996; Project End 31-JUL-2007 Summary: (provided by applicant): The broad overall objective of this competing renewal grant application is to develop novel prodrug strategies to improve ocular antiviral drug therapy, in the treatment of human cytomegalovirus (HCMV) retinitis. In the previous grant period, microdialysis technique has been utilized to study ocular pharmacokinetics in anesthetized and conscious animal models. Retinal drug delivery may be enhanced by exploiting the membrane transporters on the neural retina, RPE and/or endothelial cells of the retinal blood vessels. We propose to synthesize a series of dipeptide, amino acid and folate mono- and di- ester prodrugs of ganciclovir (GCV) to target peptide, amino acid and folate transporters/receptors respectively. The proposed prodrugs would not only improve the ocular bioavailability of GCV, but also may exhibit diminished cytotoxicity, require lower doses, and a decreased frequency of administration. By simultaneous targeting of multiple transporters having no overlapping substrate specificity, we can achieve higher intracellular concentrations of GCV due to enhanced uptake of the prodrugs followed by enzymatic conversion in the retinal cells. The specific aims of this renewal application are: 1. To synthesize monoand di-ester derivatives of GCV targeting peptide transporters - Val-Val-GCV, Val-GlyGCV, Gly-Val- GCV, Gly-Tyr-GCV and Val-Tyr-GCV; amino acid transporters gamma,-Glu-GCV, Phe-GCV, Tyr-GCV and Trp-GCV; and folate transport systems folate ester of GCV. 2. To determine antiviral efficacy and cytotoxicity of the proposed compounds against in vitro viral screens of HCMV, HSV-1, HSV-2, VZV, and EBV and to conduct in vivo efficacy studies against HCMV retinitis in SCID mouse model, by NIAID supported research at the University of Alabama, Birmingham (P.I. Dr. Earl Kern). 3. To conduct uptake studies of dipeptide, amino acid (targeted to glutamate, LNAA transporters) and folate (targeted to folic acid receptors/transporters) monoand di-ester prodrugs of GCV, a) in vitro, using ARPE-19 cell line, and b) ex vivo/in vivo, using rabbit retina. Our aim is also to study the retinal concentrations of GCV following simultaneous administration of a prodrug combination targeted towards peptide, amino acid and folate transporters. 4. To evaluate in vivo ocular bioavailability of GCV in the vitreous and anterior chambers utilizing dual probe ocular microdialysis technique following IV and intravitreal administrations. The ocular bioavailability of GCV upon administration of a prodrug combination targeted towards peptide, amino acid and folate transporters will be determined. 5. i) to develop a novel injectable, biodegradable, thermosensitive in situ gel forming system, containing drug and drug loaded microspheres and (ii) to evaluate in vivo ocular bioavailability of GCV with microdialysis technique following episcleral deposition of the gel formulation in a conscious animal model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: B12 NUTRITION IN THE AGED Principal Investigator & Institution: Stabler, Sally P.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508

8

Folic Acid

Timing: Fiscal Year 2003; Project Start 01-SEP-1997; Project End 30-JUN-2008 Summary: (provided by applicant): Hyperhomocysteinemia (high serum total homocysteine) remains a problem for seniors even in this era of highly folate-fortified food in the United States. This paradox is explained because many seniors continue to have undiagnosed and untreated vitamin B 12 deficiency as shown by elevated serum methylmalonic acid concentrations. Hyperhomocysteinemia due to vitamin deficiency or renal failure may cause elevations of S-adenosylhomocysteine with a low Sadenosylmethionine/S-adenosylhomocysteine ratio, which may impair crucial methylations of brain neurotransmitters, phospholipids and myelin. A new stable isotope dilution liquid chromatography/mass spectrometry method will be used to explore the relationships between homocysteine and S-adenosylmethionine, Sadenosylhomocysteine and ratio in human seniors and rats with vitamin deficiency and renal failure. The pattern of the serum and urine metabolites will be studied after high dose oral vitamin B 12 and folic acid treatment in seniors who have vitamin B 12 deficiency and/or elevated serum S-adenosylhomocysteine concentrations. The baseline and post treatment S-adenosylmethionine and S-adenosylhomocysteine and ratio will be correlated with depression and neurologic symptoms. Enzymes of methionine metabolism such as cystathionine beta-synthase, gamma-cystathionase, methionine adenosyltransferase and S-adenosylhomocysteine hydrolase will be studied in tissues from B 12 deficient rats and in cell culture models. The long term goals of these studies are to determine whether vitamin B 12 deficiency impairs the balance of Sadenosylmethionine and S-adenosylhomocysteine. It will be determined whether the pattern of urine and serum metabolites in renal insufficiency could be differentiated from vitamin B 12 deficiency since treatment and complications might be different. New understanding of the control of regulation of methionine metabolism will be obtained in the setting of vitamin B 12 deficiency and renal insufficiency, conditions which continue to be important clinically and for which treatment with vitamins or Sadenosylmethionine supplements will be safe and widely available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIRTH DEFECTS TREATMENT AND PREVENTION PROGRAM Principal Investigator & Institution: Murray, Jeffrey C.; Professor; Pediatrics; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2001; Project Start 17-AUG-2001; Project End 30-APR-2006 Summary: (Provided by applicant): Cleft lip and cleft palate can serve as a sentinel for birth defects in general for the impact that they have on fetal and maternal health. As sentinels, they are easy to identify and require a high input of surgical and medical care, but also commonly result in long-term survival of affected individuals, even when untreated. They are common with the average frequency of about 1:1000 in most South American countries. Their etiology is complex, although it is clear that genes and genetic and environment interactions play an important role. Nutritional factors in clefts are well recognized and have been studied for over 40 years. Recent evidence that folate or B6 deficiency, as well as a role for smoking and alcohol use, suggest that environmental interventions in the form of supplementation or preventive strategies may be effective in decreasing the frequency of these birth defects. The South American birth defects registry, Estudio Collaborativo Latinoamericano de Malformaciones Congenitas (ECLAMC), has for many years provided epidemiologic information on the frequency of birth defects throughout South America. At the present time, folate supplementation has been introduced to one country in South America (Chile) and it is now possible to measure changes in outcomes of this based around the known preventive effect of folic

Studies

9

acid supplementation for neural tube defects and the likely effect that it may have on cleft lip and cleft palate. Extensive populations of affected individuals such as those followed by the Centrinho clinic in Bauru provide high risk populations in which targeted interventions can be effectively studied. In this proposal, the applicants will use cleft lip and cleft palate as a sentinel defect to study the impact of birth defects in general on maternal, fetal and neonatal health and to carry out direct interventions on decreasing the number of these birth defects using both behavioral and medical interventions. The specific aims will include measuring the impact of the interventional use of folic acid supplementation on cleft lip and cleft palate and neural tube defects, measuring the impact of having a child born with a cleft on subsequent maternal, infant and family health, and finally, interventions to decrease the number of birth defects through the direct prevention strategies of smoking intervention and vitamin supplementation. The outcome of this project will be to further strengthen collaborative relationships in the area of craniofacial anomalies between Brazil and the US, to better understand the effects of birth defects and craniofacial anomalies in particular on maternal family units and to decrease the burden of these defects directly. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BXR SIGNALING IN VERTEBRATE DEVELOPMENT Principal Investigator & Institution: Blumberg, Bruce; Assistant Professor; Developmental and Cell Biology; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: (adapted from investigator's abstract): How cells acquire, transfer and interpret positional information to shape the developing embryo is a fundamental embryological question. Positional information is involved in important developmental processes including embryonic induction, differential competence of the responding tissue, and cytoplasmic specification. The long term goals of this research are to understand the role of hormonal signaling in establishing positional information in the early embryo and physiologic function in the adult. One class of information transfer is mediated by morphogens, diffusible chemicals responsible for causing morphogenesis. An interest in identifying novel morphogens led the investigators to design a strategy where candidate nuclear hormone receptor homologs were first isolated from a developmental system and then used to identify the corresponding ligand. Xenopus was chosen as a model because it affords an ideal combination of embryological and biochemical approaches to study embryonic signaling while remaining an appropriate model for higher vertebrates. The hypothesis is that identifying new signaling systems will provide important insights into positional specification during embryonic development. The investigators previously isolated and characterized a novel nuclear receptor activated by a class of endogenous substituted alkyl benzoates. These compounds comprise a novel class of hormone receptor ligand and are related the Bcomplex vitamins p-aminobenzoic acid and folic acid suggesting a further link between development and nutrition. This BXR (benzoate 'X' receptor) represents a hitherto unknown hormonal signaling pathway. They aim to fully characterize the BXR signaling pathway during Xenopus development and subsequently extend these results to mouse and human. They will exploit the unique accessibility of the early Xenopus embryo to experimental manipulations to I) test the effects of locally increasing or decreasing BXR signaling during development, 2) Identify the true endogenous ligand for BXR in Xenopus embryos and bovine serum, 3) determine the temporal and spatial localization of the BXR ligand during early development, and 4) Isolate and characterize mammalian homologs of BXR. Aberrant signaling processes, especially those related to cellular

10

Folic Acid

identity, are particularly relevant to cancer and its treatment. Identification of developmental signaling molecules and their receptors could lead to the identification of novel morphogens, teratogens, and hormones. Moreover, because nearly all hormones regulate cell growth and differentiation they and their antagonists are natural candidates in the treatment of human disease, especially cancers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER CAM VITAMINS AND CHEMOTHERAPY RESISTANCE Principal Investigator & Institution: Johanning, Gary L.; Nutrition Sciences; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The focus at the National Cancer Institute continues to be on increasing survivorship and on enhancing the quality of life for cancer survivors. One contribution toward this goal would be to identify environmental factors that contribute to cancer survivorship, including nutritional factors that are commonly recommended for supplementation in cancer complementary and alternative medicine (CAM). The optimal vitamin nutriture of cancer patients is not well established. Our preliminary data provide evidence that rapid depletion of the vitamin folic acid is associated with increased resistance of cultured human lung cancer cells to the chemotherapeutic agent cisplatin. The overall goal of this project is to examine the hypothesis that folic acid influence the resistance in cancer cells to the action of agents used for cancer chemotherapy. We hypothesize, based on our preliminary data, that folic acid will prevent intrinsic and acquired resistance to anticancer agents commonly used in lung and ovarian cancer chemotherapy. To test this hypothesis, we propose the following three Specific Aims: Specific Aim 1: To determine whether high doses of folic acid can inhibit development of resistance to cisplatin. Specific Aim 2: To evaluate changes in folic acid levels and DNA methylation as a function of vitamin status during the development of resistance to cisplatin. Specific Aim 3: To evaluate the mechanisms by which high doses of folic acid alter resistance to cisplatin. These studies will tell us whether a vitamin used in cancer orthomolecular medical therapies and in cancer CAM is effective in preventing the development of resistance to commonly used cancer chemotherapeutic agents. We will compare very high folic acid concentrations, similar to what might be used in CAM treatment protocols, with deficient, normal and moderately elevated levels of folic acid, in order to get a clear picture of the effectiveness of very high doses of folic acid relative to the modest doses that would likely be tested in cancer patients in conventional clinical protocols. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CARDIOVASCULAR AND RENAL EVENTS IN KIDNEY DISEASE Principal Investigator & Institution: Ojo, Akinlolu O.; Associate Professor; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 24-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant):The aim of this proposal is to enable Dr. Ojo to devote 50% effort to conduct clinical research and to mentor patient-oriented research trainees. The research projects that will be principally utilized for the proposed mentoring plan are: (1) The Chronic Renal Insufficiency Cohort Study (CRIC); (2) The Folic Acid for Vascular Outcome Reduction in Transplantation Study (FAVORIT); and (3) The Scientific Registry for Transplant Recipients (SRTR). CRIC is an NIH-sponsored,

Studies

11

multicenter, prospective cohort study designed to determine the risk factors for accelerated decline in renal function and to evaluate the incidence and risk factors for cardiovascular disease (CVD) in patients with chronic renal insufficiency (CRI). The CRIC will provide the mentored trainees with hands-on application of a nonexperimental study design. The FAVORIT is an NIH-sponsored, multicenter, randomized, double-blind controlled clinical trial designed to determine whether total homocysteine (tHcy)-lowering treatment with a standard multivitamin augmented by a high dose combination of folic acid, vitamin B 12, and vitamin B6 versus treatment with a standard multivitamin devoid of these three B-vitamins, reduces the pooled rate of recurrent and de novo CVD outcomes in stable renal transplant recipients. The FAVORIT will be used as a template to instruct the trainees in the design, conduct and analysis of randomized clinical trials. The SRTR is a longitudinal database designed to conduct scientific investigations of patient-centered outcomes relevant to solid organ retrieval, allocation, and transplantation in the U.S. The SRTR will serve the trainee as a practicum for hypothesis-driven clinical epidemiologic outcome studies. Mentoring Plan: This award will entail the development and implementation of an integrated mentoring program starting from the first year of fellowship and consisting of three key components: (1) the practical experience of an observational study of 500 patients (CRIC), a randomized therapeutic clinical trial of 200 patients (FAVORIT) and outcomes analyses with a database of 300,000 organ recipients (SRTR); (2) rigorous didactic instructions in patient-oriented research methodologies through a Master degree in Clinical Research or Epidemiology program or flexibly designed set of course work; and (3) continuous training on rights, ethics and responsibilities in research with human subjects through the University of Michigan Research Responsibility Program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--ANALYTICAL FACILITY /ONE CARBON METABOLISM Principal Investigator & Institution: Wagner, Conrad; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2001 Summary: (adapted from the application): The rationale for establishing a new Core Laboratory devoted to One-carbon Metabolism is the enormous current interest in this area of research, not only by nutritional scientists, but also among the public at large. This is a result of two major developments in Nutritional Research over the past several years. The first is the recognition that about 75% of all births with neural tube defects may be prevented by periconceptional supplementation with folic acid. The second development is the identification of elevated plasma homocysteine levels as an independent risk factor for vascular disease. Since January 1997 there have been published over 1300 journal articles about folic acid and over 700 articles about homocysteine. At Vanderbilt we are fortunate to have a group of investigators who are among the leaders in studies of folate and one-carbon metabolism. The impetus to establish the one-carbon Core has been the desire to make this expertise available to other CNRU investigators. It is clear that patients with homocystinuria having very high levels of plasma homocysteine develop vascular occlusive disease at an early age if untreated. Recently, attention has been focused on patients with moderately elevated homocysteine levels (hyperhomocysteinemia) and an association with cardiovascular, cerebrovascular and peripheral vascular disease has been established. Even more recently, the increased levels of plasma homocysteine in patients with renal disease has suggested that this may be related to the high incidence of coronary heart disease in this

12

Folic Acid

group of patients. In addition, plasma homocysteine has been shown to be significantly elevated in patients with Alzheimer's disease and in dementia of Alzheimer's type. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADMINISTRATION

CORE--MORPHOLOGY-NEUROPATHOLOGY

AND

Principal Investigator & Institution: Armstrong, Dawna L.; Professor; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 23-JUL-2001; Project End 31-MAY-2006 Summary: The Morphology-Neuropathology portion of this Core will be the histology facility for all the projects and will provide the expertise required to perform the detailed morphologic studies that have been proposed for the animal models of Rett Syndrome, and for comparative studies on Rett and non-Rett brain. The Core will work intimately with each of the projects as follows: For projects 1 and 2: To support studies on the relation between genotype and phenotype in Rett syndrome, the core has autopsy material on a number of patients suitable for clinical, morphologic-molecular correlation studies. For project 1: The core will perform the morphologic characterization of the proposed animal model for Rett syndrome, comparing it to wild-type animals and to defined alterations seen in Rett. For project 3: The core will test and titrate the MeCP2 antibodies for use with human and animal tissues and will use them for detailed investigation of the cellular expression of the MeCP2 protein in the developing and adult human and mouse brain, and in Rett syndrome. The investigation of brain specific candidate proteins (e.g. trophic factors) defined by cDNA micro array analysis to be disrupted in cells expressing mutant MeCP2 will be studied in Rett tissues using immunohistochemical methods. The differentiation of cell types in the established embryoid bodies will be characterized by the Core using antibodies to neuro-epithelial precursor cells and the effects of the introduction of mutated MeCP2 into this system will be characterized morphologically The morphologic effects of folic acid treatment on the normal mouse and on the MeCP2 deficient mouse will be determined with gross and microscopic examination of body and brain tissues. The core director, Dawna Armstrong and her associate, Barbara Antalffy, have successfully provided a similar core facility for the Mental Retardation Research Center at Baylor College of Medicine. Moreover, they have been directly involved with the neuropathological study of Rett syndrome wince 1986 and have a well established autopsy and neuropathology data base for Rett syndrome. The Morphology- Neuropathology Core laboratory is located near the main Baylor laboratories where completely equipped to perform routine histology with frozen, fixed or cultured tissues, classic neuropathologic studies of neurons, myelin, axons, dendrites and spines, histochemistry and immunocytochemistry. The Administrative and Data Analysis Core portion of this Core is small but essential to the smooth operation of the Program Project. Huda Zoghbi will be responsible for the overall administration of the Project. She will work closely with the other principal investigators who compose the Executive Committee Regular meetings of the Executive Committee with the Internal Advisory Board will gauge progress, aid in scientific problems, and assist during major administrative decisions. The External Advisor will visit the site once a year for 2 days. Research will be presented, and a formal meeting of the Executive Committee and the External Board on the second day will review the progress of the work and provide thoughtful suggestions on how to improve or hasten that progress. Dr. Zoghbi will be assisted in the administrative and financial management of the Project by Gay Horelica, Administrative Assistant. Gay will coordinate daily administrative and financial affairs

Studies

13

of the researchers and will ensure seamless communication and interaction among the researchers. Dr. Alan Percy will travel to Baylor twice a year for this project, and Gay will see to his travel needs. Dr. O'Brian Smith will assist the various investigators (Glaze, Zoghbi, Van den Veyver, Percy, and Armstrong) with analysis of data from phenotype/genotype correlation studies (Projects 1, 2), microarray gene expression studies (Projects 1, 3) quantitative neuropathological studies provided in the various projects under the relevant specific aims. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CROOKED TAIL: GENE EXPRESSION IN A NEURAL TUBE DEFECT Principal Investigator & Institution: Ross, Margaret E.; Professor; Neurology and Neuroscience; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 15-DEC-1997; Project End 31-DEC-2006 Summary: (provided by applicant): The goal of this ongoing project is to characterize the gene mutated in the Crooked tail (Cd) mouse as a new locus associated with folic acid (FA) sensitive neural tube defects (NTD). Homozygous Cd are prone to rostral NTD and those completing neurulation display a subtle cortical dysplasia. In the first 3 years of funding, we have shown that the incidence of NTD is reduced in Cd by dietary folate in a manner closely resembling clinical observation, making it an important model for human NTD. Linkage analysis has fine-mapped the Cd locus to a 0.2 cM region of chromosome 6. Physical mapping and sequencing of the Cd critical region has identified 3 candidate genes. The project will identify the Cd gene, investigate the pathogenesis of its CNS malformations at the cellular and molecular levels and examine the relation between folate metabolism and these defects. First, the Cd gene will be sought through positional cloning and testing of identified candidates. Linkage analysis has beer completed and a genomic DNA contig covering the critical region has been established. In the renewal period we will identify Cd by: (a) cloning cDNAs corresponding to the genomic contig; (b) analysis of candidate genes from the region for large and small mutations in Cd mice. The identity of the gene producing Cd will be confirmed through demonstration that the phenotype can be rescued by introduction of BACs encompassing at entire candidate gene. Alternatively, the putative Cd mutation will be "knocked-in" to recapitulate the Cd phenotype. Second, The mechanisms leading to the Cd phenotype will be determined, whether due to altered cell proliferation, neuronal migration or programmed cell death. Morphogenesis of individual Cd embryos in culture will be examined by time-lapse confocal microscopy. In addition Cd brain histogenesis will be defined using markers of neural fate determination and CNS pattern formation. Third, Investigation of dietary folate will continue, to determine whether FA alters the proliferation of cells during neurulation, and whether FA can also ameliorate Cd cerebral cortical maldevelopment. Fourth, Functional studies of Cd will begin with structural analysis of the gene product. The status of FA-related metabolic pathways in Cd animals will be investigated for clues to potential mechanisms leading to FA-sensitive NTD. Function will be investigated by over-expression of Cd in mice, introduced by BAC vectors to permit transgene expression in appropriate temporal and anatomic sequence. Further functional studies will inactivate Cd in normal mice by a conditional homologous recombinant knockout. Study of the genetic, molecular and cellular events leading to abnormalities in Cd will contribute to mechanistic understanding of NTD and may lead to strategies for prenatal assessment of an individual family?s risk and tailored prevention of human brain maldevelopment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

14

Folic Acid

•

Project Title: DIET AND SOMATIC MUTATIONS IN COLON CANCER Principal Investigator & Institution: Slattery, Martha L.; Professor; Huntsman Cancer Institute; University of Utah 200 S University St Salt Lake City, Ut 84112 Timing: Fiscal Year 2002; Project Start 01-AUG-1995; Project End 31-AUG-2007 Summary: (provided by applicant): It is most probable that both genetic and environmental factors contribute to colon cancer etiology. At present, we have the capabilities to look at the interaction between dietary intake and genes that have been linked to colon cancer. In this study, we will evaluate DNA obtained from tumor tissue from cases enrolled in a large population-based case-control study of colon cancer (CA61757; CA 48998); we propose to collect tumor blocks from a population-based casecontrol study of rectal cancer to further evaluate associations (continuation of CA48998). Tumor DNA will be analyzed to determine specific mutations and CIMP pathway phenotype. We will evaluate the associations between these genetic mutations and tumor stage at diagnosis and survival. These data will be linked to environmental data, that includes extensive information on dietary intake within the population, to determine the impact that diet has on causing these somatic mutations (location and type of mutation). Total calories, fat, protein, calcium, fiber, beta carotene, and folic acid will be assessed with these genetic mutations, as will meats (along with method of and degree of cooking), dairy products, legumes, soy products, and fruits and vegetables. Other factors such as physical activity and body size which are closely related to dietary intake will be assessed both for their associations with somatic mutations. It is hypothesized that dietary intake (as specified above), physical inactivity, and a larger body size will contribute to the CIMP phenotype. Using data from the original studies, we will use statistical methods to better define disease pathways. We will include previously collected information on p53, K-ras, and microsatellite instability in tumors as well as information on CIMP phenotype. Rectal tumors will be characterized in the same manner as colon cancer tumors were originally characterized (i.e. p53, K-ras, and microsatellite instability). Differences in colon and rectal tumors will be compared. Additionally data from rectal tumors will be combined with that from colon tumors to define disease pathways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: DIET, HYPERLIPIDEMIA

ENDOTHELIAL

FUNCTION

AND

PEDIATRIC

Principal Investigator & Institution: Engler, Marguerite M.; Physiological Nursing; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-DEC-2004 Summary: Coronary heart disease (CHD) remains the leading cause of death in the United States. The pathogenesis of atherosclerosis and CHD is thought to be initiated by endothelial dysfunction or injury. Factors that contribute to oxidative stress such as elevated cholesterol-rich low density and very low-density lipoproteins (LDL and VLDL) result in endothelial dysfunction. The long term goal of this proposal is to develop dietary interventions for the prevention and treatment of endothelial dysfunction in children and adolescents who are at high risk for premature CHD due to the genetic lipid disorders of familial hypercholesterolemia (FH) or familial combined hyperlipidemia (FCH). This experimental, randomized, double blind crossover, placebocontrolled clinical trial will include 96 hyperlipidemic children and adolescents aged 10 to 18 years who will receive dietary supplements and an intensive dietary educational program. The following hypothesis will be evaluated: Specific nutrients in the diet will

Studies

15

have direct beneficial vascular effects and/or indirect effects on lipoprotein composition which will in turn decrease the oxidation of LDL and the level of vascular oxidative stress, thereby improving endothelial function. The primary specific aims are: 1) to determine whether a National Cholesterol Education Program (NCEP) Step II diet alone or together with one of four putative vasculoprotective supplements (Vitamins C & E, w-3 fatty acids, L-arginine, folic acid) will improve endothelial function in children and adolescents with FH and FCH, and 2) to evaluate the effects of these supplements on plasma lipoprotein profiles, LDL composition, lipoprotein-associated antioxidant enzymes (paraoxonase and platelet activating factor acetyl hydrolase), indices of oxidative stress (oxidized LDL, 8-hydroxy-2'-deoxyguanosine), immune function (inflammatory cytokines, plasma adhesion molecules), and blood pressure. Vascular reactivity, a sensitive indicator of endothelial function, will be measured noninvasively using high-resolution external vascular ultrasound of the brachial artery. The secondary aims are: 1) to examine children and adolescents psychological well being, beliefs and feelings about their cardiovascular status and its relation to health outcomes, and 2) To explore their practices and health risk behaviors specifically in the area of dietary adherence. These studies will provide important insight into the mechanism of endothelial dysfunction and should serve to identify potential treatments for pediatric hyperlipidemia. Preventive nursing strategies aimed at early detection of endothelial dysfunction and dietary modification may restore endothelial function in children and adolescents at high risk for CHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DNA METHYLATION AND COLORECTAL POLYPS Principal Investigator & Institution: Haile, Robert W.; Professor; Preventive Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2001; Project Start 20-JAN-2000; Project End 31-DEC-2003 Summary: (Adapted from the Applicant's Abstract): Our overall objective is to better define the role DNA methylation in the etiology of colorectal adenomas, and to assess potential risk factors for de novo methylation in adenomas. We propose to accomplish our objective by adding a methylation component onto an existing sigmoidoscopybased case-control study of environmental and genetic risk factors for adenomatous polyps of the large bowel that will have 1,000 cases and 1,000 controls, with food frequency and risk factors questionnaires, a fasting blood sample, and, for cases, pathology reports and tumor blocks. We propose the following aims: First, we will conduct a descriptive study of de novo methylation in five specific genes, three known tumor suppressor genes (APC, hMLH1, and p16) involved in colorectal of hypermethylation of the promoter region cancer, the estrogen receptor (ER), which may or may not be directly involved in the etiology of colorectal polyps, and a "control" gene, MYOD, that is clearly not involved in colorectal cancer. Second, we will assess two hypotheses regarding risk factors for hypermethylation. The first is that decreased dietary or RBC folic acid will be associated with an increase prevalence of hypermethylation of the promoter region of the ER. As part of this hypothesis, we will assess modification of the folic acid-methylation relationship by a gene, methylenetetrahydrofolate reductase (MTHFR), that is involved in folic acid metabolism. The second hypothesis is that use of postmenopausal hormones will be associated with a lower prevalence of hypermethylation of the ER. Third, we will determine if there are differences in the methylation status of the five target genes in adenomas with the replication error phenotype (RER+) compared to adenomas without that phenotype (RER-). We propose to measure methylation status with a new procedure (COBRA),

16

Folic Acid

developed by Dr. Peter Laird , that more sensitive and quantitative than other assays that can feasibly be conducted on a large sampled of paraffin-embedded tissue. Combining this assay with our ongoing study will provide us with a powerful means of addressing important questions about methylation and its role on cancer. We propose to measure methylation status with a new procedure (COBRA), developed by Dr. Peter Laird, that is more sensitive and quantitative than other assay with our ongoing study will provide a powerful means of addressing important questions about methylation and its role on cancer etiology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DYNAMIC AND KINETIC BEHAVIOR OF FOLATE METABOLISM Principal Investigator & Institution: Clifford, Andrew J.; Professor; Nutrition; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2001; Project Start 01-JAN-1997; Project End 30-JUN-2002 Summary: Our present understanding of the in vivo dynamics of folate is inadequate in light of the importance that folate plays in the pathogenesis of many diseases. The marginal to poor folate nutrition status of at least one in ten Americans is associated with several chronic and developmental diseases that include neural tube defects, cancer, and homocysteinemia, an independent risk factor for coronary heart disease. The mechanisms behind the pathology are believed to involve a dysfunction in the dynamic and kinetic behavior of folate metabolism; accordingly, quantitative information on the in vivo metabolism of folate has emerged as a high scientific priority. New isotope tracer methodologies employing radiocarbon tagged folates coupled with Accelerator Mass Spectrometry (AMS) detection promise to revolutionize in vivo tracer studies in humans. Using this approach, [14C]folate is reliably detected at attomole concentrations (moles x 10-18) in plasma, erythrocytes, urine and feces up to 200 days following a single, physiologic (35 mug) oral dose. At these levels of sensitivity, doses are virtually non-radioactive, permitting testing in both healthy subjects and at-risk subpopulations for folate-dependent disease. Our long-range goal is to understand the dynamics of human folate metabolism in terms of known hereditary and environmental factors that modulate incidence and progression of folate-related diseases. Relevant examples include how derangements of the genetic material, such as the common methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (a key folate metabolizing enzyme) may lead to homocysteinemia, or how pregnancy effects the mobilization and utilization of body folate stores. In pursuit of this goal, we propose long-term (7 month) tracer studies using [14C]folic acid and AMS detection to define the kinetics of folate metabolism in healthy female and male subjects. These investigations will fill a critical knowledge-gap surrounding folate metabolism. A kinetic approach offers a precise mode of quantitating the relative importance of absorption, distribution and elimination in the individual response to folic acid. Analysis of kinetic data will facilitate the construction of kinetic models and the establishment of metabolic phenotypes; this information will serve as a reference point for future investigations within at-risk sub-populations and individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: EFFECT OF FOLIC ACID AND VITAMIN B6 ON HOMOCYSTEINE Principal Investigator & Institution: Schirch, Laverne G.; Biochemistry; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2001; Project Start 01-MAY-2000; Project End 31-JAN-2005

Studies

17

Summary: Elevated homocysteine (Hcy) in the blood is an established risk factor for cardiovascular disease. Increases in dietary folate and B6 have been shown to lower Hcy levels. There are however, certain groups with other health problems where Hcy remains elevated, these include heart transplant recipients, diabetics, women with preclampsia or retarded fetal growth, end stage renal disease and Parkinson's disease. The aim of this proposal is to elucidate how nutritional insufficiency of folate and B6 affect the pathways of Hcy metabolism in mammalian cells. There are four specific aims: (1) the development of rapid enzyme-based assays for 5,10-methyleneTHF, B6 vitamers and homocysteine; (2) to determine the direction of flux of 1-carbon (1-C) groups in the cytosol and mitochondria of cells in culture, with special emphasis on serine hydroxmethyltransferase (SHMT); (3) to determine the role of mitochondria in the supply of 1-C groups to the cytosol; and (4) to determine the relationship of folate pools and metabolic levels of homocysteine with several different cell lines when either folate or B6 are limiting growth factors. Three hypotheses will be tested, which are: (1) that the role of cytosolic SHMT is not to generate 1-C units but to regulate the levels of glycine and 5,10-methyleneTHF in the cytosol; (2) that 1-C groups used by the cytosol are generated by the mitochondria as formate; and (3) Hcy levels are related to the level of 5,10-methyleneTHF in the cytosol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF RACE AND MIHFR GENOTYPE ON FOLATE REQUIREMENTS Principal Investigator & Institution: Caudill, Maria A.; California State Poly U Pomona 3801 W Temple Ave Pomona, Ca 91768 Timing: Fiscal Year 2001 Summary: The importance of adequate folate is unequivocal. Sub-optimal folate status is associated with increased risk for cardiovascular disease, neural tube defects and certain types of cancer. Methylene tetrahydrofolate reductase (MTHFR) is a critical enzyme that regulates folate metabolism. A common polymorphism (677 C->T) in the MTHFR gene is associated with decreased enzyme activity, lower concentrations of plasma folate, higher concentrations of plasma total homocysteine (tHcy) and increased risk for neural tube defects and possibly cardiovascular disease. Conversely, the same mutation is associated with decreased risk of certain forms of cancer providing that folate status is adequate. Observational data suggest decreased risk of certain forms of cancer providing that folate status is adequate. Observational data suggest that individual homozygous for the MTHFR mutation (T/T), approximately 12% of the population, may have higher folate requirements compared to individuals with either heterozygous (C/T) or homozygous wild-type (C/C) genotype. Potential differences in folate metabolism/requirements between racial or ethnic groups have also been described, although not under controlled conditions. The purpose of this study is to determine if the 1998 RDA for folate, 400 mug/d as dietary folate equivalents (DFE), is sufficient to maintain normal folate status in pre-menopausal women (18-45 yo) representing different ethnic/racial groups and different MTHFR genotypes. Mexican American (n=12; C/C genotype), African American (n=12; C/C genotype) and Caucasian women (n=36; C/C, C/T and T/T genotypes) will be randomly assigned to consume controlled folate intakes of either 400 or 800 mug/d as DFE and the remainder will be provided as synthetic folic acid. Folate status response will be assessed by baseline and thereafter weekly measures of serum and red cell folate, plasma tHcy, lymphocyte DNA methylation, lymphocyte deoxynucleotide content as well as urinary excretion of folic acid and 5- methyl-tetrahydrofolate. We hypothesize that the folate needed to satisfy the

18

Folic Acid

pathways of homocysteine metabolism and deoxynucleotide synthesis will differ among ethnic/racial groups as well as MTHFR genotypes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FASEB METABOLISM

SUMMER

CONFERENCE:

FOLATE,

B12

AND

1C

Principal Investigator & Institution: Finkelstein, James D.; Medical Investigator; Federation of Amer Soc for Exper Biology Bethesda, Md 208143998 Timing: Fiscal Year 2002; Project Start 02-AUG-2002; Project End 01-AUG-2003 Summary: (provided by applicant): Funds are requested for partial support of the 9th FASEB Summer Research Conference on Folic Acid, Vitamin B12 and One Carbon Metabolism to be held from August 3- August 8, 2002 at Snowmass Village, Colorado. This conference offers a unique opportunity for productive, formal and informal interactions between clinician investigators, basic scientists and those involved in health and science policy. The participants represent a diverse and broad group of disciplines. The last seven conferences, which met every second year, were fully subscribed. The current conference will be limited to 210 participants. The requested funds will support the attendance of graduate students; resident physicians; postdoctoral fellows; and established national and international investigators. A detailed program, led by senior scientist, emphasizes the participation of junior scientists new to the field. Thus the topics selected cover basic sciences and clinical research with particular emphasis on the interaction and potential synergy between the two. The specific subjects include (1) One Carbon Metabolism, Enzymology and Regulation; (2) Folate-Dependent Enzymes: Mechanisms and Structure; (3) Mammalian Methionine Metabolism-Regulation of the Integrated Pathways; (4) Metabolic Studies of Human Metabolism; (5) Sadenosylhomocysteine - Synthesis and Regulatory Potential; (6) Inborn errors of Folate, Cobalamin and Methionine Metabolism; (7) Knock Out Mice as Models of Human Genetic Diseases; (8) One Carbon Metabolism and Neoplasia of the Liver and Colon; (9) The Pathophysiology of Homocysteine Toxicity. In addition, poster sessions and workshops supplement these formal sessions. The workshops will provide expert and current analyses of (1) Preliminary Reports from the Folate Supplementation and Intervention Trials; (2) Hyperhomocysteinemia and Cognitive Dysfunction; (3) The Clinical Value of Homocysteine determinations; (3) Changing criteria for cobalamin deficiency; and (5) The Mechanism of Hyperhomocysteinemia in Renal Failure. The format encourages discussions between the presenters and the fellows, residents and junior investigators in attendance. Similarly, the poster sessions also highlight the activities and the needs of the younger participants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FOLATE DENDRIMERS AS TUMOR SPECIFIC CONTRAST AGENTS Principal Investigator & Institution: Wiener, Erik C.; Nuclear , Plasma & Radiological Engineering; University of Illinois Urbana-Champaign Henry Administration Bldg Champaign, Il 61820 Timing: Fiscal Year 2002; Project Start 26-APR-2002; Project End 31-MAR-2005 Summary: Ovarian cancer is the leading killer of women with tumors of gynecological origin, and intracranial ependymomas are the third most common primary brain tumors found in children. The long term goal of this project is to develop a magnetic resonance imaging (MRI) contrast agent specific for ovarian tumors, childhood ependymomas, and choroid plexus tumors thus improving the specificity of both the diagnosis of these

Studies

19

tumors and the monitoring of the treatment of these tumors. The specific aim of this project is to develop a high relaxivity dendrimer-Gd(III)-chelate based MRI contrast agent with strong avidity to cells expressing the high affinity folate receptor using low molecular weight targeting agents (folic acid) and actively target it to tumor cells in vivo. We are testing two hypotheses. One is that bifunctional Gd(III) chelates with faster proton exchange rates will have higher relaxivities (better efficiency) than those already achieved with bifunctional chelates of clinically approved agents following conjugation to dendrimers, and the other is that these agents have a high enough molecular efficiency (relaxivity) to enhance T1 weighted images, at 1.5 T, of tumors that express the high affinity folate receptor. The experimental approach consists of attaching a new bifunctional Gd(III) macrocyclic chelate to a new class of dendrimers. This class of dendrimers allows us to control the exact number of targeting and reporter molecules and provides a pure compound. Following the synthesis of this agent we will characterize the magnetic properties, determine the optimum number of targeting molecules, determine the number of Gd(III)- chelate complexes needed to alter the tumor contrast, prove targeting specificity in vivo, and determine the pharmacokinetics and biodistribution. We have two in vivo tumor models consisting of human ovarian tumor xenografts in nude mice that either express the high affinity folate receptor or lack it. The significance of developing a relatively low molecular weight (relative to antibody targeted systems) tumor specific MRI contrast agent is that it will allow better tumor visualization, interpretation for cancer diagnosis, and most significantly a noninvasive method for monitoring tumor therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FOLATE PATHWAY GENES AND RISK FOR OROFACIAL CLEFTS Principal Investigator & Institution: Shaw, Gary M.; Senior Epidemiologist; March of Dimes Birth Defects Foundation 1900 Powell St, Ste 1050 Emeryville, Ca 94608 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2003 Summary: The research program will investigate nutritional and genetic risk factors for orofacial clefts. The specific aims for the 3-year study are to assess the potential "geneenvironmental" interplay between genetic variation of 3 potential folate pathway genes (folate receptor gene, reduced folate carrier, and the N-acetal transferace 1 gene) among probands, maternal folic acid/multivitamin intake, and the risk of orofacial clefts. We propose to investigate the hypothesis that one or more of the 3 folate pathway genes are responsible for inadequate transport, accumulation, or metabolism of folate during critical stages of craniofacial development, making embryos susceptible to orofacial clefts even in the presence of clinically adequate maternal folate intake. By combining state-of-the-art molecular biology approaches, new genetic findings, and one of the largest case-control studies done on orofacial clefts, we will determine if maternal supplemental folic acid intake overcomes folate transport or metabolic dysfunction that may occur as a result of the embryo's genotypic variation for the 3 folate pathway genes and thus reduce the risk for orofacial clefting. The project has 3 collaborating research centers: California Birth Defects Monitoring Program, University of Nebraska, and Children's Hospital, Oakland. The research design will be case-control, including approximately 1200 cafes and controls, and will utilize maternal interview data in conjunction with genotyping of the folate receptor gene. Infants' DNA for genotyping will be obtained from residual newborn screening bloodspots, of which about 1250 DNA samples will be available for this study. Information on a variety of relevant covariates, such as parental cigarette smoking and the infant's genotype for transforming growth factor-alpha polymorphisms, will be available to analytically

20

Folic Acid

assess their contribution to risk for orofacial clefts. As one of the first attempts at investigating environmental and molecular genetic interactions in the epidemiology of congenital anomalies, this study endeavors to enhance our general understanding of the causes of orofacial clefts as well as our specific understanding of the apparent protective effect of folate supplementation on the occurrence of clefts. We observed a 50% reduction in risk for orofacial clefts among pregnant women who used vitamins. If this association ultimately proves causal, many of these anomalies will be preventable every year in the United States once it is understood what vitamin/diet component is important in facilitating the reduction in risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FOLATE RECEPTORS IN CRANIOFACIAL MALFORMATIONS Principal Investigator & Institution: Finnell, Richard H.; Professor & Director; None; Texas A&M University Health Science Ctr College Station, Tx 778433578 Timing: Fiscal Year 2001; Project Start 01-MAY-1999; Project End 30-APR-2003 Summary: (adapted from the Investigator's abstract): Over the past two decades, the accumulated literature suggests that periconceptional folic acid supplementation can reduce both the occurrence and recurrence of orofacial clefts and neural tube defects in humans by about 50%. This has major public health implications, as about 10,000 pregnancies per year in the United States are complicated by either neural tube defects or orofacial clefts. These malformations are among the most common of all human birth defects, yet their etiologic basis and underlying embryology remain poorly understood. The epidemiological evidence suggests that the protective effects of folic acid are unlikely to simply be maternal folate deficiency. Rather it may be deficient fetal folate metabolism, as well as the teratogenic effects of the elevated homocysteine levels that accompany folate deficiency. The applicant has developed a transgenic "knockout" mouse model lacking functional folate binding protein (FBP-1 and FBP-2). Homozygous null embryos for the FBP-1 have lethal neural tube defects. The general hypothesis is that an abnormal maternal and/or fetal folate receptor increases the risk for orofacial clefts and/or neural tube defects due to an inability to adequately bind and transport folate to both the oral and neural epithelia of the developing embryo. Experiments are proposed to determine the function of the FBPs during palatal and neural tube closure in the offspring of dams whose genes have been inactivated by homologous recombination in embryonic stem cells. The experimental model uses manipulation of folate and homocysteine levels of the dams and embryos by genetic or dietary means, with a number of morphological, molecular and biochemical endpoints. The conclusion of these studies have the potential to lead to a greater mechanistic appreciation for the protective effect of folic acid supplementation on embryonic development, the relative importance of folate and homocysteine metabolites and a better understanding regarding the role of cellular proliferation and/or cell death in craniofacial and neural tube development under conditions of variable folate and homocysteine availability. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: FOLATE, 1-CARBON NUTRIENTS, GENE VARIANTS & COLON CANCER Principal Investigator & Institution: Hunter, David J.; Director; Epidemiology; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02460 Timing: Fiscal Year 2003; Project Start 18-SEP-2003; Project End 31-AUG-2008

Studies

21

Summary: (provided by applicant): Most of the over twenty epidemiologic studies that have examined the relationship between dietary folate intake and the risk of developing colorectal neoplasms, have reported that higher folate intakes are associated with lower risk. Animal studies, using either carcinogen-induced or genetically engineered rodent models of colorectal cancer, have indicated an inverse relationship between dietary folate and the risk of colorectal cancer. The folate metabolic pathway influences genomic methylation and the supply of nucleotides for DNA synthesis; these can also be influenced by adequacy of supply of vitamins B12, B6, and B2, all co-factors for critical enzymatic reactions in the pathway. The overall long-term objective of our Team is to establish the role of folate and other nutritional contributors to one-carbon metabolism in colorectal cancer by combining animal, mechanistic, human observational studies and clinical trials. We will accomplish this by establishing a Cooperative Specialized Center for the study of Folate, One carbon nutrients, Gene variants and Colorectal cancer. This Center will be a Collaborative Program between Harvard and Tufts Universities in Boston, Dartmouth University in New Hampshire, the International Agency for Research in Cancer and the University of Bergen in Europe, Variagenics Inc. in Boston, and the Division of Cancer Prevention and the Center for Cancer Research at the NCI. We are organized into three projects, developmental projects, and two cores. Project 1 will pool data from three large prospective cohort studies with 2,700 expected colorectal cancer cases to establish whether higher intake of folic acid reduces risk of colorectal cancer and examine whether this reduced risk is greater among persons with low methionine intake, low plasma folate, vitamins B12, B6, and B2 levels, consumers of more than one alcoholic beverage per day, and homozygotes for the methylenetetrahydrofolatereductase (MTHFR) C677T polymorphism, and compound heterozygotes for the MTHFR A1298C polymorphism. Project 2 will validate mouse models of colon carcinogenesis as systems to examine modification of risk by folate and other contributors to one-carbon metabolism. Project 3 will assess whether the degree of uracil misincorporation and genomic methylation in peripheral blood lymphocytes and distal colon biopsies represent biomarkers of one-carbon nutrient adequacy and colorectal adenoma risk, using data and samples from two randomized clinical trials of folate supplementation. The projects will be supported by innovative Developmental Projects. In initial Developmental Project 1 transgenic mice with the null allele of MTHFR, and the homologous C677T polymorphism; these mice will be available for incorporation into feeding studies in Project 2. In Developmental Project 2 we will explore five folate-metabolism genes for polymorphisms that influence plasma folate and homocysteine levels. All Projects will be supported by the Administrative and Statistical Core (based at the Harvard School of Public Health), and the Measurement Core (based at the Human Nutrition Research Center at Tufts University). These highly interrelated studies will help integrate epidemiologic and mechanistic observations and help provide a basis for public health recommendations on optimal levels of folate and B vitamin intake. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FOLIC ACID & HOMOCYSTEINE-- DOSE RESPONSE STUDY Principal Investigator & Institution: Beresford, Shirley a A.; Professor; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 30-NOV-2001 Summary: We will examine chronically stressed individuals (spouse caregivers of persons with Alzheimer's disease (AD). Spouse caregivers lose the companionship and support of their AD spouses. These losses, coupled with chronic physical, emotional and

22

Folic Acid

financial demands (1, 2) as well as biobehavioral vulnerabilities, put spouse caregivers at increased risk for psychophysiological distress and physical health problems (3). In previous work with caregivers and matched controls, we studied a variety of psychobehavioral (e.g., hassles, anger/hostility, exercise, diet) and physiological measures. Of the metabolic, cardiovascular (CV), and immune measures examined, metabolic variables (Body Mass Index/obesity, insulin, and glucose) showed the strongest relationships with caregiving, whereas CV measures showed some relationships. These results lead us to focus now on metabolic/neuroendocrine measures. Such measures qualify as mediators of the relationship between caregiving and coronary heart disease (CHD) because they are related to both stress and CHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FOLIC ACID AND HOMOCYSTEINE: MECHANISMS OF HEART DEFECTS Principal Investigator & Institution: Rosenquist, Thomas H.; Von Housen Professor; Cell Biology and Anatomy; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 30-AUG-2006 Summary: The central theme and overall objective of this program is to determine the biological mechanisms whereby folic acid insufficiency and hyperhomocysteinemia may contribute to abnormal development of the heart. This program project is designed to provide maximum focus upon this theme, and to optimize scientific and intellectual synergy among members of the research team. Discovery of the cellular mechanisms that provide this protection is the objective of the research program proposed here. Two hypotheses will be tested: Hyperhomocysteinemia that results from folic acid insufficiency may induce abnormal development of the conotruncal region of the heart, as well as other neural crest and neural tube derivatives, by inhibiting the function of Nmethyl-D-aspartate receptors (NMDA). Folate insufficiency also may induce abnormal development by a direct effect upon the growth and differentiation of neural crest and neural tube cells directly, for example, by limiting the availability of methyl groups for gene methylation. A principle objective of this research program is to sort out the biological effects of low folate from those of hyperhomocysteinemia; and to determine how these two mechanisms may interact. It is inferred that they converge upon processes that are especially critical to the cardiac neural crest, other regions of the neural crest, and the neural tube. Project 1 will examine the teratogenic interaction of homocysteine with other NMDA antagonists, and will determine the degree to which embryos can be rescued by NMDA activation. Project 2 will investigate the impact of impaired folate binding and transport on the development of the heart, as well as other neural crest and neural tube derivatives, using transgenic mouse embryos models made for this purpose. Project 3 will concentrate upon the relative roles of hyperhomocysteinemia and the NMDA on the one hand, and folate insufficiency on the other, as they impact on neural crest cell migration and differentiation. Project 4 will test the elements of each of these hypotheses in a population-based study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: FOLIC ACID REQUIREMENTS AND ONE CARBON METABOLISM Principal Investigator & Institution: Shane, Barry; Professor and Chair; Nutritional Sciences; University of California Berkeley Berkeley, Ca 94720 Timing: Fiscal Year 2001; Project Start 01-JAN-1990; Project End 31-DEC-2004

Studies

23

Summary: Folylpolyglutamates are coenzymes in, and potential regulators of, a large number of reactions known collectively as one carbon (1-C) metabolism. These reactions which include the metabolic cycles for the synthesis of thymidylate, purines and the amino acids, methionine, serine and glycine, are compartmentalized in the mitochondria and cytosol of cells. This application is for the continuation of a series of studies aimed at investigating the control of the 1-C metabolism in cells and animals, and the role that mitochondrial folate metabolism plays in this process. The new application has five specific aims that are designed to test four hypotheses. The specific aims are: (1) to investigate the interrelationship between mitochondrial and cytosolic 1-C metabolism; (2) to study the regulation of 1-C entry and loss from the folate pool via the two compartmental forms of serine hydroxymethyltransferase; (3) to study the heterozygous disruption of the mouse methionine synthase gene and other genes for folate-dependent enzymes on the flux of 1-C units through the various metabolic cycles; (4) to investigate the use of the mouse methionine synthase heterozygous knockout as a model for the pathological and metabolic effects of vitamin B12 deficiency; and (5) to examine the regulation of expression of methionine synthase, methylenetetrahydrofolate reductase and serine hydroxymethyltransferase and to clone and characterize additional other genes of folate-dependent 1-C metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE-NUTRIENT INTERACTIONS IN REDOX HOMEOSTASIS Principal Investigator & Institution: Banerjee, Ruma; Willa Cather Professor of Biochemistry; Biochemistry; University of Nebraska Lincoln 14Th and R Sts Lincoln, Ne 68588 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2003 Summary: (provided by applicant) There is a growing literature on the role of dietary and environmental modulators in the control of reactive oxygen species that are implicated in the etiology of multiple and complex diseases such as cardiovascular diseases, Alzheimer's disease, Parkinson's disease, arthritis, certain cancers as well as in aging and apoptosis. Glutathione is a key endogenous antioxidant that plays a major role in cellular defense against reactive oxygen species and xenobiotics. The biosynthesis of glutathione is comprised of: (1) the upstream trans-sulfuration pathway that provides an avenue for conversion of the essential amino acid, methionine, to cysteine, the limiting amino acid in glutathione synthesis; and (2) the downstream pathway representing the final 2 steps catalyzed by gamma-glutamyl-cysteine synthetase and glutathione synthetase. The upstream pathway is present only in tissues with the highest concentration of glutathione, whereas the downstream pathway is ubiquitous. Tissues lacking the upstream pathway depend on an exogenous supply of cysteine, and inter-organ transport of glutathione plays a key role in providing this nonessential amino acid to these cells. A number of vitamins (B6, B12 and folic acid) and cofactors (heme and Zn2+) converge at this metabolic focal point and could potentially affect glutathione synthesis and, therefore, cellular redox homeostasis. The research design of this project is guided by 3 specific aims: (1) to address how regulation of the up- and downstream pathways is coordinated by using a mouse knockout model for cystathionine beta-synthase, the first enzyme in the trans-sulfuration pathway. These studies will be a prelude to characterizing the effects of macro- (methionine, cysteine) and micronutrients (B6, B12 and folate) on modulating glutathione pools in the 3 genetic backgrounds (+/+, +/-and -/- cbs); (2) to elucidate the relative efficacies of the different genotypes in handling oxidative and xenobiotic challenges; and (3) to initiate studies to elucidate the molecular mechanism of redox regulation of gamma-glutamyl- cysteine

24

Folic Acid

synthetase, the rate-limiting enzyme in glutathione biosynthesis, by focusing on the properties of the regulatory subunit that the principal investigator has discovered is a member of the aldo-keto reductase superfamily. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENES, MALFORMATIONS

MICRONUTRIENTS

AND

HOMEOBOX

RELATED

Principal Investigator & Institution: Hobbs, Charlotte A.; Assistant Professor of Pediatrics; Arkansas Children's Hospital Res Inst Research Institute Little Rock, Ar 72202 Timing: Fiscal Year 2001; Project Start 25-SEP-2000; Project End 31-MAY-2005 Summary: (Adapted from the Applicant's Description): Strong epidemiologic evidence has accumulated in recent years to suggest that periconceptional folic acid is an effective agent in reducing the occurrence and recurrence of several common congenital malformations. The metabolic and molecular basis for this preventive effect is completely unknown, and provides a unique opportunity to dissect the interacting etiologic factors that are positively affected by exogenous folic acid. The investigators designed a series of experiments to explore both the nutritional and genetic scope of folate- related factors that may interact in the etiology of neural tube and heart defects. It is hypothesized that common polymorphism in genes coding for critical enzymes in the folate pathway will interact with inadequate maternal micronutrient status to negatively affect the fetal microenvironment, and promote alterations in homeobox gene expression and tissue-specific developmental malformations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MEMBRANE

GENETIC

ANALYSIS

OF

GPI-PROTEIN

RECYCLING

VIA

Principal Investigator & Institution: Ratnam, Manohar; Professor; Biochem and Molecular Biology; Medical College of Ohio at Toledo Research & Grants Admin. Toledo, Oh 436145804 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2003 Summary: (provided by applicant): The glycosyl-phosphatidylinositol (GPI)-anchored folate receptor (FR) binds folate compounds and folate conjugates and mediates their uptake by cells. FR-mediated transport is believed to occur via a novel sphingolipid-rich membrane microdomain that also contains other GPI-anchored proteins and that recycles between the cell surface and endocytic compartments, but the molecular components of this transport machinery have not been identified. We propose to identify genes whose products are essential for FR recycling and the associated folate uptake by genetic analysis in a yeast system. The system is chosen because of its versatility and based on the close similarity in known membrane transport mechanisms between yeast and mammalian cells as well as the similarity in membrane-associated characteristics of yeast and mammalian GPI-anchored proteins. We will use a yeast folate auxotroph in which folate uptake (presumably by diffusion) requires a very high (about 100 microM) exogenous folate concentration. We have introduced human FR into this yeast strain under control of a Cu++-inducible promoter and found that the receptor mediates [3H]folic acid uptake at nanomolar extracellular concentrations, supports cell growth in less than 0.1 microM folinic acid and sensitizes the cells to low concentrations of the potent antifolate drug, dideazatetrahydrofolate (DDATHF). We will mutagenize the FR expressing yeast chemically or by transposon insertion and initially select for

Studies

25

mutants that are resistant to low concentrations of DDATHF. A second more stringent replica plating screen will narrow mutants defective in FR-mediated transport by selecting for those that require a high (about 100 microM) concentration of exogenous folinic acid for normal growth. The transport defects will be confirmed by [3H]folic acid uptake studies. Alternatively, temperature-sensitive mutants defective in folate uptake will also be isolated. FR mutants, as well as mutants with impaired FR synthesis or GPImodification, will not be considered. A yeast genomic library and a human cDNA expression library will be used to complement the transport defects. The yeast and human genes complementing the mutant phenotypes as well as the yeast mutations will be examined by DNA sequence analysis. For the yeast genes thus identified, putative human homologs will be tested for complementation of mutant phenotypes. The mechanistic roles of such known and novel proteins in FR-mediated transport will be the subject of future investigations. The studies are expected to provide new insights of a fundamental nature into membrane transport processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICS OF NEURAL TUBE DEFECTS Principal Investigator & Institution: Speer, Marcy C.; Associate Research Professor; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2006 Description (provided by applicant): Failed closure of the neural tube, the embryonic structure from which the brain and spinal cord are formed, leads to neural tube defects (NTDs). The NTD complex includes the two most common forms of NTDs, spina bifida and anencephaly, as well as other less frequent manifestations such as encephalocele, craniorachischisis, and iniencephaly. The frequency of NTD births in the United States is approximately 1/1000. Numerous studies have implicated both environmental and genetic factors. Multiple lines of evidence in humans and studies in experimental organisms provide compelling evidence that the predisposition to the development of NTDs includes a hereditary component. For instance, the increase in risk to siblings over the general population rate (lambda), frequently used as one measure of the genetic contribution to a disorder, is estimated at 25-50. In this application, the investigators propose to identify genetic factors involved in NTD development from factors and pathways identified through the sister projects. The candidate genes will be investigated using mutation screening and/or detection techniques. The investigators will also perform a high density genomic screen on a single large pedigree with six affected family members to identify regions of the genome that may harbor NTD susceptibility loci. These regions may identify novel regions of interest to be investigated in model systems. In addition, the investigators will expand their available dataset of NTD families to include the phenotype of anencephaly, at the severe spectrum of the NTD phenotype. Extensive family history data and blood for DNA extraction will be obtained from these pedigrees in which one or more members are affected with anencephaly. These pedigrees will be exhaustively characterized clinically, including radiographic assessment of level of lesion, assessment of facial dysmorphology, and cytogenetic assessments. In addition, the investigators will collect and database information on key environmental risk factors such as folic acid supplementation, maternal weight, and paternal military exposures to allow assessment of gene/environment interactions. The goal of this proposal is to illuminate the hereditary factors predisposing to NTDs, with the ultimate aim of characterizing interactions between genes and between genes and the environment, eventually leading to mechanisms for the prevention of these frequent birth defects.

26

Folic Acid

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

Project Title: HEMODIALYSIS CONSORTIUM

VASCULAR

ACCESS

CLINICAL

TRIALS

Principal Investigator & Institution: Allon, Michael; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 28-FEB-2006 Summary: (adapted from the application) The current approach to vascular access in dialysis patients consists of monitoring grafts and fistulas for evidence of stenosis, and intervening to correct the stenosis after it occurs. A pharmacologic intervention that prevents vascular access complications may markedly decrease the need for salvage procedures, access-related hospitalizations, and the overall cost of caring for hemodialysis patients. Plasma homocysteine levels are frequently elevated in dialysis patients. Hyperhomocysteinemia is a risk factor for cardiovascular disease in hemodialysis patients, and may also be a risk factor for vascular access thrombosis. Folate is a substrate for homocysteine, and folic acid administration can lower homocysteine levels. Whereas standard doses of folic acid (1 mg daily) have a minimal effect on homocysteine levels in dialysis patients, pharmacologic doses (15 mg daily) can reduce homocysteine levels substantially. It is not known whether aggressive reduction of homocysteine levels in dialysis patients with pharmacologic doses of folic acid can decrease the frequency of vascular access stenosis and thrombosis. The following hypotheses will be tested in this study: (1) Pharmacologic doses of folic acid (15 mg daily) are more effective than standard doses (1 mg daily) in decreasing the frequency of graft stenosis and thrombosis in hemodialysis patients. (2) This beneficial effect of highdose folic acid on graft outcome is proportionate to the magnitude of reduction in plasma homocysteine. (3) High dose folic acid administration is effective in improving graft outcomes both as primary prophylaxis (no previous stenosis or thrombosis) and as secondary prophylaxis (prevention of recurrent stenosis or thrombosis after an initial event). The study design is a prospective, randomized, double-blind, multicenter investigation in which chronic hemodialysis patients with AV grafts will be randomized to receive either high (15 mg daily) or standard (1 mg daily) doses of folic acid supplements. The primary endpoint will be overall graft survival. Secondary endpoints will be the frequency of graft interventions and cardiovascular events. The results will be analyzed to determine whether there are significant differences in graft survival or complications between the groups receiving high dose and standard dose of folic acid. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOMOCYSTEINE AND PROGRESSION OF ATHEROSCLEROSIS Principal Investigator & Institution: Taylor, Lloyd M.; Professor; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2001 Summary: Homocysteine is a chemical in the blood which has been shown to have an influence on artery blockage. Folic acid (Vitamin B group) has been shown to lower homocysteine. The purpose of this study is to measure the level of homocysteine in the blood and see if randomized treatment with folic acid to reduce the level of homocysteine will have an influence on the progression of blockage of the arteries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

•

27

Project Title: HOMOCYSTEINE DIET STUDY: EFFECTS OF DIFFERENT FOLATE SOURCES Principal Investigator & Institution: Farquhar, John W.; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2001 Summary: Homocysteine is a factor found in blood that has been found to be elevated among adults with heart disease, similar to elevated blood cholesterol levels. This relatively risk factor for heart disease has been found to respond to the dietary vitamin known as either folate or folic acid. There are three different sources of folate in the diet. One is from typical multivitamins, another is from breakfast cereals and others that have been with folate, and a third is from beans and leafy greens, which have naturally high folate levels. The purpose of this study was to determine which of those three sources of folate would be most effective in lowering homocysteine levels in adults with moderately elevated homocysteine. Sixty participants were enrolled and randomly assigned to be in one of four groups: Multivitamin, fortified foods, beans and greens, or a placebo group. After six weeks it was found that blood levels of homocysteine dropped the most for the group taking the multivitamin. The group eating the fortified foods did almost as well as the multivitamin group. The group eating beans and greens did no better than the placebo group, both showed negligible change. Knowledge of the form of folate found in each of these sources might explain the observed differences. In the multivitamins and fortified foods, the form of folate used is the smallest, best absorbed form of folate, whereas in the beans and greens the folate is found in a larger, more complex form, and is not as readily absorbed. In conclusion, two safe and readily available approaches for increasing folate in the diet were effective at lowering elevated homocysteine levels, but the approach of increasing daily consumption of beans and greens was not effective for improving this one particular heart disease risk factor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: HUMAN GAMMA GLUTAMYL HYDROLASE Principal Investigator & Institution: Ryan, Thomas J.; Wadsworth Center Empire State Plaza Albany, Ny 12237 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2005 Summary: (As Adapted From the Investigator's Abstract): Folic acid is necessary for the synthesis of metabolites that are required for cell growth. For this reason, the folate metabolic pathways have been targets for therapies aimed at blocking cell division using antifolates. Cellular uptake of antifolate monoglutamate occurs via specific transporters. Intracellular classical antifolates are converted to poly-gamma-glutamates by polyglutamate synthetase. The poly-gamma-glutamate derivatives cannot cross the cell membrane, concentrate intracellularly, and can be better substrates or inhibitors for the folate dependent enzymes. Formation of antifolyl poly-gamma-glutamates and cellular retention are countered by removal of the poly-gamma-glutamate tail catalyzed by a poorly understood enzyme, gamma-glutamyl hydrolase. Cellular folate homeostasis and the efficacy of certain antifolates such as methotrexate are determined by the balance between the activities of these two enzymes. The goal of the proposed research is to define the molecular details of the mechanism of action of human gamma-glutamyl hydrolase (hGH) and to determine the structural features that contributed to the specific mode of action of this enzyme. The mechanism of hGH will be investigated by identifying the active site residues using site directed mutagenesis to test a molecular model for the catalytic fold of the enzyme. Amino acids, which bind the poly-gamma-

28

Folic Acid

glutamate chain of substrates will be identified by site directed mutagenesis. The three dimensional structure of the enzyme will be determined by X-ray crystallography. Transfection with cDNA or antisense constructs will be used to alter hGH expression in cancer cells to establish the role of this enzyme in antifolate and fluorouracil action. These studies will determine if GH is a potential site for modulation of current therapy with these drugs. The characterization of an identified cellular inhibitor of human gamma-glutamyl hydrolase will also be carried out. The specific inhibition of hGH is necessary to determine its role in folate homeostasis and antifolate action. The results of the proposed studies may lead to the development of specific inhibitors of human gamma-glutamyl hydrolase, which could be used in conjunction with established antifolates or fluoropyrimidines in the treatment of human cancers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYPERHOMOCYSTEINEMIA AND DIABETIC ATHEROSCLEROSIS Principal Investigator & Institution: Lee, Daniel C.; Physiology/Cellualr Biophysics; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 01-JUL-2001 Summary: The Diabetes Control and Complications Trial Research Group studies demonstrated that while aggressive therapeutic efforts aimed at restoring relative euglycemia diminish complications in the microvasculature, no significant reduction in the incidence of microvascular disease was observed. These findings support the concept that factors unique to diabetes contribute to accelerated vascular disease. Many studies have demonstrated increased levels of plasma homocyst(e)ine in patients with diabetes and/or renal failure, and in patients with certain genetic mutations of genes encoding enzymes critical for metabolism of methionine and homocysteine. Indeed, elevated levels of plasma homocysteine have been linked to increased vascular disease. An important facet of hyperhomocyst(s)inemia (HHCy) is potential reversibility with vascular disease. An important facet of hyperhomocyst(s)inemia (HHCy) is its potential reversibility with increased intake of vitamins, such as folate, pyridoxine, and B12. An important question, yet to be tested in long-term human studies, is whether dietary vitamin supplementation may ameliorate the incidence of accelerate atherosclerotic vascular disease in patients with HHCy. Our laboratory has developed models of accelerated diabetic atherosclerosis in mice in which both lipid-dependent and independent mechanisms contribute, thereby allowing us to dissect the contribution of specific factors in the development of accelerated vascular disease. We propose that upon enriching normal mouse chow with methionine, along with significant reduction of vitamins, we may test the hypothesis that accelerated vascular disease will ensue as a consequence of HHCy. In subsequent experiments, increased dietary supplementation of vitamins folic acid, pyridoxine and B12 may then serve to determine if vitamin supplementation may confer vascular-protection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: HYPERHOMOCYSTEINEMIA IN ALZHEIMER'S DISEASE Principal Investigator & Institution: Diaz-Arrastia, Ramon R.; Associate Professor; Neurology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 31-JUL-2004 Summary: In the past years, two independent case control studies have established a correlation between elevated homocysteine levels and Alzheimer's Disease (AD). Since vitamin supplementation with folic acid, vitamin B12, and pyridoxine can lower

Studies

29

homocysteine levels, this association raises the exciting possibility that polyvitamin therapy may decrease the incidence of AD. The goal of this proposal is to obtain pilot data necessary to design a large multicenter trial to determine whether vitamin therapy lowers the risk of AD. We plan to do this through the following specific aims: (a) Determine whether fasting or post-methionine load (PML) are best associated with AD. The published studies analyzed homocysteine levels in fasting or randomly drawn serum samples. Since many patients have elevations in homocysteine levels only after a methionine load, and both fasting and PML hyperhomocysteinemia may be associated with dementia, we will determine whether fasting hyperhomocysteinemia, PML hyperhomocysteinemia, or both, are linked to a higher risk of AD. We will also determine whether plasma levels of S-adenosylhomocysteine (SAH) and Sadenosylmethionine (SAM) are nire sensitive markers of functional hyperhomocysteinemia (b) Determine the relative importance of nutritional and genetic factors as determinants of hyperhomocysteinemia. Elevated homocysteine levels result from a complex interplay of genetic and acquired factors, and the link between hyperhomocysteinemia and AD has so far been reported only in Europeans. In an attempt to determine which of these factors is most important in an ethnically and culturally heterogeneous US population, we will administer a nutritional questionnaire and measure vitamin levels in our patients, as well as determine the allelic frequency of the C677T polymorphism of MTHFR, a major genetic determinant of hyperhomocysteinemia. (c) Determine whether vitamin therapy is effective in lowering homocysteine levels in patients with hyperhomocysteinemia. All subjects will be treated sequentially for 12 weeks first with low dose vitamin supplementation, followed by high-dose vitamin supplementation. The effectiveness, compliance rates, and potential side effects of these therapies will be monitored. Each of these specific aims is essential to rationally design a large multicenter trial to determine whether polyvitamin therapy lowers AD risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INHIBITION OF PROSTATE SPECIFIC MEMBRANE ANTIGEN Principal Investigator & Institution: Berkman, Clifford E.; San Francisco State University 1600 Holloway Ave San Francisco, Ca 94132 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006 Summary: Prostate cancer remains the most common male malignancy and the second most common cause of cancer-related mortality in most Western societies. The incidence of prostate cancer and corresponding mortality rates vary strikingly among ethnic, racial, and national groups with noteworthy high rates among African Americans. The identification of an upregulated and strongly expressed antigenic marker on prostate cancer cells, namely prostate specific membrane antigen (PSMA), has attracted a great deal of attention as a target for immunotherapy. More recently, it has been reported that PSMA possesses at least two specific enzymatic activities; the hydrolytic cleavage and liberation of glutamic acid from both gamma-glutamyl derivatives of folic acid and the neuropeptide NAAG (Nacetylaspartylglutamate). Although these enzymatic activities have been clearly identified, questions of medical interest remain to be answered for PSMA. Two such questions are: "What is the role of PSMA on the surface of prostate cancer cells?" and "How would inhibiting PSMA affect the growth, proliferation, or regulation of prostate cancer cells?" Although the proposed research will not immediately address these questions, it is anticipated that the results of this work will provide the investigators with suitable tools to study these issues in future studies. Furthermore, it is likely that the enzymatic activity of PSMA could be exploited for

30

Folic Acid

chemotherapeutic strategies, one of which being the inhibition of its activity by small molecule inhibitors. The overall objective of the proposed work is to develop potent and selective inhibitors for PSMA. This will be accomplished by first conducting substrate studies to identify optimal structural frameworks for enzyme recognition. These frameworks will then be utilized in the design and development of a first generation of phosphonopeptide inhibitors of PSMA. The most promising and potent of these inhibitors will be then further elaborated with binding probes to identify and exploit auxiliary binding sites on the enzyme leading to enhanced inhibitory potency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIPOTROPE STIMULATES BREAST CANCER CELL DEATH Principal Investigator & Institution: Park, Chung S.; Professor; Animal and Range Sciences; North Dakota State University Fargo, Nd 581055756 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Lipotropes (methyl group containing nutrients including choline, methionine, folic acid, and vitamin B12) have been shown to have oncostatic action on mammary cancer. We hypothesize that excess lipotropes may alter expression of apoptosis-related genes including bcl-2 gene, via alterations in DNA methylation, and consequently increase the sensitivity of cancer cells to programmed cell death. Specific aims of the proposed study are: 1) to confirm if excess lipotropes increase the susceptibility of breast cancer cells to apoptosis, 2) to investigate if lipotrope-supplementation alters the expression of certain genes involved in the regulation of apoptosis, and 3) to examine if an excess of lipotropes affects genomic methylation patterns of apoptosis-related genes. Tamoxifen (TAM), an anti-cancer agent, will be used to induce apoptosis in breast cancer cells. Two breast cancer cell lines, MCF-7 and T47D, as well as a normal mammary cell line, MCF-10A, will be tested in this study. Cells will be cultured in preincubation medium until 80 percent confluent and then switched to apoptosis induction media (TAM added) with (treatment) or without (control) excess lipotropes. Apoptosis will be accessed by immunohistochemistry, electrophoretic DNA fragmentation patterns, and caspase assay. Expression of apoptosis-related genes will be elucidated by gene array methodology and Northern analysis. The genomic DNA methylation patterns of apoptosis-related genes will be analyzed by methylation specific PCR and HPLC. Direct molecular and biochemical information on the possible effect of excess lipotropes upon breast cancer cell death could ultimately lead to the development of dietary compounds and chemotherapeutic agents that would reduce and treat breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ISCHEMIA

LOWERING

HOMOCYSTEINE

TO

REDUCE

MYOCARDIAL

Principal Investigator & Institution: Tawakol, Ahmed A.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2007 Summary: (provided by applicant): Mild elevations in serum homocysteine levels are associated with a two-four fold increased risk in myocardial infarctions and are present in over 40-50 percent of individuals with coronary artery disease. The investigators previously observed a defect in nitric oxide-mediated vasodilation in the peripheral vasculature of otherwise healthy humans with mild elevations in homocysteine. More recently, they employed positron emission tomography (PET) and demonstrated that

Studies

31

homocysteine acutely impairs coronary microvascular dilation in healthy humans. Lowering homocysteine levels can be readily achieved with folic acid. However, the important question of whether or not lowering homocysteine levels in these individuals reduces the manifestations of coronary artery disease remains unanswered. The proposed series of investigations represent the logical next-step, by investigating the potential benefits of homocysteine-lowering with folic acid. The first aim of this investigation tests the hypothesis that lowering mild, commonly encountered elevations of serum homocysteine improves coronary microvascular dilation, using PET. The second aim of this study tests the hypothesis that lowering mildly elevated homocysteine concentrations decreases exercise-induced myocardial ischemia, using exercise stress testing. The third aim tests the hypothesis that folic acid also acutely improves coronary micro vascular dilation independently of its homocysteine-lowering effects. As such, these investigations would appraise homocysteine's role in contributing to cardiac disease, and would assess whether patients with coronary disease might benefit from homocysteine-lowering with folic acid. In addition to addressing a question of the highest clinical importance, this proposed project would serve as a critical catalyst for the applicant's growth as a junior faculty member of the MGH and Harvard Medical School (HMS). Furthermore, this award would provide the applicant with an invaluable opportunity to advance the skills that are essential for his maturation as a significant contributor to patient oriented clinical research and to the understanding of coronary vascular physiology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MATERNAL AND INFANT HEALTH INTERVENTIONS IN BANGLADESH Principal Investigator & Institution: Rasmussen, Kathleen M.; Div/Nutritional Sciences; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2001; Project Start 31-AUG-2001; Project End 01-APR-2002 Summary: (Provided by applicant): Poor maternal nutritional status remains an important determinant of long-term maternal health as well as of fetal growth and subsequent infant health and survival, especially in South Asia. We will conduct 3 experiments among a single group of 5,000 undernourished women who live in Matlab Thana, the well-established field site of International Centre for Diarrhoeal Disease Research, Bangladesh. An on-going surveillance program identifies pregnant women within 6-8 wk of conception. An on-going government program provides a food supplement to pregnant and lactating women that contains 600 kcal/d (6 d/wk) and a daily pill that contains 60 mg iron (Fe) and 400 mcg folic acid. Intervention 1: We will randomly assign women to receive advice to begin the food supplementation program (a) immediately after diagnosis of pregnancy (early care) or (b) at the time of their choosing (usual care). We postulate that those in the early care group will have higherbirthweight infants than those in the usual care group. Intervention 2: Within each of these groups, we will randomly assign women to receive a pill that contains (a) 30 mg Fe and 400 mcg folic acid or (b) 60 mg Fe and 400 mcg folic acid (usual care) or (c) 30 mg Fe, 400 jig folic acid and additional micronutrients. We postulate that the lower-iron treatment will have the same effect on maternal hemoglobin but fewer side-effects and, thus, greater compliance than usual care. We postulate that the micronutrient supplement will increase maternal hemoglobin compared to usual care. Intervention 3: We will randomly assign all of the subjects to receive either (a) counseling for exclusive breastfeeding (EBF) or (b) a different health education message of equivalent intensity. We postulate that those who receive counseling for EBF have a longer duration of EBF

32

Folic Acid

than those who did not receive this counseling. We postulate that this treatment will increase infant growth and reduce infant morbidity. Each of these trials is designed to address an important scientific issue and also uses an intervention that could be readily incorporated into public health programs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MEASUREMENT OF FOLATE IN FORTIFIED CEREAL GRAIN PRODUCTS Principal Investigator & Institution: Selhub, Jacob; Professor; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 26-SEP-2002; Project End 30-JUN-2004 Summary: (Provided by applicant): Since January 1998, the U.S. FDA has required enriched cereal grain products to be fortified with 140 mcg folic acid per 100 g. The purpose of this fortification was to reduce the incidence of neural tube defects by increasing the folic acid consumption of women of childbearing age. Our assessment of the impact of this fortification, using folate status based on changes in plasma and red blood cell folate levels in the Framingham Offspring Cohort Study, indicated a much greater impact on folate status than anticipated. Our hypothesis is that this higher impact of fortification on plasma folate levels is due to overages of folic acid fortification on enriched cereal grain product. The overall aim of this study is to determine the amount of folic acid and natural folates in nationally representative food samples of fortified cereal grain products, using the affinity/HPLC method, which allows these folates forms to be measured separately. It is necessary to distinguish between these two forms of folate in order to calculate total folate intake in individuals or populations as Dietary Folate Equivalents (DFE= mcg of natural folate + mcg of folic acid x 1.7). It is also very important to be able to quantify folic acid intake because the Tolerable Upper Intake Level and the recommendations for women of childbearing age are expressed for folic acid alone. The food samples that we will measure are part of the National Food and Nutrient Analysis Program (NFNAP). We will then apply this information on natural folate and folic acid content in fortified products to food frequency data collected as part of the Framingham Offspring Study to provide a measure of the actual increase in folic acid intake due to this fortification, the prevalence of individuals with adequate total folate intake and the prevalence of individuals with folic acid intakes above the Tolerable Upper Intake Levels. Our measurements of natural folate and folic acid in enriched cereal grain products will contribute to update future releases of the USDA nutrient databases. Folate status is thought to impact a number of diseases including neural tube defects, cardiovascular disease and colorectal cancer. In order to assess the impact of folic acid fortification, it is necessary to have valid data on the actual synthetic folic acid content of fortified foods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MECHANISMS OF ANTIFOLATE EFFICACY Principal Investigator & Institution: Morgan, Sarah L.; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001 Summary: Low-dose methortrexate therapy suppresses autoimmune arthritis in human and animal models. It is our hypothesis that the effect of methotrexate in the treatment of rheumatoid arthritis is due to the inhibition of aminoimidazole-carboxamide ribotide transformylase, a folate-dependent enzyme which catalyzes the last step in the de novo

Studies

33

biosynthesis of inosine monophosphate. The resulting accumulation of aminoimidazole carboxamide riboside inhibits adenosine deaminase, therefore, interfering with normal adenosine metabolism. It is well known that children with adenosine deaminase deficiency have severe-combined-immunodeficiency syndrome. This suggests that adenosine deaminase activity is key to immune competence and is associated with the mechanism of efficacy in methotrexate therapy of rheumatoid arthritis. Several studies indicate that supplemental folinic acid (5- formytetrahydrofolate) used in large doses during low-dose methortrexate therapy for rheumatoid arthritis causes a flare in joint inflammation. However, supplemental folic acid (pteroylglutamic acid) does not lessen the efficacy of the therapy. We further hypothesize that if methotrexate efficacy is driven by aminoimidazole carboxamide ribotide transformylase inhibition, folic acid supplementation should not alter urinary levels of aminoimidazole carboxamide, adenosine, and deoxyadenosine, while folinic acid supplementation should prevent the accumulation of these compounds. Our hypotheses will be tested both in patients with rheumatoid arthritis and in Lewis rat adjuvant arthritis. Objectives include A) to determine whether supplemental folic acid and folinic acid during methotrexate therapy normalize adenosine metabolism in patients with rheumatoid arthritis. The information obtained from the proposed research will enhance the understanding of the biochemical action of antifolates/ antimetabolites that are effective in the treatment of human and animal arthritis. To date, six patients have been enrolled in the trial. Because the trial is blinded, no data is yet available. It is planned inthe upcoming year to enroll patients, up to a total of 50 patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF ISCHEMIC INJURY AND REPAIR Principal Investigator & Institution: Bonventre, Joseph V.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-SEP-1984; Project End 31-DEC-2001 Summary: The overall goal of the proposed studies is to understand the mechanisms involved in ischemic cell injury and repair of tissue post-ischemia. The current proposal will focus on: 1) the role of phospholipase A2 (PLA2) in the injury process; and 2) molecular events regulating tissue repair. The first Specific Aim of the application is to purify and further characterize a Ca2+-independent form of PLA2 in the kidney and to determine the contribution to injury of this form of PLA2, as well as the cytosolic 100110 kD PLA2 (cPLA2) which we have purified. The Ca2+- independent form of PLA2 will be purified from the kidney, its substrate specificity characterized, antibodies to the protein made, and its cDNA cloned. Potential changes in enzymatic activity with ischemia will be evaluated. Possible mechanisms of activation of PLA2, in particular cPLA2, in ischemia/reperfusion will be examined. These possible regulatory mechanisms include: translocation of the enzyme to the membrane, changes in levels of PLA2 activating protein (PLAP), and post- translational modifications of the enzyme such as phosphorylation. Cell lines will be established, which overexpress normal or altered cPLA2 or suppress expression of cPLA2, and these lines will be used to establish mechanisms of regulation of cPLA2 and contribution of cPLA2 to cellular injury associated with the energy depleted state. The second Specific Aim is to characterize a novel kidney-specific zinc finger putative transcription factor, Kid-1, which we have cloned, whose expression is regulated in renal ontogeny and by ischemia/reperfusion, or folic acid administration. The Kid-1 protein will be expressed, antibodies raised to it and the intrarenal expression of Kid-1 localized and correlated with immunohistochemical localization of markers of differentiation and mitotic activity. The

34

Folic Acid

effect of Kid-1 expression on cell proliferation, and early response gene expression will be evaluated. The cDNA will be transfected into kidney cells and fibroblasts, and effects of expression on cell cycle progression and on immediate-early gene expression will be evaluated. The genomic structure of Kid-1 in the rat and mouse, including potential 5' regulatory domains will be mapped. Since this gene is expressed predominantly in the kidney it is possible that a promoter or enhancer has characteristics that confer kidney specificity. These experiments will provide insight and reagents which can be used to understand the role of PLA2 and Kid-1 in physiological as well as pathophysiological processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METABOLISM OF ENDOTHELIAL DYSFUNCTION IN RENAL DISEASE Principal Investigator & Institution: Castillo, Leticia; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Cardiovascular disease (CVD) is a major cause of death among End Stage Renal Disease (ESRD) patients. CVD is caused in part by endothelial dysfunction. Three metabolic pathways have a major role in the regulation of endothelial function: the L-arginine-Nitric Oxide (NO) pathway, the methioninehomocysteine cycle and the asymmetric dimethylarginine (ADMA). This application is a comprehensive study, aimed at integrating metabolic, nutritional, physiologic and genetic aspects of endothelial dysfunction in renal patients. We will conduct a randomized, controlled, mechanistic study on the in vivo homeostasis of these metabolic pathways, and their influence on endothelial dysfunction of renal patients, and in healthy controls. The influence of dietary supplementation with arginine and folic acid on these metabolic pathways will also be explored. Relevant enzymatic genotype (MTHFR and DDAH), will be correlated with the metabolic phenotype. We hypothesize that dysregulation of the metabolism of the L-arginine-NO pathway, the methioninehomocysteine cycle and ADMA kinetics contributes to endothelial dysfunction and that arginine and folic acid supplementation will improve homeostais of these pathways. The aims are: (1) to assess NO bioavailability in CRD and ESRD patients and in healthy controls in relation to: (l.a) whole body rates of NO and arginine synthesis, methionine transmethylation, homocysteine re-methylation and transulfuration, cysteine oxidation and the rates of synthesis of whole blood glutathione, by conducting primed, constant intravenous infusions of the stable isotope tracers L4guanidino 15N2] arginine, L-2H3methyl]methionine and L- I) 3C]methionine;L-' 3Cureido]citrulline and L-' 3C]cysteine. (l.b) The plasma concentrations of the asymmetric dimethyl arginine (ADMA) and activity of DDAH. (l.c) The differences of these metabolic parameters across the three groups. And (2) To explore the regulatory effects of a 4-week dietary supplementation with (a) arginine or (b) folic acid on the homeostasis of these pathways. The primary endpoint is NO bioavailability and the predictor variables are the kinetic parameters. State-of-the-art mass spectrometric techniques and vascular imaging will be used. The long term objective is to gain new and relevant knowledge about the mechanisms of these processes and to eventually improve the outcome of CVD in these patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MTHFR MUTATIONS SCREENING IN PUETRO RICAN NEWBORNS Principal Investigator & Institution: Fragoso, Lourdes G.; University of Puerto Rico Med Sciences Medical Sciences Campus San Juan, Pr 00936

Studies

35

Timing: Fiscal Year 2001 Summary: INTRODUCTION: Neural tube defects (NTD) are currently considered preventable in a significant number of cases. Strong evidence supports that preconceptional and early prenatal folic acid supplementation can greatly reduce the incidence of NTD. The first specific genetic abnormality to be identified in NTD was a variant in 5, 10 methylenetetrahydrofolate reductase. The presence of this variant in our population has not been studied before. The prevalence of neural tube defects in the Puerto Rican population has been established recently be the Puerto Rican Health Department to be 1.6/1000 live births which is significantly higher than in other populations. In our pilot studies, are studying the presence of the genetic variant and its association to folic acid metabolism (folate, red bleed cells folate, homocysteine, vitamin B- 12) in a group of 60 pregnant patients with a diagnosis of NTD in their fetuses and 60 pregnant controls matched by gestational age. PROPOSAL: We propose a descriptive study in a 2 years period. The purpose of this study will be to determine the prevalence of the 5,10 methylenetetrahydrofolate reductase common mutations in a group of 2,000 newborns during the neonatal screening for the most prevalent inherited conditions in Puerto Rico. The proposal was approved by the Institutional Review Board. Our long term goal is to assess the prevalence of this genetic variant and its possible role in the high incidence of neural tube defects in Puerto Rico. Due to the relation of this enzyme to folate metabolism, current folate recommendations for women in childbearing age in Puerto Rico to reduce NTD may have to be re-evaluated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEW DHFR DELETION POLYMORPHISM - A RISK FACTOR FOR SB? Principal Investigator & Institution: Johnson, William G.; Professor of Neurology; Neurology; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, Nj 08854 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 30-JUN-2004 Summary: (provided by applicant): Spinal bifida (SB) is a common birth defect that is determined by multiple genetic and environmental factors. Up to 72% of SB is preventable by periconceptual maternal folate supplementation. The C677T polymorphism of the methylenetetrahydrofolate reductase gene and some other functional polymorphisms appear to be risk factors for SB in some populations but not others. However, despite extensive study, the genetic risk factors for SB are poorly understood. We hypothesize that genetic factors which diminish bioavailability of reduced foliate in the mother during pregnancy may contribute to SB in her fetus. We recently discovered a new 1 9bp deletion of dihydrofolate reductase (DHFR) that is a common polymorphism (allele frequency 0.44) and is a good candidate for such a genetic factor. We found that homozygosity for this deletion allele was significantly more frequent in SB mothers compared with controls, SB fathers, and SB patients, as predicted by the hypothesis.We propose to confirm and extend this finding in a replication series of SB families. We will use a new method devised by the PI to test for transmission/disequilibrium in SIB maternal trios (SB mother, maternal grandmother and maternal grandfather) to document the action of the DHFR deletion allele as a teratogenic locus, that is, one that acts in a mother to affect the development of her fetus. We will also document whether the deletion allele decreases DHFR transcription or affects DHFR activity by another mechanism.If this hypothesis is confirmed, it will shed light on how foliate supplements prevent SB and may lead to improved forms of foliate supplementation for pregnancy. About half of dietary foliates and all of folic acid

36

Folic Acid

supplements are unreduced and must be reduced by DHFR to be available for mother and fetus. Forms of foliate that are already reduced could be preferable as foliate supplements during pregnancy for prevention of SB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NO DAMAGE TO FOLATE CYCLE IN THE CENTRAL NERVOUS SYSTEM Principal Investigator & Institution: Hensley, Kenneth; Oklahoma Medical Research Foundation Oklahoma City, Ok 73104 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2006 Summary: (provided by applicant): Epidemiological data indicates that components of the folic acid pathway of one-carbon metabolism are compromised in aged humans, and more so in cases of dementia (such as Alzheimer's disease, AD) or motor neuron disease (such as amyotrophic lateral sclerosis, ALS). Moreover, rare congenital defects in folate pathway enzymes inevitably precipitate neurological disease. No explanations have been found to explain why the folate cycle is impaired in the aged individuals or those with neurological disease. Our laboratory has documented a pattern of protein oxidation in AD brain and in an animal model for ALS that suggests a mechanism for folate cycle impairment. We hypothesize that reactive nitrogen species (RNS) generated endogenously within the aging CNS damage key enzymes of the folate pathway, particularly the vitamin B12-dependent methionine synthase (MS), contributing to neurological disease. The corollary to this hypothesis is that nutritional supplementation strategies aimed at bolstering function of the folate cycle, particularly at the level of the MS enzyme, should mitigate some types of CNS degenerating. We seek to begin critically testing these ideas in five specific aims whose goals are as follows: (1) Determine folate cycle enzyme levels and activities in regions of the AD brain known to differentially experience RNS stress. (2) Determine whether folate cycle enzyme levels and activities are reduced in an accepted animal model for familial ALS (namely the G93A-SOD1 transgenic mouse, which experiences motor neuron degeneration commensurate with protein oxidation and nitration) and whether disease in this animal is mitigated by nutritional supplementation with folic acid plus vitamin B12 (cobalamin) analogs. (3) Determine whether folic acid, alone or in combination with cobalamin analogs, protects the folate cycle integrity in astrocytes or neurons challenged directly with nitric oxide ( NO). (4) Determine whether NO inactivates MS solely by formation of a nitrosyl-cobalamin complex or through generation of secondary carboncentered and oxyradicals and whether this process directly precipitates loss of function in the MS holoenzyme. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: NUTRIENT BIOMARKERS, GENES AND OROFACIAL CLEFTS Principal Investigator & Institution: Munger, Ronald G.; Associate Professor; Nutrition and Food Sciences; Utah State University Logan, Ut 84322 Timing: Fiscal Year 2001; Project Start 23-JUN-2000; Project End 31-MAY-2005 Summary: (Adapted from the Applicant's Description) Orofacial clefts are among the most common birth defects in the world yet little is known about their major causes and regional differences in occurrence. In our previous studies in the Philippines we recently found biochemical evidence that poor vitamin B-6 and folic acid levels of mothers are independently associated with increased risks of clefting and that the MTHFR C677T mutation is associated with a reduced risk of clefting. We propose to elaborate these

Studies

37

methods for studying nutrient-gene interactions and apply them in a population-based case- control study of orofacial clefts in Utah with the following specific aims: (1) Children with orofacial clefts (n = 686) will be ascertained by the state- wide Utah birth defects registry and their mothers will be recruited as case participants; (2) Children without clefts (n= 686) will be randomly selected from Utah birth certificates and their mothers wIll be recruited as control participants; (3) Data will be collected on dietary patterns, smoking, alcohol use and other exposures using telephone-based interviews and mailed questionnaires; (4) Venous blood samples will be drawn from mothers, rapidly processed, and assayed for biochemical indicators of vitamin B-6 and folate status; (5) DNA from mothers, children, and fathers will be prepared and genotyped for polymorphic genetic markers related to vitamin B-6 and folate metabolism. The following hypotheses will be addressed: (1) Poor maternal vitamin B-6 status is independently associated with increased risk of orofacial clefts; (2) Poor maternal folate status is independently associated with increased risk of orofacial clefts; (3) The MTHFR C677T allele is associated with a reduced risk of clefting. In addition the association between allelic variants of other folate- and vitamin B-6-related genetic markers and the risk of orofacial clefts will be examined; (4) The nutrients and candidate genes mentioned above interact, additively or multiplicatively, to increase the risk of orofacial clefting. Our multidisciplinary study of maternal nutrition and risk of clefting in the context of genes related to metabolic pathways may lead to a better understanding of the causes and prevention of orofacial clefts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ONCOGENE DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG Principal Investigator & Institution: Fuchs, Philip L.; Professor of Chemistry; Chemistry; Purdue University West Lafayette West Lafayette, in 479072040 Timing: Fiscal Year 2001; Project Start 09-AUG-1996; Project End 31-MAY-2005 Summary: (Principal Investigator's Abstract) This proposal has seven medicinal/biological goals: (1) Synthesize up to seven North 1 and South 1 'slightly simplified' hexacyclic steroidal spiroketal subunits. Convert these materials to South-pyrazine--North trisdecacyclic (thirteen rings) pyrazines using our method for unsymmetrical pyrazine synthesis and compare their anticancer activity to cephalostain 1 (1.2nM avg. NCI panel). (2) Study the contribution of the central arene moiety to anticancer activity by testing pairs of unsymmetrical annulated pyridines derived from the best simplified hexacyclic steroidal subunits. (3) Construct and evaluate one member of a designed new class of inter-phylal agents termed the cephalofurthins to evaluate whether the geranyl geranyl moiety is a recognition element. (4) Prepare and test covalent conjugates of the new agent(s) with folic acid to assay for enhanced (targeted) activity for the treatment of the around 40 percent of cancers which over-express (ten to the 4th power) the folate receptor. (5) Use the biological data from testing of the proposed new materials to complete the mapping of the minimum pharmacophore for the cephalostatin class of antieoplastics. (6) Determine the biological mechanism of action of the trisdecacyclic pyrazines; and (7) Prepare 2-5g of the material which best combines high activity with expedient synthesis to provide a set of new biological tools as well as generating enough agent to initiate clinical trials. Synthesis of the seven hexacyclic spiroketals are projected to require 9-16 operations (compared with 29-31 operations in our 'first generation' synthesis). To accomplish the medicinal/biological goals, efficient new chemistry is required. (A) Utilize a vigorous interactive calculational approach to constantly evaluate synthetic approaches and biological testing data. (B)

38

Folic Acid

Test a new siloxysulfonium triflate reagent to effect stereospecific allylic oxidation of a vinyl ether. (C) Investigate the resulting ortho-methylthiophenyldimethylsilyl ether for chemospecific ion-pair self-immolative deprotection. (D) Develop a new annulation of unsymmetrical pyridine rings from 3-ketosteroids via an intramolecular aza-Horner reaction. (E) Generation of the Southern hemispheres requires hydroxylation of the unactivated angular methyl group at the steroidal CD ring junction. This will be accomplished by systematic exploration of the potential of a previously unknown stereospecific dyatropic rearrangement of beta-hydroxyketones and beta-hydroxy lactones to accomplish this transformation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHARMACOGENETICS OF METHOTREXATE IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Bridges, S L.; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 31-DEC-2006 Summary: Methotrexate (MTX) is one of the most effective drugs for RA, but 20- 30% of patients have suboptimal clinical responses to MTX, and 15-25% have side effects limiting its use. Thus, it is important to elucidate influences on MTX efficacy and toxicity. We will test the hypothesis that single nucleotide polymorphisms (SNPs) in genes encoding key enzymes involved in folate or MTX metabolism or in the mechanism of actions of MTX (e.g. the adenosine pathway) influence clinical responses to MTX. We are uniquely positioned to utilize clinical outcomes (ACR response criteria, radiographic progression and toxicities) and genomic DNA from patients in two completed clinical trials: 153 MTX-treated RA patients from an Immunex trial comparing MTX and etanercept, and 79 MTX-treated RA patients from a UAB trial of folic acid supplementation. HLA DRB1 alleles and a total of 5 known SNPs in the following 4 key genes will be genotyped: 1) 5,10- methylenetetrahydrofolate reductase (MTHFR); 2) 5-methyl- tetrahydrofolate-homocysteine methyltransferase (methionine synthase) (MTR); 3) methionine synthase reductase (MTRR); and 4) adenosine receptor A2A [A(2A)R]. These SNPs were chosen on the basis of being common enough in the general population to allow meaningful analyses, their key roles in relevant pathways, and evidence of their biological activity. Through the MCRC Methodology Core, we will look for associations between SNP alleles and MTX efficacy or toxicity. Although these known SNPs are important, SNP haplotypes may be even more informative, aqs they allow characterization of the effect of multiple SNPs working in concert. Therefore, we will use both "in silico" in sequencing approaches to identify novel SNP haplotypes in these 4 and 3 other critical genes: dihydrofolate reductase (DHFR), 5- aminoimidazole-4carboxamide ribonucleotide transformylase (AICAR- T), and aldehyde oxidase (AO). In addition to data mining of public domain and proprietary (i.e. Celera) SNP databases, we will perform SNP discovery on 40 individuals from two racial/ethnic groups [20 African-American (A-A) and 20 Caucasian]. Differences in frequencies of novel haplotype related to disease status or race/ethnicity will be sought by analysis of 108AA Ra patients and 53-AA controls; 336 RA patients (mostly Caucasian); and 800 controls (mostly Caucasian) from established cohorts. Based on results from these studies, the role of selected novel SNP haplotypes on MTX efficacy and toxicity will be tested in patients from the folic acid and Immunex trials. We will compare the predictive power of two approaches to genetic profiling: the single SNP approach and the SNP haplotype approach. These studies may provide clinically useful markers of MTX efficacy or toxicity in RA.

Studies

39

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

Project Title: PHARMACOKINETICS AND METABOLIC EFFECTS OF FOLIC ACID Principal Investigator & Institution: Ayling, June E.; Pharmacology; University of South Alabama Mobile, Al 366880002 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2005 Summary: (provided by applicant): Homocyst(e)ine is a risk factor for vascular disease that is independent of and similar in magnitude to that from cholesterol. Currently, several clinical trials are under way world-wide to evaluate the prevention of recurrence of coronary artery disease by high doses of folic acid (0.8 to 5.0 mg/d). To be utilized folic acid, which is not found to a significant extent in nature, must be converted in the body to the active tetrahydrofolates via the action of dihydrofolate reductase. Unreduced folic acid has been previously observed in blood and urine when given orally above doses of 200 ug However, inter-individual variations in the extent to which folic acid remains unmetabolized or excreted have not been well characterized, especially with pharmacologic doses. Moreover, there is evidence to suggest that unreduced folic acid may interfere with homocysteine metabolism to methionine. The purpose of this proposal is to examine the accumulation and rate of clearance of unreduced folic acid in the plasma of healthy subjects given oral doses of folic acid ranging from 0.4mg to 5.0 mg, to measure the percent of the dose excreted unmetabolized into the urine, and any change in plasma total homocyst(e)ine over the course of 24 hours. In addition, the relation between levels of unmetabolized folic acid and non-response or paradoxical response of homocyst(e)ine in subjects chronically taking folic acid at different doses will be investigated. The literature suggests that there is little improvement in the level of homocyst(e)ine above 0.4 mg/d even up to 5 mg/d. A hypothesis to be tested is that this may, in part, be due to the limited ability of some people to convert folic acid to the active tetrahydrofolates. Moreover, folate utilizing enzymes may be inhibited by unmetabolized folic acid, as has already been observed in vitro. We propose to establish what percentage of the population cannot rapidly convert folic acid to the active folate forms, and of these what percentage have elevated homocyst(e)ine levels related to the accumulation of unmetabolized folic acid. Identifying this particular population of individuals may allow treatment of hyperhomocysteinemia to be more fully optimized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: POPULATION SCIENCES AND PREVENTION PROGRAM Principal Investigator & Institution: Severson, Rick; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2001; Project Start 01-APR-1988; Project End 30-NOV-2002 Summary: (Applicant's Description) The metropolitan Detroit area is home to a population that is ethnically and culturally diverse, and the Population Studies and Prevention Program brings together faculty with a variety of scholarly interests whose research is based on this diversity. The Program is composed of two interactive groups: 1) Population Studies, with a research emphasis on population-based studies of cancer etiology; and 2) Prevention, with a research emphasis on studies designed to prevent and/or control the development of cancer within this population. Our population-based studies focus on the interface between genetic and environmental exposures and their roles in the subsequent development of cancer. Although several different cancers are under investigation, our primary interests are in the etiology of breast, prostate, and

40

Folic Acid

lung cancers. Our prevention studies emphasize the roles that nutrition and tobacco prevention/cessation play in the prevention of cancer. Our primary interests involve the preventive effects of soy isoflavones, lycopene, folic acid, zinc, increased fruits and vegetables, and a low fat diet in a variety of cancers. The effects of these interventions on oxidative DNA damage, lipid peroxidation, serum sex-hormone levels, tissue markers of cell growth and differentiation, signal transduction, and growth factors are currently under investigation. We have 27 primary members and 10 clinical members within the Program. Currently, 18 of these members serve as Principal Investigators on 35 peerreviewed research projects that are supported at the national level. Although faculty within the Program collaborate with faculty from all the other programs of our CCC, we have especially strong inter-Programmatic collaborations with investigators in the Breast Cancer, Prostate Cancer, and Molecular Biology and Genetics Programs. Approximately 80% of the research within this Program is supported by the CCC Core facilities and the research efforts of Program investigators are considerably enhanced by these Core facilities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVENTION OF NEURAL TUBE DEFECTS BY IMMUNE STIMULATION Principal Investigator & Institution: Hrubec, Theresa C.; Biomedical Scis/Pathobiology; Virginia Polytechnic Inst and St Univ 460 Turner Street, Suite 306 Blacksburg, Va 24060 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Dr. Terry Hrubec received the D.V.M. and Ph.D. degrees and is embarking on a research career. She is a highly motivated scientist who wishes to make a career shift from clinical pathology and immunology of aquatic species to research in mammalian cellular and molecular immunology. This award would offer Dr. Hrubec an opportunity to strengthen and expand research skills by affording training in molecular mechanisms of developmental abnormalities and using animal models of human disease. The proposed research investigates the mechanism by which maternal immune stimulation prevents valproic acid (VA) induced birth defects. VA, a drug commonly used to treat epilepsy, is teratogenic and induces neural tube defects (NTDs) in one to two percent of exposed fetuses at a rate 20 times higher than in the general population. In what the investigators feel is paradigm-changing work, data from the investigators' laboratory have conclusively demonstrated that non-specific activation of the maternal immune system in rodents can dramatically reduce a variety of chemical-induced birth defects, including VA induced NTDs. Additionally, the investigators have shown that such maternal immune stimulation normalizes teratogenaltered expression of a few selected fetal cell-cycle/apoptotic regulatory genes in urethane-induced cleft palate. A more focused examination of altered gene expression in VA induced NTDs is now logical. Specifically, the investigators will test the hypotheses that: 1) VA affects the expression of genes regulating neural tube development, and that maternal immune stimulation normalizes gene expression through regulatory proteins (cytokines) secreted by activated immune cells; and 2) folic acid supplementation protects against NTDs by cytokine-related mechanisms which may in part be similar to that resulting after maternal immune stimulation. These studies are expected to significantly increase the investigators' understanding of genetic mechanisms by which maternal immune modulation reduces this specific birth defect. Clearly, this research is of importance to human health, as determining the mechanisms involved will improve the understanding of this disorder leading to a prevention or cure. This research will be conducted under the guidance of Drs. Steven Holladay and Ansar Ahmed of the

Studies

41

Virginia-Maryland Regional College of Veterinary Medicine at the VPISU, and will offer excellent training and career development for Dr. Hrubec. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROSPECTIVE STUDIES OF DIET AND CANCER IN MEN AND WONEN Principal Investigator & Institution: Willett, Walter C.; Professor and Chairman; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02460 Timing: Fiscal Year 2001; Project Start 23-AUG-1991; Project End 31-MAR-2006 Summary: (provided by Applicant) This proposed Program will use prospectively collected dietary data and frozen plasma and DNA specimens to address a series of hypotheses regarding major cancers in men and women. In addition, these nutritional and genetic exposures will be examined in relation to specific molecular characteristics of tumors. The cancers to be studied are those of the prostate, colon and rectum, bladder, lung, kidney, and ovary. This Program Project supports, and depends on, the continued follow-up of 51,529 men who completed an extensive dietary questionnaire first in 1986 and again in 1990, 1994, and 1998 (the Health Professional?s Follow-up Study, HPFS), and is also closely linked to the Nurses? Health Study (NHS) of 121,700 women. The Program Project has already contributed substantially to information on diet and cancers of the breast, prostate, colon, and bladder. The proposed continuation will extend and refine observations from the first twelve years of follow-up and will also address new hypotheses related to both cancer incidence and survival. Project 1 will examine dietary (lycopene, calcium, and N-3 fatty acid intakes) and other predictors of prostate cancer incidence in relation to risk of PSA relapse among men with apparently successful treatment for localized prostate cancer. In addition, a series of dietary and hormonal factors will be related to specific characteristics of incident cancers, including expression of PTEN and COX-2 and markers of angiogenesis. Project 2 will address hypotheses relating intakes of folic acid, calcium and red meat and plasma levels of IGF-1 and its binding proteins to risks of both colorectal cancer and adenomas. Interactions with germline polymorphisms and relationships with specific molecular tumor characteristics will be examined. Project 5 will examine dietary and related risk factors for bladder cancer in both men and women. Exposures will include intakes of cruciferous vegetables and total fluids, and biochemical indicators of selenium and arsenic exposure. Interactions with polymorphisms in carcinogen metabolizing genes and specific association with p53 expression in tumors will also be examined. Project 4 pools data from all eleven major published prospective studies of diet and cancer. Precise and unique information has already been obtained for breast, lung and colon cancers, and the proposed work will extend analyses to cancers of the pancreas and ovary. These highly interrelated studies that integrate dietary factors, established nondietary risk factors, endogenous hormone levels, genetic susceptibility, and molecular characteristics of tumors, will contribute importantly to the understanding and prevention of the major cancers of men and women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: RADIOPHARMACEUTICALS TARGETED TO TUMOR FOLATE RECEPTORS Principal Investigator & Institution: Green, Mark A.; Professor; Medicinal Chem/Molecular Pharm; Purdue University West Lafayette West Lafayette, in 479072040

42

Folic Acid

Timing: Fiscal Year 2001; Project Start 15-JUN-1996; Project End 29-FEB-2004 Summary: (Adapted from applicant's abstract): This project will continue to test the hypothesis that radiolabeled folate conjugates can serve as vehicles for selective radionuclide delivery to tumors, such as ovarian carcinoma, that overexpress a cell membrane receptor for folic acid. The specific aims of the project involve the synthesis of folate-conjugates designed for labeling with radioisotopes of In, Cu and Y, followed by characterization of their ability to selectively target tumor cells in vitro and in vivo. Novel folate-chelate and folate-peptide conjugates will be synthesized in which the radiolabeled chelate or peptide is covalently linked to the gamma-carboxylate of folic acid or a folate-analog. The affinity of the conjugate for cell uptake via the folate receptor will be determined in vitro through competitive binding assays with cultured human tumor cells. Agents exhibiting folate-receptor-mediated cell uptake in vitro will be further screened to assess their ability to target neoplastic tissue in vivo. The primary animal model for these screening studies will be athymic mice bearing folate-receptorpositive human tumor xenografts. The biodistribution and pharmacokinetics of the radiolabeled folate-conjugates will be directly evaluated in the mouse tumor model following intravenous administration of the radiopharmaceutical. Radiopharmaceuticals that exhibit significant tumor uptake and tumor selectivity will be examined in more detail to: (ii) confirm involvement of the folate-receptor; (ii) evaluate the rate of radiotracer internalization by targeted cells; and (iii) probe the metabolic fate of the radiotracer. These results will provide the basis for deciding whether more intensive pre-clinical development of a specific agent is warranted. Through independent manipulations of the targeting moiety, the radiolabeled fragment, and associated linker chemistry, these the target molecules are also designed to directly probe structureactivity relationships that should assist in rational design of improved folate-receptortargeted agents. If suitable tumor-specific tracer uptake can be achieved, such radiopharmaceuticals could find widespread clinical use in the non-invasive diagnosis and/or treatment of a variety of primary and metastatic tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RANDOMIZED TRIAL OF FOLATE AND COLORECTAL ADENOMA Principal Investigator & Institution: Giovannucci, Edward L.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 15-SEP-1995; Project End 29-FEB-2004 Summary: Given the high rates of colorectal cancer and the potential chemopreventive properties of folate or folic acid, it is crucial to demonstrate in a randomized setting that folic acid supplementation reduces the occurrence of colorectal neoplasia. We thus propose to continue to examine the hypothesis that folic acid supplementation of 1,000 micrograms daily will reduce the recurrence rate of colorectal adenomas, precursors of cancers using a randomized, placebo-controlled intervention trial. This study has been successfully initiated and has been ongoing since 1996 among 750 individuals within two ongoing cohort studies, the Health Professionals Follow-Up Study and the Nurses' Health Study. As planned, we will examine whether any influence of folate is modified by various factors, including baseline folate and vitamin B12 levels, aspirin use, family history of colorectal cancer, and intakes of alcohol and methionine. For this submission, we now propose extending follow-up from three to five years because of recent evidence of a long induction period between folate intake and colorectal cancer, and because recent fortification of food products with folic acid may reduce the contrast of folate status between intervention and placebo groups. We further propose to measure additional folate- related factors (plasma homocysteine, methylene-tetrahydrofolate

Studies

43

reductase (MTHFR) genotype) and insulin-like growth factor (IGF) parameters (insulinlike growth factor-1 and insulin-like growth factor binding protein-3), which we have found to be the strongest cluster of etiologic factors for colorectal carcinogenesis in our cohorts. Thus, it is of interest to examine the independent and interacting roles of folaterelated and IGF-related factors in adenoma recurrence. Within our existing cohorts, the intervention trial, as well as the proposed additional biomarker and genotype measures, can be conducted at a fraction of the cost of a similarly sized intervention trial of colorectal adenoma recurrence in other typical settings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RARE DISEASE CRC FOR NEW THERAPIES AND NEW DIAGNOSTICS Principal Investigator & Institution: Beaudet, Arthur L.; Professor and Chair; Molecular and Human Genetics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): This is an application from an inter-institutional group of investigators with long-standing interest in Rett syndrome, Angelman syndrome (AS), and Prader-Willi syndrome (PWS) to establish a Rare Diseases Clinical Research Center (RDCRC) that would be part of the proposed Rare Diseases Clinical Research Network (RDCRN). The Center will focus on these three disorders with the expectation that they may have near-term potential for meaningful therapy. The specific aims for Rett will be to establish a phenotype/genotype correlation over a broad spectrum of Rett phenotypes, to perform longitudinal studies on a broad sample of individuals with Rett, and to perform a survival study on a broad spectrum of Rett individuals. Clinical trials may be developed based on results of studies of animal models. The specific aims for AS are to conduct a longitudinal assessment of patients with AS according to genotype, to complete the ongoing double-blind, placebo controlled trial of folic acid and betaine in AS, and to develop a follow-on clinical trial for activation of the paternal allele for UBE3A in AS patients. The specific aims for PWS are to conduct longitudinal studies according to genotype, to develop parameters and tools for clinical trials, to test whether autistic features are more frequent in UPD than in deletion cases, and other ideas from collaborators. The aim of a pilot project using comparative genomic hybridization (CGH) on microarrays would be to develop a cytogenetic test that would detect all sizable deletions and duplications of clinical relevance on a single analysis using CGH microarrays. This new methodology would also have the potential to identify new deletion and duplication syndromes. The RDCRC will utilize GCRCs in Houston, Boston, San Diego, Gainesville, and other locations. The Center is expected to function synergistically with the Mental Retardation Research Center (MRRC) at Baylor. An extensive program is proposed for training new investigators in clinical research on rare diseases. The Center will have active affiliation with the International Rett Syndrome Association (IRSA), the Angelman Syndrome Foundation (ASF), and the Prader-Willi Syndrome Association (PWSA). A website for this RDCRC is available at www.imgen.bcm.tmc.edu/rdcm, and this site will be expanded to include a wide range of information for Rett, PWS, and AS. It is anticipated that the RDCRC will expand to include other geographic sites for the three diseases to be studied initially, and it is expected that the Center can also expand to include other disorders, such as inborn errors of metabolism amenable to hepatocyte gene therapy, disorders treatable by enzyme replacement therapy, CHARGE association, incontinentia pigmenti, Smith-Magenis syndrome, Xp deletion syndromes, and other chromosomal deletion and duplication syndromes.

44

Folic Acid

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

Project Title: REDUCED FOLATE TRANSPORT AND ANTIFOLATE RESISTANCE Principal Investigator & Institution: Melera, Peter W.; Professor; Biochem and Molecular Biology; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2001; Project Start 01-MAY-1990; Project End 31-DEC-2002 Summary: The use of classical antifolates like methotrexate (MTX) and newer drugs such as lometrexol (DDATHF) and tomudex (ZD-1694) require transport by the same mechanisms that mediate uptake and efflux of the folate vitamins. The efficacy of these drugs is at least partially dependent upon their uptake and retention, and to achieve optimal effectiveness, it becomes necessary to not only understand the mechanisms responsible for their transport but also to determine the manner in which the genes responsible are regulated. Chinese hamster lung fibroblasts (DC-3F) cultured in standard tissue culture media containing approximately 2 muM folic acid do not express folate receptors and are incapable of expressing them under conditions of folate stress eventhough they do contain the mRNA for folate receptor alpha (FRalpha). When selected for growth in 15 pM [6S]-folinic acid (leucovorin), however, these cells (DC3F/FA3) upregulate expression of FRalpha mRNA by 17 fold through a combination of gene amplification and transcription mediated events. In such cells the level of expression of the receptor itself is directly and inversely proportional to media folate concentrations and to the intracellular folate pool size and is regulated post transcriptionally. The studies proposed in this application will use a variety of recombinant DNA techniques and in vitro transcription and translation assays to determine the mechanisms responsible for both the transcriptional and post transcriptional regulation of FRalpha expression in DC-3F/FA3 cells in response to folate stress. They will also determine why DC-3F cells are not responsive to such stress. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: REDUCT OF PLASMA HOMOCYST(E)INE LEVELS BY BREAKFAST CEREAL FORTIF W/ FOLIC ACID Principal Investigator & Institution: Malinow, M R.; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2001 Summary: The Food and Drug Administration (FDA) has recommended that cerealgrain products be fortified with folic acid to prevent congenital neural-tube defects. Since folic acid supplementation reduces plasma homocyst(e)ine, or plasma total homocysteine, which is frequently elevated in arterial occlusive disease, we hypothesized that folic acid fortification might reduce plasma homocyst(e)ine levels. To test this hypothesis, we assessed the effects of breakfast cereals fortified with three levels of folic acid, and also containing the recommended dietary allowances of vitamins B6 and B12, in a randomized, double-blinded, placebo-controlled, cross-over trial in 75 men and women with coronary artery disease. Plasma folic acid increased and plasma homocyst(e)ine decreased proportionately with the folic acid content of the breakfast cereal. Cereal providing 127 ?g of folic acid daily, approximating the increased daily intake that may result from the FDA=s enrichment policy, increased plasma folic acid by 30.8% (P=0.045) but decreased plasma homocyst(e)ine by only 3.7% (P= 0.24). However, cereals providing 499 and 665 ?g folic acid daily increased plasma folic acid by 64.8% (P< 0.001) and 105.7% (P= 0.001), respectively, and decreased plasma homocyst(e)ine by 11% (P< 0.001) and 14.0% (P= 0.001), respectively. Cereal fortified

Studies

45

with folic acid has the potential to increase plasma folic acid levels and reduce plasma homocyst(e)ine levels. Further clinical trials are required to determine whether folic acid fortification may prevent vascular disease. Until then, our results suggest that folic acid fortification at levels higher than that recommended by the FDA may be warranted. FUNDING General Mills PUBLICATIONS Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, Gluckman RA, Block PC, Upson BM. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 338:1009-1015, 1998. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RELATION OF DIET TO SERUM HOMOCYSTEINE LEVEL IN YOUTHS Principal Investigator & Institution: Osganian, Stavroula K.; Assistant Professor; Medicine; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2001; Project Start 12-SEP-2000; Project End 30-NOV-2001 Summary: (Adapted from the Applicant's Abstract): Data from observational studies suggest that plasma total homocysteine (tHcy) concentration may be an independent and modifiable risk factor for cardiovascular disease (CVD) in adults. Plasma tHcy levels respond rapidly to nutrient supplementation with folic acid and vitamins Bl2 and B6, alone or in combination. The available data and the potential for prevention provide a strong rationale for understanding determinants of tHcy in youth. However, no large U.S. studies have examined the relation between tHcy levels to individuals' dietary intakes of folic acid and vitamins Bl2 and B6 in youth. This application for a competing continuation of the Child and Adolescent Trial for Cardiovascular Health (CATCH Phase 3, 1994-1997) presents a unique opportunity to examine the relation between diet and serum tHcy levels in an ethnically and geographically diverse cohort of adolescents (n=3524). During CATCH Phase 3, we conducted a cross-sectional study of serum tHcy levels in eighth grade students (Jan-June 1997). We observed higher mean tHcy levels among males, Blacks, and non-users of multi-vitamins and a strong, inverse association with serum levels of folic acid and to a lesser extent, with serum vitamin Bl2. Our aim is to conduct a second measurement of the cohort at grade 12 in order to assess the doseresponse relation between serum tHcy and dietary intakes (not measured in grade 8) of folio acid, vitamin B12 and vitamin B6. In addition and of equal importance, we aim to evaluate changes in serum folio acid and tHcy levels from grade 8 to 12, after full implementation of fortification of cereal and grain products in the U.S. with folio acid and describe its impact on the distribution of tHcy levels in adolescents. Effective January 1, 1998, the U.S. Department of Agriculture mandated the addition of folic acid to all flour and grain products in the United States (FDA, Federal Register, 1996). CATCH has a unique opportunity to examine the effect of "this natural experiment" on the distribution of serum tHcy in the cohort, because serum tHcy levels were measured in grade 8, just prior to full implementation of the mandate. Furthermore, the proposed study will have adequate sample size to examine these changes among important clemographic-subgroups such as, males vs. females and Caucasians vs. African Americans vs. Hispanics. Information generated by this study will be valuable for designing specific dietary interventions for youth and targeting subgroups of children who may be at higher risk for CVD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

46

Folic Acid

•

Project Title: RENAL TRANSPLANTATION, HOMOCYSTEINE LOWERING & COGNITION Principal Investigator & Institution: Rosenberg, Irwin H.; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-MAY-2008 Summary: (provided by applicant) This application is for an ancillary study to determine the cognitive effects of homocysteine Iowering, as an additional outcome in an ongoing, randomized, controlled, double-blind clinical trial in renal transplant recipients (RTRs). Elevated plasma homocysteine levels are associated with diminished cognitive function in the general population, and significantly increase the risk of vascular disease, cerebrovascular disease, stroke and dementia. Hyperhomocysteinemia is a pervasive feature of chronic renal insufficiency, even after a successful transplant; however, unlike in other types of chronic renal insufficiency, homocysteine levels can be lowered in RTRs by high doses of B-vitamins. The parent trial (FAVORIT - NIH NIDDK UO1 DK61700-01) is designed to determine the effect of lowering plasma total homocysteine levels on atherosclerotic cardiovascular disease outcomes in chronic, stable RTRs. The FAVORIT trial aims to randomize 4000 RTRs with a stable functioning renal graft of > six months to a treatment or placebo group, and to follow them for 4 years or until the occurrence of a cardiovascular event or death. Treatment consists of a standard multivitamin with additional high dose folic acid, vitamin B12 and vitamin B6 and placebo consists of a multivitamin devoid of these vitamins. This application specifically aims to: (1) determine the cognitive effect of homocysteine lowering under this treatment regime; and (2), characterize cognitive function in relation to homocysteine and other risk factors for vascular disease in this high-risk, non-demented population. To do so we will measure cognitive outcomes in 1000 participants in the FAVORIT trial, at randomization and after a 3-4 year follow up. The outcome of this application may be highly significant in improving health care for RTRs and other groups with chronic renal insufficiency. Our long-term goal is to identify risk factors for cognitive impairment that can be modified through nutritional intervention or dietary supplementation in order to reduce the incidence of cognitive decline and dementia in elderly and other vulnerable populations. Demonstrating the cognitive benefits of lowering homocysteine may pave the way to nutritional modification of cognitive decline in RTRs and other high-risk groups and even in the general population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: RHOMOCYSTEINASE FOR HOMOCYSTEINE ASSAY Principal Investigator & Institution: Tan, Yuying; Anticancer, Inc. 7917 Ostrow St San Diego, Ca 92111 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-AUG-2003 Summary: (applicant's abstract): There is an important need to develop accurate, simple and economic methods to determine total homocysteine (tHCY) levels in order to make such an assay a recognized part of standard medical practice available for the general population. HPLC methods for tHCY measurement have been developed and have been used as the standard assay for tHCY. HPLC is highly specialized and low throughput, however. A fluorescence polarization immunoassay for tHCY has also been developed. However, it appears that this method can only be practiced with specialized lowthroughput instrumentation. The currently used assays are therefore neither suitable for high-throughput tHCY measurement and nor for routine clinical laboratories. In Phase I, a simple high specificity and sensitivity tHCY enzymatic assay was developed

Studies

47

using a homocysteine-speciflc recombinant homocysteinase (rHCYase) and H2Sspecific chromogenic agent N, N-dibutylphenylenediamine (DBPDA). The tHCY enzymatic assay highly correlates to the standard HPLC tHCY assay. The goal of Phase II is to apply the total homocysteine (tHCY) enzymatic assay developed in Phase I for broad base clinical use to enable tHCY to be a routine test as a risk factor for cardiovascular and other diseases. In order to achieve this specific goal, the specific aims of the Phase II application are to adapt the tHCY enzymatic assay on examples of widely-used instruments, a robotic microtiter plate reader and an automatic chemistry analyzer adapted for high throughput screening and routine testing. To adapt the tHCY enzymatic assay for robotic rnicrotiter plate readers, the Tecan Genesis (100/8) Robotic Sampler Processor will be used. To adapt the tHCY enzymatic assay for automatic chemistry analyzers, the Hitachi 912 automated chemistry analyzer will be used. Validation of the robotic microtiter plate reader and automatic chemistry analyzer tHCY enzymatic assays will be carried out by comparing their performance with the manual tHCY enzymatic assay thus far developed and the HPLC tHCY assay in a prospective clinical trial of the efficacy of high-dose folic acid to lower tHCY levels and improve outcome of patients having both end stage renal disease and cardiovascular disease. The tHCY enzymatic kits for these applications will be ready for commercial launch at this point. PROPOSED COMMERCIAL APPLICATION: Not Available Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SAME AND FOLATE DEFICIENCY IN ALCOHOLIC MIRCROPIGS Principal Investigator & Institution: Halsted, Charles H.; Professor; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): The overall hypothesis of the proposed research is that the pathogenesis of alcoholic liver disease (ALD) is regulated by changes in intrahepatic methionine metabolism that result from chronic ethanol consumption. Previously, we found that the combination of dietary ethanol and a folate deficient diet both maximized perturbations in methionine metabolism and accelerated the development of ALD in micropigs. The objective of the proposed research is to prove the hypothesis by demonstrating that the biochemical and histopathological features of ALD can be prevented or reversed by provision of supplemental S-adenosylmethionine (SAM) or folic acid to pigs maintained on chronic ethanol feeding with and without folate deficient diet. The first specific aim is to determine the efficacy and metabolic effects of intervention with SAM or folic acid in the prevention and treatment of ALD in micropigs. The second specific aim is to study the effects of abnormal methionine metabolism on known mediators and signal pathways of alcoholic liver injury. Micropigs will be fed diets with ethanol that are either folate sufficient or deficient and with or without supplemental SAM during development of liver injury, and with or without supplemental SAM or folic acid after development of alcoholic liver injury. Data collection will include methionine metabolites in plasma and liver, liver histopathology, markers of inflammation, necrosis, and apoptosis, products of lipid, protein, and DNA oxidation, antioxidant enzymes, and signal pathways of apoptosis. The data will be interpreted to confirm the role and establish potential mechanisms for abnormal methionine metabolism in the pathogenesis of ALD. While furthering understanding of interactions of methionine metabolites on pathways of liver injury, the project may establish novel approaches to the prevention and treatment of ALD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

48

Folic Acid

•

Project Title: SOCIAL AND PHYSICAL ENVIRONMENTS AND HEALTH DISPARITIES Principal Investigator & Institution: Schulz, Amy J.; Assistant Research Scientist; Health Behavior and Hlth Educ; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-JUL-2005 Summary: (Taken from the Investigator's Abstract) Social inequalities have been linked to health disparities at the individual and the population levels and are associated with income inequalities, not simply with absolute income. There is clear evidence of a strong association between socioeconomic status (SES), economic development, and cardiovascular disease (CVD), the largest contributor to all-cause mortality in the U.S. The pathways linking these social and economic inequalities to health are not yet well understood. The Social and Physical Environments and Health Disparities Project is a community-based, participatory research partnership of the University of Michigan School of Public Health, community-based organizations, and healthcare institutions in Detroit. The specific aims of the proposed project are to 1) estimate the relationship between racial and ethnic group status, SES, and mental and physical health in a stratified, multistage probability sample (n = 1000) of an adult population in Detroit, Michigan, and estimate the relationship between racial or ethnic group status, SES, and specific biomarkers for cardiovascular risk factors in a subset of this sample (n = 200); 2) examine the relationships between neighborhood sociodemographic context (e.g., concentrated poverty), selected aspects of the physical environment (exposure to PM 10 and PM 2.5 airborne particulate matter), and selected aspects of the social environment (e.g., acute life events); 3) investigate independent and cumulative effects of exposure to psychosocial stressors on biological risk markers for CVD (e.g., total serum cholesterol and LDL); 4) document the strength of the association between airborne particulate matter and selected proximate risk and protective factors (e.g., elevated plasma homocysteine, F2 isoprostane) for CVD; 5) investigate potential mediating and moderating effects of behavioral and psychosocial responses to stressors (e.g., smoking), and micronutrient intake (e.g., intake of folic acid, B-6, and B-12) on the relationships between selected aspects of the physical and social environments and biological markers for CVD, and self-reported CVD and depression; and 6) create a Community Outreach and Education Program to disseminate and translate knowledge gained from the study to inform new and established intervention and policy efforts in Detroit. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: SUPPLEMENT B-VITAMIN ATHEROSCLEROSIS INTERVENTION TRIAL Principal Investigator & Institution: Hodis, Howard N.; Associate Professor; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2001; Project Start 20-SEP-2000; Project End 31-AUG-2005 Summary: (adapted from the application): Although primary prevention strategies have focused on key modifiable risk factors for development and progression of atherosclerosis, such as hypercholesterolemia, coronary heart disease (CHD) remains the leading cause of death in the United States. Many individuals who present with clinical sequelae of atherosclerosis do not have identifiable conventional risk factors for CHD. Epidemiological studies indicate a strong association of plasma tHcy levels with atherosclerosis from childhood to the elderly. A large number of studies have shown plasma tHcy levels to be an independent risk factor for CHD that is easily modifiable

Studies

49

with the B-vitamins, folic acid, vitamin B12, and vitamin B6. Plasma tHcy levels rise 25 % after 50 years of age and may partially account for the age-related risk for CHD. The rise in plasma tHcy levels parallel the age-related decrease in serum levels of folate, vitamin B12, and vitamin B6. Elevated they levels result even with these vitamin levels in the normal to low-normal range. Elderly individuals seem to be most susceptible to development of subclinical vitamin deficiencies since dietary intake of these B-vitamins is approximately 50% the Daily Value after 50 years of age. Low serum folate and vitamin B6 levels are significantly associated with CHD risk. Therefore, low B-vitamin status and elevated plasma tHcy levels are important risk factors for atherosclerosis. Evidence, including data from the investigator's laboratory suggests that B-vitamin supplementation can reduce the progression of subclinical atherosclerosis in healthy individuals. Therefore, the investigators propose a multisite, randomized, double-blind, placebo-controlled, 2.5-year, arterial imaging clinical trial with folic acid 5 mg, vitamin B12 2 0.4 mg, and vitamin B6 50 mg versus placebo in healthy men and women >40 years old with LDL-C >130 mg/dL and plasma tHcy >8.5/micromol/L. They will target a cohort of 50% elderly (2-60 years old), 50 % women and 50 % minority subjects. The impact of B-vitamins on the progression of subclinical atherosclerosis will be noninvasively quantitated across several vascular beds with computer image processed B-mode ultrasonograms of carotid artery intima-media thickness and EBCT of the coronary arteries and abdominal aorta. B-vitamin supplementation may provide a promising approach for reducing the progression of atherosclerosis since it is natural, inexpensive, highly tolerable, and safe. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYNTHESIS AND EVALUATION OF BORONATED FOLATES FOR BNCT Principal Investigator & Institution: Tjarks, Werner; None; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-AUG-2003 Summary: (Applicant's Abstract) The development of boron compounds for the treatment of squamous cell carcinoma of the head and neck (SCCHN) by Boron Neutron Capture Therapy (BNCT) requires the synthesis and evaluation of non-toxic agents which selectively target these malignant cells in contrast with adjacent normal tissue and are retained intracellularly. Cell membrane receptors mediating endocytotic transport of folic acid into cells are expressed in elevated levels in a variety of human tumors. The affinity of folic acid for its cell membrane receptors and its ability to be endocytosed remains essentially unaltered when a macromolecule is covalently linked to its gamma-carboxylate function. It has been shown that large numbers of conjugates of folic acid with therapeutic agents are internalized into tumor cells that overexpress the folate receptors by receptor-mediated endocytosis and are retained intracellularly. Therefore, folic acid may be an excellent carrier for the selective delivery of boron species to SCCHN. The specific aims of this proposal are: To develop the chemical methodology to design and synthesize suitable folic acid derivatives possessing 1 to 9 carborane and polyhedral borane clusters with or without a DNA-targeting entity. To prepare folic acid conjugates with boronated starburst dendrimers using polyethylene glycol spacers as binding elements. To synthesize and incorporate boronated polyamines into a liposomal formulation using folic acid-PEG-liposomes. To determine the in vitro uptake, persistence and subcellular distribution of boronated folic acid derivatives and liposomal formulations of boronated polyamines in human squamous cell carcinoma. To study the in vivo pharmacokinetics and tumor-localizing properties

50

Folic Acid

in tumor bearing rodents of those boronated folate derivatives and liposomal formulations of polyamines that show high in vitro cellular uptake and persistence. To evaluate the therapeutic efficacy for BNCT of those folic acid conjugates having favorable in vivo tumor-localizing properties. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYNTHESIS OF POTENTIAL ANTITUMOR AGENTS Principal Investigator & Institution: Ray, Partha S.; Chemistry; State University of West Georgia 1600 Maple St Carrollton, Ga 30118 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2005 Summary: The discovery of new and more selective anticancer agents is of fundamental importance in our struggle against cancers. In 1985 the drug 5,10-dideaza-5,6,7,8tetrahydrofolic acid (DDATHF) was discovered by Taylor et. al. and shown to exhibit excellent antitumor activity against a broad range of tumors. It was also active against tumors that have become resistant to methotrexate (MfX), a commonly used antifolate drug used in cancer chemotherapy. DDATHF has shown some remarkable results in animal trials (complete inhibition of tumor growth at 6.25 mg/kg per day for ten days without evidence of host toxicity up to 100 mg/kg per day). The primary site of action of DDATHF has been shown to be inhibition of the enzyme glycinamide ribonucleotide formyltransferase (GARFT) which plays a critical role in de novo purine biosynthesis. The (6R) diastereomer of DDATHF, Lometrexol (LTX), is currently in clinical trials for the treatment of human neoplastic diseases. However, one study has indicated that the observed selectivity of this drug in the animal experiments was not apparent in humans and the compound was reported to show "severe toxicity". This delayed, cumulative toxicity is reported to be ameliorated if the drug is co-administered with folic acid. The overall effectiveness of the drug is, however, somewhat diminished. A thiophene analog of LTX, (LY309887; 5) discovered by Lilly Research Laboratories, has been reported to have a 3-fold greater therapeutic index compared to LTX, and has recently entered phase I clinical trials. Also, Taylor and bowling have recently reported that a pyrimidoazepine-based derivative of DDATHF (8b) shows similar antitumor properties to DDATHF, via inhibition of GARFT. We have recently reported the synthesis and antitumor activity of a one-carbon shortened side chain analog of 8b, namely 8a. In this proposal we describe our rationale and proposed method to prepare four selected pyrimidodiazepine-based analogs of DDATHF and 8b, where the stereogenic carbon in the heterocyclic ring is replaced with a nitrogen atom. Consequently, unlike DDATHF and 8b which were prepared as a mixture of two diastemmers, only one stereoisomer of the drug will be isolated alleviating the need for a laborious separation of the diastereomers at the end of the synthesis or an expensive asymmetric synthetic approach We are confident that our designed pyrimidodiazepine-based folates will show promising antitumor properties via inhibition of GARFT. We are also hopeful that at least one of our four targets will possess a better therapeutic index than LTX and LY309887. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: TARGETED TRACHOMATIS

GENETIC

MODIFICATIONS

OF

CHLAMYDIA

Principal Investigator & Institution: De Mars, Robert I.; Professor; Medical Genetics; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005

Studies

51

Summary: (provided by applicant): Chlamydia trachomatis is the most common cause of bacterial sexually transmitted disease and of preventable blindness in humans. Antibiotics (not inexpensive) are used to control ongoing infections but common reinfection frequently causes serious pathology, e.g. pelvic inflammatory disease, infertility and blindness. Despite growing evidence of versatile human B cell and T cell immune responses to Ct antigens, there is little evidence of long-lasting protective immunity following infection; somehow, the organism evades repulse or elimination by the immune system. Current inability to genetically manipulate Ct has impeded analysis that might increase understanding of how Ct infections work and how the immune system might be better engaged in the management of Ct infection. The proposed work is aimed at developing a method of introducing planned genetic modifications into many targeted Ct genes following a three step work plan: (i) Demonstrate how to genetically transform Ct by means of homologous recombination between cloned Ct DNA that is transferred into Ct and chromosomal DNA of recipient Ct. A cloned mutant gyr A gene that renders Ct resistant to ofloxacin (OFX) will be transferred into sensitive Ct and resistant transformants will be isolated by selection with OFX. (ii) Demonstrate how to use the results of (i) to replace a normal Ct gene with a cloned mutant allele by the use of a model 'homologous recombination vector' (HRV). The same mutant gyr A gene used for (i) will be used, but transformants will be isolated by selection for a different, non Ct- derived 'selection marker' that is part of the HRV. Homologus recombination in Ct-derived parts of the HRV will incorporate the selection marker and closely linked Ct DNA into the Ct chromosome, thereby replacing the indigenous gene with the mutant trans-gene. (iii) Use the results of (ii) to create model knockout mutant Ct strains that can be studied in animal models. A knockout mutant allele of the folA gene will be used for this model because folA - deficient transformants that normally would be unviable can be isolated by supplementation of the culture medium with reduced folic acid. A multitude of mutation/function investigations that could be based on these model demonstrations includes the possible development of attenuated strains of Ct that might be useful protective vaccines. Pairs of mutants used in (i) - (iii) above will also be used to detect genetic recombination in mixedly infected human host cells. There is clinical evidence that such recombination occurs in humans and may contribute to Ct evasion of protective immune responses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEUKEMIA

TARGETED

LIPOSOMAL

DOXORUBICIN

DELIVERY

TO

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

52

Folic Acid

ATRA, which induced FR-beta upregulation. Moreover, f-L-DOX exhibited greater therapeutic efficacy than non-targeted liposomal DOX (LDox) in FR positive murine L1210JF and human KG-1 AML ascitic tumor models. Increased survival due to treatment with f-L-Dox was further enhanced by ATRA in the KG-1 engrafted mice. FRtargeted liposomal Dox delivery has also been shown to bypass the P-glycoproteinmediated drug efflux in FR positive tumor cells exhibiting resistance to free Dox. The objective of this project is to evaluate f-L-Dox, combined with ATRA-induction of FRbeta upregulation, for the treatment of AML, a concept based on the selective targeting of the FR positive tumor cells. The specific aims are: 1. To evaluate the effect of ATRA on FR-beta expression by AML cells in vivo. 2. To evaluate liposome formulation and FRbeta level as factors in the binding and in vitro cytotoxicity of f-L-Dox to AML cells, as well as the pharmacokinetic properties of the liposomes; the effect of dietary folate will also be studied. 3. To evaluate the selective cytotoxicity of f-L-Dox, alone or combined with ATRA, against AML blast cells, clonogenic progenitor cells (CFUs), and primitive AML stem cells (SL-Ics); and 4. To evaluate the in vivo therapeutic efficacy of f-L-Dox alone or combined with ATRA in murine leukemia models. This project should lead to the development of a novel therapeutic strategy based on the combination of targeted drug delivery to tumor cells and upregulation of the cellular target for the treatment of chemotherapy refractory AMLs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TARGETING CARCINOMA

ENDOGENOUS

ANTIBODIES

TO

OVARIAN

Principal Investigator & Institution: Cho, Moo J.; Associate Professor; Drug Delivery & Disposition; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Humans and Old World primates naturally produce a significant amount of antibodies which recognize a particular galactosyl epitope, GAL alpha 1-3GAL. We have been interested in testing if these anti-Gal antibodies can be targeted to undesirable cancerous cells. Specifically we wish to explore a possibility of redirecting these endogenous antibodies to ovarian carcinoma cells which overexpress folate receptor isotype alpha (FR-alpha) by means of chemical conjugates of folic acid to the galactosyl epitope. The end result should be the cytolysis of the target cell. Towards this goal, the present application is concerned with the total synthesis of the folatedigalactose conjugates and development of an ovarian cancer model in immune competent mice. Preparation of the conjugate which can mediate anti-Gal binding to FR+ cells with high avidity is the main chemistry goal of the project. Our strategy is to introduce multiple copies, 2 and 4 copies, of the epitopes to one molecule of folic acid at an optimal distance between them. Chemical synthesis will be carried out on a solidphase support. The conjugates will be tested with FR+/Gal- human nasopharyngeal carcinoma KB cells for their ability of promoting the anti-Gal binding to FR on the cell surface. Specificity of the interaction will be tested in the presence of free folic acid or free disaccharide as well as with a conjugate that contains lactose instead of GAL alpha 1-3GAL. The antibody binding will be conveniently characterized by means of FACS procedure. The biological goal of this project is to develop a mouse model of ovarian cancer that is suitable for testing anti-tumor activity of our folate conjugates in vivo. Since normal mice express the galactosyl epitopes in their tissue, we will have to use alpha 1,3-GALactosyltransferase-knockout (GT/KO) mice. It is known that GT/KO mice produce anti-Gal as in humans. We plan to transform the ovarian epithelial cells

Studies

53

harvested from these mice in culture to tumor-forming cell lines following a procedure we have recently developed. They will be then transfected with murine cDNA encoding full length FR-alpha. Finally these GAL-/FR+cells will be introduced into peritoneum of healthy GT/KO mice. Our current approach to immunotherapy of ovarian cancer is unique in that we are using naturally occurring endogenous antibodies. Immune modulators in this application are all small molecules with MW < 3 kDa, rendering pharmacokinetic properties most favorable for sustained activity in peritoneal cavity as well as reduced potential side effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEUKEMIA

TARGETING

LIPOSOMAL

DAUNORUBICIN

TO

MYELOID

Principal Investigator & Institution: Pan, Xing Q.; Sibyl Pharmaceutical, Inc. 2266 St. Roberts Ln Toledo, Oh 43617 Timing: Fiscal Year 2003; Project Start 22-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Targeted drug delivery has the potential to improve the efficacy of a therapeutic agent while reducing its side effects. Folate receptor typebeta (FR-beta) is a cell surface marker selectively expressed by approximately 70% of acute myeloid leukemias (AMLs). Increased FR-beta expression can be specifically induced by all-trans retinoic acid (ATRA) in primary AML cells and in FR-b (+) KG-1 cells, without inducing cellular differentiation or growth inhibition. Folic acid is a high affinity ligand for FR-beta (Kd < 1 nM). Importantly, FR-beta expressed by normal hematopoietic cells cannot bind folate in contrast to that in primary AML cells, KG- 1 cells, and FR-beta-transfected CHO cells, all of which mediate selective uptake and cytotoxicity of folate-coated liposomal doxorubicin (f-L-DOX). FR-beta-targeted uptake and cytotoxicity of f-L-DOX were further enhanced by inducing FR-beta upregulation using ATRA. F-L-DOX also exhibited greater therapeutic efficacy than non-targeted liposomal DOX (L-DOX) in FR (+) murine L1210JF and human KG-1 AML ascitic tumor models. Moreover, ATRA treatment further increased survival in response to treatment with f-L-DOX in the KG-1 cell engrafted SCID mice. FR-targeted liposomal DOX delivery has also been shown to bypass P-glycoprotein-mediated drug efflux in FR (+) tumor cells exhibiting resistance to free DOX. The objective of this Phase I project is to extend and further establish the value of this type of selective targeting using a related but potentially superior anthracycline drug, daunorubicin (DNR) and the superior NOD/SCID engraftment model. F-L-DNR combined with ATRA, will be evaluated as a therapy for AML using an animal model that more closely mimics human leukemia. The Specific Aims are: 1) to extend a human AML murine NOD/SCID engraftment model to different AML subtypes; 2) to evaluate the effect of ATRA on FR-beta expression by AML cells in the NOD/SCID model; 3) to evaluate the therapeutic efficacy of f-L-DNR, alone or combined with ATRA, in the NOD/SCID model. The data will be used to develop a plan for clinical studies of f-L-DNR/ATRA therapy in a Phase II project. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE BIOAVILAIBILITY OF FOLATE IN HUMANS Principal Investigator & Institution: Van Breemen, Richard B.; Professor of Medicinal Chemistry; Medicinal Chem & Pharmacognosy; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005

54

Folic Acid

Summary: (provided by applicant): The active metabolites of the B vitamin folic acid are essential cofactors for many biochemical reactions involving one-carbon transfers. Folate deficiency has been associated with an increased incidence of several forms of cancer and recent studies with the human colon cancer cell lines suggest that only certain forms of folate might inhibit colon cancer cell proliferation. In addition, maternal folate has been shown to prevent neural tube defects such as spina bifida and anencephalus. Since folic acid fortification of enriched cereal was initiated in the US, the incidence of spina bifida has declined 20 percent, but the incidence of anencephaly remains unchanged, which supports the need for alternate types or higher levels of dietary folates. Since folic acid must be metabolized to its reduced forms for biological activity, perhaps one of these pre-formed active metabolites of folic acid would be more effective for the prevention of cancer and birth defects. Furthermore, a greater understanding of the bioavailability of dietary folates including polyglutamyl forms of folate is essential for establishing dietary guidelines for specific population groups and for making accurate decisions with respect to food fortification. To address these issues, new highly sensitive and selective analytical methods are needed to simultaneously measure multiple forms of folates in blood and cells. We have reported a new HPLC-tandem mass spectrometry (LC-MS-MS) assay based on hydrophilic interaction chromatography coupled with negative ion tandem mass spectrometry for the analysis of 5'-methyl-tetrahydrofolate in human plasma. As Specific Aim 1 of our investigation, we propose to expand this assay to include the simultaneous measurement of multiple forms of folate including folic acid, tetrahydrofolate (THF), 5-methyl-THF, and 5'-formyl THF in human plasma and human cells grown in culture. To the best of our knowledge, no other laboratory has reported the measurement of all of these folates in human plasma or tissues. Then as Specific Aim 2, we will apply our new LC-MS-MS assay to the quantitative analysis of multiple forms of labeled and unlabeled folates in human plasma in support of an ongoing clinical study of the bioavailability of intrinsically labeled [13C11]-folic acid and [13C6]-hexaglutamyl folic acid. These studies will open a wide range of clinical and basic science research opportunities for nutrition-based cancer chemoprevention, which will become the basis of subsequent R01-type grant applications. Finally as Specific Aim 3, the transport and metabolism of labeled folic acid, hexaglutamyl folic acid, 5-methylTHF, 5-formyl-THF, and THF will be investigated using Caco-2, which form a highly differentiated monolayer in cell culture that is a standard model for the human instestinal uptake of orally administered compounds. Our new LC-MS-MS assay and the use of 13C-labeled folate species will provide new and more detailed information on the uptake, metabolism, and bioavailability of folates than has been possible previously. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE EFFECT OF ETOH AND FOLATE ON HORMONE RELATED CANCERS Principal Investigator & Institution: Assaf, Annlouise R.; Associate Professor of Community Health; Memorial Hospital of Rhode Island 111 Brewster St Pawtucket, Ri 02860 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2003 Summary: (provided by applicant): Introduction: The heavy, regular use of alcohol has been associated with significant morbidity and mortality, particularly in postmenopausal women. The consumption of high levels of alcohol has been associated with increased risk for breast, endometrial, and ovarian cancer. The risks associated with low to moderate alcohol consumption are much less clear. This may be due to differences in hormone replacement therapy or folic acid intake or to the difficulty associated with

Studies

55

accurately assessing level of drinking. We hypothesize that high levels of alcohol use will be associated with a higher likelihood of developing breast, endometrial, and ovarian cancer and that folic acid intake will moderate the effect of alcohol on these cancers. Design: The Women's Health Initiative Observational Study cohort consists of 93,717 post-menopausal women who were enrolled between September 1993 until December 1998, nationwide. To date, there have been 1,999 incident cases of breast cancer, 253 cases of endometrial cancer, and 188 cases of ovarian cancer among the women enrolled in this study. Data regarding the use of alcohol, dietary folic acid, and the use of folic acid supplements was collected on each participant at baseline and again at a followup visit. We propose to conduct a secondary data analysis of the effect of alcohol consumption and folic acid intake on the risk of developing these hormonerelated cancers. Conclusions: Breast cancer now ranks second in cancer deaths among United States' women and is a leading cause of morbidity. While the incidence of endometrial cancer is not as high, and because of early detection, mortality rates are low, endometrial cancer resulted in over 6,500 deaths in 2001. Ovarian cancer, though much less common, is associated with a very high mortality rate (approximately 50% for all stages) because it is often not detected until late stage. The Women's Health Initiative database provides a unique opportunity to explore the relationship of alcohol and folic acid intake with hormone-related cancers in post-menopausal women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE MOLECULAR GENETIC BASIS OF CARDIAC DEFECTS Principal Investigator & Institution: Wenstrom, Katharine D.; Professor of Obstetrics and Gynecology,; Obstetrics and Gynecology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 21-JAN-2002; Project End 31-DEC-2003 Summary: (Provided by Applicant): We hypothesize that certain congenital cardiac malformations are caused by hypomethylation at the cellular level during organogenesis, leading to abnormally slow tissue growth and abnormal cell migration. Cellular methylation status strongly influenced by folic acid nutriture and the enzyme methylene tetrahydrafolate reductase (MTHFR) hypomethylation is possible if an inadequate amount of folate reaches the multiplying cells or the fetus inherits mutation in MTHFR. To test this hypothesis, we will access the University of Alabama's Congenital Heart Disease Collection, a multidisciplinary teaching and research registry of archived heart specimens with cardiovascular malformations. This registry, established and maintained by one of the co-investigators (0 F-P), contains over 550 that have been catalogued by lesion group and cross referenced by individual defect, with all known etiologies and/or diagnoses (e.g. aneuploidy, genetic syndrome, teratogen exposure, etc) noted. Approximately 100 cardiac specimens representing each of the five basic mechanisms of cardiac development will be selected for study. That is, we will include defects caused by abnormally slow tissue growth (hypoplastic left or right ventricle, aortic stenosis, bifid aortic valve, coarctation of the aorta, pulmonary atresia), abnormally cell migration (conotruncal defects), extraneous cell, (Ebstein anomaly), abnormal growth of the extracellular matrix (AV canal), and abnormal targeted growth (anomalous pulmonary venous return). We will also study a control group of similarly archived normal cardiac specimens. After employing a novel procedure to remove the formalin, DNA will be extracted from the abnormally and normal cardiac tissue samples and tested for the presence or absence of two well-characterized MTHFR mutations. We will then quantitate level of methylation in abnormal and normal heart tissue via an assay utilizing 3H]-methyl-S-adenosylmethionine an extracted genomic DNA. Finally,

56

Folic Acid

the specific location of any hypomethylated tissue within each cardiac structure will be determined by exposing representative sections of cardiac tissue to anti Smethylcytosine antibody. If our hypothesis is correct, cardiac defects resulting from abnormally slow tissue growth and abnormal cell migration will be the most hypomethylated. Additionally, confirmation of our hypothesis would suggest that certain types of cardiac malformations might be prevented by folic acid supplementation Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESISTANCE

THYMIDYLATE

SYNTHASE

AND

FLUORODEOXYURIDINE

Principal Investigator & Institution: Berger, Franklin G.; Professor; Biological Sciences; University of South Carolina at Columbia Byrnes Bldg., Room 501 Columbia, Sc 29208 Timing: Fiscal Year 2002; Project Start 01-MAR-1990; Project End 31-JUL-2007 Summary: (provided by applicant): Thymidylate synthase (TS) is an indispensable enzyme in the de novo synthesis of dTMP in dividing cells. As such, it is an excellent target at which anti-cancer drugs are directed. A number of pharmacological agents, such as 5-fluoropyrimidines (e.g., 5-fluorouracil and 5-fluoro-2'-deoxyuridine) and folic acid analogs (e.g., raltitrexed and BW1843U89), are cytotoxic to proliferating cells as a consequence of their ability to generate metabolites that inhibit TS. It has long been recognized that treatment of cells or tumors with TS inhibitors results in induction of the enzyme's concentration. Such induction has been viewed as a primary mechanism for the emergence of cellular resistance to these inhibitors, and, therefore, as an obstacle to effective chemotherapeutic response. Our laboratory has shown that the induction of TS in drug-exposed cells is due to stabilization of the enzyme by the binding of inhibitory ligands. Building on crystal structures of human TS, along with recent experiments indicating that the enzyme is degraded by the 26S proteasome, we have proposed a molecular mechanism for ligand-mediated stabilization of the TS polypeptide. We postulate that the ligand-free enzyme, which exhibits a disordered conformation in the region between residues 107-128, is readily ubiquitinated and targeted to the 26S proteasome; it is therefore unstable and expressed at low levels. The ligand-bound enzyme, on the other hand, becomes ordered in the 107-128 region, which decreases ubiquitination and allows "escape" from the proteasome; this results in stabilization of the enzyme, and higher levels of expression. In the present grant, we propose experiments that will rigorously test this model. We will determine if TS is ubiquitinated in a ligand-dependent manner (AIM 1). In addition, we will establish whether or not ubiquitination is critical to proteasome-mediated degradation of the TS polypeptide (AIMS 2, 3). Finally, we will assess the role(s) of the disordered region and nearby lysine residues (AIMS 4-6). The proposed experiments will provide novel information on the role of TS turnover in regulating the enzyme's function as a drug target. As such, they will have application in the use of TS inhibitors as anti-cancer agents, and will be useful in designing high expressing TS genes for protection of normal tissues against the toxic effects of these inhibitors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRIAL OF ANTIOXIDANT THERAPY OF CVD IN WOMEN Principal Investigator & Institution: Manson, Joann E.; Associate Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-MAY-1993; Project End 28-FEB-2006

Studies

57

Summary: (provided by applicant): This application proposes to extend the Trial of Antioxidant Therapy of CVD in Women (Women's Antioxidant Cardiovascular Study ) for an additional 3.5 years of randomized treatment and follow-up. WACS is an ongoing randomized, double-blind, placebo-controlled, 2x2x2x2 factorial trial of vitamin C, vitamin E, beta-carotene, and folic acid/vitamin B6/vitamin B12 in the prevention of cardiovascular events among women aged > 40 years with preexisting cardiovascular disease or > 3 coronary risk factors. Its goal is to provide clear positive results or definitive null results on which to base clinical and public health recommendations about the use of antioxidants and B vitamins for the secondary prevention of cardiovascular disease. The current mean duration is 4.8 years in the antioxidant arm (n=8,171) and 2.6 years in the folic acid/vitamin B6/vitamin B12 arm (n=5,442). Based on a May 2000 review of the unblinded data, the trial's Data and Safety Monitoring Board unanimously recommended extending WACS beyond its scheduled termination in August 2002 in order to provide informative and conclusive results. With an additional 3.5 years of randomized treatment and follow-up, WACS will not only meet its original objectives but will also be able to assess the effects of antioxidant vitamins on individual endpoints and test whether antioxidant combinations are more effective than individual supplements alone, a valuable aim given conflicting results from single-agent trials. Archived blood samples (n=5,922) allow for the assessment of possible modifying effects of baseline vitamin and homocysteine levels. The WACS population, women at high risk of cardiovascular events, has been historically underrepresented in secondary prevention trials. Given its committed participants with high compliance, excellent follow-up, and willingness to continue, the trial is in an exceptional position to conclusively answer its central questions, as well as to evaluate the effects of homocysteine-lowering agents and antioxidant vitamins among women with diabetes, at less than $60/randomized participant/year in direct costs, a fraction of the usual cost of a secondary prevention trial. With the gaps in knowledge this study is intended to address and the certain intense interest in its findings by the medical, lay, and regulatory communities, the proposed extension of this trial in women is both important and timely. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TUMOR-SPECIFIC TARGETING OF FOLATE-DERIVATIZED DRUGS Principal Investigator & Institution: Low, Philip S.; Joseph F. Foster Distinguished Professor; Chemistry; Purdue University West Lafayette West Lafayette, in 479072040 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: (provided by applicant): The receptor for folic acid is an established tumor marker, showing elevated expression in many epithelial cancers, including cancers of the ovary, cervix, endometrium, kidney, brain and head and neck. When folic acid is covalently linked to another molecule or particle, it may still bind with high affinity (KD -1 0-9M) to the folate receptor (FR), but will lose all affinity for the reduced folate carrier (a transport protein that mediates folate uptake by many nonmalignant cells). Folate conjugates are, therefore, bound and internalized only by FR-expressing cells. Because of FR upregulation on cancer cells, folate ligation has been hypothesized to convert the vitamin into a molecular "Trojan Horse" that can facilitate targeting and delivery of attached therapeutic or imaging agents into malignant cells. While results from cell culture studies have been very encouraging, few quantitative data are available to permit an assessment of the therapeutic potential of folatemediated drug targeting in human patients. In our first two aims, we propose to first obtain this quantitative information. In the last two aims, we will test the therapeutic potential of the strategy in

58

Folic Acid

mouse tumor models. First, we will measure the in vivo recycling rate of FR in several relevant cancer models. Together with published data on the levels of FR expression in various human cancers, this recycling information should enable a more quantitative estimate of the total uptake and delivery capacity of the folate-mediated targeting pathway. Second, we will address how the size of a folate conjugate impacts its accessibility to cancer cells in vivo. Recent data indicate that the ability of folate conjugates to bind to and decorate cells throughout a tumor mass may be limited by molecular size. Quantitative data on this matter will be required to guide the design of folate-linked therapeutics. Third, we will synthesize and test folate-conjugated cytotoxic drugs for therapeutic efficacy in vivo. And finally, we will define the molecular and cellular bases of a novel folate-targeted immunotherapy that we have already shown can eradicate established tumors in mice without damaging normal tissues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VITAMIN INTERVENTION FOR STROKE PREVENTION Principal Investigator & Institution: Hanna, Joseph; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001 Summary: This multicenter, double-blinded, randomized clinical trial has been designed to determine whether the addition of a multivitamin with high dose folic acid, pyridoxine (vitamin B6) and cyanocobalamin (vitamin B12) to best medical/surgical management and risk factor modification reduces recurrent cerebral infarction (primary end point) and myocardial infarction or fatal coronary heart disease (CHD, secondary endpoint) in patients with a nondisabling cerebral infarctioin(NDCI) who have basal homocyst(e)ine levels above 9.5 millimol/L at screening. The fundamental eligibility criteria are the occurrence of a NDCI within 120 days prior to randomization and a qualifying homocyst(e)ine level. All patients will receive best management for risk factor reduction, which includes counseling and interventions for hypertension, high low-density lipoprotein, low high -density lipoprotein, tobacco use, diabetes and other recognized factors which add excess risk for cerebral and myocardial infarction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: VITAMIN INTERVENTION FOR STROKE PREVENTION Principal Investigator & Institution: Meissner, Irene; Associate Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 30-NOV-2001 Summary: This is a multi-center study funded by NIH to determine whether the addition of pharmacological doses of folic acid, pyridoxine, and cyanocobalamin reduces recurrent cerebral infarction as a primary endpoint and myocardial infarction or fatal coronary heart disease as a secondary endpoint. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: VITAMIN INTERVENTION FOR STROKE PREVENTION (VISP) Principal Investigator & Institution: Brass, Lawrence M.; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001 Summary: This study is designed to determine whether folic acid, vitamin B6 and vitamin B12 will prevent recurrent stroke by reducing levels of homocysteine in patients

Studies

59

suffering a stroke. The effect of homocysteine reduction on reduced risk for myocardial infarction and fatal coronary heart disease will also be looked at. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VITAMIN INTERVENTION IN STROKE PREVENTION Principal Investigator & Institution: Gerber, Oded; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001 Summary: This multicenter, double-blind, randomized, controlled clinical trial has been designed to determine whether the addition of a multivitamin with high dose folic acid, pyridoxine (vitamin B6), and cyanocobalamin (vitamin B12) to best medical/surgical management and risk factor modification reduces recurrent cerebral infarction (primary end point) and myocardial infarction or fatal coronary heart disease (CHD, secondary endpoint) in patients with a nondisabling cerebral infarction (NDCI) who have basal homocyst(e)ine levels above 9.5 umol/L at screening. The fundamental eligibility criteria are the occurrence of a NDCI within 120 days prior to randomization and a qualifying homocyst(e)ine level. All patients will receive best management for risk factor reduction, which includes counseling and interventions for hypertension, high LDL (low-density lipoprotein), low HDL (high-density lipoprotein), tobacco use, diabetes and other recognized factors which add excess risk for cerebral and myocardial infarction. The study is designed to recruit 3600 patients (1800 in each of two groups) for 80% power for detection of a 30% treatment effect, allowing for 20% non-compliance in the high-dose treatment group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: VITAMIN INTERVENTION IN STROKE PREVENTION Principal Investigator & Institution: Pettigrew, L. Creed.; Professor; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2001 Summary: This study is to determine whether folic acid, vitamin B6, and vitamin B12 will reduce levels of homocysteine in patients suffering nondisabling cerebral infarction, thereby preventing recurrent infarctions and reducing the risk of myocardial infarction and fatal coronary heart disease. 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

3 4

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

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age.

60

Folic Acid

unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “folic acid” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for folic acid in the PubMed Central database: •

Effect of mass media campaign to reduce socioeconomic differences in women's awareness and behaviour concerning use of folic acid: cross sectional study. by de Walle HE, van der Pal KM, den Berg LT, Jeeninga W, Schouten JS, de Rover CM, Buitendijk SE, Cornel MC.; 1999 Jul 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28182

•

Folic acid fortification: time for a concentrated effort. by Oakley GP Jr.; 2002 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128390

•

Folic acid fortification: time for a concentrated effort. by Van den Hof MC, Persad VL.; 2002 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128391

•

Folic acid supplementation: more work is needed. by Bjorklund NK, Evans JA, Greenberg CR.; 2000 Oct 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=80238

•

Folic acid supplementation: more work is needed. by Friel JK.; 2000 Oct 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=80239

•

Homocysteine induces congenital defects of the heart and neural tube: Effect of folic acid. by Rosenquist TH, Ratashak SA, Selhub J.; 1996 Dec 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26385

•

Incidence of open neural tube defects in Nova Scotia after folic acid fortification. by Persad VL, Hof M, Dube JM, Zimmer P.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117468

•

Low rate of adequate folic acid supplementation in well-educated women of high socioeconomic status attending a genetics clinic. by Dawson LE, Pham B, Hunter AG.; 2001 Apr 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=80971

•

Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. by Collaboration HL.; 1998 Mar 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28491

•

Neural tube defects and periconceptional folic acid in England and Wales: retrospective study. by Kadir RA, Sabin C, Whitlow B, Brockbank E, Economides D.; 1999 Jul 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28158

•

Neural tube defects and periconceptional folic acid. by Kadir RA, Economides DL.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117471

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.

Studies

61

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

A comparison of folic acid and 5-methyltetrahydrofolate for prevention of DNA damage and cell death in human lymphocytes in vitro. Author(s): Wang X, Fenech M. Source: Mutagenesis. 2003 January; 18(1): 81-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12473740&dopt=Abstract

•

A comparison of the effect of advice to eat either '5-a-day' fruit and vegetables or folic acid-fortified foods on plasma folate and homocysteine. Author(s): Ashfield-Watt PA, Whiting JM, Clark ZE, Moat SJ, Newcombe RG, Burr ML, McDowell IF. Source: European Journal of Clinical Nutrition. 2003 February; 57(2): 316-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571666&dopt=Abstract

•

A comparison of two combined iron-folic acid preparations in the prevention of anaemia in pregnancy. Author(s): Gringras M. Source: J Int Med Res. 1982; 10(4): 268-70. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7117682&dopt=Abstract

•

A national survey as a basis of public health policy: a case study with folic acid. Author(s): Leventhal A, Kaluski DN. Source: Public Health Rev. 2001; 29(2-4): 153-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12418705&dopt=Abstract

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

62

Folic Acid

•

A nationwide program for the use of preconceptional folic acid to prevent the development of open neural tube defects. Who is really using folic acid? Author(s): de la Vega A, Salicrup E, Verdiales M. Source: P R Health Sci J. 2002 March; 21(1): 7-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12013683&dopt=Abstract

•

A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). Author(s): MacMahon M, Kirkpatrick C, Cummings CE, Clayton A, Robinson PJ, Tomiak RH, Liu M, Kush D, Tobert J. Source: Nutr Metab Cardiovasc Dis. 2000 August; 10(4): 195-203. Erratum In: Nutr Metab Cardiovasc Dis 2001 Aug; 11(4): Iii. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11079257&dopt=Abstract

•

A randomized double-blind placebo-controlled trial of the effect of homocysteinelowering therapy with folic acid on endothelial function in patients with coronary artery disease. Author(s): Thambyrajah J, Landray MJ, Jones HJ, McGlynn FJ, Wheeler DC, Townend JN. Source: Journal of the American College of Cardiology. 2001 June 1; 37(7): 1858-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11401123&dopt=Abstract

•

Absorption of folic acid, water and electrolytes in apparently normal proximal jejunum of patients with Crohn's disease studied by the technique of intestinal perfusion. Author(s): Morgan RJ, Nelson LM, Russell RI, Main AN, Hall MJ. Source: Digestion. 1982; 24(1): 60-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7128951&dopt=Abstract

•

Acceptability trials of maize meal fortified with niacin, riboflavin and folic acid. Author(s): Walker AR, Walker BF, Metz J. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 1983 September 3; 64(10): 343-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6612529&dopt=Abstract

•

Accumulation of plasma reduced folates after folic acid administration. Author(s): Priest DG, Schmitz JC, Bunni MA. Source: Seminars in Oncology. 1999 April; 26(2 Suppl 6): 38-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10598553&dopt=Abstract

Studies

63

•

Addition of folic acid to staple foods as a selective nutrition intervention strategy. Author(s): Colman N. Source: Nutrition Reviews. 1982 August; 40(8): 225-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6752767&dopt=Abstract

•

Altered jejunal surface pH in coeliac disease: its effect on propranolol and folic acid absorption. Author(s): Kitis G, Lucas ML, Bishop H, Sargent A, Schneider RE, Blair JA, Allan RN. Source: Clinical Science (London, England : 1979). 1982 October; 63(4): 373-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7105632&dopt=Abstract

•

An educational intervention about folic acid and healthy pregnancies targeted at college-age women. Author(s): DiPietro NA, Kier KL. Source: Journal of the American Pharmaceutical Association (Washington,D.C. : 1996). 2001 March-April; 41(2): 283-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11297338&dopt=Abstract

•

Aplastic anemia induced by phenytoin: a geriatric case with severe folic acid deficiency. Author(s): Blain H, Hamdan KA, Blain A, Jeandel C. Source: Journal of the American Geriatrics Society. 2002 February; 50(2): 396-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12028229&dopt=Abstract

•

Ascorbic acid, vitamin A, folic acid, and amino acids in blood of patients with hemophilia. Author(s): Toy L, Young EA, Longenecker JB. Source: Blood. 1983 September; 62(3): 532-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6882915&dopt=Abstract

•

Assessment of student pharmacists' knowledge concerning folic acid and prevention of birth defects demonstrates a need for further education. Author(s): Lynch SM. Source: The Journal of Nutrition. 2002 March; 132(3): 439-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11880568&dopt=Abstract

•

Assessment of three levels of folic acid on serum folate and plasma homocysteine: a randomised placebo-controlled double-blind dietary intervention trial. Author(s): Venn BJ, Mann JI, Williams SM, Riddell LJ, Chisholm A, Harper MJ, Aitken W, Rossaak JI. Source: European Journal of Clinical Nutrition. 2002 August; 56(8): 748-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12122551&dopt=Abstract

64

Folic Acid

•

Association between folic acid food fortification and hypertension or preeclampsia in pregnancy. Author(s): Ray JG, Mamdani MM. Source: Archives of Internal Medicine. 2002 August 12-26; 162(15): 1776-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12153382&dopt=Abstract

•

Association of neural tube defects and folic acid food fortification in Canada. Author(s): Ray JG, Meier C, Vermeulen MJ, Boss S, Wyatt PR, Cole DE. Source: Lancet. 2002 December 21-28; 360(9350): 2047-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12504403&dopt=Abstract

•

Awareness regarding use of folic acid for prevention of congenital neural tube defects. Author(s): Gupta P, Gupta A. Source: Natl Med J India. 2000 March-April; 13(2): 105. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10835862&dopt=Abstract

•

Becoming proactive about birth defects. National Folic Acid Information Campaign begins. Author(s): Drake P, Morin KH, LaRose K. Source: Awhonn Lifelines / Association of Women's Health, Obstetric and Neonatal Nurses. 1999 August-September; 3(4): 21-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10766524&dopt=Abstract

•

Behavioural responses of young anaemic Indian children to iron-folic acid supplements. Author(s): Seshadri S, Hirode K, Naik P, Malhotra S. Source: The British Journal of Nutrition. 1982 September; 48(2): 233-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7115656&dopt=Abstract

•

Beneficial effects of folic acid supplementation in the prevention of neural tube defects (NTDs) Author(s): Murphy PA. Source: Journal of Nurse-Midwifery. 1993 January-February; 38(1): 54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8380852&dopt=Abstract

•

Benefit of folic acid supplementation in parkinsonian patients treated with levodopa. Author(s): Muller T, Woitalla D, Kuhn W. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 April; 74(4): 549. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640094&dopt=Abstract

Studies

65

•

Benefits and risks of folic acid to the nervous system. Author(s): Reynolds EH. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 May; 72(5): 567-71. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11971038&dopt=Abstract

•

Binding of folic acid activity (FAA) to proteins in mother's milk. Author(s): Markkanen T, Pajula RL, Virtanen S, Himanen P. Source: Int J Vitam Nutr Res. 1974; 44(2): 195-202. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4850757&dopt=Abstract

•

Binding of folic acid to serum proteins. 3. The effect of pernicious anaemia. Author(s): Markkanen T, Himanen P, Pajula RJ. Source: Acta Haematologica. 1974; 51(4): 193-203. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4136242&dopt=Abstract

•

Binding of folic acid to serum proteins. II. The effect of diphenylhydantoin treatment and of various diseases. Author(s): Markkanen T, Himanen P, Pajula RL, Molnar G. Source: Acta Haematologica. 1973; 50(5): 284-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4202632&dopt=Abstract

•

Binding of folic acid to serum proteins. IV In some animal species. Author(s): Markkanen T, Pajula RL, Himanen P, Virtanen S. Source: Int J Vitam Nutr Res. 1974; 44(3): 347-56. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4142481&dopt=Abstract

•

Bioavailability of a combination preparation of trimethoprim and folic acid. Author(s): Soininen K, Kleimola T. Source: J Int Med Res. 1983; 11(5): 294-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6642070&dopt=Abstract

•

Bioavailability of folic acid in fortified food. Author(s): Tamura T. Source: The American Journal of Clinical Nutrition. 1997 December; 66(6): 1299-300. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9394677&dopt=Abstract

•

Biological effects of folic acid antagonists with antineoplastic activity. Author(s): Jackson RC. Source: Pharmacology & Therapeutics. 1984; 25(1): 61-82. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6387725&dopt=Abstract

66

Folic Acid

•

Blood folic acid and vitamin B12 in relation to neural tube defects. Author(s): Wald NJ, Hackshaw AD, Stone R, Sourial NA. Source: British Journal of Obstetrics and Gynaecology. 1996 April; 103(4): 319-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8605127&dopt=Abstract

•

Blood vitamin status (B1, B2, B6, folic acid and B12) in patients with alcoholic liver disease. Author(s): Majumdar SK, Shaw GK, O'Gorman P, Aps EJ, Offerman EL, Thomson AD. Source: Int J Vitam Nutr Res. 1982; 52(3): 266-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7174224&dopt=Abstract

•

Blood-brain barrier transport of reduced folic acid. Author(s): Wu D, Pardridge WM. Source: Pharmaceutical Research. 1999 March; 16(3): 415-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10213373&dopt=Abstract

•

Bone marrow status of anaemic pregnant women on supplemental iron and folic acid in a Nigerian community. Author(s): Okafor LA, Diejomaoh FM, Oronsaye AU. Source: Angiology. 1985 August; 36(8): 500-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4037416&dopt=Abstract

•

Brain atrophy, peripheral neuropathy and folic acid deficiency. Author(s): Monaco F, Sechi GP, Piras MR, Lamberti A, Mutani R. Source: Italian Journal of Neurological Sciences. 1983 April; 4(1): 113-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6305873&dopt=Abstract

•

Bread fortification with folic acid, vitamin B12, and vitamin B6 in Hungary. Author(s): Czeizel AE, Merhala Z. Source: Lancet. 1998 October 10; 352(9135): 1225. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9777867&dopt=Abstract

•

Bread is fortified with folic acid in Hungary. Author(s): Czeizel AE, Kokeny M. Source: Bmj (Clinical Research Ed.). 2002 August 17; 325(7360): 391. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183320&dopt=Abstract

Studies

67

•

Breast milk folic acid and zinc concentrations of lactating, low socioeconomic, Amazonian women and the effect of age and parity on the same two nutrients. Author(s): Lehti KK. Source: European Journal of Clinical Nutrition. 1990 September; 44(9): 675-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2261899&dopt=Abstract

•

Can women live on bread alone? Folic acid supplementation revisited. Author(s): Page RL 2nd, Jones KW, Jebaily GC. Source: J S C Med Assoc. 1997 February; 93(2): 57-62. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9046130&dopt=Abstract

•

Carrier-mediated transport of folic acid in BeWo cell monolayers as a model of the human trophoblast. Author(s): Takahashi T, Utoguchi N, Takara A, Yamamoto N, Nakanishi T, Tanaka K, Audus KL, Watanabe Y. Source: Placenta. 2001 November; 22(10): 863-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11718574&dopt=Abstract

•

Changes in plasma homocysteine in arthritis patients starting treatment with lowdose methotrexate subsequently supplemented with folic acid. Author(s): Slot O. Source: Scandinavian Journal of Rheumatology. 2001; 30(5): 305-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11727846&dopt=Abstract

•

Chloroquine prophylaxis, iron-folic acid supplementation or case management of malaria attacks in primigravidae in western Uganda: effects on maternal parasitaemia and haemoglobin levels and on birthweight. Author(s): Ndyomugyenyi R, Magnussen P. Source: Trans R Soc Trop Med Hyg. 2000 July-August; 94(4): 413-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11127247&dopt=Abstract

•

Classification of folic acid. Author(s): van Dusseldorp M. Source: Lancet. 1997 January 25; 349(9047): 289. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9014945&dopt=Abstract

•

Clinical and laboratory features and sequelae of deficiency of folic acid (folate) and vitamin B12 (cobalamin) in pregnancy and gynecology. Author(s): Frenkel EP, Yardley DA. Source: Hematology/Oncology Clinics of North America. 2000 October; 14(5): 1079-100, Viii. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11005035&dopt=Abstract

68

Folic Acid

•

Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation. Author(s): Yerby MS. Source: Epilepsia. 2003; 44 Suppl 3: 33-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790884&dopt=Abstract

•

College women's awareness and consumption of folic acid for the prevention of neural tube defects. Author(s): Quillin JM, Silberg J, Board P, Pratt L, Bodurtha J. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2000 July-August; 2(4): 209-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11252704&dopt=Abstract

•

Comment: treatment of hyperhomocysteinemia with folic acid. Author(s): Leblhuber F, Walli J, Artner-Dworzak E, Vrecko K, Fuchs D. Source: The Annals of Pharmacotherapy. 2000 October; 34(10): 1207-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11054993&dopt=Abstract

•

Commentary: three decades of folic acid antagonists in dermatology. Author(s): Weinstein GD. Source: Archives of Dermatology. 1983 June; 119(6): 525-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6859893&dopt=Abstract

•

Commercially available folic acid supplements and their compliance with the British Pharmacopoeia test for dissolution. Author(s): Sculthorpe NF, Davies B, Ashton T, Allison S, McGuire DN, Malhi JS. Source: Journal of Public Health Medicine. 2001 September; 23(3): 195-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11585191&dopt=Abstract

•

Comparative effects of methotrexate, two nonclassic folic acid antagonists, and cytarabine on hematopoietic precursor cells. Author(s): Marsh JC. Source: Cancer Treat Rep. 1982 March; 66(3): 499-504. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6460555&dopt=Abstract

•

Comparative use and knowledge of preconceptional folic acid among Spanish- and English-speaking patient populations in Phoenix and Yuma, Arizona. Author(s): Perlow JH. Source: American Journal of Obstetrics and Gynecology. 2001 May; 184(6): 1263-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11349199&dopt=Abstract

Studies

69

•

Comparison of national policies on periconceptional use of folic acid to prevent spina bifida and anencephaly (SBA). Author(s): Cornel MC, Erickson JD. Source: Teratology. 1997 February; 55(2): 134-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9143094&dopt=Abstract

•

Comparison of Prenate Advance with other prescription prenatal vitamins: a folic acid dissolution study. Author(s): Giebe K, Counts C. Source: Adv Ther. 2000 July-August; 17(4): 179-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11185056&dopt=Abstract

•

Comparison of the effect of low-dose supplementation with L-5methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebocontrolled study. Author(s): Venn BJ, Green TJ, Moser R, Mann JI. Source: The American Journal of Clinical Nutrition. 2003 March; 77(3): 658-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12600857&dopt=Abstract

•

Concomitant supplemental vitamin A enhances the response to weekly supplemental iron and folic acid in anemic teenagers in urban Bangladesh. Author(s): Ahmed F, Khan MR, Jackson AA. Source: The American Journal of Clinical Nutrition. 2001 July; 74(1): 108-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11451725&dopt=Abstract

•

Content of folic acid and free homocysteine in blood serum of human papillomavirus-infected women with cervical dysplasia. Author(s): Kwasniewska A, Tukendorf A, Gozdzicka-Jozefiak A, Semczuk-Sikora A, Korobowicz E. Source: Eur J Gynaecol Oncol. 2002; 23(4): 311-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12214730&dopt=Abstract

•

Coronary endothelial function in hyperhomocysteinemia: improvement after treatment with folic acid and cobalamin in patients with coronary artery disease. Author(s): Willems FF, Aengevaeren WR, Boers GH, Blom HJ, Verheugt FW. Source: Journal of the American College of Cardiology. 2002 August 21; 40(4): 766-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12204509&dopt=Abstract

•

Cost-effectiveness of periconceptional supplementation of folic acid. Author(s): Postma MJ, Londeman J, Veenstra M, de Walle HE, de Jong-van den Berg LT. Source: Pharmacy World & Science : Pws. 2002 February; 24(1): 8-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11980171&dopt=Abstract

70

Folic Acid

•

Decline of neural tube defects cases after a folic acid campaign in Nuevo Leon, Mexico. Author(s): Martinez de Villarreal L, Perez JZ, Vazquez PA, Herrera RH, Campos Mdel R, Lopez RA, Ramirez JL, Sanchez JM, Villarreal JJ, Garza MT, Limon A, Lopez AG, Barcenas M, Garcia JR, Dominguez AS, Nunez RH, Ayala JL, Martinez JG, Gonzalez MT, Alvarez CG, Castro RN. Source: Teratology. 2002 November; 66(5): 249-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12397633&dopt=Abstract

•

Declining rate of folate insufficiency among adults following increased folic acid food fortification in Canada. Author(s): Ray JG, Vermeulen MJ, Boss SC, Cole DE. Source: Canadian Journal of Public Health. Revue Canadienne De Sante Publique. 2002 July-August; 93(4): 249-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12154524&dopt=Abstract

•

Decrease birth defects by increasing the number of women who take folic acid before they are pregnant. Author(s): Nakamura P. Source: Alaska Med. 1999 July-September; 41(3): 73. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10540499&dopt=Abstract

•

Delaying folic acid fortification of flour. Author(s): Oakley GP. Source: Bmj (Clinical Research Ed.). 2002 June 8; 324(7350): 1348-9. Erratum In: Bmj 2002 August 3; 325(7358): 259. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052788&dopt=Abstract

•

Determination of serum B12 vitamin and folic acid levels in patient with stroke. Author(s): Yilmaz N, Yilmaz M, Pence S, Ozaslan J, Kocoglu H, Yilmaz G. Source: Acta Medica (Hradec Kralove). 2001; 44(1): 37-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11367891&dopt=Abstract

•

Dietary folic acid deficiency leading to megaloblastic anaemia in infancy. A case report. Author(s): Rohm GF, Schraader EB, Kwak PJ. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 1982 October 23; 62(18): 659-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7135118&dopt=Abstract

Studies

71

•

Dietary intake of folate by adolescents and the potential effect of flour fortification with folic acid. Author(s): Moynihan PJ, Rugg-Gunn AJ, Butler TJ, Adamson AJ. Source: The British Journal of Nutrition. 2001 October; 86(4): 529-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11591241&dopt=Abstract

•

Dietary intake of folic acid and colorectal cancer risk in a cohort of women. Author(s): Terry P, Jain M, Miller AB, Howe GR, Rohan TE. Source: International Journal of Cancer. Journal International Du Cancer. 2002 February 20; 97(6): 864-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11857369&dopt=Abstract

•

Dietary intake of vitamin E and folic acid in a defined population in Sri Lanka. Author(s): Mendis S, Bulugahapitiya DU, Ranatunga PK, Gunawardene PR, Kandegedera PG. Source: Ceylon Med J. 1999 March; 44(1): 25-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10643094&dopt=Abstract

•

Difference in the homocysteine-lowering effect of folic acid in haemodialysis patients with and without occlusive vascular disease. Author(s): Descombes E, Boulat O, Bersier LF, Fellay G. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2001 March; 16(3): 585-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11239036&dopt=Abstract

•

Diminished serum folic acid levels in renal transplant recipients. Author(s): Zazgornik J, Druml W, Balcke P, Kopsa H, Marosi L, Neumann E, Schmidt P. Source: Clinical Nephrology. 1982 December; 18(6): 306-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6759002&dopt=Abstract

•

Distribution of plasma folate forms in hemodialysis patients receiving high daily doses of L-folinic or folic acid. Author(s): Ghandour H, Bagley PJ, Shemin D, Hsu N, Jacques PF, Dworkin L, Bostom AG, Selhub J. Source: Kidney International. 2002 December; 62(6): 2246-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12427152&dopt=Abstract

•

Do patients receiving regular haemodialysis need folic acid supplements? Author(s): Sharman VL, Cunningham J, Goodwin FJ, Marsh FP, Chaput de Saintonge DM, Evans SW. Source: British Medical Journal (Clinical Research Ed.). 1982 July 10; 285(6335): 96-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6805843&dopt=Abstract

72

Folic Acid

•

Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Author(s): Griffith SM, Fisher J, Clarke S, Montgomery B, Jones PW, Saklatvala J, Dawes PT, Shadforth MF, Hothersall TE, Hassell AB, Hay EM. Source: Rheumatology (Oxford, England). 2000 October; 39(10): 1102-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11035130&dopt=Abstract

•

Do we need another randomized controlled trial of folic acid alone? Author(s): Turner LA, Morrison H, Prabhakaran VM. Source: Epidemiology (Cambridge, Mass.). 2001 March; 12(2): 262-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11246591&dopt=Abstract

•

Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure? Author(s): Thambyrajah J, Landray MJ, McGlynn FJ, Jones HJ, Wheeler DC, Townend JN. Source: Circulation. 2000 August 22; 102(8): 871-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10952955&dopt=Abstract

•

Does oral folic acid lower total homocysteine levels and improve endothelial function in children with chronic renal failure? Author(s): Bennett-Richards K, Kattenhorn M, Donald A, Oakley G, Varghese Z, Rees L, Deanfield JE. Source: Circulation. 2002 April 16; 105(15): 1810-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11956124&dopt=Abstract

•

Dose-dependent effect of folic acid on the prevention of orofacial clefts. Author(s): Czeizel AE, Timar L, Sarkozi A. Source: Pediatrics. 1999 December; 104(6): E66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10586000&dopt=Abstract

•

Dose-dependent effects of folic acid on plasma homocysteine in a randomized trial conducted among 723 individuals with coronary heart disease. Author(s): Neal B, MacMahon S, Ohkubo T, Tonkin A, Wilcken D; PACIFIC Study Group. Source: European Heart Journal. 2002 October; 23(19): 1509-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12395803&dopt=Abstract

•

Down syndrome and folic acid update. Author(s): Hine RJ, James SJ. Source: Journal of the American Dietetic Association. 2000 September; 100(9): 1004. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11019341&dopt=Abstract

Studies

73

•

Effect of folic acid and vitamin C supplementation on folate status and homocysteine level: a randomised controlled trial in Italian smoker-blood donors. Author(s): Cafolla A, Dragoni F, Girelli G, Tosti ME, Costante A, De Luca AM, Funaro D, Scott CS. Source: Atherosclerosis. 2002 July; 163(1): 105-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12048127&dopt=Abstract

•

Effect of folic acid on fenofibrate-induced elevation of homocysteine and cysteine. Author(s): Melenovsky V, Stulc T, Kozich V, Grauova B, Krijt J, Wichterle D, Haas T, Malik J, Hradec J, Ceska R. Source: American Heart Journal. 2003 July; 146(1): 110. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12851616&dopt=Abstract

•

Effect of folic acid on nitrate tolerance in healthy volunteers: differences between arterial and venous circulation. Author(s): Gori T, Saunders L, Ahmed S, Parker JD. Source: Journal of Cardiovascular Pharmacology. 2003 February; 41(2): 185-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12548078&dopt=Abstract

•

Effect of folic acid supplementation on plasma zinc concentrations of young women. Author(s): Green TJ, Skeaff CM, Whiting SJ, Gibson RS. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2003 June; 19(6): 522-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781852&dopt=Abstract

•

Effect of folic acid therapy on serum homocysteine level in renal transplant recipients. Author(s): Savaj S, Rezakhani S, Porooshani F, Ghods AJ. Source: Transplantation Proceedings. 2002 September; 34(6): 2419. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12270462&dopt=Abstract

•

Effect of food fortification on folic acid intake in the United States. Author(s): Quinlivan EP, Gregory JF 3rd. Source: The American Journal of Clinical Nutrition. 2003 January; 77(1): 221-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499345&dopt=Abstract

•

Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. Author(s): Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Source: Jama : the Journal of the American Medical Association. 2002 August 28; 288(8): 973-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12190367&dopt=Abstract

74

Folic Acid

•

Effect of implementation of folic acid fortification of food on homocysteine concentrations in subjects with coronary artery disease. Author(s): Anderson JL, Horne BD, Carlquist JF, Bair TL, Habashi J, Hart NI, Jones SK, Muhlestein JB; Intermountain Heart Collaborative Study Group. Source: The American Journal of Cardiology. 2002 September 1; 90(5): 536-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12208419&dopt=Abstract

•

Effect of long-term carbamazepine therapy on serum lipids, vitamin B12 and folic acid levels in children. Author(s): Deda G, Caksen H, Icagasioglu D. Source: J Pediatr Endocrinol Metab. 2003 February; 16(2): 193-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12713256&dopt=Abstract

•

Effect of low doses of 5-methyltetrahydrofolate and folic acid on plasma homocysteine in healthy subjects with or without the 677C-->T polymorphism of methylenetetrahydrofolate reductase. Author(s): Litynski P, Loehrer F, Linder L, Todesco L, Fowler B. Source: European Journal of Clinical Investigation. 2002 September; 32(9): 662-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12486865&dopt=Abstract

•

Effect of low levels of serum vitamin B12 and folic acid on cognitive performance in old age: a population-based study. Author(s): Jelicic M, Jonker C, Deeg DJ. Source: Developmental Neuropsychology. 2001; 20(3): 565-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12002093&dopt=Abstract

•

Effect of treatment with folic acid and vitamin B6 on lipid and homocysteine concentrations in patients with coronary artery disease. Author(s): Mark L, Erdei F, Markizay J, Kondacs A, Katona A. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2002 May; 18(5): 428-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11985950&dopt=Abstract

•

Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients. Author(s): Righetti M, Ferrario GM, Milani S, Serbelloni P, La Rosa L, Uccellini M, Sessa A. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 April; 9(4): Pi19-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12709680&dopt=Abstract

Studies

75

•

Effects of folic acid. Author(s): Abramsky L, Noble J. Source: Lancet. 2002 June 8; 359(9322): 2039-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12076582&dopt=Abstract

•

Effects of folic acid. Author(s): Reynolds E. Source: Lancet. 2002 June 8; 359(9322): 2039. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12076581&dopt=Abstract

•

Effects of folic acid. Author(s): Davis RE. Source: Lancet. 2002 June 8; 359(9322): 2038-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12076580&dopt=Abstract

•

Effects of homocysteine on proliferation, necrosis, and apoptosis of vascular smooth muscle cells in culture and influence of folic acid. Author(s): Buemi M, Marino D, Di Pasquale G, Floccari F, Ruello A, Aloisi C, Corica F, Senatore M, Romeo A, Frisina N. Source: Thrombosis Research. 2001 November 1; 104(3): 207-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11672763&dopt=Abstract

•

Effects of valproate and carbamazepine on serum levels of homocysteine, vitamin B12, and folic acid. Author(s): Karabiber H, Sonmezgoz E, Ozerol E, Yakinci C, Otlu B, Yologlu S. Source: Brain & Development. 2003 March; 25(2): 113-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12581807&dopt=Abstract

•

Efficient gene delivery via non-covalent complexes of folic acid and polyethylenimine. Author(s): Guo W, Lee RJ. Source: Journal of Controlled Release : Official Journal of the Controlled Release Society. 2001 November 9; 77(1-2): 131-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11689266&dopt=Abstract

•

Estimated folic acid intakes from simulated fortification of the New Zealand food supply. Author(s): Green T, Newton R, Bourn D. Source: N Z Med J. 2003 January 24; 116(1168): U294. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12607547&dopt=Abstract

76

Folic Acid

•

Folic acid alone prevents neural tube defects: evidence from the China study. Author(s): Berry RJ, Li Z. Source: Epidemiology (Cambridge, Mass.). 2002 January; 13(1): 114-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11805598&dopt=Abstract

•

Folic acid and human malformations: misunderstandings. Author(s): Czeizel AE. Source: Reproductive Toxicology (Elmsford, N.Y.). 2001 July-August; 15(4): 441-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11515501&dopt=Abstract

•

Folic acid and NTD-disputed connection. Author(s): Kalter H. Source: Teratology. 2001 December; 64(6): 318-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11754174&dopt=Abstract

•

Folic acid and prevention of neural tube defects in 2000 improved awareness--low peri-conceptional uptake. Author(s): Oleary M, Donnell RM, Johnson H. Source: Ir Med J. 2001 June; 94(6): 180-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11495236&dopt=Abstract

•

Folic acid antagonism of sulfa drug treatments. Author(s): Bayly AM, Macreadie IG. Source: Trends in Parasitology. 2002 February; 18(2): 49-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11832284&dopt=Abstract

•

Folic acid awareness, knowledge, and consumption among women of childbearing age in Utah, 1998-2000. Author(s): Feldkamp M, Friedrichs M, Marti K. Source: American Journal of Medical Genetics. 2002 January 1; 107(1): 67-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11807872&dopt=Abstract

•

Folic acid fortification increases red blood cell folate concentrations in the Framingham study. Author(s): Choumenkovitch SF, Jacques PF, Nadeau MR, Wilson PW, Rosenberg IH, Selhub J. Source: The Journal of Nutrition. 2001 December; 131(12): 3277-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11739880&dopt=Abstract

Studies

77

•

Folic acid fortification: informed mothers, healthy babies. Author(s): McCaffree J. Source: Journal of the American Dietetic Association. 2001 August; 101(8): 872. Erratum In: J Am Diet Assoc 2001 September; 101(9): 997. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11501857&dopt=Abstract

•

Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Author(s): Doshi SN, McDowell IF, Moat SJ, Payne N, Durrant HJ, Lewis MJ, Goodfellow J. Source: Circulation. 2002 January 1; 105(1): 22-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11772871&dopt=Abstract

•

Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Author(s): Gori T, Burstein JM, Ahmed S, Miner SE, Al-Hesayen A, Kelly S, Parker JD. Source: Circulation. 2001 September 4; 104(10): 1119-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11535566&dopt=Abstract

•

Folic acid supplementation and risk for imperforate anus in China. Author(s): Myers MF, Li S, Correa-Villasenor A, Li Z, Moore CA, Hong SX, Berry RJ; China-US Collaborative Project for Neural Tube Defect Prevention. Source: American Journal of Epidemiology. 2001 December 1; 154(11): 1051-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11724722&dopt=Abstract

•

Folic acid supplementation in dementia: a preliminary report. Author(s): Sommer BR, Hoff AL, Costa M. Source: Journal of Geriatric Psychiatry and Neurology. 2003 September; 16(3): 156-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12967058&dopt=Abstract

•

Folic acid supplements during pregnancy and risk of miscarriage. Author(s): Gindler J, Li Z, Berry RJ, Zheng J, Correa A, Sun X, Wong L, Cheng L, Erickson JD, Wang Y, Tong Q; Jiaxing City Collaborative Project on Neural Tube Defect Prevention. Source: Lancet. 2001 September 8; 358(9284): 796-800. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11564486&dopt=Abstract

•

Folic acid. Preconception knowledge and use by infertile women. Author(s): Frishman GN, Spurrell TP, Heber WW. Source: J Reprod Med. 2001 December; 46(12): 1025-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11789081&dopt=Abstract

78

Folic Acid

•

Folic acid: are current fortification levels adequate? Author(s): Neuhouser ML, Beresford SA. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2001 October; 17(10): 868-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11684394&dopt=Abstract

•

Folic acid: Is self reported use of supplements accurate? Author(s): Burton A, Wilson S, Gillies AJ. Source: Journal of Epidemiology and Community Health. 2001 November; 55(11): 841-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11604442&dopt=Abstract

•

Folic acid-responsive neurological diseases in Japan. Author(s): Yukawa M, Naka H, Murata Y, Katayama S, Kohriyama T, Mimori Y, Nakamura S. Source: J Nutr Sci Vitaminol (Tokyo). 2001 June; 47(3): 181-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11575572&dopt=Abstract

•

Folic acid--what's it all about? Author(s): Cox SR. Source: Journal of Midwifery & Women's Health. 2003 September-October; 48(5): 365-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14526352&dopt=Abstract

•

Fortification of flour with folic acid. Author(s): Wharton B, Booth I. Source: Bmj (Clinical Research Ed.). 2001 November 24; 323(7323): 1198-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11719398&dopt=Abstract

•

Fortification of food with vitamin B12 in addition to folic acid might reduce cardiovascular disease risk. Author(s): SoRelle R. Source: Circulation. 2002 January 29; 105(4): E9070. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11831213&dopt=Abstract

•

Gamma glutamyl carboxypeptidase (conjugase), the folic acid-releasing enzyme of intestinal mucosa. Author(s): Bernstein LH, Gutstein S, Weiner SV. Source: The American Journal of Clinical Nutrition. 1970 July; 23(7): 919-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5455554&dopt=Abstract

Studies

79

•

Giardiasis: haematological status and the absorption of vitamin B12 and folic acid. Author(s): Hjelt K, Paerregaard A, Krasilnikoff PA. Source: Acta Paediatrica (Oslo, Norway : 1992). 1992 January; 81(1): 29-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1600300&dopt=Abstract

•

Gingival hyperplasia and folic acid deficiency from anticonvulsive drug therapy: a theoretical relationship. Author(s): Vogel RI. Source: Journal of Theoretical Biology. 1977 July 21; 67(2): 269-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=895164&dopt=Abstract

•

Girls should be taught at school about importance of folic acid. Author(s): Wild J, Schorah C, Maude K, Levene MI. Source: Bmj (Clinical Research Ed.). 1996 April 13; 312(7036): 974. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8616324&dopt=Abstract

•

Glossitis, folic acid and pernicious anemia. Author(s): Johnson BE. Source: Southern Medical Journal. 1983 November; 76(11): 1463. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6635752&dopt=Abstract

•

Good news for women and babies: folic acid prevents birth defects. Author(s): Havens DH, Levin BR. Source: Journal of Pediatric Health Care : Official Publication of National Association of Pediatric Nurse Associates & Practitioners. 1999 September-October; 13(5): 255-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10776204&dopt=Abstract

•

Homocysteine levels in elderly Spanish people: influence of pyridoxine, vitamin B12 and folic acid intakes. Author(s): Ortega RM, Jimenez A, Andres P, Faci M, Lolo JM, Lozano MC, Bermejo LM, Lopez-Sobaler AM, Requejo AM. Source: J Nutr Health Aging. 2002; 6(1): 69-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11813088&dopt=Abstract

•

Homocysteine metabolism and effects of folic acid supplementation in patients affected with spina bifida. Author(s): Brouwer IA, van Dusseldorp M, Thomas CM, van der Put NM, Gaytant MA, Eskes TK, Hautvast JG, Steegers-Theunissen RP. Source: Neuropediatrics. 2000 December; 31(6): 298-302. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11508548&dopt=Abstract

80

Folic Acid

•

Homocysteine modulation as a reason for continuous folic acid supplementation in methotrexate-treated rheumatoid arthritis patients. Author(s): Erb N, Kitas GD. Source: Rheumatology (Oxford, England). 2001 June; 40(6): 715-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11426040&dopt=Abstract

•

Homocysteine, fibrinogen, and lipoprotein(a) levels are simultaneously reduced in patients with chronic renal failure treated with folic acid, pyridoxine, and cyanocobalamin. Author(s): Naruszewicz M, Klinke M, Dziewanowski K, Staniewicz A, Bukowska H. Source: Metabolism: Clinical and Experimental. 2001 February; 50(2): 131-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11229418&dopt=Abstract

•

Homocysteine, folic acid, B vitamins and cardiovascular risk. Author(s): Blacher J, Safar ME. Source: J Nutr Health Aging. 2001; 5(3): 196-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11458292&dopt=Abstract

•

Homocysteine-lowering effect of 500 microg folic acid every other day versus 250 microg/day. Author(s): Brouwer IA, van Rooij IA, van Dusseldorp M, Thomas CM, Blom HJ, Hautvast JG, Eskes TK, Steegers-Theunissen RP. Source: Annals of Nutrition & Metabolism. 2000; 44(5-6): 194-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11146323&dopt=Abstract

•

Homocysteine-lowering treatment with folic acid plus vitamin B6 lowers urinary albumin excretion but not plasma markers of endothelial function or C-reactive protein: further analysis of secondary end-points of a randomized clinical trial. Author(s): Vermeulen EG, Rauwerda JA, van den Berg M, de Jong SC, Schalkwijk C, Twisk JW, Stehouwer CD. Source: European Journal of Clinical Investigation. 2003 March; 33(3): 209-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12641538&dopt=Abstract

•

How does folic acid prevent neural tube defects? Author(s): Scott JM. Source: Nature Medicine. 1998 August; 4(8): 895-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9701237&dopt=Abstract

•

How many pregnant women in Christchurch are using folic acid supplements in early pregnancy? Author(s): Schader I, Corwin P. Source: N Z Med J. 1999 December 10; 112(1101): 463-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10678210&dopt=Abstract

Studies

81

•

How much do you know about folic acid? Author(s): Scowen P. Source: Prof Care Mother Child. 1997; 7(1): 25-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9137047&dopt=Abstract

•

Human red blood cell membrane oxidase and horseradish peroxidase cleavage of folic acid: evidence for formation of singlet oxygen. Author(s): Innocentini LH, Duran N. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 1982 April; 15(1): 11-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6897521&dopt=Abstract

•

Hyperhomocysteinaemia therapy in haemodialysis patients: folinic versus folic acid in combination with vitamin B6 and B12. Author(s): Ducloux D, Aboubakr A, Motte G, Toubin G, Fournier V, Chalopin JM, Drueke T, Massy ZA. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2002 May; 17(5): 86570. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11981075&dopt=Abstract

•

Hyperhomocysteinaemia, folate and vitamin B12 in unsupplemented haemodialysis patients: effect of oral therapy with folic acid and vitamin B12. Author(s): Billion S, Tribout B, Cadet E, Queinnec C, Rochette J, Wheatley P, Bataille P. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2002 March; 17(3): 455-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11865092&dopt=Abstract

•

Hyperhomocysteinemia in children with juvenile idiopathic arthritis is not influenced by methotrexate treatment and folic acid supplementation: a pilot study. Author(s): Huemer M, Fodinger M, Huemer C, Sailer-Hock M, Falger J, Rettenbacher A, Bernecker M, Artacker G, Kenzian H, Lang T, Stockler-Ipsiroglu S. Source: Clin Exp Rheumatol. 2003 March-April; 21(2): 249-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12747286&dopt=Abstract

•

Hyperhomocysteinemia in chronic alcoholism: relations to folic acid and vitamins B(6) and B(12) status. Author(s): Cravo ML, Camilo ME. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2000 April; 16(4): 296-302. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10758367&dopt=Abstract

82

Folic Acid

•

Hyperhomocysteinemia in high-aged subjects: relation of B-vitamins, folic acid, renal function and the methylenetetrahydrofolate reductase mutation. Author(s): Herrmann W, Quast S, Ullrich M, Schultze H, Bodis M, Geisel J. Source: Atherosclerosis. 1999 May; 144(1): 91-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10381282&dopt=Abstract

•

Hyperhomocysteinemia in Japanese patients with convalescent stage ischemic stroke: effect of combined therapy with folic acid and mecobalamine. Author(s): Sato Y, Kaji M, Kondo I, Yoshida H, Satoh K, Metoki N. Source: Journal of the Neurological Sciences. 2002 October 15; 202(1-2): 65-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12220694&dopt=Abstract

•

Hyperhomocysteinemia in rheumatoid arthritis: influence of methotrexate treatment and folic acid supplementation. Author(s): Jensen OK, Rasmussen C, Mollerup F, Christensen PB, Hansen H, Ekelund S, Thulstrup AM. Source: The Journal of Rheumatology. 2002 August; 29(8): 1615-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12180718&dopt=Abstract

•

Hyperhomocysteinemia in type 2 diabetes mellitus: cardiovascular risk factors and effect of treatment with folic acid and pyridoxine. Author(s): Baliga BS, Reynolds T, Fink LM, Fonseca VA. Source: Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2000 November-December; 6(6): 435-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11155214&dopt=Abstract

•

Hyperhomocysteinemia, and low intakes of folic acid and vitamin B12 in urban North India. Author(s): Misra A, Vikram NK, Pandey RM, Dwivedi M, Ahmad FU, Luthra K, Jain K, Khanna N, Devi JR, Sharma R, Guleria R. Source: European Journal of Nutrition. 2002 April; 41(2): 68-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12083316&dopt=Abstract

•

Impact of an educational seminar on high school students' knowledge of folic acid supplementation and its role in the prevention of birth defects. Author(s): Johnson PA, Stadler DD, Feldkamp M, Webber B. Source: Journal of the American Dietetic Association. 2002 March; 102(3 Suppl): S78-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11902395&dopt=Abstract

Studies

83

•

Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. Author(s): Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LY. Source: Jama : the Journal of the American Medical Association. 2001 June 20; 285(23): 2981-6. Erratum In: Jama 2001 November 14; 286(18): 2236. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11410096&dopt=Abstract

•

Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Author(s): Quinlivan EP, McPartlin J, McNulty H, Ward M, Strain JJ, Weir DG, Scott JM. Source: Lancet. 2002 January 19; 359(9302): 227-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11812560&dopt=Abstract

•

Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Author(s): Butterworth CE Jr, Hatch KD, Gore H, Mueller H, Krumdieck CL. Source: The American Journal of Clinical Nutrition. 1982 January; 35(1): 73-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7064879&dopt=Abstract

•

In praise of folic acid. Author(s): Gorman C. Source: Time. 2002 February 25; 159(8): 73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11881186&dopt=Abstract

•

In vitro effects of folic acid on gamma-glutamyltransferase and glutathione reductase activities in malignant lung and thymus tumors. Author(s): Karelin AA, Korotkina RN, Matskevich GN, Borisov VV, Vishnevskii AA, Polikarpova LV, Kunitsyn AG. Source: Bulletin of Experimental Biology and Medicine. 2000 October; 130(10): 973-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11177297&dopt=Abstract

•

Inadequate folic acid intakes are prevalent among young women with neural tube defects. Author(s): Gross SM, Caufield LA, Kinsman SL, Ireys HT. Source: Journal of the American Dietetic Association. 2001 March; 101(3): 342-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11269615&dopt=Abstract

•

Incidence of open neural tube defects in Nova Scotia after folic acid fortification. Author(s): Persad VL, Van den Hof MC, Dube JM, Zimmer P. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2002 August 6; 167(3): 241-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12186168&dopt=Abstract

84

Folic Acid

•

Increased plasma homocyst(e)ine after withdrawal of ready-to-eat breakfast cereal from the diet: prevention by breakfast cereal providing 200 microg folic acid. Author(s): Malinow MR, Duell PB, Irvin-Jones A, Upson BM, Graf EE. Source: Journal of the American College of Nutrition. 2000 August; 19(4): 452-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10963464&dopt=Abstract

•

Increased red cell folate concentrations in women of reproductive age after Canadian folic acid food fortification. Author(s): Ray JG, Vermeulen MJ, Boss SC, Cole DE. Source: Epidemiology (Cambridge, Mass.). 2002 March; 13(2): 238-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11880771&dopt=Abstract

•

Increased urinary excretion and prolonged turnover time of folic acid during ethanol ingestion. Author(s): Russell RM, Rosenberg IH, Wilson PD, Iber FL, Oaks EB, Giovetti AC, Otradovec CL, Karwoski PA, Press AW. Source: The American Journal of Clinical Nutrition. 1983 July; 38(1): 64-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6407299&dopt=Abstract

•

Increasing evidence in favour of mandatory fortification with folic acid. Author(s): McNulty H. Source: The British Journal of Nutrition. 2001 October; 86(4): 425-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11591228&dopt=Abstract

•

Inertia on folic acid has caused thousands of unnecessary deaths. Author(s): Ellis A. Source: Bmj (Clinical Research Ed.). 2003 May 17; 326(7398): 1054. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12750190&dopt=Abstract

•

Influence of educational level on determinants of folic acid use. Author(s): van der Pal-de Bruin KM, de Walle HE, de Rover CM, Jeeninga W, Cornel MC, de Jong-van den Berg LT, Buitendijk SE, Paulussen TG. Source: Paediatric and Perinatal Epidemiology. 2003 July; 17(3): 256-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839537&dopt=Abstract

•

Influence of reporting error on the relation between blood folate concentrations and reported folic acid-containing dietary supplement use among reproductive-aged women in the United States. Author(s): Yang Q, Erickson JD. Source: The American Journal of Clinical Nutrition. 2003 January; 77(1): 196-203. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499342&dopt=Abstract

Studies

85

•

Insufficient folic acid intake in the Netherlands: what about the future? Author(s): de Walle HE, de Jong-van den Berg LT. Source: Teratology. 2002 July; 66(1): 40-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12115779&dopt=Abstract

•

Interaction of phenytoin and folic acid. Author(s): MacCosbe PE, Toomey K. Source: Clin Pharm. 1983 July-August; 2(4): 362-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6883965&dopt=Abstract

•

Is folic acid the best thing in sliced bread? Author(s): Ockenden J. Source: Pract Midwife. 2001 February; 4(2): 14-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12026293&dopt=Abstract

•

Is the jury still out on folic acid and congenital anomalies? Author(s): Moore LL. Source: Epidemiology (Cambridge, Mass.). 2001 March; 12(2): 141-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11246572&dopt=Abstract

•

Is weekly iron and folic acid supplementation as effective as daily supplementation for decreasing incidence of anemia in adolescent girls? Author(s): Perrin E, Rothman R, Coyne-Beasley T, Ford C, Bordley WC. Source: Archives of Pediatrics & Adolescent Medicine. 2002 February; 156(2): 128-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11814372&dopt=Abstract

•

Jejunal pH and folic acid. Author(s): Blair JA, Cooke WT, Swan CH. Source: British Medical Journal. 1971 May 22; 2(759): 465-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5576014&dopt=Abstract

•

Jejunal pH and folic acid. Author(s): Elsborg L. Source: British Medical Journal. 1971 May 8; 2(757): 340. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5575249&dopt=Abstract

•

Jejunal pH and folic acid. Author(s): Doe WF, Hoffbrand AV, Reed PI, Scott JM. Source: British Medical Journal. 1971 March 20; 1(750): 669-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5548849&dopt=Abstract

86

Folic Acid

•

Kinetic modeling of folate metabolism through use of chronic administration of deuterium-labeled folic acid in men. Author(s): Stites TE, Bailey LB, Scott KC, Toth JP, Fisher WP, Gregory JF 3rd. Source: The American Journal of Clinical Nutrition. 1997 January; 65(1): 53-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8988913&dopt=Abstract

•

Kinetics of folate turnover in pregnant women (second trimester) and nonpregnant controls during folic acid supplementation: stable-isotopic labeling of plasma folate, urinary folate and folate catabolites shows subtle effects of pregnancy on turnover of folate pools. Author(s): Gregory JF 3rd, Caudill MA, Opalko FJ, Bailey LB. Source: The Journal of Nutrition. 2001 July; 131(7): 1928-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11435509&dopt=Abstract

•

Knowledge about folic acid and the prevention of neural tube defects in two general practice populations. Author(s): Krischer J. Source: The British Journal of General Practice : the Journal of the Royal College of General Practitioners. 1997 April; 47(417): 231-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9196967&dopt=Abstract

•

Knowledge and clinical practice regarding folic acid among obstetriciangynecologists. Author(s): Power ML, Holzman GB, Schulkin J. Source: Obstetrics and Gynecology. 2000 June; 95(6 Pt 1): 895-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10831987&dopt=Abstract

•

Knowledge and use of folic acid among North Carolina women. Author(s): Meyer RE, Wall A, Morgan A, Devine J, Powers K. Source: N C Med J. 2002 January-February; 63(1): 18-22. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11989307&dopt=Abstract

•

Knowledge and use of folic acid supplementation: a study of Colorado women whose pregnancies were affected by a fetal neural tube defect. Author(s): Callender ES, Rickard R, Miller L, Rinsky-Eng J. Source: Clinical and Investigative Medicine. Medecine Clinique Et Experimentale. 2001 June; 24(3): 124-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11437063&dopt=Abstract

•

Knowledge and use of peri-conceptional folic acid among antenatal patients. Author(s): Sayers G, Scallan E, McDonnell R, Johnson Z. Source: Ir Med J. 1997 October; 90(6): 236-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9611928&dopt=Abstract

Studies

87

•

Knowledge and use of periconceptual folic acid supplements by British Forces Germany personnel and dependents. Author(s): Roberts LJ. Source: J R Army Med Corps. 1996 October; 142(3): 116-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8933472&dopt=Abstract

•

Knowledge of folic acid and neural tube defects among inner-city residents: have they heard about it? Author(s): Perez-Escamilla R, Himmelgreen D, Segura-Millan S, Gonzalez A, Mendez I, Haldeman L. Source: Journal of the American Dietetic Association. 1999 January; 99(1): 80-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9917737&dopt=Abstract

•

Knowledge of periconceptional folic acid for the prevention of neural tube defects. The missing links. Northeastern Ontario Primary Care Research Group. Author(s): Bonin MM, Bretzlaff JA, Therrien SA, Rowe BH. Source: Archives of Family Medicine. 1998 September-October; 7(5): 438-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9755736&dopt=Abstract

•

Knowledge on periconceptional use of folic acid in women of British Columbia. Author(s): Morin VI, Mondor M, Wilson RD. Source: Fetal Diagnosis and Therapy. 2001 March-April; 16(2): 111-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11173959&dopt=Abstract

•

Knowledge, use, and education regarding folic acid supplementation: continuation study of women in Colorado who had a pregnancy affected by a neural tube defect. Author(s): Rinsky-Eng J, Miller L. Source: Teratology. 2002; 66 Suppl 1: S29-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12239741&dopt=Abstract

•

Lack of association between plasma homocysteine and angiographic coronary artery disease in the era of fortification of cereal grain flour with folic acid. Author(s): Brilakis ES, McConnell JP, Ballman KV, Klee GG, Berger PB. Source: Atherosclerosis. 2002 December; 165(2): 375-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12417290&dopt=Abstract

•

Latent coeliac disease in a child with epilepsy, cerebral calcifications, drug-induced systemic lupus erythematosus and intestinal folic acid malabsorption associated with impairment of folic acid transport across the blood-brain barrier. Author(s): Calvani M Jr, Parisi P, Guaitolini C, Parisi G, Paolone G. Source: European Journal of Pediatrics. 2001 May; 160(5): 288-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11388596&dopt=Abstract

88

Folic Acid

•

Let's increase folic acid fortification and include vitamin B-12. Author(s): Oakley GP Jr. Source: The American Journal of Clinical Nutrition. 1997 June; 65(6): 1889-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9174489&dopt=Abstract

•

Levels of folic acid in plasma and in red blood cells of colorectal cancer patients. Author(s): Porcelli B, Frosi B, Rosi F, Arezzini L, Civitelli S, Tanzini G, Marinello E. Source: Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 1996; 50(6-7): 303-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8952872&dopt=Abstract

•

Localized deficiencies of folic acid in aerodigestive tissues. Author(s): Heimburger DC. Source: Annals of the New York Academy of Sciences. 1992 September 30; 669: 87-95; Discussion 95-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1444061&dopt=Abstract

•

Long-term folic acid (but not pyridoxine) supplementation lowers elevated plasma homocysteine level in chronic renal failure. Author(s): Chauveau P, Chadefaux B, Coude M, Aupetit J, Kamoun P, Jungers P. Source: Mineral and Electrolyte Metabolism. 1996; 22(1-3): 106-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8676798&dopt=Abstract

•

Long-term homocysteine-lowering treatment with folic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiffness: a 2-year, randomized, placebo-controlled trial. Author(s): van Dijk RA, Rauwerda JA, Steyn M, Twisk JW, Stehouwer CD. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2001 December; 21(12): 2072-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11742887&dopt=Abstract

•

Long-term improvement in homocysteine levels and arterial endothelial function after 1-year folic acid supplementation. Author(s): Woo KS, Chook P, Chan LL, Cheung AS, Fung WH, Qiao M, Lolin YI, Thomas GN, Sanderson JE, Metreweli C, Celermajer DS. Source: The American Journal of Medicine. 2002 May; 112(7): 535-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12015244&dopt=Abstract

Studies

89

•

Low rate of adequate folic acid supplementation in well-educated women of high socioeconomic status attending a genetics clinic. Author(s): Dawson LE, Pham B, Hunter AG. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2001 April 17; 164(8): 1149-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11338800&dopt=Abstract

•

Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Author(s): Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C, Williamson RE, Dufour DR. Source: The American Journal of Clinical Nutrition. 2003 June; 77(6): 1474-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791626&dopt=Abstract

•

Low vitamin B6 but not homocyst(e)ine is associated with increased risk of stroke and transient ischemic attack in the era of folic acid grain fortification. Author(s): Kelly PJ, Shih VE, Kistler JP, Barron M, Lee H, Mandell R, Furie KL. Source: Stroke; a Journal of Cerebral Circulation. 2003 June; 34(6): E51-4. Epub 2003 May 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738890&dopt=Abstract

•

Low-dose folic acid lowers plasma homocysteine levels in women of child-bearing age. Author(s): Daly S, Mills JL, Molloy AM, Conley M, McPartlin J, Lee YJ, Young PB, Kirke PN, Weir DG, Scott JM. Source: Qjm : Monthly Journal of the Association of Physicians. 2002 November; 95(11): 733-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12391385&dopt=Abstract

•

Low-Dose folic acid supplementation decreases plasma homocysteine concentrations: a randomised trial. Author(s): Brouwer IA, van Dusseldorp M, Thomas CMG, Duran M, Hautvast JGAJ, Eskes TKAB, Steegers-Theunissen RP. Source: Indian Heart J. 2000 November-December; 52(7 Suppl): S53-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11339442&dopt=Abstract

•

Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomized trial. Author(s): Brouwer IA, van Dusseldorp M, Thomas CM, Duran M, Hautvast JG, Eskes TK, Steegers-Theunissen RP. Source: The American Journal of Clinical Nutrition. 1999 January; 69(1): 99-104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9925130&dopt=Abstract

90

Folic Acid

•

Low-dose folic acid supplementation does not influence plasma methionine concentrations in young non-pregnant women. Author(s): Brouwer IA, van Dusseldorp M, Duran M, Thomas CM, Hautvast JG, Eskes TK, Steegers-Theunissen RP. Source: The British Journal of Nutrition. 1999 August; 82(2): 85-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10743479&dopt=Abstract

•

Low-dose folic acid supplementation reduces plasma levels of the cardiovascular risk factor homocysteine in postmenopausal women. Author(s): De Leo V, La Marca A, Morgante G, Ciani F, Zammarchi E, Setacci C. Source: American Journal of Obstetrics and Gynecology. 2000 October; 183(4): 945-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11035344&dopt=Abstract

•

Lowering plasma homocysteine with folic acid in cardiovascular disease: what will the trials tell us? Author(s): Doshi SN, Moat SJ, McDowell IF, Lewis MJ, Goodfellow J. Source: Atherosclerosis. 2002 November; 165(1): 1-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12208464&dopt=Abstract

•

Masked deficit of B(12) and folic acid in thalassemia. Author(s): Mazzone A, Vezzoli M, Ottini E. Source: American Journal of Hematology. 2001 August; 67(4): 274. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11443645&dopt=Abstract

•

Maternal knowledge, attitude and practice regarding folic acid intake during the periconceptional period. Author(s): Sen S, Manzoor A, Deviasumathy M, Newton C. Source: Public Health Nutrition. 2001 August; 4(4): 909-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11527515&dopt=Abstract

•

Methylenetetrahydrofolate reductase (MTHFR) 677C>T and methionine synthase reductase (MTRR) 66A>G polymorphisms: association with serum homocysteine and angiographic coronary artery disease in the era of flour products fortified with folic acid. Author(s): Brilakis ES, Berger PB, Ballman KV, Rozen R. Source: Atherosclerosis. 2003 June; 168(2): 315-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801615&dopt=Abstract

Studies

91

•

Methylenetetrahydrofolate reductase 677C-->T genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: a randomized controlled trial. Author(s): Ashfield-Watt PA, Pullin CH, Whiting JM, Clark ZE, Moat SJ, Newcombe RG, Burr ML, Lewis MJ, Powers HJ, McDowell IF. Source: The American Journal of Clinical Nutrition. 2002 July; 76(1): 180-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12081832&dopt=Abstract

•

Methylenetetrahydrofolate reductase C677T polymorphism does not alter folic acid deficiency-induced uracil incorporation into primary human lymphocyte DNA in vitro. Author(s): Crott JW, Mashiyama ST, Ames BN, Fenech MF. Source: Carcinogenesis. 2001 July; 22(7): 1019-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11408344&dopt=Abstract

•

Micronuclei, nucleoplasmic bridges and nuclear buds induced in folic acid deficient human lymphocytes-evidence for breakage-fusion-bridge cycles in the cytokinesisblock micronucleus assay. Author(s): Fenech M, Crott JW. Source: Mutation Research. 2002 July 25; 504(1-2): 131-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12106653&dopt=Abstract

•

Minimum fully effective dose of folic acid for the prevention of neural tube defects. Author(s): Oakley GP Jr. Source: Epidemiology (Cambridge, Mass.). 2001 July; 12(4): 475. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11416789&dopt=Abstract

•

Miscarriage and use of multivitamins or folic acid. Author(s): Czeizel AE. Source: American Journal of Medical Genetics. 2001 November 22; 104(2): 179-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11746052&dopt=Abstract

•

Motherisk alert: Folic acid fortification of flour--three years later. Author(s): Kapur B, Koren G. Source: Can J Clin Pharmacol. 2001 Summer; 8(2): 91-2. English, French. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11493937&dopt=Abstract

•

Multicentric study of efficacy of periconceptional folic acid containing vitamin supplementation in prevention of open neural tube defects from India. Author(s): Central Technical Co-ordinating Unit, ICMRCentral Technical Co-ordinating Unit, ICMR. Source: The Indian Journal of Medical Research. 2000 December; 112: 206-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11247198&dopt=Abstract

92

Folic Acid

•

Neural tube defects among Mexican Americans living on the US-Mexico border: effects of folic acid and dietary folate. Author(s): Suarez L, Hendricks KA, Cooper SP, Sweeney AM, Hardy RJ, Larsen RD. Source: American Journal of Epidemiology. 2000 December 1; 152(11): 1017-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11117610&dopt=Abstract

•

Neural tube defects and folic acid knowledge and use in Mississippi women. Author(s): Norman M, Penman A. Source: J Miss State Med Assoc. 2001 September; 42(9): 270-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11569130&dopt=Abstract

•

Neural tube defects and periconceptional folic acid in England and Wales: retrospective study. Author(s): Kadir RA, Sabin C, Whitlow B, Brockbank E, Economides D. Source: Bmj (Clinical Research Ed.). 1999 July 10; 319(7202): 92-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10398632&dopt=Abstract

•

Neural tube defects and periconceptional folic acid. Author(s): Kadir RA, Economides DL. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2002 August 6; 167(3): 255-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12186171&dopt=Abstract

•

Neural tube defects in relation to use of folic acid antagonists during pregnancy. Author(s): Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Source: American Journal of Epidemiology. 2001 May 15; 153(10): 961-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11384952&dopt=Abstract

•

New use for folic acid. Author(s): Hayden MR. Source: Mo Med. 2003 January-February; 100(1): 14-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12664703&dopt=Abstract

•

Nitration and chlorination of folic acid by peroxynitrite and hypochlorous acid, and the selective binding of 10-nitro-folate to folate receptor beta. Author(s): Nakamura M, Nagayoshi R, Ijiri K, Nakashima-Matsushita N, Takeuchi T, Matsuyama T. Source: Biochemical and Biophysical Research Communications. 2002 October 11; 297(5): 1238-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372420&dopt=Abstract

Studies

93

•

No change in impaired endothelial function after long-term folic acid therapy of hyperhomocysteinaemia in haemodialysis patients. Author(s): van Guldener C, Janssen MJ, Lambert J, ter Wee PM, Jakobs C, Donker AJ, Stehouwer CD. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 1998 January; 13(1): 106-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9481724&dopt=Abstract

•

Non-clinical delivery systems: an alternative approach for distribution of iron and folic acid tablets. Author(s): Ghaturvedi S, Chaturvedi S. Source: J Indian Med Assoc. 1997 April; 95(4): 118. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9357277&dopt=Abstract

•

Nutritional amblyopia. Folic acid, vitamin B-12, and other vitamins. Author(s): Knox DL, Chen MF, Guilarte TR, Dang CV, Burnette J. Source: Retina (Philadelphia, Pa.). 1982; 2(4): 288-93. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6101136&dopt=Abstract

•

On folic acid in pregnancy. Author(s): Berryman GH. Source: Gp. 1968 July; 38(1): 98-100. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5666475&dopt=Abstract

•

On folic acid metabolism in human normal leukocytes of peripheral blood. Author(s): Onicescu D, Stoica I, Popescu M. Source: Rev Roum Physiol. 1973; 10(2): 163-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4513657&dopt=Abstract

•

Optic neuropathy from folic acid deficiency without alcohol abuse. Author(s): Hsu CT, Miller NR, Wray ML. Source: Ophthalmologica. Journal International D'ophtalmologie. International Journal of Ophthalmology. Zeitschrift Fur Augenheilkunde. 2002 January-February; 216(1): 65-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11901292&dopt=Abstract

•

Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype. Author(s): Pullin CH, Ashfield-Watt PA, Burr ML, Clark ZE, Lewis MJ, Moat SJ, Newcombe RG, Powers HJ, Whiting JM, McDowell IF. Source: Journal of the American College of Cardiology. 2001 December; 38(7): 1799-805. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11738277&dopt=Abstract

94

Folic Acid

•

Optimization of folic acid, vitamin B(12), and vitamin B(6) supplements in pediatric patients with sickle cell disease. Author(s): van der Dijs FP, Fokkema MR, Dijck-Brouwer DA, Niessink B, van der Wal TI, Schnog JJ, Duits AJ, Muskiet FD, Muskiet FA. Source: American Journal of Hematology. 2002 April; 69(4): 239-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11921017&dopt=Abstract

•

Oral changes in a folic acid deficient patient precipitated by anticonvulsant drug therapy. Author(s): Stein GM, Lewis H. Source: J Periodontol. 1973 October; 44(10): 645-50. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4518014&dopt=Abstract

•

Oral folic acid improves endothelial dysfunction in cigarette smokers. Author(s): O'Grady HL, Leahy A, McCormick PH, Fitzgerald P, Kelly CK, BouchierHayes DJ. Source: The Journal of Surgical Research. 2002 August; 106(2): 342-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12175990&dopt=Abstract

•

Oral folic acid supplementation for cervical dysplasia: a clinical intervention trial. Author(s): Butterworth CE Jr, Hatch KD, Soong SJ, Cole P, Tamura T, Sauberlich HE, Borst M, Macaluso M, Baker V. Source: American Journal of Obstetrics and Gynecology. 1992 March; 166(3): 803-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1312773&dopt=Abstract

•

Oral folic acid versus placebo in the treatment of males with the fragile X syndrome. Author(s): Hagerman RJ, Jackson AW, Levitas A, Braden M, McBogg P, Kemper M, McGavran L, Berry R, Matus I, Hagerman PJ. Source: American Journal of Medical Genetics. 1986 January-February; 23(1-2): 241-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3513567&dopt=Abstract

•

Oral vitamin B(12) and high-dose folic acid in hemodialysis patients with hyperhomocyst(e)inemia. Author(s): Manns B, Hyndman E, Burgess E, Parsons H, Schaefer J, Snyder F, ScottDouglas N. Source: Kidney International. 2001 March; 59(3): 1103-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11231366&dopt=Abstract

•

Periconceptional use of folic acid supplements in Oslo. Author(s): Braekke K, Staff AC. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 July; 82(7): 620-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790843&dopt=Abstract

Studies

95

•

Peri-conceptual folic acid. Author(s): Daly L, Doyle S. Source: Ir Med J. 2002 October; 95(9): 280. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12470004&dopt=Abstract

•

Phase II study of pemetrexed with and without folic acid and vitamin B12 as frontline therapy in malignant pleural mesothelioma. Author(s): Scagliotti GV, Shin DM, Kindler HL, Vasconcelles MJ, Keppler U, Manegold C, Burris H, Gatzemeier U, Blatter J, Symanowski JT, Rusthoven JJ. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 April 15; 21(8): 1556-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12697881&dopt=Abstract

•

Pregnancy intendedness and the use of periconceptional folic acid. Author(s): Rosenberg KD, Gelow JM, Sandoval AP. Source: Pediatrics. 2003 May; 111(5 Part 2): 1142-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12728127&dopt=Abstract

•

Pregnancy planning and folic acid supplement use: results from a survey in Quebec. Author(s): Morin P, De Wals P, Noiseux M, Niyonsenga T, St-Cyr-Tribble D, Tremblay C. Source: Preventive Medicine. 2002 August; 35(2): 143-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12200099&dopt=Abstract

•

Pregnancy planning: a determinant of folic acid supplements use for the primary prevention of neural tube defects. Author(s): Morin P, De Wals P, St-Cyr-Tribble D, Niyonsenga T, Payette H. Source: Canadian Journal of Public Health. Revue Canadienne De Sante Publique. 2002 July-August; 93(4): 259-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12154526&dopt=Abstract

•

Pregnancy tests and folic acid. Author(s): Alto WA, Czarnecki DF. Source: J Reprod Med. 2002 September; 47(9): 776. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12380461&dopt=Abstract

•

Prevalence of micronutrient deficiency particularly of iron, zinc and folic acid in pregnant women in South East Asia. Author(s): Seshadri S. Source: The British Journal of Nutrition. 2001 May; 85 Suppl 2: S87-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11509095&dopt=Abstract

96

Folic Acid

•

Preventing birth defects with folic acid. Author(s): Stein Q, Keppen L, Watson WJ. Source: S D J Med. 2002 September; 55(9): 389-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12360641&dopt=Abstract

•

Provide the citizens of New Zealand the miracle of folic acid fortification. Author(s): Oakley G, Wald N, Omenn G. Source: N Z Med J. 2003 January 24; 116(1168): U302. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12601425&dopt=Abstract

•

Quantifying the effect of folic acid. Author(s): Wald NJ, Law MR, Morris JK, Wald DS. Source: Lancet. 2001 December 15; 358(9298): 2069-73. Review. Erratum In: Lancet 2002 February 16; 359(9306): 630. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11755633&dopt=Abstract

•

Quantitation of folic acid enhancement of antifolate synergism. Author(s): Gaumont Y, Kisliuk RL, Parsons JC, Greco WR. Source: Cancer Research. 1992 April 15; 52(8): 2228-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1532766&dopt=Abstract

•

Quantitative responses of serum folate to increasing intakes of folic acid in healthy women. Author(s): Truswell AS, Kounnavong S. Source: European Journal of Clinical Nutrition. 1997 December; 51(12): 839-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9426359&dopt=Abstract

•

Radioisotopic determination of cerebrospinal fluid (CSF) folic acid and vitamin B12 in neurological disorders. Author(s): Papageorgiou C, Mavrikakis M, Kesse-Elias M, Anastasiou-Nana M, Germanides J. Source: Experientia. 1983 April 15; 39(4): 432-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6832334&dopt=Abstract

•

Recurrent cleft lip and palate in siblings of a patient with malabsorption syndrome, probably caused by hypovitaminosis a associated with folic acid and vitamin B(2) deficiencies. Author(s): Faron G, Drouin R, Pedneault L, Poulin LD, Laframboise R, Garrido-Russo M, Fraser WD. Source: Teratology. 2001 March; 63(3): 161-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11283973&dopt=Abstract

Studies

97

•

Reduction of plasma homocysteine by folic acid in children with chronic renal failure. Author(s): Kang HG, Lee BS, Hahn H, Lee JH, Ha IS, Cheong HI, Choi Y. Source: Pediatric Nephrology (Berlin, Germany). 2002 July; 17(7): 511-4. Epub 2002 May 29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12172764&dopt=Abstract

•

Reduction of total homocysteine levels by oral folic acid fails to improve endothelial function in children with chronic renal failure. Author(s): Chan NN, Chan WB, Chan JC. Source: Circulation. 2003 January 7; 107(1): E6-7; Author Reply E6-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12515761&dopt=Abstract

•

Reference values for serum levels of vitamin B12 and folic acid in a population-based sample of adults between 35 and 80 years of age. Author(s): Wahlin A, Backman L, Hultdin J, Adolfsson R, Nilsson LG. Source: Public Health Nutrition. 2002 June; 5(3): 505-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12003664&dopt=Abstract

•

Relation of Helicobacter pylori infection to plasma vitamin B12, folic acid, and homocysteine levels in patients who underwent diagnostic coronary arteriography. Author(s): Tamura A, Fujioka T, Nasu M. Source: The American Journal of Gastroenterology. 2002 April; 97(4): 861-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12003420&dopt=Abstract

•

Relationship between plasma homocysteine and vitamin status in the Framingham study population. Impact of folic acid fortification. Author(s): Selhub J, Jacques PF, Bostom AG, Wilson PW, Rosenberg IH. Source: Public Health Rev. 2000; 28(1-4): 117-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11411265&dopt=Abstract

•

Relationship of plasma folic acid and status of DNA methylation in human gastric cancer. Author(s): Fang JY, Xiao SD, Zhu SS, Yuan JM, Qiu DK, Jiang SJ. Source: Journal of Gastroenterology. 1997 April; 32(2): 171-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9085163&dopt=Abstract

•

Renal insufficiency, vitamin B(12) status, and population attributable risk for mild hyperhomocysteinemia among coronary artery disease patients in the era of folic acid-fortified cereal grain flour. Author(s): Liaugaudas G, Jacques PF, Selhub J, Rosenberg IH, Bostom AG. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2001 May; 21(5): 849-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11348885&dopt=Abstract

98

Folic Acid

•

Risk of gestational hypertension in relation to folic acid supplementation during pregnancy. Author(s): Hernandez-Diaz S, Werler MM, Louik C, Mitchell AA. Source: American Journal of Epidemiology. 2002 November 1; 156(9): 806-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12396998&dopt=Abstract

•

Secondary prevention with folic acid: effects on clinical outcomes. Author(s): Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Source: Journal of the American College of Cardiology. 2003 June 18; 41(12): 2105-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821232&dopt=Abstract

•

Sequence-specific DNA damage induced by ultraviolet A-irradiated folic acid via its photolysis product. Author(s): Hirakawa K, Suzuki H, Oikawa S, Kawanishi S. Source: Archives of Biochemistry and Biophysics. 2003 February 15; 410(2): 261-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573286&dopt=Abstract

•

Serum folic acid levels and antipyrine clearance rates in smokers and non-smokers. Author(s): Nakazawa Y, Chiba K, Imatoh N, Kotorii T, Sakamoto T, Ishizaki T. Source: Drug and Alcohol Dependence. 1983 April; 11(2): 201-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6861617&dopt=Abstract

•

Serum homocysteine, B12 and folic acid concentration in Thai overweight and obese subjects. Author(s): Tungtrongchitr R, Pongpaew P, Tongboonchoo C, Vudhivai N, Changbumrung S, Tungtrongchitr A, Phonrat B, Viroonudomphol D, Pooudong S, Schelp FP. Source: Int J Vitam Nutr Res. 2003 February; 73(1): 8-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12690905&dopt=Abstract

•

Serum iron, ferritin, folic acid, and vitamin B12 levels in recurrent aphthous stomatitis. Author(s): Piskin S, Sayan C, Durukan N, Senol M. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 2002 January; 16(1): 66-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11952294&dopt=Abstract

•

Serum lipids, vitamin B12 and folic acid levels in children receiving long-term valproate therapy. Author(s): Geda G, Caksen H, Icagasioglu D. Source: Acta Neurol Belg. 2002 September; 102(3): 122-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12400250&dopt=Abstract

Studies

99

•

Short-term folic acid supplementation induces variable and paradoxical changes in plasma homocyst(e)ine concentrations. Author(s): Malinow MR, Duell PB, Williams MA, Kruger WD, Evans AA, Anderson PH, Block PC, Hess DL, Upson BM, Graf EE, Irvin-Jones A, Wang L. Source: Lipids. 2001; 36 Suppl: S27-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11837988&dopt=Abstract

•

Study of wheat breakfast rolls fortified with folic acid. The effect on folate status in women during a 3-month intervention. Author(s): Johansson M, Witthoft CM, Bruce A, Jagerstad M. Source: European Journal of Nutrition. 2002 December; 41(6): 279-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474072&dopt=Abstract

•

Sunlight, skin color, and folic acid. Author(s): Cohn BA. Source: Journal of the American Academy of Dermatology. 2002 February; 46(2): 317-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11807450&dopt=Abstract

•

Synthesis and evaluation of taxol-folic acid conjugates as targeted antineoplastics. Author(s): Lee JW, Lu JY, Low PS, Fuchs PL. Source: Bioorganic & Medicinal Chemistry. 2002 July; 10(7): 2397-414. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11983537&dopt=Abstract

•

The Chilean flour folic acid fortification program reduces serum homocysteine levels and masks vitamin B-12 deficiency in elderly people. Author(s): Hirsch S, de la Maza P, Barrera G, Gattas V, Petermann M, Bunout D. Source: The Journal of Nutrition. 2002 February; 132(2): 289-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11823592&dopt=Abstract

•

The effect of folic acid deficiency and MTHFR C677T polymorphism on chromosome damage in human lymphocytes in vitro. Author(s): Crott JW, Mashiyama ST, Ames BN, Fenech M. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2001 October; 10(10): 1089-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11588136&dopt=Abstract

100 Folic Acid

•

The effect of folic acid on the development of stomach and other gastrointestinal cancers. Author(s): Zhu S, Mason J, Shi Y, Hu Y, Li R, Wahg M, Zhou Y, Jin G, Xie Y, Wu G, Xia D, Qian Z, Sohg H, Zhang L, Russell R, Xiao S. Source: Chinese Medical Journal. 2003 January; 116(1): 15-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667380&dopt=Abstract

•

The effect of high doses of folic acid on the overexpression of ornithine decarboxylase and S-adenosylmethionine content in human colon adenomatous polyps. Author(s): Bukin YUV, Draudin-Krylenko VA, Levchuk AA, Poddubniy BK, Mazurov ST. Source: Annals of the New York Academy of Sciences. 2001 December; 952: 175-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11795438&dopt=Abstract

•

The effect of long-term intravenous high dose B-complex vitamins with or without folic acid on serum homocysteine in hemodialysis patients. Author(s): Sombolos K, Fragia T, Natse T, Bartholomatos G, Karagianni A, Katsaris G, Christidou F, Bamichas G, Stangou M, Papagalanis N. Source: Journal of Nephrology. 2002 November-December; 15(6): 671-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495282&dopt=Abstract

•

The impact of food fortification on folic acid intake in Canada. Author(s): Quinlivan EP, Gregory JF 3rd. Source: Canadian Journal of Public Health. Revue Canadienne De Sante Publique. 2003 March-April; 94(2): 154. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12675175&dopt=Abstract

•

The prevention of congenital anomalies with periconceptional folic acid supplementation. Author(s): McDonald SD, Ferguson S, Tam L, Lougheed J, Walker MC. Source: J Obstet Gynaecol Can. 2003 February; 25(2): 115-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12577128&dopt=Abstract

•

The role of folic acid and vitamin B12 in colorectal carcinogenesis in genetically different individuals--design of a study. Author(s): Van den Donk M, Pellis EP, Keijer J, Kok FJ, Nagengast FM, Kampman E. Source: Iarc Sci Publ. 2002; 156: 499-500. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12484242&dopt=Abstract

Studies

101

•

The unnecessary epidemic of folic acid-preventable spina bifida and anencephaly. Author(s): Campbell RK. Source: Pediatrics. 2001 October; 108(4): 1048-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11589212&dopt=Abstract

•

The use of willingness to pay to assess public preferences towards the fortification of foodstuffs with folic acid. Author(s): Dixon S, Shackley P. Source: Health Expectations : an International Journal of Public Participation in Health Care and Health Policy. 2003 June; 6(2): 140-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12752742&dopt=Abstract

•

Unmetabolized folic acid and masking of cobalamin deficiency. Author(s): Markle HV. Source: The American Journal of Clinical Nutrition. 1997 December; 66(6): 1480-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9394705&dopt=Abstract

•

Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Author(s): Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Source: The American Journal of Clinical Nutrition. 1997 June; 65(6): 1790-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9174474&dopt=Abstract

•

Unpredictable intra-individual variations in serum homocysteine levels on folic acid supplementation. Author(s): Santhosh-Kumar CR, Deutsch JC, Ryder JW, Kolhouse JF. Source: European Journal of Clinical Nutrition. 1997 March; 51(3): 188-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9076410&dopt=Abstract

•

Urgent need to increase folic acid consumption. Author(s): Oakley GP Jr, Erickson JD, Adams MJ Jr. Source: Jama : the Journal of the American Medical Association. 1995 December 6; 274(21): 1717-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7474279&dopt=Abstract

•

US fills food with folic acid. Author(s): Charatan FB. Source: Bmj (Clinical Research Ed.). 1996 March 9; 312(7031): 599. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8595329&dopt=Abstract

102 Folic Acid

•

Use of an oral/intravenous dual-label stable-isotope protocol to determine folic acid bioavailability from fortified cereal grain foods in women. Author(s): Finglas PM, Witthoft CM, Vahteristo L, Wright AJ, Southon S, Mellon FA, Ridge B, Maunder P. Source: The Journal of Nutrition. 2002 May; 132(5): 936-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11983817&dopt=Abstract

•

Use of folic acid and delivery outcome: a prospective registry study. Author(s): Kallen BA, Olausson PO. Source: Reproductive Toxicology (Elmsford, N.Y.). 2002 July-August; 16(4): 327-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12220592&dopt=Abstract

•

Use of folic acid supplements in the first trimester of pregnancy. Author(s): Langley-Evans SC, Langley-Evans AJ. Source: J R Soc Health. 2002 September; 122(3): 181-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12391833&dopt=Abstract

•

Use of folic acid-fortified milk in the elderly population. Author(s): Keane EM, O'Broin S, Kelleher B, Coakley D, Walsh JB. Source: Gerontology. 1998; 44(6): 336-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9813433&dopt=Abstract

•

Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Author(s): Ericson A, Kallen B, Aberg A. Source: Twin Research : the Official Journal of the International Society for Twin Studies. 2001 April; 4(2): 63-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11665336&dopt=Abstract

•

Validation of homocyst(e)ine-lowering treatment in the era of folic acid fortification of cereal grains. Author(s): Malinow MR, Toole JF. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2002 June 1; 22(6): 1051; Author Reply 1051. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12067920&dopt=Abstract

•

Vascular and blood pressure effects of folic acid in older patients with cardiovascular disease. Author(s): Mangoni AA, Ouldred E, Swif CG, Jackson SH, Draper RP, Sherwood RA, Lambert-Hammill M, Wierzbicki AS. Source: Journal of the American Geriatrics Society. 2001 July; 49(7): 1003-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11527499&dopt=Abstract

Studies

103

•

Vitamin B12 and folic acid in children with intestinal parasitic infection. Author(s): Olivares JL, Fernandez R, Fleta J, Ruiz MY, Clavel A. Source: Journal of the American College of Nutrition. 2002 April; 21(2): 109-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11999537&dopt=Abstract

•

Vitamin B12 and folic acid in Crohn's disease. Author(s): Elsborg L. Source: Dan Med Bull. 1982 December; 29(7): 362-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7151496&dopt=Abstract

•

Vitamin B12 and folic acid plasma levels after ileocecal and ileal neobladder reconstruction. Author(s): Racioppi M, D'Addessi A, Fanasca A, Mingrone G, Benedetti G, Capristo E, Maussier ML, Valenza V, Alcini A, Alcini E. Source: Urology. 1997 December; 50(6): 888-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9426719&dopt=Abstract

•

Vitamin B-12 and folic acid supplementation. Author(s): Herbert V. Source: The American Journal of Clinical Nutrition. 1997 December; 66(6): 1479-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9394704&dopt=Abstract

•

Vitamin B12 deficiency and the fortification of food with folic acid. Author(s): Bower C, Wald NJ. Source: European Journal of Clinical Nutrition. 1995 November; 49(11): 787-93. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8557017&dopt=Abstract

•

Vitamin B12, folic acid and haematological status in elderly Thais. Author(s): Prayurahong B, Tungtrongchitr R, Chanjanakijskul S, Lertchavanakul A, Supawan V, Pongpaew P, Vudhivai N, Hempfling AA, Schelp FP, Migasena P. Source: J Med Assoc Thai. 1993 February; 76(2): 71-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8228702&dopt=Abstract

•

Vitamin B12, folic acid and haematological status of 132 Thai vegetarians. Author(s): Tungtrongchitr R, Pongpaew P, Prayurahong B, Changbumrung S, Vudhivai N, Migasena P, Schelp FP. Source: Int J Vitam Nutr Res. 1993; 63(3): 201-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8300331&dopt=Abstract

104 Folic Acid

•

Vitamin B12, folic acid, ferritin and haemoglobin status of rural women in childbearing age in northeast Thailand. Author(s): Tungtrongchitr R, Pongpaew P, Schelp FP, Phonrat B, Mahaweerawat U, Paksanont S, Sanchaisuriya P, Jotking P, Intarakhao C, Saowakhontha S. Source: J Med Assoc Thai. 1997 December; 80(12): 785-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9470332&dopt=Abstract

•

Weekly high-dose folic Acid supplementation is effective in lowering serum homocysteine concentrations in women. Author(s): Adank C, Green TJ, Skeaff CM, Briars B. Source: Annals of Nutrition & Metabolism. 2003; 47(2): 55-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12652055&dopt=Abstract

•

Weekly lometrexol with daily oral folic acid is appropriate for phase II evaluation. Author(s): Roberts JD, Poplin EA, Tombes MB, Kyle B, Spicer DV, Grant S, Synold T, Moran R. Source: Cancer Chemotherapy and Pharmacology. 2000; 45(2): 103-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10663624&dopt=Abstract

•

Weekly vs daily iron and folic acid supplementation in adolescent Nepalese girls. Author(s): Shah BK, Gupta P. Source: Archives of Pediatrics & Adolescent Medicine. 2002 February; 156(2): 131-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11814373&dopt=Abstract

•

What practitioners need to know about folic acid. Author(s): Hine RJ. Source: Journal of the American Dietetic Association. 1996 May; 96(5): 451-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8621868&dopt=Abstract

•

What they don't know could hurt them: increasing public awareness of folic acid and neural tube defects. Author(s): Vozenilek GP. Source: Journal of the American Dietetic Association. 1999 January; 99(1): 20-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9917726&dopt=Abstract

•

Withdrawal of folic acid supplementation in maintenance hemodialysis patients. Author(s): Janssen MJ, van den Berg M, van Guldener C, Boers GH, Stehouwer CD. Source: Clinical Nephrology. 1994 August; 42(2): 136-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7955576&dopt=Abstract

Studies

105

•

Women need to take folic acid sooner rather than later. Author(s): Britton T. Source: Nurs Times. 1998 March 11-17; 94(10): 16. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9735762&dopt=Abstract

•

Xanthine oxidase and folic acid. Author(s): Plachetka J. Source: Annals of Internal Medicine. 1977 August; 87(2): 252-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=889218&dopt=Abstract

•

Zinc concentration in plasma and erythrocytes of subjects receiving folic acid supplementation. Author(s): Butterworth CE Jr, Hatch K, Cole P, Sauberlich HE, Tamura T, Cornwell PE, Soong SJ. Source: The American Journal of Clinical Nutrition. 1988 March; 47(3): 484-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3279748&dopt=Abstract

107

CHAPTER 2. NUTRITION AND FOLIC ACID Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and folic acid.

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

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

108 Folic Acid

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

FDA proposes folic acid fortification. Source: Williams, R.D. FDA-consumer (USA). (May 1994). volume 28(4) page 11-14.

•

Folic acid for fighting birth defects? Source: Tufts-University-diet-and-nutrition-letter (USA). (November 1992). volume 10(9) page 1-2.

Additional consumer oriented references include: •

A nationwide program for the use of preconceptional folic acid to prevent the development of open neural tube defects. Who is really using folic acid? Author(s): Department of Obstetrics and Gynecology, Medical Sciences Campus, University of Puerto Rico, PO Box 365067, San Juan, PR, USA. Source: de la Vega, A Salicrup, E Verdiales, M P-R-Health-Sci-J. 2002 March; 21(1): 7-9 0738-0658

•

Comparative evaluation of co-processed lactose and microcrystalline cellulose with their physical mixtures in the formulation of folic acid tablets. Author(s): Laboratory of Pharmacotechnology and Biopharmacy, Catholic University of Leuven, O&N Gasthuisberg, B-3000 Leuven, Belgium. [email protected] Source: Michoel, A Rombaut, P Verhoye, A Pharm-Dev-Technol. 2002 January; 7(1): 7987 1083-7450

•

Content of folic acid and free homocysteine in blood serum of human papillomavirus-infected women with cervical dysplasia. Author(s): Clinic of Obstetrics and Gynaecology, Lublin Medical Academy, Poland. Source: Kwasniewska, A Tukendorf, A Gozdzicka Jozefiak, A Semczuk Sikora, A Korobowicz, E Eur-J-Gynaecol-Oncol. 2002; 23(4): 311-6 0392-2936

•

Diverse chemotactic responses of Dictyostelium discoideum amoebae in the developing (temporal) and stationary (spatial) concentration gradients of folic acid, cAMP, Ca(2+) and Mg(2+). Author(s): Department of Cell Biology, The J. Zurzycki Institute of Molecular Biology and Biotechnology, Jagiellonian University, Krakow, Poland. [email protected] Source: Korohoda, W Madeja, Z Sroka, J Cell-Motil-Cytoskeleton. 2002 September; 53(1): 1-25 0886-1544

•

Dose-dependent effects of folic acid on plasma homocysteine in a randomized trial conducted among 723 individuals with coronary heart disease. Source: Neal, B MacMahon, S Ohkubo, T Tonkin, A Wilcken, D Eur-Heart-J. 2002 October; 23(19): 1509-15 0195-668X

•

Estimated folic acid intakes from simulated fortification of the New Zealand food supply. Author(s): Department of Human Nutrition, University of Otago, Dunedin. Source: Green, T Newton, R Bourn, D N-Z-Med-J. 2003 January 24; 116(1168): U294 11758716

•

Folic acid and vitamin B(12) supplementation attenuates isoprenaline-induced myocardial infarction in experimental hyperhomocysteinemic rats. Author(s): Department of Pharmacology, College of Medicine & KHUH, King Saud University, PO Box 2925, Riyadh 11461, Saudi Arabia. [email protected]

Nutrition

109

Source: Hagar, H H Pharmacol-Res. 2002 September; 46(3): 213-19 1043-6618 •

Folic acid campaign and evaluation--southwestern Virginia, 1997-1999. Source: Anonymous MMWR-Morb-Mortal-Wkly-Repage 1999 October 15; 48(40): 914-7 0149-2195

•

Folic acid prevents exencephaly in Cited2 deficient mice. Author(s): MRC Centre for Developmental Neurobiology, 4th floor New Hunt's House, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK. [email protected] Source: Barbera, J P Rodriguez, T A Greene, N D Weninger, W J Simeone, A Copp, A J Beddington, R S Dunwoodie, S Hum-Mol-Genet. 2002 February 1; 11(3): 283-93 09646906

•

Folic acid, ascorbic acid and sodium selenite restore the motility of Dictyostelium discoideum inhibited by triethyllead. Author(s): Department of Cell Biology, The J. Zurzycki Institute of Molecular Biology and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland. [email protected] Source: Sroka, J Madeja, Z Michalik, M Przestalski, S Korohoda, W Toxicology. 2002 December 2; 180(3): 275-92 0300-483X

•

Low-dose folic acid lowers plasma homocysteine levels in women of child-bearing age. Author(s): Coombe Womens Hospital, Dublin, Ireland. Source: Daly, S Mills, J L Molloy, A M Conley, M McPartlin, J Lee, Y J Young, P B Kirke, P N Weir, D G Scott, J M QJM. 2002 November; 95(11): 733-40 1460-2725

•

Physiology of folic acid in health and disease. Author(s): Karl-Franzens University School of Medicine, Department of Surgery, Graz, Austria. [email protected] Source: Stanger, O Curr-Drug-Metab. 2002 April; 3(2): 211-23 1389-2002

•

Preventing birth defects with folic acid. Source: Stein, Q Keppen, L Watson, W J S-D-J-Med. 2002 September; 55(9): 389-91 00383317

•

Provide the citizens of New Zealand the miracle of folic acid fortification. Author(s): Department of Epidemiology, Rollins School of Public Health of Emory University, Atlanta, Georgia 30322, USA. [email protected] Source: Oakley, G Wald, N Omenn, G N-Z-Med-J. 2003 January 24; 116(1168): U302 1175-8716

•

Reduction of plasma homocysteine by folic acid in children with chronic renal failure. Author(s): Department of Pediatrics, Seoul National University Medical School, Clinical Research Institute, Seoul National University Hospital, Korea. Source: Kang, H G Lee, B S Hahn, H Lee, J H Ha, I S Cheong, H I Choi, Y PediatrNephrol. 2002 July; 17(7): 511-4 0931-041X

•

Serum lipids, vitamin B12 and folic acid levels in children receiving long-term valproate therapy. Author(s): Ankara University Faculty of Medicine, Ankara, Turkey. Source: Geda, G Caksen, H Icagasioglu, D Acta-Neurol-Belg. 2002 September; 102(3): 122-6 0300-9009

110 Folic Acid

•

Synthesis and in vitro antitumor activity of thiophene analogues of 5-chloro-5,8dideazafolic acid and 2-methyl-2-desamino-5-chloro-5,8-dideazafolic acid. Author(s): Dana-Farber Cancer Institute and the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Source: Forsch, R A Wright, J E Rosowsky, A Bioorg-Med-Chem. 2002 June; 10(6): 206776 0968-0896

•

The effect of long-term intravenous high dose B-complex vitamins with or without folic acid on serum homocysteine in hemodialysis patients. Author(s): Renal Unit, G. Papanikolaou General Hospital, Thessaloniki, Greece. [email protected] Source: Sombolos, K Fragia, T Natse, T Bartholomatos, G Karagianni, A Katsaris, G Christidou, F Bamichas, G Stangou, M Papagalanis, N J-Nephrol. 2002 Nov-December; 15(6): 671-5 1120-3625

•

The folic acid biosynthesis pathway in bacteria: evaluation of potential for antibacterial drug discovery. Author(s): Department of Biomolecular Sciences, UMIST, Manchester, UK. Source: Bermingham, A Derrick, J P Bioessays. 2002 July; 24(7): 637-48 0265-9247

•

The prevention of congenital anomalies with periconceptional folic acid supplementation. Author(s): Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada. Source: McDonald, S D Ferguson, S Tam, L Lougheed, J Walker, M C J-Obstet-GynaecolCan. 2003 February; 25(2): 115-21 1701-2163

•

Trends in neural tube defect prevalence, folic acid fortification, and vitamin supplement use. Author(s): National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA 30341-3724, USA. [email protected] Source: Olney, R S Mulinare, J Semin-Perinatol. 2002 August; 26(4): 277-85 0146-0005

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

A nationwide program for the use of preconceptional folic acid to prevent the development of open neural tube defects. Who is really using folic acid? Author(s): Department of Obstetrics and Gynecology, Medical Sciences Campus, University of Puerto Rico, PO Box 365067, San Juan, PR, USA. Source: de la Vega, A Salicrup, E Verdiales, M P-R-Health-Sci-J. 2002 March; 21(1): 7-9 0738-0658

•

Comparative evaluation of co-processed lactose and microcrystalline cellulose with their physical mixtures in the formulation of folic acid tablets. Author(s): Laboratory of Pharmacotechnology and Biopharmacy, Catholic University of Leuven, O&N Gasthuisberg, B-3000 Leuven, Belgium. [email protected] Source: Michoel, A Rombaut, P Verhoye, A Pharm-Dev-Technol. 2002 January; 7(1): 7987 1083-7450

•

Content of folic acid and free homocysteine in blood serum of human papillomavirus-infected women with cervical dysplasia. Author(s): Clinic of Obstetrics and Gynaecology, Lublin Medical Academy, Poland.

Nutrition

111

Source: Kwasniewska, A Tukendorf, A Gozdzicka Jozefiak, A Semczuk Sikora, A Korobowicz, E Eur-J-Gynaecol-Oncol. 2002; 23(4): 311-6 0392-2936 •

Diverse chemotactic responses of Dictyostelium discoideum amoebae in the developing (temporal) and stationary (spatial) concentration gradients of folic acid, cAMP, Ca(2+) and Mg(2+). Author(s): Department of Cell Biology, The J. Zurzycki Institute of Molecular Biology and Biotechnology, Jagiellonian University, Krakow, Poland. [email protected] Source: Korohoda, W Madeja, Z Sroka, J Cell-Motil-Cytoskeleton. 2002 September; 53(1): 1-25 0886-1544

•

Dose-dependent effects of folic acid on plasma homocysteine in a randomized trial conducted among 723 individuals with coronary heart disease. Source: Neal, B MacMahon, S Ohkubo, T Tonkin, A Wilcken, D Eur-Heart-J. 2002 October; 23(19): 1509-15 0195-668X

•

Estimated folic acid intakes from simulated fortification of the New Zealand food supply. Author(s): Department of Human Nutrition, University of Otago, Dunedin. Source: Green, T Newton, R Bourn, D N-Z-Med-J. 2003 January 24; 116(1168): U294 11758716

•

Folic acid and vitamin B(12) supplementation attenuates isoprenaline-induced myocardial infarction in experimental hyperhomocysteinemic rats. Author(s): Department of Pharmacology, College of Medicine & KHUH, King Saud University, PO Box 2925, Riyadh 11461, Saudi Arabia. [email protected] Source: Hagar, H H Pharmacol-Res. 2002 September; 46(3): 213-19 1043-6618

•

Folic acid campaign and evaluation--southwestern Virginia, 1997-1999. Source: Anonymous MMWR-Morb-Mortal-Wkly-Repage 1999 October 15; 48(40): 914-7 0149-2195

•

Folic acid prevents exencephaly in Cited2 deficient mice. Author(s): MRC Centre for Developmental Neurobiology, 4th floor New Hunt's House, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK. [email protected] Source: Barbera, J P Rodriguez, T A Greene, N D Weninger, W J Simeone, A Copp, A J Beddington, R S Dunwoodie, S Hum-Mol-Genet. 2002 February 1; 11(3): 283-93 09646906

•

Folic acid, ascorbic acid and sodium selenite restore the motility of Dictyostelium discoideum inhibited by triethyllead. Author(s): Department of Cell Biology, The J. Zurzycki Institute of Molecular Biology and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland. [email protected] Source: Sroka, J Madeja, Z Michalik, M Przestalski, S Korohoda, W Toxicology. 2002 December 2; 180(3): 275-92 0300-483X

•

Low-dose folic acid lowers plasma homocysteine levels in women of child-bearing age. Author(s): Coombe Womens Hospital, Dublin, Ireland. Source: Daly, S Mills, J L Molloy, A M Conley, M McPartlin, J Lee, Y J Young, P B Kirke, P N Weir, D G Scott, J M QJM. 2002 November; 95(11): 733-40 1460-2725

•

Physiology of folic acid in health and disease. Author(s): Karl-Franzens University School of Medicine, Department of Surgery, Graz, Austria. [email protected]

112 Folic Acid

Source: Stanger, O Curr-Drug-Metab. 2002 April; 3(2): 211-23 1389-2002 •

Preventing birth defects with folic acid. Source: Stein, Q Keppen, L Watson, W J S-D-J-Med. 2002 September; 55(9): 389-91 00383317

•

Provide the citizens of New Zealand the miracle of folic acid fortification. Author(s): Department of Epidemiology, Rollins School of Public Health of Emory University, Atlanta, Georgia 30322, USA. [email protected] Source: Oakley, G Wald, N Omenn, G N-Z-Med-J. 2003 January 24; 116(1168): U302 1175-8716

•

Reduction of plasma homocysteine by folic acid in children with chronic renal failure. Author(s): Department of Pediatrics, Seoul National University Medical School, Clinical Research Institute, Seoul National University Hospital, Korea. Source: Kang, H G Lee, B S Hahn, H Lee, J H Ha, I S Cheong, H I Choi, Y PediatrNephrol. 2002 July; 17(7): 511-4 0931-041X

•

Serum lipids, vitamin B12 and folic acid levels in children receiving long-term valproate therapy. Author(s): Ankara University Faculty of Medicine, Ankara, Turkey. Source: Geda, G Caksen, H Icagasioglu, D Acta-Neurol-Belg. 2002 September; 102(3): 122-6 0300-9009

•

Synthesis and in vitro antitumor activity of thiophene analogues of 5-chloro-5,8dideazafolic acid and 2-methyl-2-desamino-5-chloro-5,8-dideazafolic acid. Author(s): Dana-Farber Cancer Institute and the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Source: Forsch, R A Wright, J E Rosowsky, A Bioorg-Med-Chem. 2002 June; 10(6): 206776 0968-0896

•

The effect of long-term intravenous high dose B-complex vitamins with or without folic acid on serum homocysteine in hemodialysis patients. Author(s): Renal Unit, G. Papanikolaou General Hospital, Thessaloniki, Greece. [email protected] Source: Sombolos, K Fragia, T Natse, T Bartholomatos, G Karagianni, A Katsaris, G Christidou, F Bamichas, G Stangou, M Papagalanis, N J-Nephrol. 2002 Nov-December; 15(6): 671-5 1120-3625

•

The folic acid biosynthesis pathway in bacteria: evaluation of potential for antibacterial drug discovery. Author(s): Department of Biomolecular Sciences, UMIST, Manchester, UK. Source: Bermingham, A Derrick, J P Bioessays. 2002 July; 24(7): 637-48 0265-9247

•

The prevention of congenital anomalies with periconceptional folic acid supplementation. Author(s): Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada. Source: McDonald, S D Ferguson, S Tam, L Lougheed, J Walker, M C J-Obstet-GynaecolCan. 2003 February; 25(2): 115-21 1701-2163

•

Trends in neural tube defect prevalence, folic acid fortification, and vitamin supplement use. Author(s): National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA 30341-3724, USA. [email protected] Source: Olney, R S Mulinare, J Semin-Perinatol. 2002 August; 26(4): 277-85 0146-0005

Nutrition

113

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

•

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

•

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

•

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

•

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/

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

114 Folic Acid

The following is a specific Web list relating to folic acid; 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 Folic Acid Source: Healthnotes, Inc.; www.healthnotes.com Folic Acid Alternative names: Vitamin B9 (Folic Acid) Source: Integrative Medicine Communications; www.drkoop.com Folic Acid Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,887,00.html Folic Acid/Vitamin B Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,936,00.html Vitamin B Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10067,00.html Vitamin B Complex Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,962,00.html Vitamin B12 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B12 (Cobalamin) Source: Integrative Medicine Communications; www.drkoop.com Vitamin B2 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B6 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B9 (Folic Acid) Alternative names: Folate Source: Integrative Medicine Communications; www.drkoop.com Vitamin B-Complex Source: Healthnotes, Inc.; www.healthnotes.com

Nutrition

•

Minerals Betaine Hydrochloride Source: Healthnotes, Inc.; www.healthnotes.com Biotin Source: Healthnotes, Inc.; www.healthnotes.com Fluoxetine Source: Healthnotes, Inc.; www.healthnotes.com Folate Alternative names: Vitamin B9 (Folic Acid) Source: Integrative Medicine Communications; www.drkoop.com Folate Source: Prima Communications, Inc.www.personalhealthzone.com Gabapentin Source: Healthnotes, Inc.; www.healthnotes.com Magnesium Hydroxide Source: Healthnotes, Inc.; www.healthnotes.com Potassium-sparing Diuretics Source: Integrative Medicine Communications; www.drkoop.com Sodium Bicarbonate Source: Healthnotes, Inc.; www.healthnotes.com Spironolactone Source: Healthnotes, Inc.; www.healthnotes.com Zinc Source: Healthnotes, Inc.; www.healthnotes.com Zinc Source: Prima Communications, Inc.www.personalhealthzone.com

•

Food and Diet Artichoke Source: Healthnotes, Inc.; www.healthnotes.com Arugula Source: Healthnotes, Inc.; www.healthnotes.com Arugula Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com

115

116 Folic Acid

Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,123,00.html Asparagus Source: Healthnotes, Inc.; www.healthnotes.com Asparagus Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,7,00.html Atkins Diet Source: Healthnotes, Inc.; www.healthnotes.com Avocado Source: Healthnotes, Inc.; www.healthnotes.com Avocados Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,46,00.html Bananas Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,47,00.html Beet Greens Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,309,00.html Beets Source: Healthnotes, Inc.; www.healthnotes.com Beets Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,10,00.html Bibb Lettuce Source: Healthnotes, Inc.; www.healthnotes.com Bok Choy Source: Healthnotes, Inc.; www.healthnotes.com Bok Choy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,148,00.html Broccoflower Source: Healthnotes, Inc.; www.healthnotes.com

Nutrition

Broccoli Source: Healthnotes, Inc.; www.healthnotes.com Broccoli Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,11,00.html 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 Cardoon Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,239,00.html Carrots Source: Healthnotes, Inc.; www.healthnotes.com Cauliflower Source: Healthnotes, Inc.; www.healthnotes.com Chickpeas Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,106,00.html Chicory Source: Healthnotes, Inc.; www.healthnotes.com Collard Greens Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,152,00.html Collards Source: Healthnotes, Inc.; www.healthnotes.com Dandelion Greens Source: Healthnotes, Inc.; www.healthnotes.com Endive Source: Healthnotes, Inc.; www.healthnotes.com

117

118 Folic Acid

Jerusalem Artichoke Source: Healthnotes, Inc.; www.healthnotes.com Jicama Source: Healthnotes, Inc.; www.healthnotes.com Kale Source: Healthnotes, Inc.; www.healthnotes.com Kohlrabi Source: Healthnotes, Inc.; www.healthnotes.com Leeks Source: Healthnotes, Inc.; www.healthnotes.com Lentils Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,99,00.html Lettuce & Other Salad Greens Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,196,00.html Mustard Greens Source: Healthnotes, Inc.; www.healthnotes.com Napa Cabbage Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,187,00.html Nuts Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,84,00.html Oats Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,73,00.html Okra Source: Healthnotes, Inc.; www.healthnotes.com Okra Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,26,00.html

Nutrition

Onions Source: Healthnotes, Inc.; www.healthnotes.com Oranges Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,59,00.html Papaya Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,60,00.html Parsnips Source: Healthnotes, Inc.; www.healthnotes.com Peanuts Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,110,00.html Quinoa Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,74,00.html Radishes Source: Healthnotes, Inc.; www.healthnotes.com Romaine Lettuce Source: Healthnotes, Inc.; www.healthnotes.com Rutabagas Source: Healthnotes, Inc.; www.healthnotes.com Snow Peas Source: Healthnotes, Inc.; www.healthnotes.com Soybeans Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,105,00.html 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

119

120 Folic Acid

Summer Squash Source: Healthnotes, Inc.; www.healthnotes.com Sunflower Seeds Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,158,00.html Sweet Peppers Source: Healthnotes, Inc.; www.healthnotes.com Sweet Potatoes Source: Healthnotes, Inc.; www.healthnotes.com The Zone Diet Source: Healthnotes, Inc.; www.healthnotes.com Tomatoes Source: Healthnotes, Inc.; www.healthnotes.com Triticale Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,77,00.html Turnips Source: Healthnotes, Inc.; www.healthnotes.com Wild Rice Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,178,00.html Winter Squash Source: Healthnotes, Inc.; www.healthnotes.com Yams Source: Healthnotes, Inc.; www.healthnotes.com Zucchini Source: Healthnotes, Inc.; www.healthnotes.com

121

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

5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women. Author(s): Fohr IP, Prinz-Langenohl R, Bronstrup A, Bohlmann AM, Nau H, Berthold HK, Pietrzik K. Source: The American Journal of Clinical Nutrition. 2002 February; 75(2): 275-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11815318&dopt=Abstract

•

Amelioration of sodium valproate-induced neural tube defects in mouse fetuses by maternal folic acid supplementation during gestation. Author(s): Padmanabhan R, Shafiullah MM. Source: Congenit Anom Kyoto. 2003 March; 43(1): 29-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12692401&dopt=Abstract

122 Folic Acid

•

Assessment of student pharmacists' knowledge concerning folic acid and prevention of birth defects demonstrates a need for further education. Author(s): Lynch SM. Source: The Journal of Nutrition. 2002 March; 132(3): 439-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11880568&dopt=Abstract

•

Benefit of folic acid supplementation in parkinsonian patients treated with levodopa. Author(s): Muller T, Woitalla D, Kuhn W. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 April; 74(4): 549. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640094&dopt=Abstract

•

Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation. Author(s): Yerby MS. Source: Epilepsia. 2003; 44 Suppl 3: 33-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790884&dopt=Abstract

•

Commercially available folic acid supplements and their compliance with the British Pharmacopoeia test for dissolution. Author(s): Sculthorpe NF, Davies B, Ashton T, Allison S, McGuire DN, Malhi JS. Source: Journal of Public Health Medicine. 2001 September; 23(3): 195-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11585191&dopt=Abstract

•

Comparison of the effect of low-dose supplementation with L-5methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebocontrolled study. Author(s): Venn BJ, Green TJ, Moser R, Mann JI. Source: The American Journal of Clinical Nutrition. 2003 March; 77(3): 658-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12600857&dopt=Abstract

•

Corrections to: Clinical Care of Pregnant Women with Epilepsy: Neural Tube Defects and Folic Acid Supplementation. Author(s): Yerby MS. Source: Epilepsia. 2003 November; 44(11): 1465. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14636360&dopt=Abstract

•

Cost-effectiveness of periconceptional supplementation of folic acid. Author(s): Postma MJ, Londeman J, Veenstra M, de Walle HE, de Jong-van den Berg LT. Source: Pharmacy World & Science : Pws. 2002 February; 24(1): 8-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11980171&dopt=Abstract

•

Decline of neural tube defects cases after a folic acid campaign in Nuevo Leon, Mexico.

Alternative Medicine 123

Author(s): Martinez de Villarreal L, Perez JZ, Vazquez PA, Herrera RH, Campos Mdel R, Lopez RA, Ramirez JL, Sanchez JM, Villarreal JJ, Garza MT, Limon A, Lopez AG, Barcenas M, Garcia JR, Dominguez AS, Nunez RH, Ayala JL, Martinez JG, Gonzalez MT, Alvarez CG, Castro RN. Source: Teratology. 2002 November; 66(5): 249-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12397633&dopt=Abstract •

Dietary vitamin C and folic acid supplementation ameliorates the detrimental effects of heat stress in Japanese quail. Author(s): Sahin K, Onderci M, Sahin N, Gursu MF, Kucuk O. Source: The Journal of Nutrition. 2003 June; 133(6): 1882-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12771333&dopt=Abstract

•

Diverse chemotactic responses of Dictyostelium discoideum amoebae in the developing (temporal) and stationary (spatial) concentration gradients of folic acid, cAMP, Ca(2+) and Mg(2+). Author(s): Korohoda W, Madeja Z, Sroka J. Source: Cell Motility and the Cytoskeleton. 2002 September; 53(1): 1-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12211112&dopt=Abstract

•

Does oral folic acid lower total homocysteine levels and improve endothelial function in children with chronic renal failure? Author(s): Bennett-Richards K, Kattenhorn M, Donald A, Oakley G, Varghese Z, Rees L, Deanfield JE. Source: Circulation. 2002 April 16; 105(15): 1810-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11956124&dopt=Abstract

•

Effect of folic acid and glycine supplementation on embryo development and folate metabolism during early pregnancy in pigs. Author(s): Guay F, Matte JJ, Girard CL, Palin MF, Giguere A, Laforest JP. Source: Journal of Animal Science. 2002 August; 80(8): 2134-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12211383&dopt=Abstract

•

Effect of folic acid and vitamin C supplementation on folate status and homocysteine level: a randomised controlled trial in Italian smoker-blood donors. Author(s): Cafolla A, Dragoni F, Girelli G, Tosti ME, Costante A, De Luca AM, Funaro D, Scott CS. Source: Atherosclerosis. 2002 July; 163(1): 105-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12048127&dopt=Abstract

•

Effect of folic acid supplementation on plasma zinc concentrations of young women. Author(s): Green TJ, Skeaff CM, Whiting SJ, Gibson RS.

124 Folic Acid

Source: Nutrition (Burbank, Los Angeles County, Calif.). 2003 June; 19(6): 522-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781852&dopt=Abstract •

Effect of folic acid supplements on homocysteine concentration in plasma of gestating sows. Author(s): Barkow B, Pietrzik K, Flachowsky G. Source: Archiv Fur Tierernahrung. 2001; 54(1): 81-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11851018&dopt=Abstract

•

Effect of treatment with folic acid and vitamin B6 on lipid and homocysteine concentrations in patients with coronary artery disease. Author(s): Mark L, Erdei F, Markizay J, Kondacs A, Katona A. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2002 May; 18(5): 428-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11985950&dopt=Abstract

•

Effects of breed, parity, and folic Acid supplement on the expression of folate metabolism genes in endometrial and embryonic tissues from sows in early pregnancy. Author(s): Vallee M, Guay F, Beaudry D, Matte J, Blouin R, Laforest JP, Lessard M, Palin MF. Source: Biology of Reproduction. 2002 October; 67(4): 1259-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297544&dopt=Abstract

•

Effects of folic acid and vitamin B12 supplements on folate and homocysteine metabolism in pigs during early pregnancy. Author(s): Guay F, Jacques Matte J, Girard CL, Palin MF, Giguere A, Laforest JP. Source: The British Journal of Nutrition. 2002 September; 88(3): 253-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12207835&dopt=Abstract

•

Effects of folic acid supplementation on inflammatory and thrombogenic markers in chronic smokers. A randomised controlled trial. Author(s): Mangoni AA, Arya R, Ford E, Asonganyi B, Sherwood RA, Ouldred E, Swift CG, Jackson SH. Source: Thrombosis Research. 2003 April 15; 110(1): 13-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12877903&dopt=Abstract

•

Efficacy of methylcobalamin on lowering total homocysteine plasma concentrations in haemodialysis patients receiving high-dose folic acid supplementation. Author(s): Koyama K, Usami T, Takeuchi O, Morozumi K, Kimura G.

Alternative Medicine 125

Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2002 May; 17(5): 91622. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11981084&dopt=Abstract •

Efficient gene delivery via non-covalent complexes of folic acid and polyethylenimine. Author(s): Guo W, Lee RJ. Source: Journal of Controlled Release : Official Journal of the Controlled Release Society. 2001 November 9; 77(1-2): 131-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11689266&dopt=Abstract

•

Folate deficiency during treatment with orally administered folic acid, sulphadiazine and pyrimethamine in a horse with suspected equine protozoal myeloencephalitis (EPM). Author(s): Piercy RJ, Hinchcliff KW, Reed SM. Source: Equine Veterinary Journal. 2002 May; 34(3): 311-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12108754&dopt=Abstract

•

Folate status assessment and folic acid supplements in sickle cell disease. Author(s): Schnog JB, van der Dijs FP, Fokkema MR, Muskiet FD, Muskiet FA. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2001 November; 23(8): 548. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11878785&dopt=Abstract

•

Folic acid and folinic acid supplementation during low-dose methotrexate therapy for rheumatoid arthritis: comment on the article by van Ede et al. Author(s): Morgan SL, Baggott JE, Alarcon GS, Koopman WJ. Source: Arthritis and Rheumatism. 2002 May; 46(5): 1413-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12115259&dopt=Abstract

•

Folic acid and prevention of birth defects. Author(s): Van Dyke DC, Stumbo PJ, Mary JB, Niebyl JR. Source: Developmental Medicine and Child Neurology. 2002 June; 44(6): 426-9. Review. Erratum In: Dev Med Child Neurol. 2003 May; 45(5): 360. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12088312&dopt=Abstract

•

Folic acid and prevention of spina bifida and anencephaly. 10 years after the U.S. Public Health Service recommendation. Author(s): Erickson JD.

126 Folic Acid

Source: Mmwr. Recommendations and Reports : Morbidity and Mortality Weekly Report. Recommendations and Reports / Centers for Disease Control. 2002 September 13; 51(Rr-13): 1-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12353506&dopt=Abstract •

Folic acid and the elderly. Author(s): Fowler PB. Source: Qjm : Monthly Journal of the Association of Physicians. 2002 July; 95(7): 485. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12162270&dopt=Abstract

•

Folic acid and vitamin B(12) supplementation attenuates isoprenaline-induced myocardial infarction in experimental hyperhomocysteinemic rats. Author(s): Hagar HH. Source: Pharmacological Research : the Official Journal of the Italian Pharmacological Society. 2002 September; 46(3): 213-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12220963&dopt=Abstract

•

Folic acid and Vitamin E supplementation effects on homocysteinemia, endothelial function and plasma antioxidant capacity in young myocardial-infarction patients. Author(s): Assanelli D, Bonanome A, Pezzini A, Albertini F, Maccalli P, Grassi M, Archetti S, Negrini R, Visioli F. Source: Pharmacological Research : the Official Journal of the Italian Pharmacological Society. 2004 January; 49(1): 79-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14597156&dopt=Abstract

•

Folic acid awareness and use among women with a history of a neural tube defect pregnancy--Texas, 2000-2001. Author(s): Canfield MA, Anderson JL, Waller DK, Palmer SE, Kaye CI. Source: Mmwr. Recommendations and Reports : Morbidity and Mortality Weekly Report. Recommendations and Reports / Centers for Disease Control. 2002 September 13; 51(Rr-13): 16-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12353508&dopt=Abstract

•

Folic acid fortification increases red blood cell folate concentrations in the Framingham study. Author(s): Choumenkovitch SF, Jacques PF, Nadeau MR, Wilson PW, Rosenberg IH, Selhub J. Source: The Journal of Nutrition. 2001 December; 131(12): 3277-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11739880&dopt=Abstract

•

Folic acid fortification: additional issues. Author(s): Moya S, McIver G, Seiter J, Bailey D.

Alternative Medicine 127

Source: Journal of the American Dietetic Association. 2002 March; 102(3): 346. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11902364&dopt=Abstract •

Folic acid intake from fortification in United States exceeds predictions. Author(s): Choumenkovitch SF, Selhub J, Wilson PW, Rader JI, Rosenberg IH, Jacques PF. Source: The Journal of Nutrition. 2002 September; 132(9): 2792-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12221247&dopt=Abstract

•

Folic acid supplement decreases the homocysteine increasing effect of filtered coffee. A randomised placebo-controlled study. Author(s): Strandhagen E, Landaas S, Thelle DS. Source: European Journal of Clinical Nutrition. 2003 November; 57(11): 1411-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14576754&dopt=Abstract

•

Folic acid supplementation and neural tube defects. Author(s): Wald NJ, Hackshaw AK. Source: American Journal of Medical Genetics. 2002 April 15; 109(1): 79. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11933000&dopt=Abstract

•

Folic acid supplementation and prevention of birth defects. Author(s): Green NS. Source: The Journal of Nutrition. 2002 August; 132(8 Suppl): 2356S-2360S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12163692&dopt=Abstract

•

Folic acid supplementation and riboflavin status. Author(s): Murphy MM, Fernandez-Ballart JD. Source: Clinical Chemistry. 2003 August; 49(8): 1416; Author Reply 1416-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881464&dopt=Abstract

•

Folic acid supplementation and risk for imperforate anus in China. Author(s): Myers MF, Li S, Correa-Villasenor A, Li Z, Moore CA, Hong SX, Berry RJ; China-US Collaborative Project for Neural Tube Defect Prevention. Source: American Journal of Epidemiology. 2001 December 1; 154(11): 1051-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11724722&dopt=Abstract

•

Folic acid supplementation for the prevention of neural tube defects. Should it be a priority for developing countries? [letter] Author(s): Perez-escamilla R. Source: Scn News. 1997 December; (15): 34-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12293181&dopt=Abstract

128 Folic Acid

•

Folic acid supplementation in dementia: a preliminary report. Author(s): Sommer BR, Hoff AL, Costa M. Source: Journal of Geriatric Psychiatry and Neurology. 2003 September; 16(3): 156-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12967058&dopt=Abstract

•

Folic acid supplementation on red kidney bean-induced diarrhoea and enteric bacterial translocation into mesenteric lymph nodes in rats: a pilot study. Author(s): Shoda R, Mahalanabis D, Islam KN, Wahed MA, Albert MJ. Source: Acta Paediatrica (Oslo, Norway : 1992). 2002; 91(1): 51-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11883818&dopt=Abstract

•

Folic acid supplementation use among women who contact a teratology information service. Author(s): Stepanuk KM, Tolosa JE, Lewis D, Myers V, Royds C, Sabogal JC, Librizzi R. Source: American Journal of Obstetrics and Gynecology. 2002 October; 187(4): 964-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12388987&dopt=Abstract

•

Folic acid supplements and fortification affect the risk for neural tube defects, vascular disease and cancer: evolving science. Author(s): Bailey LB, Rampersaud GC, Kauwell GP. Source: The Journal of Nutrition. 2003 June; 133(6): 1961S-1968S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12771346&dopt=Abstract

•

Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine in hyperhomocysteinaemic subjects. Author(s): Holven KB, Haugstad TS, Holm T, Aukrust P, Ose L, Nenseter MS. Source: The British Journal of Nutrition. 2003 March; 89(3): 359-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628031&dopt=Abstract

•

Hyperhomocysteinemia in children with juvenile idiopathic arthritis is not influenced by methotrexate treatment and folic acid supplementation: a pilot study. Author(s): Huemer M, Fodinger M, Huemer C, Sailer-Hock M, Falger J, Rettenbacher A, Bernecker M, Artacker G, Kenzian H, Lang T, Stockler-Ipsiroglu S. Source: Clin Exp Rheumatol. 2003 March-April; 21(2): 249-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12747286&dopt=Abstract

•

Hyperhomocysteinemia in rheumatoid arthritis: influence of methotrexate treatment and folic acid supplementation. Author(s): Jensen OK, Rasmussen C, Mollerup F, Christensen PB, Hansen H, Ekelund S, Thulstrup AM. Source: The Journal of Rheumatology. 2002 August; 29(8): 1615-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12180718&dopt=Abstract

Alternative Medicine 129

•

Hyperhomocysteinemia, and low intakes of folic acid and vitamin B12 in urban North India. Author(s): Misra A, Vikram NK, Pandey RM, Dwivedi M, Ahmad FU, Luthra K, Jain K, Khanna N, Devi JR, Sharma R, Guleria R. Source: European Journal of Nutrition. 2002 April; 41(2): 68-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12083316&dopt=Abstract

•

Impact of an educational seminar on high school students' knowledge of folic acid supplementation and its role in the prevention of birth defects. Author(s): Johnson PA, Stadler DD, Feldkamp M, Webber B. Source: Journal of the American Dietetic Association. 2002 March; 102(3 Suppl): S78-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11902395&dopt=Abstract

•

In praise of folic acid. Author(s): Gorman C. Source: Time. 2002 February 25; 159(8): 73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11881186&dopt=Abstract

•

Incidence of open neural tube defects in Nova Scotia after folic acid fortification. Author(s): Persad VL, Van den Hof MC, Dube JM, Zimmer P. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2002 August 6; 167(3): 241-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12186168&dopt=Abstract

•

Inertia on folic acid has caused thousands of unnecessary deaths. Author(s): Ellis A. Source: Bmj (Clinical Research Ed.). 2003 May 17; 326(7398): 1054. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12750190&dopt=Abstract

•

Influence of educational level on determinants of folic acid use. Author(s): van der Pal-de Bruin KM, de Walle HE, de Rover CM, Jeeninga W, Cornel MC, de Jong-van den Berg LT, Buitendijk SE, Paulussen TG. Source: Paediatric and Perinatal Epidemiology. 2003 July; 17(3): 256-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839537&dopt=Abstract

•

Influence of reporting error on the relation between blood folate concentrations and reported folic acid-containing dietary supplement use among reproductive-aged women in the United States. Author(s): Yang Q, Erickson JD. Source: The American Journal of Clinical Nutrition. 2003 January; 77(1): 196-203. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499342&dopt=Abstract

130 Folic Acid

•

Interventional study of high dose folic acid in gastric carcinogenesis in beagles. Author(s): Xiao SD, Meng XJ, Shi Y, Hu YB, Zhu SS, Wang CW. Source: Gut. 2002 January; 50(1): 61-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11772968&dopt=Abstract

•

Is weekly iron and folic acid supplementation as effective as daily supplementation for decreasing incidence of anemia in adolescent girls? Author(s): Perrin E, Rothman R, Coyne-Beasley T, Ford C, Bordley WC. Source: Archives of Pediatrics & Adolescent Medicine. 2002 February; 156(2): 128-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11814372&dopt=Abstract

•

Knowledge, use, and education regarding folic acid supplementation: continuation study of women in Colorado who had a pregnancy affected by a neural tube defect. Author(s): Rinsky-Eng J, Miller L. Source: Teratology. 2002; 66 Suppl 1: S29-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12239741&dopt=Abstract

•

Long-term improvement in homocysteine levels and arterial endothelial function after 1-year folic acid supplementation. Author(s): Woo KS, Chook P, Chan LL, Cheung AS, Fung WH, Qiao M, Lolin YI, Thomas GN, Sanderson JE, Metreweli C, Celermajer DS. Source: The American Journal of Medicine. 2002 May; 112(7): 535-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12015244&dopt=Abstract

•

Management issues for women with epilepsy: Neural tube defects and folic acid supplementation. Author(s): Yerby MS. Source: Neurology. 2003 September 1; 61(6 Suppl 2): S23-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14504306&dopt=Abstract

•

Methylenetetrahydrofolate reductase 677C-->T genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: a randomized controlled trial. Author(s): Ashfield-Watt PA, Pullin CH, Whiting JM, Clark ZE, Moat SJ, Newcombe RG, Burr ML, Lewis MJ, Powers HJ, McDowell IF. Source: The American Journal of Clinical Nutrition. 2002 July; 76(1): 180-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12081832&dopt=Abstract

•

Neural tube defects and folic acid knowledge and use in Mississippi women. Author(s): Norman M, Penman A. Source: J Miss State Med Assoc. 2001 September; 42(9): 270-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11569130&dopt=Abstract

Alternative Medicine 131

•

New use for folic acid. Author(s): Hayden MR. Source: Mo Med. 2003 January-February; 100(1): 14-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12664703&dopt=Abstract

•

Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype. Author(s): Pullin CH, Ashfield-Watt PA, Burr ML, Clark ZE, Lewis MJ, Moat SJ, Newcombe RG, Powers HJ, Whiting JM, McDowell IF. Source: Journal of the American College of Cardiology. 2001 December; 38(7): 1799-805. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11738277&dopt=Abstract

•

Optimization of folic acid, vitamin B(12), and vitamin B(6) supplements in pediatric patients with sickle cell disease. Author(s): van der Dijs FP, Fokkema MR, Dijck-Brouwer DA, Niessink B, van der Wal TI, Schnog JJ, Duits AJ, Muskiet FD, Muskiet FA. Source: American Journal of Hematology. 2002 April; 69(4): 239-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11921017&dopt=Abstract

•

Periconceptional use of folic acid supplements in Oslo. Author(s): Braekke K, Staff AC. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 July; 82(7): 620-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790843&dopt=Abstract

•

Plasma reduced folates, reproductive performance, and conceptus development in sows in response to supplementation with oxidized and reduced sources of folic acid. Author(s): Harper AF, Knight JW, Kokue E, Usry JL. Source: Journal of Animal Science. 2003 March; 81(3): 735-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12661654&dopt=Abstract

•

Pregnancy intendedness and the use of periconceptional folic acid. Author(s): Rosenberg KD, Gelow JM, Sandoval AP. Source: Pediatrics. 2003 May; 111(5 Part 2): 1142-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12728127&dopt=Abstract

•

Pregnancy planning and folic acid supplement use: results from a survey in Quebec. Author(s): Morin P, De Wals P, Noiseux M, Niyonsenga T, St-Cyr-Tribble D, Tremblay C. Source: Preventive Medicine. 2002 August; 35(2): 143-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12200099&dopt=Abstract

132 Folic Acid

•

Pregnancy planning: a determinant of folic acid supplements use for the primary prevention of neural tube defects. Author(s): Morin P, De Wals P, St-Cyr-Tribble D, Niyonsenga T, Payette H. Source: Canadian Journal of Public Health. Revue Canadienne De Sante Publique. 2002 July-August; 93(4): 259-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12154526&dopt=Abstract

•

Risk of gestational hypertension in relation to folic acid supplementation during pregnancy. Author(s): Hernandez-Diaz S, Werler MM, Louik C, Mitchell AA. Source: American Journal of Epidemiology. 2002 November 1; 156(9): 806-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12396998&dopt=Abstract

•

Sex-related differences in procarbazine-induced cleft palate and microgenia and the anti-teratogenic effect of prenatal folic acid supplementation in rats. Author(s): Malek FA, Moritz KU, Fanghanel J, Bienengraber V. Source: Ann Anat. 2003 October; 185(5): 465-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14575274&dopt=Abstract

•

Short-term folic acid supplementation induces variable and paradoxical changes in plasma homocyst(e)ine concentrations. Author(s): Malinow MR, Duell PB, Williams MA, Kruger WD, Evans AA, Anderson PH, Block PC, Hess DL, Upson BM, Graf EE, Irvin-Jones A, Wang L. Source: Lipids. 2001; 36 Suppl: S27-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11837988&dopt=Abstract

•

Supplementation with micronutrients in addition to iron and folic acid does not further improve the hematologic status of pregnant women in rural Nepal. Author(s): Christian P, Shrestha J, LeClerq SC, Khatry SK, Jiang T, Wagner T, Katz J, West KP Jr. Source: The Journal of Nutrition. 2003 November; 133(11): 3492-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14608063&dopt=Abstract

•

Synthesis and evaluation of taxol-folic acid conjugates as targeted antineoplastics. Author(s): Lee JW, Lu JY, Low PS, Fuchs PL. Source: Bioorganic & Medicinal Chemistry. 2002 July; 10(7): 2397-414. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11983537&dopt=Abstract

•

The effect of folic acid supplementation on plasma homocysteine in an elderly population. Author(s): Rydlewicz A, Simpson JA, Taylor RJ, Bond CM, Golden MH.

Alternative Medicine 133

Source: Qjm : Monthly Journal of the Association of Physicians. 2002 January; 95(1): 2735. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11834770&dopt=Abstract •

The effect of long-term intravenous high dose B-complex vitamins with or without folic acid on serum homocysteine in hemodialysis patients. Author(s): Sombolos K, Fragia T, Natse T, Bartholomatos G, Karagianni A, Katsaris G, Christidou F, Bamichas G, Stangou M, Papagalanis N. Source: Journal of Nephrology. 2002 November-December; 15(6): 671-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495282&dopt=Abstract

•

The enrichment of eggs with folic acid through supplementation of the laying hen diet. Author(s): House JD, Braun K, Ballance DM, O'Connor CP, Guenter W. Source: Poultry Science. 2002 September; 81(9): 1332-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12269612&dopt=Abstract

•

The pregnancy-related decrease in fasting plasma homocysteine is not explained by folic acid supplementation, hemodilution, or a decrease in albumin in a longitudinal study. Author(s): Murphy MM, Scott JM, McPartlin JM, Fernandez-Ballart JD. Source: The American Journal of Clinical Nutrition. 2002 September; 76(3): 614-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12198008&dopt=Abstract

•

The prevention of congenital anomalies with periconceptional folic acid supplementation. Author(s): McDonald SD, Ferguson S, Tam L, Lougheed J, Walker MC. Source: J Obstet Gynaecol Can. 2003 February; 25(2): 115-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12577128&dopt=Abstract

•

The unnecessary epidemic of folic acid-preventable spina bifida and anencephaly. Author(s): Campbell RK. Source: Pediatrics. 2001 October; 108(4): 1048-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11589212&dopt=Abstract

•

Toward better compliance with iron-folic acid supplements: understanding the behavior of poor urban pregnant women through ethnographic decision models in Vadodara, India. Author(s): Ghanekar J, Kanani S, Patel S. Source: Food Nutr Bull. 2002 March; 23(1): 65-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11975371&dopt=Abstract

134 Folic Acid

•

Trends in neural tube defect prevalence, folic acid fortification, and vitamin supplement use. Author(s): Olney RS, Mulinare J. Source: Semin Perinatol. 2002 August; 26(4): 277-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12211618&dopt=Abstract

•

Trends in periconceptional folic acid use by relatives in Irish families with neural tube defects. Author(s): Byrne J, Byrne C, Collins D. Source: Ir Med J. 2001 November-December; 94(10): 302-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11837628&dopt=Abstract

•

Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Author(s): Ericson A, Kallen B, Aberg A. Source: Twin Research : the Official Journal of the International Society for Twin Studies. 2001 April; 4(2): 63-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11665336&dopt=Abstract

•

Variations in the lipid profile of patients with chronic renal failure, treated with folic acid. Author(s): de Gomez Dumm NT, Giammona AM, Touceda LA. Source: Int J Vitam Nutr Res. 2003 May; 73(3): 215-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12847999&dopt=Abstract

•

Weekly high-dose folic Acid supplementation is effective in lowering serum homocysteine concentrations in women. Author(s): Adank C, Green TJ, Skeaff CM, Briars B. Source: Annals of Nutrition & Metabolism. 2003; 47(2): 55-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12652055&dopt=Abstract

•

Weekly vs daily iron and folic acid supplementation in adolescent Nepalese girls. Author(s): Shah BK, Gupta P. Source: Archives of Pediatrics & Adolescent Medicine. 2002 February; 156(2): 131-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11814373&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/

•

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

Alternative Medicine 135

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

The following is a specific Web list relating to folic acid; 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 Abnormal Pap Smear Source: Healthnotes, Inc.; www.healthnotes.com Alzheimer's Disease Source: Healthnotes, Inc.; www.healthnotes.com Anemia Source: Integrative Medicine Communications; www.drkoop.com Arteriosclerosis Source: Integrative Medicine Communications; www.drkoop.com Atherosclerosis Source: Healthnotes, Inc.; www.healthnotes.com Atherosclerosis Source: Integrative Medicine Communications; www.drkoop.com Bipolar Disorder Source: Healthnotes, Inc.; www.healthnotes.com Birth Defects Source: Integrative Medicine Communications; www.drkoop.com Birth Defects Prevention Source: Healthnotes, Inc.; www.healthnotes.com

136 Folic Acid

Bone Loss Source: Integrative Medicine Communications; www.drkoop.com Breast Cancer Source: Healthnotes, Inc.; www.healthnotes.com Cancer Source: Integrative Medicine Communications; www.drkoop.com Cancer Prevention (Reducing the Risk) Source: Prima Communications, Inc.www.personalhealthzone.com Canker Sores Source: Healthnotes, Inc.; www.healthnotes.com Celiac Disease Source: Healthnotes, Inc.; www.healthnotes.com Cervical Dysplasia Source: Integrative Medicine Communications; www.drkoop.com Cervical Dysplasia Source: Prima Communications, Inc.www.personalhealthzone.com Colon Cancer Source: Healthnotes, Inc.; www.healthnotes.com Colorectal Cancer Source: Integrative Medicine Communications; www.drkoop.com Congestive Heart Failure Source: Integrative Medicine Communications; www.drkoop.com Coronary Artery Disease Source: Integrative Medicine Communications; www.drkoop.com Crohn's Disease Source: Healthnotes, Inc.; www.healthnotes.com Depression Source: Healthnotes, Inc.; www.healthnotes.com Depression Source: Integrative Medicine Communications; www.drkoop.com Depression (Mild to Moderate) Source: Prima Communications, Inc.www.personalhealthzone.com Dermatitis Herpetiformis Source: Healthnotes, Inc.; www.healthnotes.com

Alternative Medicine 137

Diabetes Source: Healthnotes, Inc.; www.healthnotes.com Diabetes Mellitus Source: Integrative Medicine Communications; www.drkoop.com Diarrhea Source: Healthnotes, Inc.; www.healthnotes.com Eating Disorders Source: Healthnotes, Inc.; www.healthnotes.com Epilepsy Source: Healthnotes, Inc.; www.healthnotes.com Epilepsy Source: Integrative Medicine Communications; www.drkoop.com Gingivitis Source: Healthnotes, Inc.; www.healthnotes.com Gout Source: Healthnotes, Inc.; www.healthnotes.com Gout Source: Integrative Medicine Communications; www.drkoop.com Gout Source: Prima Communications, Inc.www.personalhealthzone.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com Hepatitis Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Integrative Medicine Communications; www.drkoop.com High Homocysteine Source: Healthnotes, Inc.; www.healthnotes.com HIV and AIDS Support Source: Healthnotes, Inc.; www.healthnotes.com Hypercholesterolemia Source: Integrative Medicine Communications; www.drkoop.com

138 Folic Acid

Inflammatory Bowel Disease Source: Integrative Medicine Communications; www.drkoop.com Iron-deficiency Anemia Source: Healthnotes, Inc.; www.healthnotes.com Kidney Stones Source: Integrative Medicine Communications; www.drkoop.com Leukemia Source: Integrative Medicine Communications; www.drkoop.com Lung Cancer Source: Healthnotes, Inc.; www.healthnotes.com Lung Cancer Source: Integrative Medicine Communications; www.drkoop.com Migraine Headache Source: Integrative Medicine Communications; www.drkoop.com Miscarriage Source: Integrative Medicine Communications; www.drkoop.com Osteoporosis Source: Healthnotes, Inc.; www.healthnotes.com Osteoporosis Source: Integrative Medicine Communications; www.drkoop.com Pelvic Inflammatory Disease Source: Integrative Medicine Communications; www.drkoop.com Periodontal Disease Alternative names: Gum Disease Source: Prima Communications, Inc.www.personalhealthzone.com Peripheral Vascular Disease Source: Healthnotes, Inc.; www.healthnotes.com Preeclampsia Source: Healthnotes, Inc.; www.healthnotes.com Pregnancy Source: Integrative Medicine Communications; www.drkoop.com Pregnancy and Postpartum Support Source: Healthnotes, Inc.; www.healthnotes.com Psoriasis Source: Healthnotes, Inc.; www.healthnotes.com

Alternative Medicine 139

Psychological Conditions and Disorders Source: Integrative Medicine Communications; www.drkoop.com Pyloric Stenosis Source: Integrative Medicine Communications; www.drkoop.com Restless Legs Syndrome Source: Healthnotes, Inc.; www.healthnotes.com Schizophrenia Source: Healthnotes, Inc.; www.healthnotes.com Seborrheic Dermatitis Source: Healthnotes, Inc.; www.healthnotes.com Seizure Disorders Source: Integrative Medicine Communications; www.drkoop.com Sickle Cell Anemia Source: Healthnotes, Inc.; www.healthnotes.com Skin Cancer Source: Integrative Medicine Communications; www.drkoop.com Spontaneous Abortion Source: Integrative Medicine Communications; www.drkoop.com Stroke Source: Healthnotes, Inc.; www.healthnotes.com Stroke Source: Integrative Medicine Communications; www.drkoop.com Transient Ischemic Attacks Source: Integrative Medicine Communications; www.drkoop.com Ulcerative Colitis Source: Healthnotes, Inc.; www.healthnotes.com Ulcerative Colitis Source: Integrative Medicine Communications; www.drkoop.com Vitiligo Source: Healthnotes, Inc.; www.healthnotes.com Warts Source: Integrative Medicine Communications; www.drkoop.com •

Herbs and Supplements 5-aminosalicylic Acid Derivatives Source: Integrative Medicine Communications; www.drkoop.com

140 Folic Acid

Aluminum Hydroxide Source: Healthnotes, Inc.; www.healthnotes.com Amiloride Source: Healthnotes, Inc.; www.healthnotes.com Aminoglycosides Source: Integrative Medicine Communications; www.drkoop.com Antacids Source: Prima Communications, Inc.www.personalhealthzone.com Antibiotic Combination: Sulfa Drugs Source: Integrative Medicine Communications; www.drkoop.com Anticonvulsants Source: Healthnotes, Inc.; www.healthnotes.com Aspirin Source: Healthnotes, Inc.; www.healthnotes.com Azathioprine Source: Healthnotes, Inc.; www.healthnotes.com Barbiturates Source: Integrative Medicine Communications; www.drkoop.com Betaine Alternative names: Trimethylglycine Source: Integrative Medicine Communications; www.drkoop.com Betaine (Trimethylglycine) Source: Healthnotes, Inc.; www.healthnotes.com Biguanides Source: Integrative Medicine Communications; www.drkoop.com Bile Acid Sequestrants Source: Healthnotes, Inc.; www.healthnotes.com Bile Acid Sequestrants Source: Integrative Medicine Communications; www.drkoop.com Celery Seed Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Cephalosporins Source: Integrative Medicine Communications; www.drkoop.com

Alternative Medicine 141

Chemotherapy Source: Healthnotes, Inc.; www.healthnotes.com Cobalamin Source: Integrative Medicine Communications; www.drkoop.com Colestipol Source: Healthnotes, Inc.; www.healthnotes.com Cycloserine Source: Healthnotes, Inc.; www.healthnotes.com Diuretics Source: Healthnotes, Inc.; www.healthnotes.com Electrolytes Source: Integrative Medicine Communications; www.drkoop.com Erythromycin Source: Healthnotes, Inc.; www.healthnotes.com Famotidine Source: Healthnotes, Inc.; www.healthnotes.com Fennel Source: Healthnotes, Inc.; www.healthnotes.com Fenofibrate Source: Healthnotes, Inc.; www.healthnotes.com H2 Blockers Source: Prima Communications, Inc.www.personalhealthzone.com Histamine H2 Antagonists Source: Integrative Medicine Communications; www.drkoop.com Hydantoin Derivatives Source: Integrative Medicine Communications; www.drkoop.com Indomethacin Source: Healthnotes, Inc.; www.healthnotes.com Isoniazid Source: Healthnotes, Inc.; www.healthnotes.com Lansoprazole Source: Healthnotes, Inc.; www.healthnotes.com Lipotropic Combination Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,861,00.html

142 Folic Acid

Lithium Source: Healthnotes, Inc.; www.healthnotes.com Loop Diuretics Source: Healthnotes, Inc.; www.healthnotes.com L-tyrosine Source: Healthnotes, Inc.; www.healthnotes.com Macrolides Source: Integrative Medicine Communications; www.drkoop.com Medroxyprogesterone Source: Healthnotes, Inc.; www.healthnotes.com Metformin Source: Healthnotes, Inc.; www.healthnotes.com Methionine Source: Healthnotes, Inc.; www.healthnotes.com Methionine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10084,00.html Methotrexate Source: Healthnotes, Inc.; www.healthnotes.com Methotrexate Alternative names: Rheumatrex Source: Prima Communications, Inc.www.personalhealthzone.com Miscellaneous Source: Integrative Medicine Communications; www.drkoop.com Miscellaneous Preparations Source: Integrative Medicine Communications; www.drkoop.com Neomycin Source: Healthnotes, Inc.; www.healthnotes.com Nitrous Oxide Source: Healthnotes, Inc.; www.healthnotes.com Nitrous Oxide Source: Prima Communications, Inc.www.personalhealthzone.com Nizatidine Source: Healthnotes, Inc.; www.healthnotes.com

Alternative Medicine 143

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Source: Integrative Medicine Communications; www.drkoop.com Omeprazole Source: Healthnotes, Inc.; www.healthnotes.com Oral Contraceptives Source: Healthnotes, Inc.; www.healthnotes.com Oral Contraceptives Source: Prima Communications, Inc.www.personalhealthzone.com Paba Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10049,00.html Penicillin Derivatives Source: Integrative Medicine Communications; www.drkoop.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 Phosphatidylserine (PS) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,813,00.html Piroxicam Source: Healthnotes, Inc.; www.healthnotes.com Primidone Alternative names: Mysoline Source: Prima Communications, Inc.www.personalhealthzone.com Probiotics Source: Healthnotes, Inc.; www.healthnotes.com Proteolytic Enzymes Source: Prima Communications, Inc.www.personalhealthzone.com Proton Pump Inhibitors Source: Prima Communications, Inc.www.personalhealthzone.com

144 Folic Acid

Proton Pump Inhibitors (gastric Acid Secretion Inhibitors) Source: Integrative Medicine Communications; www.drkoop.com Quinolones Source: Integrative Medicine Communications; www.drkoop.com Ranitidine Source: Healthnotes, Inc.; www.healthnotes.com S-Adenosylmethionine (SAMe) Source: Integrative Medicine Communications; www.drkoop.com Salicylates Source: Integrative Medicine Communications; www.drkoop.com Salsalate Source: Healthnotes, Inc.; www.healthnotes.com Sulfamethoxazole Source: Healthnotes, Inc.; www.healthnotes.com Sulfasalazine Source: Healthnotes, Inc.; www.healthnotes.com Sulindac Source: Healthnotes, Inc.; www.healthnotes.com Tetracycline Source: Healthnotes, Inc.; www.healthnotes.com Tetracycline Derivatives Source: Integrative Medicine Communications; www.drkoop.com Thiazide Diuretics Source: Healthnotes, Inc.; www.healthnotes.com Triamterene Source: Healthnotes, Inc.; www.healthnotes.com Trimethoprim Source: Healthnotes, Inc.; www.healthnotes.com Trimethoprim/sulfamethoxazole Source: Healthnotes, Inc.; www.healthnotes.com Trimethylglycine Source: Integrative Medicine Communications; www.drkoop.com Uricosuric Agents Source: Integrative Medicine Communications; www.drkoop.com

Alternative Medicine 145

Valproic Acid Source: Healthnotes, Inc.; www.healthnotes.com Valproic Acid Derivatives Source: Integrative Medicine Communications; www.drkoop.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.

147

CHAPTER 4. DISSERTATIONS ON FOLIC ACID Overview In this chapter, we will give you a bibliography on recent dissertations relating to folic acid. 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 “folic acid” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on folic acid, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Folic Acid 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 folic acid. 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: •

A Comparison of Folic Acid Awareness and Intake in Young Women by Hilton, Judith Johnson; PhD from Duquesne University School of Nursing, 2003, 71 pages http://wwwlib.umi.com/dissertations/fullcit/3085109

•

A Study of the Measurement and Degradation of Folic Acid by Ruddick, Jane Elizabeth; PhD from The University of British Columbia (Canada), 1978 http://wwwlib.umi.com/dissertations/fullcit/NK40773

•

The Metabolism of Alicyclic Acids and Phenylpropanoids by Cereal Rust Uredospores and the Folic Acid Components of Wheat Stem Rust Uredospores by Jackson, Andrew Otis; Advdeg from The University of Manitoba (Canada), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK05436

148 Folic Acid

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.

149

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

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

Chemoprevention with Folic Acid Condition(s): Colon Cancer; Adenoma; Colonic Polyps Study Status: This study is currently recruiting patients. Sponsor(s): Department of Veterans Affairs Medical Research Service Purpose - Excerpt: Colorectal neoplasia is the second most common cancer in the United States and other Western countries with about 140,000 newly diagnosed cases per year in the United States with a mortality rate of about 40%. The identification of a specific natural or synthetic compound with the ability to reverse or suppress the process of colon carcinogenesis would have profound implication in the development of colorectal adenomas and their subsequent transformation to colon cancer. Furthermore, the establishment of a correlative relationship between biomarkers of cell proliferation, differentiation, apoptosis and adenoma recurrence would provide pivotal data required to elucidate cell signaling mechanisms in future colon cancer chemoprevention trials. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00018551

8

These are listed at www.ClinicalTrials.gov.

150 Folic Acid

•

Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) Condition(s): Renal transplant recipients Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Office of Dietary Supplements (ODS) Purpose - Excerpt: The purpose of this randomized clinical trial is to determine if lowering homocysteine levels in renal transplant recipients with a multivitamin will reduce the occurrence of cardiovascular disease outcomes. Phase(s): Phase II; Phase III; MEDLINEplus consumer health information Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00064753

•

Randomized Study of Folic Acid Therapy for Hyperhomocysteinemia in Patients with End Stage Renal Disease Receiving Hemodialysis Condition(s): End Stage Renal Disease; Hyperhomocysteinemia Study Status: This study is currently recruiting patients. Sponsor(s): FDA Office of Orphan Products Development; Georgetown University Purpose - Excerpt: Objectives: I. Compare the efficacy of two doses of folic acid in normalizing plasma total homocysteine concentration in patients with end stage renal disease receiving regular hemodialysis therapy resulting in hyperhomocysteinemia. II. Determine the requirement of cosupplementation with extra pyridoxine (vitamin B6) and cyanocobalamin (vitamin B12) daily in these patients. III. Assess the safety and tolerability of this therapy in these patients. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004495

•

Aspirin and/or Folic Acid in Preventing Recurrent Colorectal Polyps Condition(s): prevention of colorectal cancer; Colon Cancer; Rectal Cancer Study Status: This study is no longer recruiting patients. Sponsor(s): Queen's Medical Centre Purpose - Excerpt: RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. The use of aspirin and/or folic acid may be effective in preventing recurrent polyps in patients who have had polyps removed previously. PURPOSE: Randomized clinical trial to determine the effectiveness of aspirin and/or folic acid in preventing the recurrence of colorectal polyps. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00033319

Clinical Trials 151

•

Lometrexol Plus Folic Acid in Treating Patients With Stage IIIB or Stage IV NonSmall Cell Lung Cancer Condition(s): stage IV non-small cell lung cancer; adenosquamous cell lung cancer; squamous cell lung cancer; stage IIIB non-small cell lung cancer; recurrent non-small cell lung cancer; adenocarcinoma of the lung; large cell lung cancer Study Status: This study is no longer recruiting patients. Sponsor(s): Tularik Purpose - Excerpt: RATIONALE: Lometrexol may stop or slow the growth of tumor cells by blocking the enzymes necessary for tumor cell growth. Folic acid may be effective in preventing or lessening the side effects of lometrexol. Combining lometrexol with folic acid may be an effective treatment for non-small cell lung cancer. PURPOSE: Phase II trial to study the effectiveness of combining lometrexol with folic acid in treating patients who have stage IIIB or stage IV non-small cell lung cancer that has been previously treated. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00033722

•

Paclitaxel, Folic Acid, and Lometrexol in Treating Patients With Locally Advanced or Metastatic Solid Tumors Condition(s): Drug Toxicity; unspecified adult solid tumor, protocol specific Study Status: This study is no longer recruiting patients. Sponsor(s): National Cancer Institute (NCI); Jonsson Comprehensive Cancer Center Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Folic acid may protect normal cells from the side effects of chemotherapy and may increase the effectiveness of chemotherapy by making tumor cells more sensitive to the drug. Lometrexol may stop the growth of tumors by blocking one of the enzymes necessary for cancer cell growth. Combining chemotherapy with folic acid and lometrexol may kill more tumor cells. PURPOSE: Phase I trial to study the effectiveness of combining paclitaxel, folic acid, and lometrexol in treating patients who have locally advanced or metastatic solid tumors. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00024310

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.

152 Folic Acid

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 “folic acid” (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/

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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/

•

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

•

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

•

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

•

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

•

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

•

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

153

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

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

9Adapted

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

154 Folic Acid

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

Antimicrobial prevention and treatment of human immunedeficiency virus and other infectious diseases Inventor(s): Squires; Meryl (Willowbrook, IL) Assignee(s): Squires; Meryl J. (Barrington Hills, IL) Patent Number: 6,350,784 Date filed: March 26, 1997 Abstract: An improved medical treatment and medicine is provided to quickly and safely resolve HIV and other microbial infections. The inexpensive medicine can be self administered and maintained for the prescribed time. The attractive medicine comprises an antimicrobial concentrate comprising microbe inhibitors, phytochemicals or isolates. Desirably, the effective medicine comprises a surfactant and an aqueous carrier or solvent and a nutrient. In the preferred form, the medicine comprises: Echinacea and Commiphora myrrha phytochemicals, benzalkonium chloride, a sterile water solution, and folic acid. Excerpt(s): The present invention relates to human immunedeficiency virus, and more particularly, to medical treatments and preventions for human immunedeficiency virus and other microbial infections. It has been reported that there are currently about 22 million people infected with human immunedeficiency virus (HIV) throughout the world. The largest proportion of new HIV cases have originated in Africa and the Caribbean. The typical progression of HIV infection is divided into different stages: 1) viral transmission; 2) acute retroviral syndrome; 3) seroconversion; 4) a clinical latent period with or without persistent generalized lymphadenopathy (PGL); 5) early symptomatic HIV infection previously known as AIDS-related complex or ARC and more recently referred to as "B symptoms" according to the 1993 CDC classification); 6) acquired immune deficiency syndrome (AIDS) (AIDS indicator condition according to the 1987 CDC criteria and revised 1993 CDC criteria that include a CD4 cell count <200/mm.sup.3); and 7) advanced HIV infection characterized by a CD4 cell count <50/mm.sup.3. CD4 cells are lymphocytes targeted by HIV. In 1993 the CDC changed the definition of AIDS to include all patients with a CD4 count <200/mm.sup.3; this definition includes patients in stages 4-7 regardless of symptoms. The initial acute retroviral syndrome is accompanied by a precipitous decline in CD4 cell counts, high culturable plasma viremia, and high concentrations of HIV RNA in plasma. Clinical recovery occurs and high level HIV RNA plasma viremia is reduced with development of cytotoxic T lymphocyte (CPL) response. The CD4 cell count gradually declines over several years and then shows an accelerated decline at 1.5-2 years before an AIDSdefining diagnosis. HIV RNA concentrations in plasma are relatively stable until the HIV is in a late stage when the CD4 count is <200/mm.sup.3 and the clinical course is characterized by infections, selected tumors, wasting, and neurologic complications. Generally, about 10% of patients develop an AIDS-defining diagnosis before the CD4 count decreases to 200/mm.sup.3. The present median time to an AIDS-defining complication after the CD4 count is 200/mm.sup.3 is 12-18 months. In the absence of therapy directed against HIV or PCP prophylaxis, the average time from viral transmission to an AIDS-defining diagnosis is about 10 years, and survival after an AIDS-defining complication was previously about one year. Web site: http://www.delphion.com/details?pn=US06350784__

Patents 155

•

Brain delivery of folic acid for the prevention of alzheimer's disease and stroke Inventor(s): Dittert; Lewis W. (Lexington, KY), Hussain; Anwar A. (Lexington, KY), Traboulsi; Ashraf (Lexington, KY) Assignee(s): New Millennium Pharmaceutical Research Inc. (Lexington, KY) Patent Number: 6,369,058 Date filed: January 14, 2000 Abstract: This invention provides a method of rapidly and reliably delivering folic acid, alone or in combination with other compounds, to the systemic circulation by administration via the nasal route to produce rapid onset of beneficial effects in the treatment or prevention of Alzheimer's Disease and stroke. The present invention further provides intranasal pharmaceutical compositions comprising folic acid, and/or pharmaceutically acceptable salts thereof in a variety of unique pharmaceutical dosage forms, with and without other anti-Alzheimer's or anti-stroke compounds. Excerpt(s): This invention relates to a method for greatly accelerating the rate of delivery of folic acid, and derivatives thereof, to the central nervous system by administration via the nasal route to provide extremely rapid response in the prevention or treatment of Alzheimer's disease or stroke in a patient in need of such prevention or treatment. This method also provides for direct absorption of folic acid into the central nervous system, bypassing the metabolic enzymes circulating in the bloodstream that would otherwise destroy folic acid administered by another route. Alzheimer's Disease (AD) is a slowly debilitating neurodegenerative chronic illness that may progress for a decade or longer before death ensues. The disease often strikes later in life. This is evidenced by the fact that half of those over the age of 80 years are afflicted with the disorder. At present, it is the fourth leading cause of adult deaths in the US alone, at an annual cost of approximately $100 billion. As the longevity of the world's population increases, this disease will become an even greater problem unless a better understanding of the disease process and its management is achieved. Alois Alzheimer is credited with being the first to diagnose what is now known as Alzheimer's disease (AD). In 1906, Alzheimer reported a case of what he termed "presenile dementia" in a 51 year old patient at a psychiatric meeting in Southwest Germany. He recognized certain characteristics that he felt differentiated it from the usual diagnosis of dementia. First was the early onset of the disease in an otherwise healthy young woman. More importantly, however, were the histological changes he found in sections of brain tissue from the patient. Alzheimer described seeing amyloid (starch-like) plaques and coarsefibered proliferations of neurofibrils under the microscope. Several other researchers in years following reported similar findings of presenile dementia, and in 1910 a textbook of psychiatric disorders defined this form of dementia as "Alzheimer's disease." The eponym was adopted in the literature and became the standard. It is perhaps fitting since Alzheimer's original observations are still the main criteria of diagnosis for the disease. Web site: http://www.delphion.com/details?pn=US06369058__

156 Folic Acid

•

Carbonated fortified milk-based beverage and method of making carbonated fortified milk-based beverage for the supplementation of essential nutrients in the human diet Inventor(s): Clark; George H. (Woburn, MA), Clark; Mary Ann (Woburn, MA) Assignee(s): Mac Farms, Inc. (Burlington, MA) Patent Number: 6,403,129 Date filed: December 27, 1999 Abstract: Dairy or non-dairy based fortified carbonated beverage solutions that supply essential nutrients in the human diet. The solution contains per 354 ml, calcium, magnesium and potassium ions in the form of salts and optionally vitamins A, D, C and folic acid in specified amounts to provide dietary supplementation. Sweeteners, stabilizers, flavors and carbonation can also be added to enhance flavor, taste, mouthfeel, ingredient solubilization and product appearance. A method of making the beverages is also described. Excerpt(s): This invention relates to fortified, carbonated milk-based or non-dairy based beverages for the supplementation of essential nutrients in the human diet. More specifically, this invention relates to flavored, fortified, carbonated milk-based or nondairy based beverages and methods for making same for consumption by individuals of all ages to provide supplemental amounts of essential vitamins, amino acids, minerals and trace nutrients in the everyday diet. It is now well known that good nutrition is essential to the process of bone physiology. Poor dietary habits will prevent normal bone development in childhood and early adulthood and can contribute to the softening of bones and teeth as well as the acceleration of bone loss with advancing age. Milk has long been recognized as an excellent nutritional source of essential minerals such as calcium and magnesium, high quality protein and vitamins such as D, A, B.sub.2, B.sub.1, B.sub.6 and B.sub.12. Proper levels of these elements are essential in the diets of children and adolescents for the development and maintenance of healthy teeth and bones and to enhance growth; in adults to improve the tone and elasticity of muscles and ligaments. Such elements also assist in and promote healthy pregnancies, enhance appetite, and in the elderly, help to prevent osteoporosis, colon cancer and heart disease. Web site: http://www.delphion.com/details?pn=US06403129__

•

Cisplatin and folic acid administered to treat breast cancer Inventor(s): Shaw; Jiajiu (Ann Arbor, MI) Assignee(s): Unitech Pharmaceuticals (Ann Arbor, MI) Patent Number: 6,297,245 Date filed: July 21, 1999 Abstract: A novel pharmaceutical composition, comprising cisplatin and folic acid is disclosed. The preparation of this pharmaceutical composition is also disclosed. The composition may be used to treat cancers and Acquired Immune Deficiency Syndrome (AIDS). Excerpt(s): There is no Federally sponsored research and development in this application. Cisplatin (cis-diamminedichloroplatinum, cis-Pt(NH3)2Cl12, molecular weight 300.05) has been used as a chemotherapeutic agent for many years since the discovery of its anti-tumor activity by B. Rosenberg et al. (Nature, 1965, 205, 698; Nature,

Patents 157

1972, 222, 385). The physician's Desk Reference (PDR) reports that cisplatin (the commercial name is Platinol.RTM.) can be used to treat testicular cancer, ovarian cancer, and bladder cancer. Web site: http://www.delphion.com/details?pn=US06297245__ •

Color stable iron and zinc fortified compositions Inventor(s): Favre; Michel Lucien Hubert Lannelongue (Cincinnati, OH), Henry, Jr.; William John (Taylor Mill, KY), Li; Jianjun (West Chester, OH), Mehansho; Haile (Fairfield, OH), Mellican; Renee Irvine (Woodlawn, OH), Xi; Xiaobing (West Chester, OH) Assignee(s): The Procter & Gamble Co. (Cincinnati, OH) Patent Number: 6,358,544 Date filed: December 9, 1999 Abstract: The present invention relates to color and flavor improvements in iron and zinc supplemented dry beverage powders having fruit and/or botanical flavor. Vitamins such as the B vitamins, vitamin A, vitamin C, and vitamin E can be added to the dry beverage mix. The supplemented dry beverage mix can also contain iodine, niacin and folic acid. In particular, methods for fortifying dry beverage mixes with certain bioavailable zinc and iron compounds without producing reconstituted beverages having undesirable color or flavor are disclosed. Also disclosed are beverages and foods fortified preferably with amino acid chelated iron that do not impart objectionable color due to the inclusion of a ferric ion reducing agent such as ascorbic acid and/or an agent such as citric acid that is capable of preferentially complexing ferric ion in the presence of polyphenols or flavonoids that are typically present in these beverages or foods. Excerpt(s): The present invention relates to dry beverage mixes, ready-to-drink beverages and foods other than beverages supplemented with iron and optionally zinc compounds that have excellent bioavailability. The iron and zinc compounds herein do not cause an off-flavor/aftertaste, are stable, and overcome the problem of discoloration often caused by the addition of these minerals to foods and beverages. The compositions may also include vitamin A, vitamin C, vitamin E, the B vitamins, folic acid and iodine. The present invention further relates to beverages and foods fortified with iron, especially amino acid chelated iron, without imparting objectionable color. In many countries, the average diet does not contain sufficient levels of iron, zinc, iodine, vitamin A or the B vitamins. Iron deficiency is well documented. Although iron deficiency is one of the few nutritional deficiencies in the U.S., it is common in most developing countries. Recent evidence suggests that nutritional zinc deficiency may be common among the people of many developing countries where they subsist on diets of plant origin (e.g. cereal and legume). Marginal zinc deficiency may be widespread even in the U.S. because of self-imposed dietary restriction, use of alcohol and cereal proteins, and the increasing use of refined foods which decrease the intake of trace minerals. Iron and zinc deficiencies can be overcome by taking supplements. Other methods of addressing these deficiencies include increasing the intake of foods naturally containing these minerals or fortifying food and beverage products. Usually, in countries where the people suffer from these deficiencies, the economy is such that providing minerals and vitamins as a supplement is expensive and presents significant distribution logistics problems. In addition, compliance, i.e., having the people take the vitamin and mineral supplements on a daily basis, is a serious problem. Accordingly, the delivery of iron and

158 Folic Acid

zinc along with other vitamins and minerals in a form that has high bioavailability and at the same time a non-objectionable taste and appearance, and in a form that would be consumed by a high proportion of the population at risk is desirable. Web site: http://www.delphion.com/details?pn=US06358544__ •

Combination of benzoquinazoline antifolates and protecting agents Inventor(s): Duch; David Stanley (Cary, NC), Ferone; Robert (Raleigh, NC), Koch; Arthur (Bloomington, IN), Smith; Gary Keith (Raleigh, NC) Assignee(s): SmithKline Beecham Corporation (Philadelphia, PA) Patent Number: 6,358,952 Date filed: June 6, 1995 Abstract: The use of a protecting agent, for example a folate derivative such as folic acid or leucovorin, in combination with a non-competitive folic acid analogue, for example benzoquinazoline derivatives, for use in reducing the side effects associated with the administration of such non-competitive folic acid analogues, and pharmeceutical formulations comprising such combinations are disclosed. Excerpt(s): The present invention relates to novel combinations of non-competitive folic acid analogues with protecting agents, and to methods of treatment using these combinations. European Patent Application 0505640 provides a method for improving the therapeutic utility of GAR-transformylase inhibitors and other antifolates by coadministering a folate binding protein binding agent to the host undergoing treatment. Thymidylate synthase is an enzyme catalysing the terminal step in the de novo synthesis of thymidylate required for DNA synthesis. It has been postulated that inhibitors of this enzyme may be expected to have anti-tumour activity and it has been reported (Jones et al, J. Med. Chem. 1986, 22, 468) that the in-vivo antitumour activity of N.sup.10 propargyl-5,8-dideazafolic acid arises solely from its inhibitory effect on this enzyme. Web site: http://www.delphion.com/details?pn=US06358952__

•

Composition and method of use in treating sexual dysfunction using cGMP-specific phosphodiesterase type 5 inhibitors Inventor(s): Niazi; Sarfaraz K (20 Riverside Dr., Deerfield, IL 60015) Assignee(s): none reported Patent Number: 6,338,862 Date filed: March 26, 2001 Abstract: The inhibitors of cyclic guanosine monophosphate (cGMP) phosphodiesterases type 5 (cGMP-PDE5) such as sildenafil citrate (Viagra.RTM.) act by increasing the level of cGMP in sexual organs to produce enhanced blood flow and an erectile response of sexual organs. Though sildenafil citrate is a specific inhibitor of cGMP-PDE5, its effects on other body organs produce many side effects including fatalities. Described here is a method of combining cGMP-PDE5 inhibitors with natural sources of nutrients that instantly enhance the levels of endogenous cGMP and thus reduce the therapeutic dose and therefore the side effects of cGMP-PDE5 inhibitors. We have discovered that if sildenafil citrate, as a prototype of cGMP-PDE5, is combined with L-arginine, ginseng, vitamin B6, vitamin B12, and folic acid, all natural and safe ingredients, the dose

Patents 159

requirements for sildenafil citrate can be reduced substantially. The specific composition described here assists in the action of sildenafil primarily by increasing the production of cGMP through modulation of nitric oxide pathway (L-arginine.fwdarw.nitric oxide.fwdarw.cGMP) and secondarily by having its own effect on improving blood circulation to sexual organs. Excerpt(s): Adequate sexual function is a complex interaction of hormonal events and psychosocial relationships. The term "sexual dysfunction" generally includes any sexual dysfunction in an animal, preferably a mammal, more preferably a human. The animal can be male or female. Sexual dysfunction may include, for example, sexual desire disorders, sexual arousal disorders, orgasmic disorders and sexual pain disorders. Female sexual dysfunction refers to any female sexual dysfunction including, for example, sexual desire disorders, sexual arousal dysfunction, orgasmic dysfunction, sexual pain disorders, dyspareunia, and vaginismus. The female can be pre-menopausal or menopausal. Male sexual dysfunction refers to any male sexual dysfunction including, for example, male erectile dysfunction and impotence. There are four stages to sexual response as described in the International Journal of Gynecology & Obstetrics, 51(3): 26-77 (1995). The first stage of sexual response is desire. The second stage of sexual response is arousal. Both physical and emotional stimulation may lead to breast and genital vasodilation and clitoral engorgement (vasocongestion). In the female, dilation and engorgement of the blood vessels in the labia and tissue surrounding the vagina produce the "orgasmic platform," an area at the distal third of the vagina where blood becomes sequestered. Localized perivaginal swelling and vaginal lubrication make up the changes in this stage of sexual response. Subsequently, ballooning of the proximal portion of the vagina and elevation of the uterus occurs. In the male, vasodilation of the cavernosal arteries and closure of the venous channels that drain the penis produce an erection. The third stage of sexual response is orgasm, while the fourth stage is resolution. Interruption or absence of any of the stages of the sexual response cycle can result in sexual dysfunction. One study found that 35% of males and 42% of females reported some form of sexual dysfunction. Read et al, J. Public Health Med., 19(4): 387391 (1997). In both pre-menopausal and menopausal females, sexual dysfunction can include, for example, sexual pain disorders, sexual desire disorders, sexual arousal dysfunction, orgasmic dysfunction, dyspareunia, and vaginismus. Sexual dysfunction can be caused, for example, by pregnancy, menopause, cancer, pelvic surgery, chronic medical illness or medications. The vasculature, which serves erectile tissue in males and females, is similar. In particular, the arterial circulation of the erectile tissues of the genitalia derives from the common iliac artery which branches from the abdominal aorta. The common iliac artery bifurcates into the internal and external iliac arteries. The internal pudic artery arises from the smaller of two terminal branches of the anterior trunk of the internal iliac artery. In the female, the internal pudic artery branches into the superficial perineal artery, which supplies the labia pudenda. The internal pudic artery also branches into the artery of the bulb, which supplies the bulbi vestibuli, and the erectile tissue of the vagina. The artery of the corpus cavernosum, another branch of the internal pudic artery supplies the cavernous body of the clitoris. Still another branch of the internal pudic artery is the arteria dorsalis clitoridis, which supplies the dorsum of the clitoris and terminates in the glans and membranous folds surrounding the clitoris, which correspond to the prepuce of the male. In the male, the internal pudic artery branches into the dorsal artery of the penis (which itself branches into a left and right branch) and the artery of the corpus cavernosum, all of which supply blood to the corpus cavernosum. The dorsal artery of the penis is analogous to the artery dorsalis clitoridis in the female, while the artery of the corpus cavernosum in the male is analogous to the artery of the same name in the female.

160 Folic Acid

Web site: http://www.delphion.com/details?pn=US06338862__ •

Composition for reducing the risk or progression of cardiovascular diseases Inventor(s): Lang; Philip C. (Toms River, NJ), Sosnowski; Robert E. (Manasquan, NJ) Assignee(s): DexGen Pharmaceuticals, Inc. (Manasquan, NJ) Patent Number: 6,583,152 Date filed: April 30, 2001 Abstract: Elevated levels of homocysteine have been implicated as an important risk factor for cardiovascular and other diseases. A composition for decreasing levels of plasma homocysteine and a method for administering the composition are provided the composition containing dextromethorphan (DM), folic acid and vitamins B.sub.6 and B.sub.12. The composition provides a synergistic therapeutic effect so that lower amounts of the above ingredients may be employed to minimize any undesirable side effects caused by the use of high levels of a component such as DM. Preferred compositions for cardiovascular diseases further include lecithin, vitamin E, betacarotene, procyanidins/flavonoids, trimethylglycine, garlic oil and minerals. Other compositions for treating glaucoma include bilberry, bioflavonoids and beta-carotene and for treating tardive dyskinesia include an antioxidant such as grape seed extract and pine bark extract, lecithin and oligomeric proanthocyanidins. The compositions may be administered using any suitable means such as orally or intravenous. Excerpt(s): The present invention relates to a composition and method for reducing the risk or progression of cardiovascular, glaucoma and tardive dyskinesia diseases and, more particularly, to a composition containing a number of ingredients which are present in amounts lower than amounts considered harmful to the body but which act synergistically to provide enhanced disease inhibition. Cardiovascular disease is the most frequent cause of death in industrialized countries. Atherosclerosis (AS) is the principal cause of cardiovascular disease. AS is a disease of the intima of the arteries that leads to fatty lesions called artheromatous plaques on the inside surface of the arteries. This deposit of fat and cholesterol narrows the arteries, and often becomes calcified, providing sites for abnormal blood clots to form, leading to high blood pressure, heart attacks and strokes. Elevated plasma homocysteine (Hcy) concentrations have repeatedly been associated with increased vascular risk. Hcy causes cells to decrease their production of clot preventing and clot dissolving substances and increases production of clot promoting substances. Hcy is an intermediate sulfhydryl alpha-amino acid formed during conversion of methionine to cysteine. Web site: http://www.delphion.com/details?pn=US06583152__

•

Compounds for cardiovascular treatment comprising multi-vitamin and anti-platelet aggregating agents and methods for making and using the same Inventor(s): Abbott; John J. (1500 Redfern Dr., Pittsburgh, PA 15241), Heibel; Richard (20 N. Port Royal Dr., Hilton Head Island, SC 29928) Assignee(s): none reported Patent Number: 6,274,170 Date filed: February 18, 1999

Patents 161

Abstract: Compounds comprising multi-vitamins, zinc and an anti-platelet aggregating agent for the treatment of atherosclerotic cardiovascular disease (ASCVD) are disclosed. The compounds are provided in dosage form, and preferably include selected amounts of ascorbic acid, folic acid, vitamin E, vitamin B6 and vitamin B12. The anti-platelet aggregating agent preferably comprises aspirin. A protective coating is preferably provided between the aspirin and the other vitamin and mineral constituents. The dosages are effective in the treatment of ASCVD, and possess extended shelf lives. Excerpt(s): The present invention relates to compounds for the prevention and treatment of diseases such as atherosclerotic cardiovascular disease (ASCVD). More particularly, the present invention encompasses a comprehensive approach including the use of antiplatelet aggregating agents in conjunction with certain vitamins and minerals which, in combination, have a positive effect on normalizing elevated homocysteine levels in vivo, and which impact free radicals with the use of anti-oxidants implicated in the initiation of atherosclerotic cardiovascular disease. Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in most industrial countries. This disease involves large, medium and small arteries throughout the body. In addition to family history, the atherogenic risk factors are known to include smoking, hypertension, diabetes mellitus, cholesterol abnormalities and homocysteinuria. The presence of each additional risk factor markedly aggravates the potential for development of the disease. Although seemingly diverse, the risk factors all damage the artery wall and effect formation of thrombosis. In the aorta, the largest artery, the artery wall damage may lead to aortic aneurysm or embolism. ASCVD in medium and small arteries can result in sudden occlusion of the vessel or progressive narrowing of the arterial lumen. The symptoms of persons with this disease are dictated by the organs supplied by the effected arteries. Lumenal narrowing of the arteries supplying the heart with blood is called coronary artery disease (CAD). The symptoms include angina, unstable angina, myocardial infarction (MI) and sudden death. Cerebral vascular disease (CVD) symptoms include progressive neural deterioration, transient ischemic attack (TIA), seizures, and cerebral vascular accident (CVA), i.e., stroke. Kidney effects include hypertension, renal infarction and renal failure. Abdominal vascular insufficiency results in abdominal angina and bowel infarction. Peripheral vascular disease (PVD) symptoms include intermittent claudication, gangrene and amputation. Web site: http://www.delphion.com/details?pn=US06274170__ •

Dietary supplement nutrient soft drink composition with psychoactive effect Inventor(s): Pearson; Durk (P.O. Box 2160, Tonapah, NV 89049), Shaw; Sandy (P.O. Box 2160, Tonapah, NV 89049) Assignee(s): none reported Patent Number: 6,261,589 Date filed: March 2, 2000 Abstract: A composition and method for causing a positive psychoactive effect in which phenylalanine, vitamin B-6, vitamin C, copper, folic acid, taurine, vitamin B-5 (or provitamin B-5), choline, fruit sugar, caffeine, and optionally green tea are combined in a carbonated mixture. The mixture is orally administered in beverage form to support the production of and to stimulate release of neurotransmitters and neuromodulators in the brain and to enhance and modulate their effects to produce a positive psychoactive effect.

162 Folic Acid

Excerpt(s): The present invention relates to soft drinks and, more particularly, to an improved dietary supplement nutrient soft drink composition and method for taking the same to induce an uplifting psychoactive effect by promoting bodily production of noradrenaline, dopamine, acetylcholine and beta phenylethylamine. The most common complaint that doctors hear is that their patients don't have enough energy or feel tired most of the time. The cause is often a nutritional deficiency. A nutritional survey by the U.S. Department of Agriculture of 37,000 Americans (chosen to represent a cross-section of all Americans) found that over 80% of Americans are getting less than the FDA's recommended RDA for one or more nutrients that are essential for the production of noradrenaline and dopamine. A shortage of these essential nutrient enzyme co-factors results in chronic tiredness. It would be helpful to provide a nutritious, nonprescription, inexpensive and flavorful solution that can be administered in the form of a soft drink. There have been prior clinical attempts to find a solution. For example, U.S. Pat. No. 4,624,852 issued to Wurtman shows a process and composition for treating neurological disorders and aging by potentiating the effect of neurotransmitters in the brain. The process entails the concomitant administration of choline or a choline precursor, and an amino acid (which is a precursor to a neurotransmitter) such as tyrosine, tryptophan or threonine. This combination results in increased release of both their corresponding neurotransmitters, i.e., (a) acetylcholene and (b) dopamine, serotonin or glycine. The choline or choline precursor and amino acid are administered concomitantly to treat neurological disease including senility, Alzheimer's Disease or Parkinson's Disease. It is also said to be useful in normal older people, or younger people with obscure deficits in neurons releasing particular neurotransmitters. Web site: http://www.delphion.com/details?pn=US06261589__ •

Foliar fertilizer and method for using the same Inventor(s): Yamashita; Thomas T. (3631 Bogue Rd., Denair, CA 95316) Assignee(s): none reported Patent Number: 6,475,258 Date filed: September 25, 2000 Abstract: Foliar fertilizer compositions and methods for their use are provided. The subject compositions are aqueous solutions of at least one coenzyme, where the coenzyme(s) is preferably a vitamin B, and more preferably folic acid and/or pyridoxine, where in many preferred embodiments the compositions include both folic acid and pyridoxine. The subject compositions may further include at least one of a carbohydrate source, a complexing agent and a preservative. The subject foliar fertilizer compositions find use in enhancing the growth of a variety of plants through foliar application. Excerpt(s): The field of this invention is fertilizers. Fertilizers are materials that are used to supply elements needed for plant nutrition. Fertilizer materials may be in the form of solids, semi-solids, slurry suspensions, pure liquids, aqueous solutions and gases. Fertilizing materials may be introduced into a plant's environment in a number of different ways, including through addition to the soil, through application directly to a plant's foliage, and the like. The use of fertilizers is critical to commercial agriculture as fertilizers are essential to correct natural deficiencies and/or replace components in soil. In many instances, it is beneficial to apply a fertilizer directly to the foliage of a plant, i.e. to use a foliar fertilizer. Such instances include situations where a given soil has characteristics such that the transport properties of nutrients through the soil are poor.

Patents 163

In such instances, the use of a foliar fertilizing composition overcomes the soil disadvantages. Web site: http://www.delphion.com/details?pn=US06475258__ •

Folic acid and/or vitamin B12-lactoferrin complex Inventor(s): Harjinder; Singh (Massey University, NZ), Suguri; Toshiaki (Tokyo, JP), Uchida; Toshiaki (Kawagoe, JP) Assignee(s): Snow Brand Milk Products Co., Ltd. (Hokkai-do, JP) Patent Number: 6,500,472 Date filed: February 27, 2001 Abstract: Folic acid and/or vitamin B.sub.12 and lactoferrin are mixed to produce a folic acid and/or vitamin B.sub.12 -lactoferrin complex. The complex can be used for enriching foods or drink. Excerpt(s): The present invention relates to a complex in which lactoferrin holds folic acid and/or vitamin B.sub.12 (hereinafter referred to as folic acid and/or vitamin B12lactoferrin complex), a method for the production thereof, and use thereof. A folic acid and/or vitamin B.sub.12 -lactoferrin complex of the present invention is characterized in that folic acid in the complex exhibits improved photostability, acid tolerance and solubility as compared to folic acid present by itself, and vitamin B.sub.12 in the complex exhibits improved acid tolerance as compared to vitamin B.sub.12 present by itself, and accordingly is useful as a material for foods, drinks and medicines. Folic acid which was discovered as an antianemic factor a long time ago is one of the vitamins essential for the body. Further, various enzymes are known to require folic acid as a coenzyme. Also, folic acid is extensively involved in the metabolisms of nucleotides, glycine, histidine, or the like, and the biosyntheses of proteins. Pteroylglutamate, 7,8dihydropteroylglutamate, or the like and polyglutamin compounds thereof are also known as folic acid in a broad sense, and all of these compounds have physiological activities as folic acid. A deficiency in folic acid is known to cause abnormal myelopoietic functions (megaloblastic anemia), nervous disorder, intestinal dysfunction, or the like. Recently, the higher probability of newborns having abnormal neural tubes due to a nutrient deficiency in mothers during pregnancy having particularly attracted attention in Europe and the United States, it has been revealed that this risk can be reduced by administering folic acid (Czeizel, A. E., J. Pediat. Gastroenterol. Nutr., vol. 20, pp. 4-16, 1995). Furthermore, it has been reported that an increase in homocysteine, which is associated with heart diseases, and a depletion of folic acid in the serum occur simultaneously (Jacob, R. A., M. M. Wu, S. M. Henning & M. E. Swendseid, J. Nutr., vol. 124, p. 1072, 1994). It has been also reported that folic acid exerts a preventive effect on cancer, particularly epithelial cancer (Glynn, S. A., D. Albanes, Nutr. Cancer, vol. 22, p. 101, 1994). Thus, the importance of folic acid is being recognized again. Web site: http://www.delphion.com/details?pn=US06500472__

164 Folic Acid

•

Folic acid derivatives Inventor(s): Fuchs; Philip L. (West Lafayette, IN), Lantrip; Douglas A. (Lafayette, IN), Luo; Jin (West Lafayette, IN) Assignee(s): Purdue Research Foundation () Patent Number: 6,291,673 Date filed: April 17, 2000 Abstract: Novel folic acid derivatives and their use in preparation of.gamma.-esters of folic acid via a pteroyl azide intermediate are described. Folic acid.gamma.-esters are useful intermediates in the synthesis of folic acid conjugates capable of binding folate receptors in vitro and in vivo. Excerpt(s): This invention relates to the preparation of folic acid derivatives. More particularly this invention relates to a method of preparing.gamma.-esters of folic acid. A recent trend in cancer chemotherapy is the highly aggressive application of high-dose multiple drug treatment regimens at the earliest point of diagnosis. These protocols are limited by drug toxicity and severe physiological effects and patient fatalities are not uncommon. This situation has caused several members in the medical community to question whether the benefit/risk boundary has been exceeded with the agents currently available. Enhancement of the differential specificity of anticancer agents by selective targeting mechanisms might diminish such problems. The vitamin folic acid has attracted considerable attention as a potential means to selectively deliver covalently bound drug conjugates. Many human cancer cell lines have been found to have highly overexpressed membrane-associated folate receptor proteins which binds folic acid. Previously, it has been shown that the natural receptor-mediated endocytosis pathway for the vitamin folic acid can be exploited to selectively and non-destructively deliver folate-conjugated small molecules, macromolecules, and drug carriers such as liposomes into cultured tumor cells. When folate is covalently linked to a folate molecule via its.gamma.-carboxyl moiety, the affinity of the covalent conjugate for the folate cell surface receptor remains essentially unaltered. Further, following binding to the cell surface receptor, the conjugated folate is internalized by the cell in much the same manner as the unmodified vitamin. Recycling of the folate receptor can then lead to further accumulation of the folate conjugates in such target cells. Web site: http://www.delphion.com/details?pn=US06291673__

•

Folic acid supplement Inventor(s): Kirschner; Mitchell I. (St. Louis, MO), Levinson; R. Saul (Chesterfield, MO), Paradissis; George (St. Louis, MO) Assignee(s): DrugTech Corporation (Wilmington, DE) Patent Number: 6,261,600 Date filed: April 30, 1999 Abstract: The present invention is directed to novel chewable or dissolvable nutritional supplements for improving the absorption of folic acid in humans and other animals and methods of using said supplements. The nutritional supplements contain folic acid and non-toxic acid neutralizing alkaline compounds in chewable or dissolvable forms. Excerpt(s): The present invention is directed to novel chewable or dissolvable nutritional supplements in improved forms that optimize absorption of folic acid in humans and

Patents 165

other animals, and methods of using said supplements. The nutritional supplements are formulated with folic acid and non-toxic acid neutralizing alkaline compounds in chewable or dissolvable forms which provide highly absorbable or highly bioavailable forms of folic acid. Folic acid deficiency is the most common vitamin deficiency experienced by individuals in the U.S. See USP DI.TM. Drug Information for the Health Care Professional, 18.sup.th Ed., 1988. It is crucial that an adequate level of folic acid be maintained in the body because folic acid plays an especially important physiological role. Folic acid, also known as pteroylglutamic acid and vitamin B.sub.9, plays an important role in cell division, erythropoiesis and protein synthesis, all of which are processes very important to growing tissues. Folic acid is part of an enzyme complex that changes vitamin B.sub.12 into its active form and helps synthesize amino acids into the new DNA required for dividing cells. See Whitney, E. and Rolfe, S., Understanding Nutrition, 6.sup.th Ed., 311 (1993). Folic acid delivered to the body in food is often bound to glutamic acid, but the body prefers to absorb the folic acid in its "free" state. Therefore, folic acid has a low bioavailability. Id. In fact, only about half of dietary folic acid is available to the body. The Recommended Daily Allowance (RDA) for folic acid takes this low bioavailability into account. For example, in the U.S., the RDA for folic acid is as follows: 150-200 mcg for adult males, 150-180 mcg for adult females, 400 mcg for pregnant females, 260-280 mcg for lactating women and 25-50 mcg for infants and children. See Current Pediatric Diagnosis and Treatment, 13.sup.th Ed., 1997. Web site: http://www.delphion.com/details?pn=US06261600__ •

Fortified rice bran food product and method for promoting cardiovascular health Inventor(s): Hoffpauer; Diane Wright (P.O. Box 393, Crowley, LA 70526), Wright, lll; Salmon L. (POB 1425, Crowley, LA 70527) Assignee(s): none reported Patent Number: 6,436,431 Date filed: July 2, 2001 Abstract: A fortified rice bran food product for preventing and/or treating cardiovascular disease in animals, contains in admixture:(a) rice bran as a carrier;(b) at least about 12.5 milligrams of vitamin B.sub.1 per 30 grams of the rice bran;(c) at least about 250 milligrams of vitamin C per 30 grams of the rice bran;(d) at least about 12.5 milligrams of vitamin B.sub.6 per 30 grams of the rice bran;(e) at least about 75 micrograms of vitamin B.sub.12 per 30 grams of the rice bran;(f) at least about 100 International Units of vitamin E per 30 grams of the rice bran;(g) at least about 0.25 milligrams of folic acid per 30 grams of the rice bran; and(h) at least about 250 milligrams of omega-3-fatty acids per 30 grams of the rice bran.A method for preventing and/or treating cardiovascular disease in an animal involves orally administering a therapeutically effective amount of the fortified rice bran food product to the animal for a therapeutically effective period of time. Excerpt(s): This invention relates to a fortified food product which can be used as a dietary supplement or as an added ingredient for fortifying various food components. More particularly, this invention relates to a fortified rice bran food product that is capable of preventing and/or treating cardiovascular disease including, e.g., hypertension. In addition, this invention relates to a method of preventing and/or treating cardiovascular disease involving oral ingestion of the food product of this invention. Cardiovascular disease is a major health issue in the United States. Several compositions and methods have been developed over the years in an attempt to prevent

166 Folic Acid

or treat this disease. U.S. Pat. No. 6,126,943 (Cheruvanky et al.) discloses a method for reducing mammalian serum total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride levels, by ingesting a stabilized rice bran derivative selected from the group consisting of an enzyme treated stabilized rice bran, an insolubilized fraction and mixtures thereof. The patent teaches that the rice bran used therein is rich in B-complex vitamins, vitamin E and its isomers, minerals like potassium, magnesium, and phosphorous, and several potent antioxidants. Web site: http://www.delphion.com/details?pn=US06436431__ •

Hair growth stimulant Inventor(s): Olguin; Marsha E. (1065 W. Lomita Blvd., Space 396, Harbor City, CA 90710) Assignee(s): none reported Patent Number: 6,365,199 Date filed: August 10, 2000 Abstract: A hair growth formulation. The two basic main ingredients are castor oil and a special lemon extract. The special lemon extract is made from fresh lemon peel. The peel, including the bioflavonoids membrane, is blended with purified water until it is liquidified. Then the mixture is filtered through a sanitized cloth. Other ingredients that have been found helpful include: inositol, choline (from bitartate), niacinamide or nicotinic acid, manganese in chelated form, bioflavonoids, and folic acid. Finally perfume and sodium benzoate (as a preservative) can be added. Excerpt(s): The present invention relates to the field of scalp stimulation and in particular to the field of hair growth stimulants. There are many products on the market that claim to grow hair. Most do not. Products on the market that can actually grow hair are expensive and available only by prescription. Furthermore, cessation of use usually results in immediate hair loss. In other words, once a user starts using this prescription product, he or she must continue for life in order to maintain hair. In the past it was believed that, once the hair root would not produce a follicle, the root was dead and could not be restored. But little research has been done for periods of seven and up to eleven years after the hair root has failed to produced a shaft. Results produced with this invention have proved that there is a window of time in which one can, in fact, regenerate or revive the hair root. Web site: http://www.delphion.com/details?pn=US06365199__

•

Immune stimulating dietary supplement and method of use thereof Inventor(s): Meydani; Mohsen (Newton, MA), Meydani; Simin Nikbin (Newton, MA) Assignee(s): Trustees of Tufts College (Medford, MA) Patent Number: 6,642,259 Date filed: March 25, 2002 Abstract: The immune system of middle aged and elderly individuals is stimulated with a dietary supplement. The dietary supplement includes Vitamin E, Vitamin B6 and conjugated linoleic acid. The dietary supplement can further include glutathione alone or in combination with Vitamin C, folic acid, zinc, selenium, Vitamin D, copper and

Patents 167

Vitamin B12. The dietary supplement is administered to middle aged and elderly individuals in a suitable form for consumption by the individual. Suitable forms of consumption can include a snack bar, tablet, capsule, powder, drink, or dairy products. Excerpt(s): Immune responses gradually decline with increasing age. Coincident with a decline in immune responses is a concomitant increase in the incidence of tumor development, infection and inflammatory diseases in middle aged and elderly populations of individuals. ("Fundamental Immunology" ed. W.E. Paul, Raven Press, NY (1989); Miller, R. A., Exp. Gerontol. 29:21-35 (1994). Compromised nutritional status can contribute to the impaired immunological state and, hence, declining health of aging individuals. Thus, there is a need to develop convenient and effective methods that augment the nutritional requirements of middle aged and elderly individuals, thereby stimulating the immune system to combat disease. The present invention relates to a dietary supplement. It also is directed to a method to stimulate the immune system of middle aged and elderly individuals or to stimulate proliferation of a lymphocyte by administration of the dietary supplement. In one embodiment, the dietary supplement comprises Vitamin E, Vitamin B6 and conjugated linoleic acid. In a specific embodiment, the dietary supplement includes Vitamin E in an amount in a range of between about 10 milligrams and about 267 milligrams per milligram of Vitamin B6, and conjugated linoleic acid in an amount in a range of between about 17 milligrams and about 100 milligrams per milligram of Vitamin B6. In another specific embodiment, the dietary supplement further includes glutathione Vitamin C, folic acid, zinc, selenium, Vitamin D, copper, Vitamin B12 and glutathione. Preferably, the dietary supplement includes Vitamin C in an amount in a range of between about 17 milligrams and about 200 milligrams per milligram of Vitamin B6; folic acid in an amount in a range of between about 0.05 milligrams and about 0.2 milligrams per milligram of Vitamin B6; zinc in an amount in a range of between about 1.67 milligrams and about 10 milligrams per milligram of Vitamin B6; selenium in an amount in a range of between about 0.005 milligrams and about 0.02 milligrams per milligram of Vitamin B6; Vitamin D in an amount in a range of between about 0.0008 milligrams and about 0.005 milligrams per milligram of Vitamin B6; copper in an amount in a range of between about 0.00008 milligrams and about 0.0007 milligrams per milligram of Vitamin B6; Vitamin B12 in an amount in a range of between about 0.0002 milligrams and about 0.001 milligrams per milligram of Vitamin B6; and glutathione in an amount in a range of between about 4 milligrams and about 33 milligrams per milligram of Vitamin B6. Web site: http://www.delphion.com/details?pn=US06642259__ •

Infant formula Inventor(s): Bindels; Jacob Geert (Zoetermeer, NL), Boehm; Gunther (Echzell, DE), Georgi; Gilda (Friedrichsdorf, DE), Hageman; Robert Johan Joseph (Wageningen, NL), Sawatzki; Gunther (Munzenberg, DE), Wells; John Cowper Kingston (Gloucestershire, GB) Assignee(s): N.V. Nutricia (Zoetermeer, NL) Patent Number: 6,613,367 Date filed: October 24, 2001 Abstract: The invention relates to products for complete nutrition of infants. The products are characterized by the type and amount of protein and carbohydrate and the increased levels of folic acid, vitamin B6 and vitamin B12 or their functional equivalents. These products improve feelings of well-being of infants, especially those of

168 Folic Acid

young age, and are useful in the treatment and prevention of diseases that are associated with disorders of serotonin- and melatonin metabolism. Excerpt(s): The invention is related to infant formulae, i.e. artificial products for complete nutrition of infants, for improving feelings of well-being, compensation of immaturity and problems in the metabolic capacity of the infant. The nutritional products provide complete nutrition to the infant and their composition is characterised by a selected protein and carbohydrate composition and the increased amounts of folic acid, and vitamin B6 and B12 or their functional analogues. At present a large part of the population of babies in industrialised countries are fed with specialised infant formulae. It has been reported that consumption of these formulae is associated with several medical problems that may occur at young age, such as increased frequency of gastrointestinal problems and decreased immune status, but perhaps also at later age, because infants that are exclusively fed with human breast milk would score better on these parameters. It has also been reported that infants that are exclusively fed with these artificial formulae suffer from longer episodes of crying compared to those that are fed with human breast milk. This suggests a general feeling of discomfort due to perhaps hunger, pain or even medical problems. These problems may delay development of the child and produce concerns and practical problems to the parents. In a first aspect of the invention it is aimed to develop a new infant formula for complete nutrition that decreases the number of crying episodes and promotes sleeping behaviour for the child, especially for infants of young gestational age. Web site: http://www.delphion.com/details?pn=US06613367__ •

Method for preventing peripheral nerve damage Inventor(s): Herbert; Victor D. (NY, NY) Assignee(s): Upsher-Smith Laboratories, Inc. (Minneapolis, MN) Patent Number: 6,265,391 Date filed: April 14, 2000 Abstract: A vitamin B.sub.12 supplement composition comprising vitamin B.sub.12 with and/or without added folic acid that is essentially free of antioxidants, such as vitamin C, as well as iron is disclosed. Also disclosed are methods of using this vitamin composition to prevent brain and nervous system damage, such as peripheral nerve damage, as well as pernicious anemia, such as where such anemia is caused by a deficiency of vitamin B.sub.12 deficiency. Excerpt(s): Homocystinuria is characterized by high serum homocysteine levels and leads to blood vessel damage, excretion of homocysteine in the urine, mental retardation, ectopia lentis, sparse blonde hair, convulsive tendency, thromboembolic episodes, and fatty changes of liver and is associated with defective formation of cystathionine synthetase. Homocysteine is a homolog of cysteine and is produced by the demethylation of methionine, and is an intermediate in the biosynthesis of cysteine from methionine via cystathionine by cystathioninase. High serum homocysteine-related blood vessel damage may account for up to 20% of U.S. heart attacks, 40% of strokes and 60% of peripheral venous occlusions, in addition to those in the placenta associated with neural tube defects in about 2,000 infants a year. Web site: http://www.delphion.com/details?pn=US06265391__

Patents 169

•

Method for the prevention of struvite in fish Inventor(s): Graham, Jr.; Elwood E. (Castro Valley, CA) Assignee(s): Cargill Incorporated (Wayzata, MN) Patent Number: 6,379,730 Date filed: March 23, 2000 Abstract: The invention is directed to a method and composition for the prevention of struvite in containers such as cans. The method includes combining a water soluble vitamin selected from the group consisting of pantothenic acid, the calcium salt of pantothenic acid, vitamin B12, folic acid, niacin and mixtures thereof with the fish. The composition is a tablet comprising the water soluble vitamin and sodium chloride. Excerpt(s): This invention is directed to a method and composition for the prevention of struvite in canned fish. More particularly, the invention is directed to the prevention of struvite by adding a water soluble vitamin selected from the group consisting of pantothenic acid, the calcium salt of pantothenic acid, vitamin B12, folic acid, niacin and mixtures thereof into the canned fish. The invention is particularly effective in preventing struvite in canned salmon. The composition of the invention includes a tableted water soluble vitamin and sodium chloride. Small crystals resembling small pieces of broken glass frequently are found in canned fish, such as salmon. These crystals are transparent and tasteless particles of struvite which is magnesium ammonium phosphate. Struvite generally is regarded as harmless, but commercially is highly undesirable because struvite crystals may be confused with glass particles and result in product rejection by the consumer. It generally is thought that struvite is formed as a result of magnesium which exists from water used in and resulting from the processing of the fish. This water includes magnesium and phosphates. While it is known that the formation struvite can be minimized or prevented by the addition of acids such as citric acid, hydrochloric acid or acetic acid, or the addition of ascorbic acid in combination with citric acid, the addition of such acids can cause deleterious off flavors, and may require labeling problems in that the acids will be seen as an "unnatural" additive to the food. Web site: http://www.delphion.com/details?pn=US06379730__

•

Method for treating a subject afflicted with intestinal malabsorption Inventor(s): Ayling; June E. (Mobile, AL), Bailey; Steven W. (Mobile, AL) Assignee(s): South Alabama Medical Science Foundation (Mobile, AL) Patent Number: 6,451,360 Date filed: June 25, 2001 Abstract: A composition for human or animal consumption for supplying folate which includes a natural isomer of reduced folate, such as (6S)-tetrahydrofolic acid, 5-methyl(6S)-tetrahydrofolic acid, 5-formyl-(6S)-tetrahydrofolic acid, 10-formyl-(6R)tetrahydrofolic acid, 5,10-methylene-(6R)-tetrahydrofolic acid, 5,10-methenyl-(6R)tetrahydrofolic acid, 5-formimino-(6S)-tetrahydrofolic acid, and their polyglutamyl derivatives is disclosed. Such compositions include multivitamin preparations (with or without minerals and other nutrients); breakfast foods such as prepared cereals, toaster pastries and breakfast bars; infant formulas; dietary supplements and complete diet and weight-loss formulas and bars; animal feed (for example pet foods) and animal feed

170 Folic Acid

supplements (such as for poultry feed). The amount of the natural isomer of a reduced folate in a composition for human consumption can range between about 5% and about 200% of the daily requirement for folic acid per serving or dose. Excerpt(s): The present invention relates generally to the field of nutrition, and more specifically to food and vitamin preparations containing the natural isomer of reduced folates. The folates are ubiquitous to nearly all forms of life. Humans and many other animals lack the capacity to make their own folate which thus is an essential vitamin, one type of essential nutrient. Anemia especially during pregnancy and in the geriatric population was an early indication of a dietary requirement for folate. A major function of folate is to remove one-carbon units from molecules being metabolized and then deliver them to molecules being synthesized. As an example, folate participates in the formation of the nucleic acids. Further, the activity of DNA is controlled, in part, by methylation, and the primary methylating agent of the body (S-adenosylmethionine) is made in a metabolic cycle involving a folate. Many studies have, therefore, focused on the relationship of folate status to cancer susceptibility, especially colorectal adenoma. The importance of folate to proper growth is clearly evident in the occurrence of neural tube defects in newborn infants. Reports from several countries have shown that a majority of such cases are associated with low folate levels in the mother. The incidence of these defects as well as of cleft lip/palate is considerably reduced when women are given folic acid (I) starting early in pregnancy. Recently, a significant correlation has been discovered between vitamin deficiency, especially of folate, and peripheral vascular disease, a major cause of death. A high percentage of individuals with this affliction have abnormal blood levels of homocysteine, a precursor to methionine in the folate dependent step of the S-adenosylmethonine cycle. Folate deficiency has also been linked to defective maturation of a number of different cell types, to nervous system disorders, and to decreased immune response. Web site: http://www.delphion.com/details?pn=US06451360__ •

Method for treatment, preventing and reduction of elevated serum metabolite levels Inventor(s): Allen; Robert H. (Denver, CO), Stabler; Sally P. (Denver, CO) Assignee(s): Metabolite Laboratories, Inc. (Denver, CO) Patent Number: 6,297,224 Date filed: March 22, 1999 Abstract: A method for orally administering vitamin preparations is described which combine vitamin B.sub.12 (B.sub.12, cobalamin) and folic acid (folate), with and without pyridoxine (B.sub.6), for preventing and treating elevated serum homocysteine (HC), cystathionine (CT), methylmalonic acid (MMA), or 2-methylcitric acid (2-MCA) levels. These metabolites have been shown to be indicative of B.sub.12 and/or folic acid deficiencies. Further, it is likely that a B.sub.6 deficiency may be present with a B.sub.12 or folate deficiency. The method of the invention is also for use in lowering serum HC, CT, MMA, or 2-MCA in patients with or at risk for neuropsychiatric, vascular, renal or hematologic diseases. One embodiment of the invention is the use of a non-prescription formulation containing 2.0 mg B.sub.12 and 0.4 mg folic acid, with and without 25 mg B.sub.6. Another embodiment uses a prescription strength formulation containing 2.0 mg B.sub.12 and 1.0 mg folic acid, with and without 25 mg B.sub.6. The method of the present invention eliminates the costly and time consuming steps of distinguishing between vitamin deficiencies once a deficiency is found by measurement of serum metabolite levels. The present invention is of particular benefit to the populations at risk

Patents 171

for elevated serum metabolite levels, such as the people over the age of 65, and populations that have or are at risk for neuropsychiatric, vascular, renal and hematologic diseases. Excerpt(s): This invention relates to the field of nutrition. Specifically, the invention is comprised of new oral vitamin preparations combining vitamin B.sub.12 (B.sub.12, cobalamin) and folic acid (folate), and vitamin B.sub.12, folate, and pyridoxine (B.sub.6) for use in patients with elevated serum metabolite levels of homocysteine (HC), cystathionine (CT), methylmalonic acid (MMA), or 2-methylcitric acid (2-MCA). The elevation of these metabolites has been shown to be indicative of tissue deficiencies of B.sub.12 and/or folate and/or B.sub.6, and related to increased risk of neuropsychiatric, vascular, renal and hematologic diseases. One embodiment of the present invention uses a non-prescription formulation comprising between 0.3-10.0 mg B.sub.12 and 0.1-0.4 mg folate, with the preferred embodiment using 2.0 mg B.sub.12 and 0.4 mg folate. Another embodiment of the non-prescription formulation uses 0.3-10 mg B.sub.12, 0.1-0.4 mg folate, and 5-75 mg B.sub.6, with the preferred embodiment using 2.0 mg B.sub.12, 0.4 mg folate, and 25 mg B.sub.6. Another embodiment of the present invention uses a prescription strength formulation comprising between 0.3-10.0 mg B.sub.12 and 0.4-1.0 mg folate, with the preferred embodiment using 2 mg B.sub.12 and 1.0 mg folate. In a further embodiment of the present invention, a prescription strength formulation is used comprising 0.3-10 mg B.sub.12, 0.4-1.0 mg folate, and 5-75 mg B.sub.6, with the preferred embodiment using 2 mg B.sub.12, 1.0 mg folate, and 25 mg B.sub.6. The formulations of the present invention eliminate the costly and time-consuming steps of distinguishing between vitamin deficiencies once a deficiency is found by measurement of serum metabolite levels. The present invention is of particular benefit to the populations at risk for tissue deficiencies of B.sub.12, folate, and B.sub.6, such as people over the age of 65, and populations that have or are at risk for neuropsychiatric, vascular, renal and hematologic diseases. Vitamins B.sub.12, folate, and B.sub.6 are required cofactors in metabolic pathways involving methionine, homocysteine, cystathionine, and cysteine. B.sub.12 in the form of 5'-deoxyadenosylcobalamin is an essential cofactor in the enzymatic conversion of methylmalonylCoA to succinylCoA. The remethylation of homocysteine (HC) to methionine catalyzed by methionine synthase requires folate (methyltetrahydrofolate) and B.sub.12 in the form of methylcobalamin. HC is condensed with serine to form cystathionine (CT) in a reaction catalyzed by cystathionine.beta.-synthase which requires B.sub.6 (pyridoxal phosphate). CT is hydrolyzed in another B.sub.6 -dependent reaction to cysteine and.alpha.ketobutyrate. It is important to diagnose and treat B.sub.12, folate, and B.sub.6 deficiencies because these deficiencies can lead to life-threatening hematologic abnormalities which are completely reversible by proper treatment. B.sub.12 deficiency is a multisystem disorder with extremely varied clinical presentation which has been thought to occur in 0.4% of the population, e.g., about 1 million people in the United States. Symptoms of B.sub.12 deficiency include significant anemia, displayed for example in decreased hematocrit (e.g., <25%) or hemoglobin (e.g.,.ltoreq.8 g %), with macrocytic red blood cells (i.e., mean cell volume generally greater than 100 fl), or neurologic symptoms of peripheral neuropathy and/or ataxia. See, for example, Babior and Bunn (1983) in Harrison's Principles of Internal Medicine, (Petersdorf et al., eds.), McGraw-Hill Book Co., New York; Lee and Gardner (1984) in Textbook of Family Practice, 3rd Ed. (Rakel, ed.), Saunders & Co., Philadelphia). The hematological abnormalities seen are due to intracellular folate deficiency since folate is required for a number of essential enzymatic reactions involved in DNA and RNA synthesis and since the form of folate in serum (5-methyltetrahydrofolate) must be metabolized to tetrahydrofolate by the B.sub.12 -dependent enzyme methionine synthase before it can

172 Folic Acid

be utilized by the RNA- and DNA-related enzymes. While it has been well recognized that individuals with B.sub.12 deficiency could display neurologic disorders in the absence of anemia, such situations were believed to be exceptional and rare. See, Beck (1985) in Cecil Textbook of Medicine, 17th Ed., (Wyngaarden and Smith, eds.), W. B. Saunders, Philadelphia, pp. 893-900; Babior and Bunn (1987) in Harrison's Principles of Internal Medicine, 11th Ed. (Braunwald et al., eds.) McGraw-Hill, New York, pp. 14981504; Walton (1985) in Brain's Diseases of the Nervous System. 9th Ed., Oxford University Press, Oxford, UK. The neurologic symptoms of B.sub.12 deficiency were considered to be late manifestations of the disease most typically occurring after the onset of anemia or, if they occurred first, were soon to be followed by the onset of anemia. See, Woltmann (1919) Am. J. Med. Sci. 157:400-409 Victor and Lear (1956) Am. J. Med. 20:896-911. Web site: http://www.delphion.com/details?pn=US06297224__ •

Nutritional composition containing methionine Inventor(s): Hageman; Robert Johan Joseph (Waddinxveen, NL) Assignee(s): N. V. Nutricia (Zoetermeer, NL) Patent Number: 6,544,547 Date filed: January 31, 2000 Abstract: An enteral food composition for clinical or dietary use, comprises, in addition to carbohydrates and proteins or their hydrolysates the following components or their nutritional equivalents, per daily dosage: methionine (0.6-7 g), cysteine (0.5-2.5 g), folic acid (0.4-8 mg), pyridoxal (vitamin B.sub.6) (3-20 mg), zinc (18-120 mg) and at least 400 kcal energy in the form of carbohydrates. These amounts are well above the Recommended Daily Allowance (RDA) values. Further preferred components include lecithin, cyanocobalamine, betaine and magnesium, as well as transsulfuration metabolites, ATP enhancers and antioxidants. Excerpt(s): The present invention relates to a module of nutritional components which supports total methionine metabolism in man, for use in a universal medicinal food. The invention also relates to food products containing this module and to a method of producing food products by using selected amounts of the module. Methionine is metabolised in man via a multi-step pathway, the transsulfuration pathway. Several intermediate products are formed in this pathway, which play a dominant role in other biochemical pathways as well. For example, the reaction product S-adenosyl methionine is extensively used in many methylation reactions; homocysteine is the main methyl acceptor in folate metabolism and also the conversion of betaine to dimethylglycine (via methylation of homocysteine) strongly influences folate metabolism. Another intermediate in the transsulfuration pathway is cystathionine generated by reaction between homocysteine and serine, that may split into cysteine and 2-oxy-butyrate. The latter is involved in the metabolism of several other compounds (e.g. threonine). Cysteine is metabolised to various useful products such as taurine and sulphates. It is also an important precursor for glutathione in the liver and some other tissues. Glutathione that is produced in the liver has to be transported to cell compartments in some peripheral organs in order to exhibit its activity. Intracellular glutathione levels are in turn strongly influenced by the presence of reducing equivalents and amino acids in the cell. Web site: http://www.delphion.com/details?pn=US06544547__

Patents 173

•

Nutritional methyl supplements change DNA methylation and related characteristics of mammalian offspring Inventor(s): Cooney; Craig Anthony (12413 Timberr Bend Dr., Little Rock, AR 72211), Wolff; George Louis (2802 Millbrook Rd., Little Rock, AR 72227) Assignee(s): none reported Patent Number: 6,541,680 Date filed: June 11, 1999 Abstract: Increasing methylation of DNA in an unborn offspring of a pregnant mammal results in changing the epigenetically determined phenotype of the unborn offspring, inhibiting parasitic DNA sequences in the unborn offspring, and/or reducing susceptibility to tumor formation in the unborn offspring. Increased methylation is achieved by administering to the pregnant mammal a pharmaceutical composition which includes at least three of the following: Choline, Betaine, Folic acid, Vitamin B.sub.12, L-Methionine, and Zinc. The effective amount for each of these ingredients is: about 5-15 g/kg diet/day of Choline, about 5-15 g/kg diet/day of Betaine, about 5-15 mg/kg diet/day of Folic acid, about 0.5-1.5 mg/kg diet/day of Vitamin B.sub.12, about 0 to 7.5 g/kg diet/day of L-Methionine, and about 0 to 150 mg/kg diet/day of Zinc. Excerpt(s): The invention relates generally to a dietary supplement that increases DNA methylation, methods for altering the phenotype of offspring using the supplement, and methods for inhibiting retroviral expression using the supplement. The invention also relates to an animal model for epigenetic regulation of phenotypic expression. The maternal reproductive tract, arguably, is the environment most critical to the developing mammalian embryo. Its metabolic and physiologic characteristics modulate the zygote's development through all embryonic stages until birth. Indeed, the conditions in the embryo's immediate milieu seem to determine many characteristics and susceptibilities of the adult organism. Mammalian development is dependent on DNA methyltransferase (MTase) and its product 5-methylcytosine (5MC) to help establish, define, or stabilize the various cell types that constitute the developing embryo. In mammals, 5MC is a major epigenetic mechanism, with some 5MC patterns being inherited epigenetically. DNA MTase requires S-adenosylmethionine (SAM) and uses zinc as a cofactor. Web site: http://www.delphion.com/details?pn=US06541680__

•

Nutritional system for nervous system disorders Inventor(s): Foreman; David J. (Chesterfield, VA) Assignee(s): C & D Foreman, Inc. (Chesterfield, VA) Patent Number: 6,399,114 Date filed: May 24, 2001 Abstract: A novel composition for treating nervous system disorders. The composition is formed by preparing a mixture comprising an effective amount of vitamin B-6, folic acid, vitamin C, magnesium, vitamin B-3, copper, probiotics, fructo-oligosaccharide (FOS), betaine, pancreatin, papain, pepsin, vitamin B-1, vitamin B-2, vitamin B-12, biotin, pantothenic acid, chromium polynicotinate and a digestive support ingredient selected from the group consisting of dandelion root, juniper, aloe vera, burdock, ginger

174 Folic Acid

root, artichoke, and kelp. Other ingredients may include: beta carotene, vitamin E, selenium, zinc, sea vegetation, alfalfa, trace minerals and molybdenum. Excerpt(s): The present invention pertains to the field of nutritional formulas. Specifically, the present invention pertains to an improved formula for nervous system disorders. There are many disorders that affect the proper functioning of the nervous system. Examples of these disorders include autism, ADD, ADHD, hyperactivity disorder, and depression. People who suffer from these disorders often have common secondary symptoms including allergies, sluggish digestion, weak immune function and poor diet. Treatment for these various nervous system disorders include the use of synthetic drugs. Specifically, for ADD and ADHD mild central nervous system stimulant drugs such as Ritalin.RTM., Cylert.RTM. and Dexedrine.RTM. have been used. These drugs are not always successful. Moreover, such drugs may lead to undesirable side effects such as loss of appetite, insomnia, headaches, stomachaches, drowsiness and cardiac arrhythmia. Web site: http://www.delphion.com/details?pn=US06399114__ •

Oral combinations of hydroxocobalamin and folic acid Inventor(s): Gouaille; Christina (Helsingborg, SE), Horrobin; David Frederick (Stirling, GB) Assignee(s): Kilgowan Limited (Douglas Isle of Man, GB) Patent Number: 6,369,041 Date filed: March 23, 2000 Abstract: A variety of conditions is known wherein vitamin B.sub.12 is deficient, or wherein the administration of vitamin B.sub.12 is beneficial.Classically, once detected and if appropriate, these have been treated by the parenteral administration of vitamin B.sub.12 as oral administration is believed to be ineffective. Available oral preparations of vitamin B.sub.12 all contain cyanocobalamin which is less desirable than hydroxocobalamin.In accordance with the invention, effective oral formulations are provided which include, in addition to the hydroxocobalamin, folic acid or other folate precursor. The formulation for oral administration should be such as to provide, for a given daily dose, 0.5 to 59 mg hydroxocobalamin and 0.5 to 50 mg folic acid. Excerpt(s): This invention relates to the field of treating vitamin deficiency conditions and to preparations for use in such treatment. Vitamin B.sub.12 is a cobalt-containing vitamin which is involved in a number of biochemical reactions. The two most important are the conversion of homocysteine to methionine and the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A. Homocysteine is potentially harmful to many body tissues, including the vascular system and the nervous system, if it is present in excess. Methionine is required for the formation of S-adenosylmethionine which is used as a methyl donor in many different essential reactions including the regulation of DNA and RNA function and the synthesis of phospholipids, neurotransmitters and complex carbohydrates. The formation of succinyl-coenzyme A is required for the normal metabolism of fats and carbohydrates. It is thus apparent that an inadequate supply of vitamin B.sub.12 will lead to many different abnormalities in the body. The best known are the haematological abnormality of megaloblastic anaemia, and neurological damage which can lead to fatigue and to a range of neurological and psychiatric symptoms which are caused by loss of neuronal function proceeding to neurodegeneration. Vitamin B.sub.12 has a particularly close interaction with folic acid.

Patents 175

The conversion of homocysteine to methionine is achieved by the enzyme methionine synthetase where methyl-cobalamin plays an essential role. A required co-factor for this enzyme is folic acid in the form of 5-methyltetrahydrofolate: in the course of the reaction a methyl group is transferred from 5-methyltetrahydrofolate to homocysteine, so producing tetrahydrofolate and methionine. As a result of this reaction deficiencies of folic acid and of vitamin B.sub.12 interact. This interaction is important both in the lowering of homocysteine and in the generation of S-adenosyl-methionine for methylation reactions. Web site: http://www.delphion.com/details?pn=US06369041__ •

Pharmaceutical or dietetic preparation for improvement of fertility and sperm quality Inventor(s): Hageman; Robert Johan Joseph (Waddinxveen, NL), Nieuwenhuizen; Arie (Wageningen, NL), Steegers-Theunissen; Regine Patricia Maria (Nijmegen, NL) Assignee(s): N.V. Nutricia (Zoetermeer, NL) Patent Number: 6,576,634 Date filed: July 7, 2000 Abstract: A composition for improving the fertility of a male, and/or for improving the quality of the semen produced by a male includes at least one source of folic acid, preferably 0.05-8 mg; at least one source of zinc, preferably 5-50 mg; and optionally one or more of vitamin B12, magnesium, betaine, choline, SAM, vitamin B2, and Vitamin B6; and/or optionally one or more carriers, excipients and/or adjuvants. Excerpt(s): The present invention relates to preparations and compositions for improving the fertility of, and/or for improving the quality of the semen produced by, male individuals of mammalian species, including but not limited to human beings. More in particular, the invention concerns a pharmaceutical or dietetic preparation that after oral intake can increase fertility and improve sperm quality in male animals in general and men in particular. The preparations and compositions of the invention can inter alia be used to prevent and/or treat, in male individuals of mammalian species including but not limited to human beings, low fertility, disorders in fertility and/or conditions of poor semen quality, including but not limited to phenomena such as low sperm count, aberrations in morphology of the sperm cells, low motility of the sperm cells, or generally low sperm quality. Web site: http://www.delphion.com/details?pn=US06576634__

•

Pharmaceutical preparation for treating or preventing cardiovascular or neurological disorders by modulating of the activity of nitric oxide synthase Inventor(s): Moser; Rudolf (Schaffhausen, CH), Rabelink; Ton J. (Utrecht, NL) Assignee(s): Eprov AG (Schaffhausen, CH) Patent Number: 6,544,994 Date filed: June 7, 2000 Abstract: The invention relates to the use of at least folic acid or a folate and tetrahydrobiopterin (BH.sub.4) or derivatives thereof for treating or preventing cardiovascular or neurological disorders by modulation of the activity of nitric oxide synthase (NOS). The present invention also relates to the use of at least folio acid or a

176 Folic Acid

folate and tetrahydrobiopterin (BH.sub.4) or derivatives thereof for the production of a pharmaceutical preparation suitable for influencing the nitric oxide (NO) level, particularly by modulation of the activity of nitric oxide synthase (NOS) by reducing superoxide (O.sub.2.) production and enhancing nitric oxide (NO) synthesis. This effect occurs in absence of negative changes in other risk factors, e.g. lipids, blood pressure and homocysteine. Clinical areas of application include all anomalies of the nitric oxide level, particularly the prevention and treatment of cardiovascular and of neurological disorders. The present invention also relates to pharmaceutical preparations comprising at least one compound selected from the group consisting of 5-formyl-(6S)tetrahydrofolic acid, 5-methyl-(6S)-tetrahydrofolic acid, 5,10-methylene-(6R)tetrahydrofolic acid, 5,10-methenyl-(6R)-tetrahydrofolic acid, 10-formyl-(6R)tetrahydrofolic acid, 5-formimino-(6S)-tetrahydrofolic acid or (6S)-tetrahydrofolic acid or pharmaceutically compatible salts thereof, together with tetrahydrobiopterin (BH.sub.4) and with pharmaceutically compatible active and adjuvant substances, such as L-arginine, for influencing the nitric oxide (NO) level. Excerpt(s): Within this text the term a folate or a derivative thereof, if not explicitly defined otherwise, always refers to the natural and unnatural stereoisomeric form of each substance, pharmaceutically compatible salts thereof and any mixtures of the isomers and the salts. As drugs, tetrahydrofolates have predominantly been used hitherto as the calcium salt of 5-formyl-5,6,7,8-tetrahydrofolic acid (leucovorin) or of 5methyl-5,6,7,8-tetrahydrofolic acid (MTHF) for the treatment of megaloblastic folic acid deficiency anemia, as an antidote for increasing the compatibility of folio acid antagonists, particularly of aminopterin and methotrexate in cancer chemotherapy ("antifolate rescue"), for increasing the therapeutic effect of fluorinated pyrimidines and for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis, for increasing the compatibility of certain antiparasitic agents, for instance trimethoprimsulfamethoxazole, and for decreasing the toxicity of dideazatetra-hydrofolates in chemotherapy and for influencing the homocysteine level, particularly for assisting the remethylation of homocysteine. The term tetrahydrobiopterin (BH.sub.4) or a derivative thereof, if not explicitly defined otherwise, always refers to all natural and unnatural stereoisomeric forms of tetrahydrobiopterin, pharmaceutically compatible salts thereof and any mixtures of the isomers and the salts. The term tetrahydrobiopterin also includes any precursors of tetrahydrobiopterin, especially 7,8-dihydrobiopterin. (6R)tetrahydrobiopterin is a naturally occuring cofactor of the aromatic amino acid hydroxylases and is involved in the synthesis of the three common aromatic amino acids tyrosine, phenylalanine, tryptophan and the neurotransmitters dopamine and serotonin. It is also essential for nitric oxide synthase catalysed oxidation of L-arginine to Lcitrullin and nitric oxide. Tetrahydrobiopterin is involved in many other biochemical functions, many of which have been just recently discovered. Web site: http://www.delphion.com/details?pn=US06544994__ •

Preparation in particular for use as a medication and/or food supplement Inventor(s): Engel; Dieter (Zuzwil, CH), Kokkinis; Georg (Freidorf, CH) Assignee(s): Peter Greither (Kirchberg, CH) Patent Number: 6,368,621 Date filed: July 27, 2000 Abstract: The present invention relates to a preparation which contains at least one physiologically effective iron complex and at least one polyunsaturated fatty acid in free

Patents 177

or chemically bonded form, in particular for use as a medication and/or food supplement. The preparation according to the invention may be preferably used for manufacturing a medication and/or food supplement for treating or the prevention of deficiency symptoms as they may occur during pregnancy and breastfeeding. Furthermore antioxidizing agents and folic acid may be contained in the preparation according to the invention. Excerpt(s): I claim priority under 35 U.S.C.sctn. 119 for European application Nr. 99810681.9-2114 which is hereby incorporated by reference in its entirety and for all purposes. The invention relates to a preparation according to the preamble of claim 1, in particular for the use as a medication and/or as a food supplement. The human body relies on the supply of a series of essential substances which it is not in the position to synthesise itself. There is a risk of an under-nourishment of these substances with an insufficient or one-sided food intake. In spite of a sufficient and balanced food intake, an undersupply of certain substances may occur under certain stress situations. Stress situations occur to the first degree with particular physical exertion, such as for example with serious sports, or also during pregnancy and breastfeeding. Web site: http://www.delphion.com/details?pn=US06368621__ •

Process to modulate disease risk with doses of a nutraceutical Inventor(s): Block; Jerome Bernard (Rancho Palos Verdes, CA), Evans; Steven (Omaha, NE) Assignee(s): Genetic Services Management, Inc. (Omaha, NE) Patent Number: 6,630,160 Date filed: September 5, 2000 Abstract: A dietary supplement is created, comprised of material from the following nutrients, vitamins, herbs, minerals, and food and plant substances and food and plant derivatives: lycopene, vitamin E, selenium, green tea, coenzyme Q10, garlic, folic acid, vitamin C, curcumin, seaweed, Cordyceps sinsensis mushroom, Lentinus edodes (shiitake) mushroom, and Ganoderma lucidum (reishi) mushroom. The composition is administered orally for individuals who wish to reduce their risk of disease, particularly cancer-risk. Excerpt(s): Cancer care is reported to have cost Americans more than $110 billion in 1992, more than 11% of all expenditures spent on diseases in America. Researchers have indicated that from 50-90% of all cancers could be prevented through proper nutrition. There has evolved a new professional descriptive term "nutraceuticals" which combines the term "nutrient" and the term "pharmaceuticals" to describe this genre of medicinal agents that may be comprised of one or more complex combinations of ingredients made from nutrients, vitamins, minerals, herbs, and food and plant derivatives. We shall employ this term "nutraceutical" to refer to such a composition of one or more ingredients. This invention addresses the need for a dietary supplement that can reduce risk of disease, particularly cancer risk, that will be efficacious for a significant segment of the population. There have been tests and clinical trials on numerous individual agents for their role as cancer preventatives, such as coenzyme Q10 or selenium, but the daunting task of intelligently combining complex compositions has precluded exploration of complex compositions of nutraceuticals for cancer risk reduction. Thus in the past, one single ingredient would be selected and tested for its role as a cancer preventative for some specific cancer, usually in individuals who already had cancer.

178 Folic Acid

For example, selenium was tested for cancer prevention in patients who had had carcinoma of the skin [Clark, L. C., Combs; G. F., Jr., Turnbull, B. W., Slate, E. H., Chalker, D. K., Chow, J., Davis, L. S., Glover, R. A., Graham, G. F., Gross, E. G., Krongrad, A., Lesher, J. L., Park, H. K., Sanders, B. B., Jr., Smith, C. L., Taylor, J. R. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. JAMA. 276 (24): 1957-1963, Dec. 1996]. Similarly the effects of coenzyme Q10 suggested possible efficacious results in limited case studies with individuals with breast cancer [Lockwood, K., Moesgaard, S., Folkers, K. Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10. Biochem Biophys Res Comm. 199: 1504-1508, 1994]. However researchers as noted have been preoccupied with traditional experimental design methodology whereby these investigators wish to determine whether one specific ingredient is effective or not, usually for one specific cancer, and even then, as a treatment rather than a preventative. Another reason single individual ingredients were selected is because researchers have focused on just one of the following biologic, cancer-fighting, etiologically-oriented domains of interest: (1) anti-tumor activity, or (2) immune stimulating activity, or (3) anti-viral activity, or (4) anti-inflammatory activity, or (5) antimutagenic activity, or (6) antiproliferative activity, or (7) anti-free-radical development. This micro-focus has precluded the realization that by combining all those ingredients which work for one subset or another of the population, for one type of cancer or another, for one etiological reason or another, a powerful net effect can be achieved, along with the synergy of the ingredients working together. The present invention provides a complex composition (a "nutraceutical") comprising material from known nutrients, vitamins, herbs, minerals, and food and plant substances and food and plant derivatives which are useful to reduce risk of disease, particularly cancer risk, for one or more of all the known etiological factors that affect cancer development and hence yields cancer prevention for the consumer of this nutraceutical. This nutraceutical profoundly reduces risk of cancers through the multiple actions of all the etiological factors addressing cancer-causing conditions, such as providing (1) anti-tumor activity, and (2) immune stimulating activity, and (3) anti-viral activity, and (4) anti-inflammatory activity, and (5) antimutagenic activity, and (6) antiproliferative activity, and (7) anti-free-radical development. The nutraceutical is comprised of lycopene, vitamin E, selenium, green tea polyphenols, Coenzyme Q-10, garlic, folic acid, vitamin C, curcumin, seaweed, Cordyceps sinsensis mushroom, Lentinus edodes (shiitake) mushroom, and Ganoderma lucidum (reishi) mushroom. Preferably the material from each of such entries is in dried powder form. Web site: http://www.delphion.com/details?pn=US06630160__ •

Scours treatment and method of making same Inventor(s): McKinney; Randy R. (Grangeville, ID) Assignee(s): Bovine Health Products, Inc. (Grangeville, ID) Patent Number: 6,365,152 Date filed: March 15, 2001 Abstract: A new and improved formulation and method for making same, for a treatment for scours in farm animals is provided. More particularly, the present invention relates to a treatment which enables rapid relief of symptoms in an affected animal with a mortality of 1% or less by providing trace organic minerals in microgram quantities which act as nutrients for the animal. The treatment provides further

Patents 179

nutritional requirements in the form of vitamin A, folic acid and vitamin D.sub.3 supplements, cobalt amino acid chelates and dried kelp, a source of minerals, amino acids, simple and complex carbohydrates, iodine and fiber. In addition, a bacterial innoculum consisting of Acidophilus species is introduced which would inhibit growth of pathogenic or opportunistic species of bacteria by competition for nutrients as well as providing for required vitamins as a by-product of metabolism. Excerpt(s): The present invention relates to a new and improved scours treatment for young animals and method of using it. More particularly, the present invention relates to a composition composed of two groups of compounds, when combined and properly administered to young animals suffering from diarrhea, infectious diarrhea, scours and dehydration, acts to rapidly relieve the symptoms associated with the disease. The compounds utilized in the two groups radically depart from conventional treatments. Cattle are a major source of protein and wealth in a major portion of the world today. With a number of third world countries struggling to feed a growing number of impoverished people, affordable, efficient treatments for common diseases of cattle are becoming increasingly important. Calf scours complex is a worldwide malady affecting calves ranging from birth to three weeks of age with a high mortality rate in untreated cases. Dairy calves are weaned at 3 weeks to 90 days. At the time of weaning, young calves are stressed by the change in diet and other conditions. A significant percentage of calves develop diarrhea, a condition generally referred to as scours. Even in treated calves, there is still an unacceptably high rate of mortality. The loss of young livestock to this cause is a substantial burden to the livestock industry worldwide. Web site: http://www.delphion.com/details?pn=US06365152__ •

Treatment and prevention of cardiovascular diseases, heart attack, and stroke, primary and subsequent, with help of aspirin and certain vitamins Inventor(s): Weissman; Donald L. (P.O. Box 15927, Beverly Hills, CA 90209) Assignee(s): none reported Patent Number: 6,323,188 Date filed: September 10, 1999 Abstract: Disclosed is the method of reducing the incidence and severity of stroke, primary heart attack, and any subsequent heart attack or stroke in humans by daily administration of an effective amount of a combination of acetylsalicylic acid (ASA),a cyanocobalamin compound (Vitamin B12), a folic acid compound, and a pyridoxine compound (Vitamin B6) in an easy to take daily administration pack. Excerpt(s): This invention relates to a combination of aspirin, certain B vitamins and folic acid to prevent and or decrease cardiovascular diseases, heart attack and stroke, to a stable daily administration pack for such combination to facilitate the patient's compliance with recommendation or instruction to take such combination, and to the method of treating and preventing cardiovascular diseases with the help of such combination. Cardiovascular disease ranks as the leading cause of mortality and morbidity in the United States today. This year, it is estimated that 1.5 million people will have a heart attack and that one third of those will die as a result of CAD. The American College of Cardiology recently identified other abnormalities as factors for which intervention is likely to lower stroke and heart disease risk. Elevated total blood cholesterol is frequently considered a risk factor for coronary artery disease (CAD), but

180 Folic Acid

it is important to note that in the Framingham study 80% of CAD patients had the same total cholesterol as those who did not develop CAD. Web site: http://www.delphion.com/details?pn=US06323188__ •

Wildlife nutritional supplement Inventor(s): Fuhr; David R. (Winigan, MO), Hauser; David (Winigan, MO) Assignee(s): 4 Seasons Wildlife Nutrition, LLC (Winigan, MO) Patent Number: 6,572,903 Date filed: May 8, 2002 Abstract: The present invention is a wildlife nutritional supplement for free ranging ruminants including about 7.5-8.5% calcium, about 3.5% phosphorus, about 32-37% salt, at least one "B" series vitamin is selected from a group consisting of pantothenic acid, folic acid, riboflavin, niacin, thiamine, cobalamin, and pyridoxine hydrocholoride, about 16-19% sodium, about 0.15% magnesium, about 0.15% potassium, about 2.5% sulfur, about 1,200 PPM iron, about 20 PPM copper, about 105 PPM manganese, about 45 PPM zinc, about 5 PPM cobalt, about 1 PPM selenium, about 1 PPM iodine, about 50,000 IU/LB Vitamin A, about 20,000 IU/LB Vitamin D, about 50 IU/LB Vitamin E, about 134 MG/LB biotin, about 60 MG/LB ascorbic acid, oxytetracycline and fenbendazole. Excerpt(s): This invention relates to wildlife nutritional supplements, and more particularly to a ruminant feed supplement having enhanced palatability and immunesystem bolstering effects. The reduction of habitat due to human development has left a noticeable impact on the health and vitality of wild ruminant animals. Ruminant animals such as deer, elk and the like, suffer diminished reproduction, decreased weight, smaller antlers, and susceptibility to disease and parasites. There are seven major minerals that have an important effect on wildlife: (1) calcium aids in the growth of bones, teeth and antlers and is important in the function of muscles and nerves; (2) phosphorus aids in the growth of bones, teeth and antlers, enhances energy metabolism and enzymation as well as proper protein utilization; (3) potassium is integral in the function of nerves, enzyme processes, as well as mineral and water balance; (4) sulfur is an essential component of some proteins; (5) sodium is vital to the function of muscles and nerves and also maintains water balance; (6) chloride of sodium forms hydrochloric acid in the abomasums which aids in protein breakdown; and (7) magnesium is an important component is almost all body processes. Web site: http://www.delphion.com/details?pn=US06572903__

Patent Applications on Folic Acid 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 folic acid:

10

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

Patents 181

•

Aminosugar, glycosaminoglycan, and S-adenosylmethionine composition for the treatment and repair of connective tissue Inventor(s): Hammad, Tarek; (Baltimore, MD), Henderson, Robert W.; (Baldwin, MD) Correspondence: Covington & Burling; Patent Docketing; 1201 Pennsylvania Avenue, NW; Washington; DC; 20004-2401; US Patent Application Number: 20020032169 Date filed: April 16, 2001 Abstract: A composition for the protection, treatment and repair and for reducing the inflammation of connective tissue in mammals and a method for the treatment of connective tissue in mammals by the administration of the composition. The composition includes S-Adenosylmethionine (SAM), and a component selected from an aminosugar or salts thereof (e.g., glucosamine) or glycosaminoglycans (e.g., chondroitin salts) or mixtures or fragments thereof. The composition optionally includes manganese which promotes the production of connective tissue matrix. The composition also optionally includes methyl donors or methyl donor cofactors, such as vitamin B12, vitamin B6, folic acid, dimethylglycine or trimethylglycine. Excerpt(s): The present application is a continuation-in-part of U.S. patent application Ser. No. 08/779,996, filed Dec. 23, 1996, the disclosure of which is incorporated by reference herein in its entirety. The present invention relates to compositions for the repair and reduction of inflammation of connective tissue in humans and animals and, in particular, to compositions capable of promoting anti-inflammation, chondroprotection, chondromodulation, chondrostabilization, chondrometabolization and the repair and replacement of human and animal connective tissue. The connective tissues of humans and animals are constantly subjected to stresses and strains from mechanical forces and from diseases that can result in afflictions, such as arthritis, joint inflammation and stiffness. Indeed, connective tissue afflictions are quite common, presently affecting millions of Americans. Further, such afflictions can be not only painful but, in their extreme, debilitating. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Antimicrobial prevention and treatment of human immunedeficience virus and other infectious diseases Inventor(s): Squires, Meryl J.; (Barrington Hills, IL) Correspondence: Welsh & Katz, LTD.; Thomas W. Tolpin; 22nd Floor; 120 South Riverside Plaza; Chicago; IL; 60606; US Patent Application Number: 20030104082 Date filed: February 26, 2002 Abstract: An improved medical treatment and medicine is provided to quickly and safely resolve HIV and other microbial infections. The inexpensive medicine can be self administered and maintained for the prescribed time. The attractive medicine comprises an antimicrobial concentrate comprising microbe inhibitors, phytochemicals or isolates. Desirably, the effective medicine comprises a surfactant and an aqueous carrier or solvent and a nutrient. In the preferred form, the medicine comprises: Echinacea and Commiphora myrrha phytochemicals, benzalkonium chloride, a sterile water solution, and folic acid.

182 Folic Acid

Excerpt(s): This application is a continuation-in-part of the application of Meryl Squires, Ser. No. 08/646,988, filed May 8, 1996, for an Antimicrobial Treatment for Herpes Simplex Virus and Other Infectious Diseases, which is a continuation-in-part of the application of Meryl Squires, Ser. No. 08/600,217, filed Feb. 12, 1996, for a Method and Topical Treatment Composition for Herpesvirus Homines. The present invention relates to human immunedeficiency virus, and more particularly, to medical treatments and preventions for human immunedeficiency virus and other microbial infections. It has been reported that there are currently about 22 million people infected with human immunedeficiency virus (HIV) throughout the world. The largest proportion of new HIV cases have originated in Africa and the Caribbean. The typical progression of HIV infection is divided into different stages: 1) viral transmission; 2) acute retroviral syndrome; 3) seroconversion; 4) a clinical latent period with or without persistent generalized lymphadenopathy (PGL); 5) early symptomatic HIV infection previously known as AIDS-related complex or ARC and more recently referred to as "B symptoms" according to the 1993 CDC classification); 6) acquired immune deficiency syndrome (AIDS) (AIDS indicator condition according to the 1987 CDC criteria and revised 1993 CDC criteria that include a CD4 cell count <200/mm.sup.3); and 7) advanced HIV infection characterized by a CD4 cell count <50/mm.sup.3. CD4 cells are lymphocytes targeted by HIV. In 1993 the CDC changed the definition of AIDS to include all patients with a CD4 count <200/mm.sup.3; this definition includes patients in stages 4-7 regardless of symptoms. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Application of phytosterols (and their isomers), folic acid, cyanocobalamin and pyridoxin in dietetic (alimentary) fibers Inventor(s): Bruno, Roberto Luis; (Bela Vista, BR), Falci, Marcio; (Vila Suzana, BR) Correspondence: Leydig Voit & Mayer, Ltd; Two Prudential Plaza, Suite 4900; 180 North Stetson Avenue; Chicago; IL; 60601-6780; US Patent Application Number: 20030133965 Date filed: June 10, 2002 Abstract: It relates to an Association of chemical agents, with intended pharmacological action to prevent the risk of infarction and brain hemorrhage caused by the development of the atherosclerotic process and of the homocysteinemia resulting from ageing.It is of the utmost importance to prevent the increase of endogenous homocysteine.High levels of homocysteine in blood, caused by genetical error and further biologic circumstances impart damaging consequences upon the human organism (occlusion of blood vessels, ocular modifications, osteoporosis and nervous system). Excerpt(s): The present invention is related to a pharmaceutical dosage formula containing fibres, phytosterols, folic acid, B6 and B12 vitamins for the treatment and prophylaxis of hypercholesteremia and hyperhomocystinemia. Hypercholesteremia is a well defined risk factor for the development of atherosclerotic disease, as well as for one of its more important complications, coronary insufficiency. In the same way, the biological properties and the cholesterol metabolism are well defined. This molecule is originated whether in the diet or through cellular synthesis, being part of cells normal structure, as well as functioning as a forerunner for the synthesis of steroids hormones. From the liver, it is taken to the organism cells through the LDL fraction of the blood lipoproteins. After the normal body cytolysis process, it is taken back to the liver by the

Patents 183

HDL in order to be excreted together with the bile. Of this excreted cholesterol, approximately 60% will be reabsorbed by the small intestine, returning to the liver through the digestive system, 2/3 come from this source and the rest comes from diet sources. Hypercholesteremia is a result of the unbalance caused by dysfunction of one of these points of metabolic processing, depending on the subtype of dyslipidemy. Occasionally, the cholesterol will accumulate itself pathologically on the vascular subendothelium, thus causing the formation of the atheromatous plate. Coronary insufficiency is the main cause of death in the western world. In 1996 in the USA, 41% of all deaths were caused by cardiovascular disease, and those with coronary nature prevailed. In the USA, it is considered that the majority of deaths due to coronary disease affects individuals with total serumal cholesterol of about 180 and 250 mg/dl. In some studies, it was shown that a 10% decrease in the total cholesterol levels would result in a 22% decrease in the coronary heart disease incidence. One of the ways to control the ingestion of cholesterol is set forth by the documents of NCEP (National Cholesterol Education Program). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

B complex vitamin compositions that protect against cellular damage caused by ultraviolet light Inventor(s): Barclay, Barry J.; (St. Albert, CA) Correspondence: Kevin S. Lemack; Nields & Lemack; 176 E. Main Street - Suite 8; Westboro; MA; 01581; US Patent Application Number: 20020035087 Date filed: July 6, 2001 Abstract: The present invention relates generally to the use of vitamin B12 (cobalamin or cyanocobalamin) alone or in combination with other photoprotective agents, including specifically other vitamins such as vitamin B9 (folic acid or folate) and vitamin B3 (niacin or niacinamide), or any chemical derivative of these vitamins and their salts, as a filter to protect cells against the damaging effects of ultraviolet (UV) light. The invention is, in one aspect, a method of reducing the rate of UV damage to cells exposed to a UV light source, by treating the celis with the vitamin composition, either alone or in combination with other photoprotective agents. Other aspects of the invention are compositions comprising effective amounts of vitamin B12 alone or in combination with other photoprotective agents including vitamin B9 and vitamin B3 and a pharmaceutically-acceptable carrier, that are useful in protecting cells, particularly skin cells, against the burning, genotoxic (mutagenic and carcinogenic), immunosuppressive and photoaging effects of UV light, especially sunlight. The invention has application as a UV light filter in oral preparations including tablets and drinks, topical creams, lotions, sprays, wipes and cosmetics. The invention also has application as a medicinal treatment for dermatological conditions caused by exposure to sunlight, such as actinic keratoses, photodermatitis, photo-induced (discoid) lupus erythematosus and the photosensitizing effects of a variety of drugs used commonly in clinical practice (e.g. certain antihistamines, ACE inhibitors, and antibiotics such as tetracycline). Excerpt(s): The invention relates generally to sunscreens and sunfilters, and to methods and compositions for protecting cells against the damaging effects of sunlight and artificial sources of UV light such as lamps and arc welding equipment. In particular, the invention is directed to the use of vitamin B12, alone or in combination with folate (used here to refer to all of the folic acid derivatives found commonly in nature), and

184 Folic Acid

niacin (specifically niacinamide) in methods and compositions for protecting cells and organisms including humans against the burning, genotoxic, immunosuppressive and photoaging effects of exposure to UV light. Over the past several decades, the worldwide incidence of skin cancer has been increasing at an alarming rate. The reason for the dramatic increase in skin cancers that has occurred over this period and the human suffering associated with these diseases is not entirely clear. Many experts believe that it is due, at least in part, to depletion of the earth's protective ozone layer. The widespread use of sunscreens that protect against some but not all of the sun's harmful UV radiation (UVB but not UVA) has also played a role. According to the National Cancer Institute (NCI), there will be over one million new cases of skin cancer reported in the United States in the year 2001 and approximately 7000 deaths. This nears the total of all other cancers combined. NCI also reports that if present trends continue 40-50% of fair skinned Americans now living are expected to develop at least one type of skin cancer by age sixty-five. These numbers are alarming, but in regions of the world closer to the equator, the rates of skin cancer are even higher. In some regions of Australia for example, the probability of non-indigenous people (most of whom are of European descent) developing skin cancer at some point during their lifetime approaches 100%. Skin cancers are now the main cause of death in Australia of all persons between the ages of 25 and 40. Worldwide, skin cancer is expected to become the leading cause of death due to malignant disease in the next decade. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Broad spectrum antimicrobial compound and treatment Inventor(s): McKinney, Randy R.; (Grangeville, ID) Correspondence: Richard D. Clarke; Law Office OF Richard D. Clarke; 3755 Avocado BLVD., #1000; LA Mesa; CA; 91941-7301; US Patent Application Number: 20030095950 Date filed: September 28, 2001 Abstract: A new and improved formulation and method for making same, for a broad spectrum antimicrobial treatment for bacterial and viral infections in cattle, horses, pigs, sheep and other domestic and non-domestic animals. More particularly, the present invention relates to a treatment which enables rapid relief of symptoms in an affected animal with a mortality of less than 1 percent by providing trace organic minerals in microgram quantities which act as nutrients for the animal. The treatment provides further nutritional requirements in the form of vitamin A, folic acid and vitamin D.sub.3 supplements, cobalt amino acid chelates and dried kelp, a source of minerals, amino acids, simple and complex carbohydrates, iodine and fiber. In addition, a bacterial innoculum consisting of Acidophilus species is introduced which would inhibit growth of pathogenic or opportunistic species of bacteria by competition for nutrients as well as providing for required vitamins as a by-product of metabolism. Excerpt(s): The present invention relates to a new and improved broad spectrum antimicrobial compound for use in treatment of bacterial and viral infections in cattle, horses, pigs, sheep, goats, dogs, cats and other domestic and non-domestic animals and the method of making and using it. More particularly, the present invention relates to a composition formulated from two groups of compounds, when combined and properly administered to infected animals suffering from a broad spectrum of pathogens including fungal, viral or bacterial infections, acts to rapidly relieve the symptoms associated with those infections and diseases. The compounds utilized in the two

Patents 185

groups radically depart from conventional treatments. Cattle, pigs, sheep and other domestic animals are a widely used source of protein and wealth in a major portion of the world today. With a number of third world countries struggling to feed a growing number of impoverished people, affordable, efficient treatments for common diseases of domestic as well as non-domestic animals are becoming increasingly important. One such disease affecting domesticated animals which is of great concern is foot and mouth disease (FMD). FMD is considered to be the most economically devastating livestock disease in the world. Although the United States as well as Central America, Australia, New Zealand and Chile as well as some countries in Europe are considered free of, local, state and federal agencies are on heightened alert against outbreaks of the disease. There have been reports of various types of foot and mouth disease virus in Africa, South America, Asia and part of Europe. The U.S. Department of Agriculture has prohibited the importation of live swine and ruminants and any fresh swine or ruminant meat or products from Great Britain or Northern Ireland and is retroactive to January 2001. In addition, enhanced surveillance of travelers coming from Europe is being enforced. This has potentially devastating ramifications for the economies of those countries as well as presenting a high cost for other countries in terms for surveillance and enforcement of import restrictions. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Carbonated fortified milk-based beverage and method for suppressing bacterial growth in the beverage Inventor(s): Clark, George H.; (woburn, MA), Clark, Mary Ann; (Woburn, MA) Correspondence: Mark D. Lorusso; Lorusso Loud & Kelly Llp; 440 Commercial Street; Boston; MA; 02109; US Patent Application Number: 20030113408 Date filed: January 27, 2003 Abstract: Dairy or non-diary based fortified carbonated beverage solutions that supply essential nutrients in the human diet. The solution contains per 354 ml, calcium, magnesium and potassium ions in the form of salts and optionally vitamins A, D, C, lutein, zeaxanthin and folic acid in specified amounts to provide dietary supplementation. Sweeteners, stabilizers, flavors and carbonation can also be added to enhance flavor, taste, mouth-feel, ingredient solubilization and product appearance. A method of making the beverages is also described. A method of using carbonation to reduce bacterial counts and reduce degradation of essential nutrients in milk-based beverages with or without pasteurization is also disclosed. Excerpt(s): This is a continuation-in-part of pending U.S. Ser. No. 10/004,149, filed Oct. 31, 2001, which is a continuation-in-part of U.S. Ser. No. 09/473,252, filed Dec. 27, 1999, now U.S. Pat. No. 6,403,129, issued Jun. 11, 2002, which claimed the benefit of U.S. Provisional Application No. 60/114,096, filed Dec. 29, 1998, the contents of which are incorporated herein by reference. This invention relates to fortified, carbonated milkbased or non-dairy based beverages for the supplementation of essential nutrients in the human diet. This invention further relates to a method for producing carbonated milkbased or non-dairy based beverages that suppresses the growth of bacterial cultures, and thereby extends product shelf life and increases the palatability of milk to populations who do not like or drink milk. The beverages are designed for consumption by individuals of all ages to provide supplemental amounts of essential vitamins, amino acids, minerals and trace nutrients in the everyday diet. It is now well known that good

186 Folic Acid

nutrition is essential to the process of bone physiology. Poor dietary habits will prevent normal bone development in childhood and early adulthood and can contribute to the softening of bones and teeth as well as the acceleration of bone loss with advancing age. Milk has long been recognized as an excellent nutritional source of essential minerals such as calcium and potassium, high quality protein and vitamins such as D, A, B.sub.2, B.sub.1, B.sub.6 and B.sub.12. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Color stable iron fortified compositions Inventor(s): Favre, Michel Lucien Hubert Lannelongue; (Cincinnati, OH), Henry, William John; (Taylor Mill, KY), Li, Jianjun; (West Chester, OH), Mehansho, Haile; (Fairfield, OH), Mellican, Renee Irvine; (Fairfield, OH), Xi, Xiaobing; (West Chester, OH) Correspondence: The Procter & Gamble Company; Patent Division; Ivorydale Technical Center - Box 474; 5299 Spring Grove Avenue; Cincinnati; OH; 45217; US Patent Application Number: 20020058088 Date filed: November 28, 2001 Abstract: The present invention relates to color and flavor improvements in iron and zinc supplemented dry beverage powders having fruit and/or botanical flavor. Vitamins such as the B vitamins, vitamin A, vitamin C, and vitamin E can be added to the dry beverage mix. The supplemented dry beverage mix can also contain iodine, niacin and folic acid. In particular, methods for fortifying dry beverage mixes with certain bioavailable zinc and iron compounds without producing reconstituted beverages having undesirable color or flavor are disclosed. Also disclosed are beverages and foods fortified preferably with amino acid chelated iron that do not impart objectionable color due to the inclusion of a ferric ion reducing agent such as ascorbic acid and/or an agent such as citric acid that is capable of preferentially complexing ferric ion in the presence of polyphenols or flavonoids that are typically present in these beverages or foods. Excerpt(s): This application is a Continuation of co-pending patent application Ser. No. 09/445,630, filed Dec. 9, 1999 and a Continuation-in-Part of application Ser. No. 08/549,109, filed Oct. 27, 1995 (now abandoned). The present invention relates to dry beverage mixes, ready-to-drink beverages and foods other than beverages supplemented with iron and optionally zinc compounds that have excellent bioavailability. The iron and zinc compounds herein do not cause an offflavor/aftertaste, are stable, and overcome the problem of discoloration often caused by the addition of these minerals to foods and beverages. The compositions may also include vitamin A, vitamin C, vitamin E, the B vitamins, folic acid and iodine. The present invention further relates to beverages and foods fortified with iron, especially amino acid chelated iron, without imparting objectionable color. In many countries, the average diet does not contain sufficient levels of iron, zinc, iodine, vitamin A or the B vitamins. Iron deficiency is well documented. Although iron deficiency is one of the few nutritional deficiencies in the U.S., it is common in most developing countries. Recent evidence suggests that nutritional zinc deficiency may be common among the people of many developing countries where they subsist on diets of plant origin (e.g. cereal and legume). Marginal zinc deficiency may be widespread even in the U.S. because of selfimposed dietary restrictions, use of alcohol and cereal proteins, and the increasing use of refined foods which decrease the intake of trace minerals.

Patents 187

Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Composition and method for reducing the risk or progression of cardiovascular, glaucoma and tardive dyskinesia diseases Inventor(s): Lang, Philip C.; (Toms River, NJ), Sosnowski, Robert E.; (Manasquan, NJ) Correspondence: Delio & Peterson; 121 Whitney Avenue; New Haven; CT; 06510 Patent Application Number: 20020164388 Date filed: April 30, 2001 Abstract: Elevated levels of homocysteine have been implicated as an important risk factor for cardiovascular and other diseases. A composition for decreasing levels of plasma homocysteine and a method for administering the composition are provided the composition containing dextromethorphan (DM), folic acid and vitamins B.sub.6 and B.sub.12. The composition provides a synergistic therapeutic effect so that lower amounts of the above ingredients may be employed to minimize any undesirable side effects caused by the use of high levels of a component such as DM. Preferred compositions for cardiovascular diseases further include lecithin, vitamin E, betacarotene, procyanidins/flavonoids, trimethylglycine, garlic oil and minerals. Other compositions for treating glaucoma include bilberry, bioflavonoids and beta-carotene and for treating tardive dyskinesia include an antioxidant such as grape seed extract and pine bark extract, lecithin and oligomeric proanthocyanidins. The compositions may be administered using any suitable means such as orally or intravenous. Excerpt(s): The present invention relates to a composition and method for reducing the risk or progression of cardiovascular, glaucoma and tardive dyskinesia diseases and, more particularly, to a composition containing a number of ingredients which are present in amounts lower than amounts considered harmful to the body but which act synergistically to provide enhanced disease inhibition. Cardiovascular disease is the most frequent cause of death in industrialized countries. Atherosclerosis (AS) is the principal cause of cardiovascular disease. AS is a disease of the intima of the arteries that leads to fatty lesions called artheromatous plaques on the inside surface of the arteries. This deposit of fat and cholesterol narrows the arteries, and often becomes calcified, providing sites for abnormal blood clots to form, leading to high blood pressure, heart attacks and strokes. Elevated plasma homocysteine (Hcy) concentrations have repeatedly been associated with increased vascular risk. Hcy causes cells to decrease their production of clot preventing and clot dissolving substances and increases production of clot promoting substances. Hcy is an intermediate sulfhydryl alpha-amino acid formed during conversion of methionine to cysteine. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Compositions and methods for decreasing the risk of or preventing neural tube disorders in mammals Inventor(s): Allan, Geoffrey; (Richmond, VA), Copp, Andrew J.; (London, GB) Correspondence: Sterne, Kessler, Goldstein & Fox Pllc; 1100 New York Avenue, N.W., Suite 600; Washington; DC; 20005-3934; US Patent Application Number: 20020193379 Date filed: May 15, 2002

188 Folic Acid

Abstract: This invention relates to compositions and methods for decreasing the risk of or preventing neural tube disorders in mammals. These compositions contain an effective amount of D-chiro-inositol or a combination of effective amounts of D-chiroinositol and folic acid. Excerpt(s): This application claims priority to U.S. Provisional Patent Application Serial No. 60/295,598, filed Jun. 5, 2001, which application is hereby incorporated by reference in its entirety. This invention relates to compositions and methods for decreasing the risk of or preventing neural tube disorders characterized by spina bifida, spina bifida anterior, spina bifida aperta, spina bifida cystica, spina bifida occulta, spina bifida posterior, anencephaly, exencephaly, meningomyelocele and/or encephalocele in mammals. Neural tube defects (NTDs) are severe malformations of the central nervous system and axial skeleton resulting from disturbances to the process of neurulation in mammals. Neurulation is the process in embryonic development denoted by the folding of the edges of the embryonic neural plate toward each other and fusing to form the neural tube followed by the closing of the open caudal end of the neural tube, or posterior neuropore. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions containing folic acid and reduced folate Inventor(s): Hahnlein, Wolfgang; (Freinsheim, DE), Hasselwander, Oliver; (Landau, DE), Kramer, Klaus; (Landau, DE), Schweikert, Loni; (Altrip, DE) Correspondence: Keil & Weinkauf; 1350 Connecticut Avenue, N.W.; Washington; DC; 20036; US Patent Application Number: 20030143304 Date filed: November 7, 2002 Abstract: Compositions are proposed which comprise folic acid in combination with 5methyltetrahydrofolic acid, and also compositions which comprise folic acid, 5methyltetrahydrofolic acid and/or 5-methyltetrahydrofolylpolyglut- amate and also comprise a dietary component and/or a nutrient preparation, and their use is also proposed. Excerpt(s): The present invention relates to the field of human and animal nutrition and dietary supplementation and relates to compositions hich comprise folic acid and 5methyltetrahydrofolic acid and/or their polyglutamates. The invention also relates to the use of these compositions. Folic acid (N-pteroyl-L-monoglutamic acid) is a widely occurring growth factor having the character of a vitamin. folic acid itself does not occur in plant and animal foods. The forms of folic acid which occur naturally are reduced folates in the form of polyglutamates. De-novo synthesis of these folates is only possible for microorganisms and plants. Before absorption, the polyglutamates are broken down to monoglutamates by the folate conjugase of the small intestine brush-border cells. Only the monoglutamates can be absorbed by the intestinal mucosa in an active transport process. The biologically inactive folic acid is reduced by the enzyme folate reductase to 7,8-dihydrofolic acid and by dihydrofolate reductase to 5,6,7,8tetrahydrofolic acid (THF). THF is the actually physiologically active form of folic acid: THF is a transport metabolite for one-carbon species, their transfer proceeding via 5methyltetrahydrofolate, 5,10-methylenetetrahydrofolate, 5-formyltetrahydrofolate (folic acid), 5-formiminotetrahydrofolate, 10-formyltetrahydrofolate or 5,10methenyltetrahydrofolate. The C1 building blocks are required, inter alia, for the

Patents 189

biosynthesis of purine nucleotides and of deoxythymidine-5'-monophosphate, that is to say as precursors of deoxyribonucleic acids (DNA). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Enzyme-based anti-cancer compositions and methods Inventor(s): Lee, Robert; (Columbus, OH), Pan, Xing Qing; (Columbus, OH) Correspondence: Calfee Halter & Griswold, Llp; 800 Superior Avenue; Suite 1400; Cleveland; OH; 44114; US Patent Application Number: 20030003114 Date filed: March 22, 2002 Abstract: A composition for treating cancer is provided. The composition is a hexosaminidase covalently attached to a cancer cell targeting ligand and improves selectively of the hexosaminidase for tumor cells. In certain embodiments, the hexosaminidase is alternately chitinase (N-acetyl-glucosaminohydrolase), chitosanase, or N-acetyl-hexosaminidase and the targeting ligand is either a monoclonal antibody, an antibody fragment immunospecific to a tumor cell or cancer cell antigen, epidermal growth factor (EGF), fibroblast growth factor (FGF), transferrin, or folic acid. Also provided is a method for treating cancerous tumors comprising administering the composition to a patient that has a cancerous tumor. Excerpt(s): This application claims priority from U.S. Provisional Patent Application Serial No. 60/278,026, which was filed on Mar. 22, 20001. The present invention relates generally to the treatment of cancerous tumors with enzyme-based compositions, and specifically to the treatment of cancerous cells and tumors with hexosaminidases. Tumorigenesis is typically accompanied by marked changes in the patterns of gene expression and post-translational modifications of gene products. These changes can lead to highly distinctive cellular phenotypes and membrane compositions among tumor cells. For example, polycarbohydrate structures and their organization on the surface of neoplastic cells can be different from those of normal cells. Common changes in cell surface carbohydrates in tumor cells include the appearance of high molecular weight glycoproteins that are not found in normal cells. Tumor-specific glycolipids may also be present. The changes in carbohydrate composition can be more pronounced in tissues of metastatic lesions. Oligosaccharides on these glycoproteins, and possibly glycolipids, can play an important role in determining the biological behavior of the tumor. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Folic acid in solid dosage forms Inventor(s): DeBernardi, Douglas P.; (Hayward, CA) Correspondence: Klarquist Sparkman, Llp; One World Trade Center; Suite 1600; 121 S. W. Salmon Street; Portland; OR; 97204; US Patent Application Number: 20030017205 Date filed: June 5, 2002

190 Folic Acid

Abstract: A nutritional tablet or caplet has a film coating that contains folic acid available for rapid release upon contact with gastric fluid. The film coating also includes a film forming polymer such as hydroxypropyl methylcellulose. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/143,385, filed Jul. 12, 1999, incorporated herein by reference. This invention relates to folic acid provided in solid dosage forms. Folic acid (folate) is a water-soluble B vitamin that is widely distributed in foods. In the body, folates function as coenzymes in amino acid metabolism and nucleic acid synthesis. Folate deficiencies lead to impaired cell division and altered protein synthesis. The physiological benefits of folic acid consumption are numerous. Newborn children of women receiving adequate folic acid in their diet show a lower incidence of spina bifida and anencephaly, both of which are neural tube defects affecting approximately 2500 newborns annually. Adequate intake of folic acid reduces homocysteine levels in the blood, significantly reducing the risk, particularly in men, of heart attack, stroke and peripheral vascular disease. Women with a high intake of folic acid have been shown to be at much reduced risk of developing colorectal adenomas. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Folic acid-polysaccharide complex, its preparation method and pharmaceutical composition containing the same as active component Inventor(s): Liu, Min; (Shanghai, CN), Lu, Weiyue; (Shanghai, CN), Pan, Jun; (Shanghai, CN) Correspondence: Darby & Darby P.C.; Post Office Box 5257; New York; NY; 10150-5257; US Patent Application Number: 20030125302 Date filed: October 17, 2002 Abstract: The present invention relates to folic acid-polysaccharide complexs and method of preparation thereof, more particularly relates to folic acid-Dextran complexs, method of preparation thereof, pharmaceutical compositions having said complex as active component and uses of said composition in therapy of tumors. The folic acidpolysaccharide complexs of the present invention have general formula of: (X).sub.n--Y, wherein X is identical or different, and is selected from folic acid, derivatives of folic acid and other substances that can enter into cell via the pathway of folic acid receptor; Y is polysaccharide; n.gtoreq.1. Excerpt(s): The present invention relates to folic acid-polysaccharide complexs and method for preparation thereof, more particularly relates to folic acid-Dextran complexs, method for preparation thereof, pharmaceutical compositions having said complex as active component and uses of said composition in therapy of tumor. There are mainly three forms of FR in human body: FR-.alpha. FR-.beta. and FR-.gamma., wherein FR.gamma. is a kind of secreting protein expressed on hematopoietic cells (Shen et al: Biochem 1995; 34: 5660). FR-.alpha. and FR-.beta. also exist in the surface of animal cell, wherein FR-.alpha. is mainly expressed on tumor cells and kidney cells, and FR-.beta. is expressed on hepatic cells. Folic acid can adjust the affinity and density of cells to a certain extent. After limiting the taking dosage of folic acid, the affinity of FR-.alpha. to folic acid decreases, the density of FR-.alpha. increases in tumor cell and decreases in kidney cell, while that of FR-.beta. is not obviously affected (Gates et al: Clin Cancer Res 1996; 2:1135). With the disclosures that the expression number or activities of FR on

Patents 191

most tumor cells are remarkably higher than that on normal cells (Cambell et al: Cancer Res 1991; 51: 5329. Coney et al: Cancer Res 1991; 51:6125. Weitman et al: Cancer Res 1992; 52:3396), the researches of using folic acid as guiding media to target tumor cells develop rapidly. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Food and vitamin preparations containing the natural isomer of reduced folates Inventor(s): Ayling, June E.; (Mobile, AL), Bailey, Steven W.; (Mobile, AL) Correspondence: Braman & Rogalskyj, Llp; P.O. Box 352; Canandaigua; NY; 14424-0352; US Patent Application Number: 20020150653 Date filed: June 18, 2002 Abstract: A composition for human or animal consumption for supplying folate which includes a natural isomer of reduced folate, such as (6S)-tetrahydrofolic acid, 5-methyl(6S)-tetrahydrofolic acid, 5-formyl-(6S)-tetrahydrofolic acid, 10-formyl-(6R)tetrahydrofolic acid, 5,10-methylene-(6R)-tetrahydro- folic acid, 5,10-methenyl-(6R)tetrahydrofolic acid, 5-formimino-(6S)-tetrahydrofolic acid, and their polyglutamyl derivatives is disclosed. Such compositions include multivitamin preparations (with or without minerals and other nutrients); breakfast foods such as prepared cereals, toaster pastries and breakfast bars; infant formulas; dietary supplements and complete diet and weight-loss formulas and bars; animal feed (for example pet foods) and animal feed supplements (such as for poultry feed). The amount of the natural isomer of a reduced folate in a composition for human consumption can range between about 5% and about 200% of the daily requirement for folic acid per serving or dose. Excerpt(s): This application claims the benefit of U.S. Provisional Patent Application Serial No. 60/010,898, filed Jan. 31, 1996. The present invention relates generally to the field of nutrition, and more specifically to food and vitamin preparations containing the natural isomer of reduced folates. The folates are ubiquitous to nearly all forms of life. Humans and many other animals lack the capacity to make their own folate which thus is an essential vitamin, one type of essential nurient. Anemia especially during pregnancy and in the geriatric population was an early indication of a dietary requirement for folate. A major function of folate is to remove one-carbon units from molecules being metabolized and then deliver them to molecules being synthesized. As an example, folate participates in the formation of the nucleic acids. Further, the activity of DNA is controlled, in part, by methylation, and the primary methylating agent of the body (S-adenosylmethionine) is made in a metabolic cycle involving a folate. Many studies have, therefore, focused on the relationship of folate status to cancer susceptibility, especially colorectal adenoma. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Hormone replacement formulation Inventor(s): Wright, Jonathan V.; (Auburn, WA) Correspondence: Jensen + Puntigam, P.S.; Suite 1020; 2033 6th Ave; Seattle; WA; 98121; US Patent Application Number: 20030050287 Date filed: September 12, 2001

192 Folic Acid

Abstract: The formulation comprises a combination of three estrogens and selected amount of other elements. The three estrogens include 2-hydroxyestrone, 17-beta estradiol, and estriol. The amount of 17-beta estradiol is substantially less than the amounts of 2-hydroxyestrone and estriol, both which are approximately equal in amount. The amounts of pyridoxine, folic acid, selenium and cobalt are therapeutically effective amounts. Excerpt(s): This invention relates generally to hormone replacement therapy, and more specifically concerns a new estrogen replacement formulation. Hormone replacement therapy has been known for some time. One particular aspect of hormone replacement therapy, known generally as estrogen replacement, has been used for over 30 years for women during or following menopause. The reason for estrogen replacement, which is usually accomplished through transdermal absorption or orally, is to make up for the decline in, or the low level of, estrogen produced by the body. Typically, estrogen production decreases and then declines dramatically during and after menopause. It is during this time period that estrogen replacement is normally prescribed by a physician. However, estrogen replacement can be prescribed in other circumstances where other causes account for a decline in estrogen production or if estrogen is produced at a lower than desirable level. This could occur in women not yet in menopause. The reasons for estrogen replacement, which have been substantiated by scientific research over a number of years, include the prevention and/or treatment of osteoporosis and cardiovascular disease, as well as preventing age-related decline in mental function. Estrogen replacement has also been used to decrease age-related changes in appearance. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and composition for improving fertility health in female and male animals and humans Inventor(s): Trant, Aileen Sontag; (Mountain View, CA) Correspondence: James C. Wray; Suite 300; 1493 Chain Bridge Road; Mclean; VA; 22101; US Patent Application Number: 20020122834 Date filed: December 22, 2000 Abstract: In a new pharmaceutical combination, the herb, Vitex agnus-castus (chasteberry), enhances hormone balance by increasing progesterone release and, therefore, ovulation frequency. The antioxidants, green tea, vitamin E, and selenium, improve overall reproductive health. L-arginine, an amino acid, stimulates the reproductive organs by improving circulation. Folic acid, vitamins B6 and B12, iron, zinc and magnesium help promote womens' fertility. Sperms are highly susceptible to free radical or oxidative damage from environmental toxicants and natural aging. Vitamins C and E, coenzyme Q10 and selenium are all potent antioxidants that help improve sperm counts and quality. Ferulic acid, an antioxidant found in Dong quai, also improves sperm quality. Zinc and B vitamins (B6, B12 and folate) are critical nutrients in male reproductive systems for hormone metabolism, sperm formation and motility. The amino acid, L-carnitine, promotes formation of healthy sperm. Excerpt(s): Because of delayed child bearing, unhealthy diets and use of tobacco, caffeine, alcohol, drugs and environmental contaminants, difficulties in conceiving have been experienced. Needs exist for pharmaceutical compounds that improve fertility in both women and men. This invention provides combinations of bioeffecting compounds

Patents 193

for promoting fertility in men and women. The combinations include nutritional components that benefit fertility health. All the components have been studied separately, to determine their individual efficacy. The invention provides the first products to put these components together synergistically in women's and men's formulations. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and composition for the prevention of struvite in fish Inventor(s): Graham, Elwood E. JR.; (Castro Valley, CA) Correspondence: Fitch Even Tabin And Flannery; 120 South LA Salle Street; Suite 1600; Chicago; IL; 60603-3406; US Patent Application Number: 20020168455 Date filed: April 11, 2002 Abstract: The invention is directed to a method and composition for the prevention of struvite in containers such as cans. The method includes combining a water soluble vitamin selected from the group consisting of pantothenic acid, the calcium salt of pantothenic acid, vitamin B12, folic acid, niacin and mixtures thereof with the fish. The composition is a tablet comprising the water soluble vitamin and sodium chloride. Excerpt(s): This invention is directed to a method and composition for the prevention of struvite in canned fish. More particularly, the invention is directed to the prevention of struvite by adding a water soluble vitamin selected from the group consisting of pantothenic acid, the calcium salt of pantothenic acid, vitamin B12, folic acid, niacin and mixtures thereof into the canned fish. The invention is particularly effective in preventing struvite in canned salmon. The composition of the invention includes a tableted water soluble vitamin and sodium chloride. Small crystals resembling small pieces of broken glass frequently are found in canned fish, such as salmon. These crystals are transparent and tasteless particles of struvite which is magnesium ammonium phosphate. Struvite generally is regarded as harmless, but commercially is highly undesirable because struvite crystals may be confused with glass particles and result in product rejection by the consumer. It generally is thought that struvite is formed as a result of magnesium which exists from water used in and resulting from the processing of the fish. This water includes magnesium and phosphates. While it is known that the formation struvite can be minimized or prevented by the addition of acids such as citric acid, hydrochloric acid or acetic acid, or the addition of ascorbic acid in combination with citric acid, the addition of such acids can cause deleterious off flavors, and may require labeling problems in that the acids will be seen as an "unnatural" additive to the food. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

METHOD AND SYNERGISTIC COMPOSITION FOR TREATING ATTENTION DEFICIT/HYPERACTIVITY DISORDER Inventor(s): Lang, Philip C.; (Toms River, NJ) Correspondence: Delio & Peterson; 121 Whitney Avenue; New Haven; CT; 06510 Patent Application Number: 20030044472 Date filed: August 28, 2001

194 Folic Acid

Abstract: A composition and method for treating Attention Deficit/Hyperactivity Disorder (ADHD) is provided which composition can be used both with and without ethical drugs now used to treat ADHD. The composition contains dimethylaminoethanol (DMAE), omega 3-fatty acids, betaine, oligomeric proanthocyanidins (OPC), folic acid, vitamins C, E, B.sub.12, B.sub.6, B.sub.5 and betacarotene and minerals (calcium, magnesium, zinc and selenium). Ethical drugs such as amphetamines, methylphenidate HCl and pemoline are known to control ADHD, but each has significant side effects when used in their therapeutic dose. When combining the composition of the invention with such ethical drugs, the amount of the ethical drug can be lowered below a level which causes undesirable side effects which is an important feature of the invention. Preferred compositions of the invention contain one or more of lecithin, choline, 5-hydroxytryptophan, tyrosine, Reishi Extract, Kava Extract, Gingko, Ginseng and St. John's Wort. Excerpt(s): The present invention relates to a composition and method for treating Attention Deficit/Hyperactivity Disorder. Attention Deficit/Hyperactivity Disorder (ADHD) is the fastest growing childhood disorder in the United States. About four million children and thirteen million adults suffer from attention deficit in the U.S. Diagnostic and Statistical Manual of Mental Disorders (DSM IV) categorization of ADHD includes terms such as "inattention, impulsiveness and hyperactivity". Three subtypes are recognized ADHD: Combined type; ADHD, Predominately Inattentive Type; and ADHD, Predominately Hyperactive/Impulsive Type. The Predominately Inattentive Type makes careless mistakes, cannot keep focused on a task, and loses attention and interest quickly. Often the person appears not to listen as if their mind is "someplace else". The predominately Hyperactive/Impulsive Type is characterized by fidgetiness, excessive unproductive movement, impulsiveness, inappropriate behavior, making noise, impatience, touching things or being disruptive. Depending on age and development stage, ADHD sufferers may exhibit low frustration tolerance, temper outbursts, stubbornness, making demands, mood lability, rejection by peers and poor self-esteem. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for treatment of neuropsychiatric disorders Inventor(s): Allen, Robert H.; (Denver, CO), Stabler, Sally P.; (Denver, CO) Correspondence: Gibson, Dunn & Crutcher Llp; Suite 4100; 1801 California Street; Denver; CO; 80202; US Patent Application Number: 20030203873 Date filed: December 4, 2002 Abstract: A method for orally administering vitamin preparations is described which combine vitamin B.sub.12 (B.sub.12, cobalamin) and folic acid (folate), with and without pyridoxine (B.sub.6), for preventing and treating elevated serum homocysteine (HC), cystathionine (CT), methylmalonic acid (MMA), or 2-methylcitric acid (2-MCA) levels. These metabolites have been shown to be indicative of B.sub.12 and/or folic acid deficiencies. Further, it is likely that a B.sub.6 deficiency may be present with a B.sub.12 or folate deficiency. The method of the invention is also for use in lowering serum HC, CT, MMA, or 2-MCA in patients with or at risk for neuropsychiatric, vascular, renal or hematologic diseases. The method of the present invention eliminates the costly and time consuming steps of distinguishing between vitamin deficiencies once a deficiency is found by measurement of serum metabolite levels. The present invention is of

Patents 195

particular benefit to the populations at risk for elevated serum metabolite levels, such as the people over the age of 65, and populations that have or are at risk for neuropsychiatric, vascular, renal and hematologic diseases. Excerpt(s): This application is a continuation or. No. 09/793,214, filed on Feb. 26, 2001, which is a continuation of Ser. No. 09/273,754 filed Mar. 22, 1999, now issued as U.S. Pat. No. 6,297,224, which is a continuation of application Ser. No. 09/012,955 filed Jan. 26, 1998 now issued as U.S. Pat. No. 5,795,873, which is a divisional of application Ser. No. 07/999,499, which was filed Dec. 29, 1992, now issued as U.S. Pat. No. 5,563,126. This invention relates to the field of nutrition. Specifically, the invention is comprised of new oral vitamin preparations combining vitamin B.sub.12 (B.sub.12, cobalamin) and folic acid (folate), and vitamin B.sub.12, folate, and pyridoxine (B.sub.6) for use in patients with elevated serum metabolite levels of homocysteine (HC), cystathionine (CT), methylmalonic acid (MMA), or 2-methylcitric acid (2-MCA). The elevation of these metabolites has been shown to be indicative of tissue deficiencies of B.sub.12 and/or folate and/or B.sub.6, and related to increased risk of neuropsychiatric, vascular, renal and hematologic diseases. One embodiment of the present invention uses a nonprescription formulation comprising between 0.3-10.0 mg B.sub.12 and 0.1-0.4 mg folate, with the preferred embodiment using 2.0 mg B.sub.12 and 0.4 mg folate. Another embodiment of the non-prescription formulation uses 0.3-10 mg B.sub.12, 0.1-0.4 mg folate, and 5-75 mg B.sub.6, with the preferred embodiment using 2.0 mg B.sub.12, 0.4 mg folate, and 25 mg B.sub.6. Another embodiment of the present invention uses a prescription strength formulation comprising between 0.3-10.0 mg B.sub.12 and 0.4-1.0 mg folate, with the preferred embodiment using 2 mg B.sub.12 and 1.0 mg folate. In a further embodiment of the present invention, a prescription strength formulation is used comprising 0.3-10 mg B.sub.12, 0.4-1.0 mg folate, and 5-75 mg B.sub.6, with the preferred embodiment using 2 mg B.sub.12, 1.0 mg folate, and 25 mg B.sub.6. The formulations of the present invention eliminate the costly and time-consuming steps of distinguishing between vitamin deficiencies once a deficiency is found by measurement of serum metabolite levels. The present invention is of particular benefit to the populations at risk for tissue deficiencies of B.sub.12, folate, and B.sub.6, such as people over the age of 65, and populations that have or are at risk for neuropsychiatric, vascular, renal and hematologic diseases. Vitamins B.sub.12, folate, and B.sub.6 are required cofactors in metabolic pathways involving methionine, homocysteine, cystathionine, and cysteine. B.sub.12 in the form of 5'-deoxyadenosylcobalamin is an essential cofactor in the enzymatic conversion of methylmalonylCoA to succinylCoA. The remethylation of homocysteine (HC) to methionine catalyzed by methionine synthase requires folate (methyltetrahydrofolate) and B.sub.12 in the form of methylcobalamin. HC is condensed with serine to form cystathionine (CT) in a reaction catalyzed by cystathionine.quadrature.-synthase which requires B.sub.6 (pyridoxal phosphate). CT is hydrolyzed in another B.sub.6-dependent reaction to cysteine and.quadrature.-ketobutyrate. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

196 Folic Acid

•

Multiple antioxidant micronutrients Inventor(s): Haase, Gerald M.; (Greenwood Village, CO), Prasad, Kedar N.; (Denver, CO) Correspondence: Ostrolenk, Faber, Gerb & Soffen, Llp; 1180 Avenue OF The Americas; New York; NY; 10036-8403; US Patent Application Number: 20030147996 Date filed: August 28, 2002 Abstract: A method for optimizing the health of humans according to their age and sex is disclosed wherein the method comprises administering to said humans a daily dose of a multiple antioxidant micronutrient composition comprising vitamin A (palmitate), beta-carotene (from natural d. salina), vitamin C (calcium ascorbate), vitamin D-3 (cholecalciferol), natural source vitamin E including both d-alpha tocopherol and dalpha tocopheryl acid succinate, thiamine mononitrate, riboflavin, niacinamide ascorbate, d-calcium pantothenate, pyridoxine hydrochloride, cyanocobalamin, folic acid (folacin), d-biotin, selenium (l-seleno methionine), chromium picolinate, zinc glycinate, calcium citrate, and magnesium citrate.For persons over the age of about 51, the composition preferably further comprises one or more of co-enzyme Q.sub.10, Nacetyl cysteine, and alpha lipoic acid. Preferably, also, vitamin D is added for women over the age of about 36. Excerpt(s): We claim the benefit under Title 35, United States Code,.sctn.120 of U.S. Provisional Application No. 60/315,523, filed Aug. 29, 2001, entitled MULTIPLE ANTIOXIDANT MICRONUTRIENTS FOR OPTIMAL HEALTH. In the beginning, the earth's atmosphere had no oxygen. Anaerobic organisms, which can live without oxygen, were thriving. About 2.5 billion years ago, blue-green algae in the ocean acquired the ability to split water into hydrogen and oxygen and this chemical reaction initiated the release of oxygen into the atmosphere. The increased levels of atmospheric oxygen caused extinction of many anaerobic organisms owing to oxygen's toxicity. This important biological event also led to the evolution of multicellular organisms, including humans, who utilize oxygen for survival. The content of oxygen in the air gradually increased to the current amounts of about 21 percent in dry air and about 34 percent in water. The use of oxygen by any organism generates free radicals that are toxic. Therefore, during this period of atmospheric oxygenation, organisms must have struggled to survive the sudden exposure to oxygen toxicity. There must have been enormous rearranging of nucleotides in genes to produce specific proteins that could protect organisms against the damage produced by free radicals. This process eventually led to the production of three antioxidant enzymes. Superoxide dismutase (SOD) requires manganese, copper, or zinc for its biological activity. Mn-SOD is present in mitochondria, whereas Cu-SOD and Zn-SOD are present in the cytoplasm and nucleus of the cell. All three can destroy free radicals and hydrogen peroxide. Another enzyme, catalase, requires iron for its biological activity and it destroys H.sub.2O.sub.2 in cells. Human tissue also contains glutathione peroxidase which requires selenium for its biological activity. It is also responsible for removing hydrogen peroxide. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 197

•

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 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

•

Novel combination of benzoquinazoline antifolates and protecting agents Inventor(s): Duch, David Stanley; (Cary, NC), Ferone, Robert; (Raleigh, NC), Koch, Arthur; (Bloomington, IN), Smith, Gary Keith; (Raleigh, NC) Correspondence: David J Levy, Corporate Intellectual Property; Glaxosmithkline; Five Moore DR.; PO Box 13398; Durham; NC; 27709-3398; US Patent Application Number: 20020137748 Date filed: March 18, 2002 Abstract: The use of a protecting agent, for example a folate derivative such as folic acid or leucovorin, in combination with a non-competitive folic acid analogue, for example benzoquinazoline derivatives, for use in reducing the side effects associated with the

198 Folic Acid

administration of such non-competitive folic acid analogues, and pharmaceutical formulations comprising such combinations are disclosed. Excerpt(s): The present invention relates to novel combinations of non-competitive folic acid analogues with protecting agents, and to methods of treatment using these combinations. European Patent Application 0505640 provides a method for improving the therapeutic utility of GAR-transformylase inhibitors and other antifolates by coadministering a folate binding protein binding agent to the host undergoing treatment. Thymidylate synthase is an enzyme catalysing the terminal step in the de novo synthesis of thymidylate required for DNA synthesis. It has been postulated that inhibitors of this enzyme may be expected to have anti-tumour activity and it has been reported (Jones et al, J. Med. Chem. 1986, 29, 468) that the in-vivo antitumour activity of N.sup.10propargyl-5,8-dideazafolic acid arises solely from its inhibitory effect on this enzyme. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Nucleosidic and non-nucleosidic folate conjugates Inventor(s): Bhat, Balkrishen; (Carlsbad, CA), Cook, Phillip Dan; (Lake San Marcos, CA), Guzzev, Andrel P.; (Carlsbad, CA), Manoharan, Muthiah; (Carlsbad, CA) Correspondence: Michael P. Straher; Woodcock Washburn Kurtz; Mackiewicz & Norris Llp; One Liberty Place - 46th Floor; Philadelphia; PA; 19103; US Patent Application Number: 20020049163 Date filed: October 9, 2001 Abstract: Oligonucleotide-folate conjugates are described wherein folates are conjugated to one or more sites on an oligonucleotide including the 2'-, 3'-, 5'-, nucleobase and internucleotide linkage sites. The folate can be attached via the.alpha.- or.gamma.carboxylate, optionally through a linking group. Methods for the regiospecific synthesis of the conjugates are diclosed. Also disclosed are nucleosidic and non-nucleosidic linkers conjugated to folic acid and related folates. Excerpt(s): This application is a continuation-in-part application of U.S. application Ser. No. 09/098,166, filed Jun. 16, 1998. The present invention is directed to mononucleosides and oligonucleotides that are conjugated to folic acid, related folates, antifolates and analogs thereof. The present invention further provides non-nucleosidic folate conjugates. The present invention also provides methods for preparation of nucleosidic and non-nucleosidic conjugates. Protein synthesis is directed by nucleic acids through the intermediary of messenger RNA (mRNA). Antisense methodology is the complementary hybridization of relatively short oligonucleotides to mRNA or DNA such that the normal, essential functions, such as protein synthesis, of these intracellular nucleic acids are disrupted. Hybridization is the sequence-specific hydrogen bonding via Watson-Crick base pairs of oligonucleotides to RNA or single-stranded DNA. Such base pairs are said to be complementary to one another. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 199

•

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

•

Nutritional preparation comprising ribose and medical use thereof Inventor(s): Hageman, Robert Johan Joseph; (Waddinxveen, NL), Smeets, Rudolf Leonardus Lodewijk; (Waddinxveen, NL), Verlaan, George; (Wageningen, NL) Correspondence: Young & Thompson; 745 South 23rd Street 2nd Floor; Arlington; VA; 22202 Patent Application Number: 20020183263 Date filed: June 25, 2002 Abstract: Trauma, surgery, inflammation, subfertility, pregnancy, lactation problems, gut disorders, infant nutrition, cancer, arthritis and other joint problems, vascular problems and cardio-or cerebro-vascular problems, ischaemia, aging, impaired immune function, burns, sepsis, malnutrition, problems with liver, pancreas or kidneys, malaria,

200 Folic Acid

cystic fibrosis, migraine, neurological problems, respiratory infections, improvement of sports results, muscle soreness, drug intoxication and pain can be treated with a nutritional composition containing effective amounts of ribose and folic acid, optionally combined with other components such as niacin, histidine, glutamine, orotate, vitamin B6 and other components. Excerpt(s): The invention is related to nutritional, pharmaceutical, or dietetic preparations that comprise ribose or folic acid or functional analogs thereof and the use of these compositions in the prevention or treatment of specific diseases that are related to disorders or insufficient of total nucleotide metabolism. Nucleotides are heterocyclic compounds that occur in all mammals. Nucleotides consist of a purine or pyrimidine base, a sugar unit and one to three phosphate groups. The major purine bases that occur in the human body are adenine (6-aminopurine), guanine (2-amino-6-hydroxypurine), hypoxanthine (6-hydroxypurine) and xanthine (2,6-dihydroxypurine); the major pyrimidines are uracil (2,4-dihydroxypyrimidine), cytosine (2,4-dihydroxy-5methylpyrimidine) and thymine (4-amino-2-hydroxypyrimidi- ne). The sugar moiety can be ribose (in ribonucleosides) or 2-deoxyribose. The sugar moiety is connected to the base through a.beta.-N-glycosidic bond at N9 of the base; the phosphate groups are connected to the sugar moiety through the 3' or 5' position. When the phosphate groups are split from nucleotides compounds called nucleosides are formed. For the purpose of this document, total nucleotide metabolism (TNM) is defined as the combination of all biochemical pathways in which nucleotides, their precursors and metabolites are directly involved as main ingredients and that occur in the body of mammals. The pathways include the synthetic routes for purines and pyrimidines, both de novo and salvage pathways, starting from carbamoyl phosphate and 5-phosphoribosyl-1pyrophosphate (PRPP), respectively. They also include the interconversions of the various nucleotides into each other, the phosphorylation and dephosphorylation reactions of respectively nucleosides and nucleotides and the catabolic pathways of nucleotides to the compounds that are cleared from the body. They do not include the further reactions of phosphoric groups thus split off from the phosphorylated nucleotides. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Nutritive media and manufactured seeds comprising same Inventor(s): Carlson, William C.; (Olympia, WA), Grob, James A.; (Auburn, WA), Hartle, Jeffrey E.; (Milton, WA), Heilesen, Mollie K.; (Tacoma, WA), Salatas, Katherine M.; (Tacoma, WA) Correspondence: Christensen, O'connor, Johnson, Kindness, Pllc; 1420 Fifth Avenue; Suite 2800; Seattle; WA; 98101-2347; US Patent Application Number: 20030167684 Date filed: February 20, 2003 Abstract: Manufactured seeds are disclosed that comprise a unit of totipotent plant tissue and a nutritive medium. The nutritive medium can contain a number of different components selected from the following: a gel solute, charcoal, a carbon source, urea, KNO.sub.3, NH.sub.4NO.sub.3, CuCl.sub.2, CuSO.sub.4, KI, KH.sub.2PO.sub.4, CaCl.sub.2, MgSO.sub.4, Na.sub.2EDTA, FeSO.sub.4, ferric citrate, MnSO.sub.4, MnCl.sub.2, H.sub.3BO.sub.3, ZnSO.sub.4, CoCl.sub.2, Na.sub.2MoO.sub.4, (NH.sub.4).sub.2MoO.sub.4, thiamine, riboflavin, pyridoxine, HCl, Ca-pantothenate, nicotinic acid, biotin, folic acid, and myo-inositol. The nutritive medium can also

Patents 201

include any of various protein amino acids, any of various polyamines, any of various oxygen-absorbing compounds, any of various non-protein amino acids, and/or a smoke suspension. Excerpt(s): This application is a divisional application of U.S. patent application Ser. No. 09/529,933, filed Apr. 21, 2000, now abandoned, which claims the benefit under 35 U.S.C.sctn.365(c) of PCT/US98/24820, filed Nov. 20, 1998, which claims the benefit under U.S.C.sctn.119(e) of U.S. Provisional Patent Application Serial No. 60/066,232, filed Nov. 20, 1997, the disclosures of all are hereby expressly incorporated by reference. The invention pertains to nutritive media, methods for using such media in the production of manufactured seeds, and manufactured seeds comprising same. In many instances it is desirable to grow large numbers of genetically identical plants. These plants can be selected and grown based on their particular qualities, such as their ability to grow in a particular climate, or their ability to produce a particular type or quality of fiber. Unfortunately, in many cases the production of such plants through standard breeding is not feasible. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Oral and topical compositions and methods related thereto in the treatment of acne Inventor(s): Mann, Morris; (Glendale, AZ) Correspondence: The Halvorson Law Firm; Ste 1; 405 W. Southern AVE.; Tempe; AZ; 85282; US Patent Application Number: 20020155171 Date filed: March 26, 2002 Abstract: Described are compositions and methods for the treatment of acne. The method and compositions comprise an orally ingested composition containing thymic peptides, vitamins, and minerals. Zinc, pantothenic acid, magnesium, pyridoxine, vitamins A and D, riboflavin, and folic acid are found to be essential to the composition. Also described is a topical composition comprising pantothenic acid that, when used in conjunction with the oral composition, resulted in a better response than either the oral or topical composition alone. Excerpt(s): The present invention generally relates to oral and topical compositions and methods for the treatment of acne. More specifically, the present invention generally relates to compositions and methods for the treatment of acne by oral treatment with a composition comprising containing thymosin fraction 5 preparation plus other beneficial ingredients, such as vitamins and the like, and concomitant use of novel topical compositions. Acne is considered by those afflicted to be a serious problem. At some point 80% of all individuals, both male and female, experience acne. Although the vast majority of individuals afflicted with acne have spontaneous resolution of the problem over time, the effects of this skin disorder can be emotionally scarring. Some people, however, have active acne, until their mid-fifties. Likewise, in the last 20 years, for reason that are currently unknown, there has been a dramatic increase in acne affecting women over the age of 30. Many causes have been proposed for acne. However, for a cause to have true validity, the treatment resolving the hypothesized cause must prove to be effective in the vast majority of cases. Causes that have been proposed include, but are not limited to: diet, hormonal disregulation, stress, bacterial overgrowth, heredity and environmental exposure; all of which may cause a deficiency of Coenzyme A. In no case has a treatment designed for any of the aforementioned

202 Folic Acid

causes proven to be uniformly effective. The only treatment that is proven effective in the vast majority of cases is the oral administration of isotretinoin (Accutane.TM.). This medication, however, has numerous side effects; the most disturbing of which being its potential to induce sever birth defects. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Oxazolidinone cotherapy Inventor(s): Dupuis, Michael J.; (Mattawan, MI), Herberg, John T.; (Portage, MI), Martin, Joseph Patrick JR.; (Richland, MI) Correspondence: Pharmacia & Upjohn; 301 Henrietta ST; 0228-32-law; Kalamazoo; MI; 49007; US Patent Application Number: 20030171331 Date filed: January 21, 2003 Abstract: The present invention describes a novel cotherapy of oxazolidinones and at least one vitamin selected from vitamin B2, vitamin B6, vitamin B12 and folic acid. Excerpt(s): This application claims the benefit of the following provisional application(s): No. 60/351,628, filed Jan. 25, 2002, under 35 USC 119(e)(i). The present invention relates to a novel cotherapy which involves coadministration of oxazolidinone and at least one vitamin selected from the group consisting of vitamin B2, vitamin B6, vitamin B12 and folic acid. Furthermore, the invention refers to a respective pharmaceutical composition and a respective medical kit. Oxazolidinones are a wellknown class of drugs which have been employed in a variety of applications. They are especially useful as antimicrobials with potent activity against a number of human and veterinary pathogens, including Gram-positive aerobic bacteria such as multiplyresistant staphylococci and streptococci, anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium. More recently oxazolidinones demonstrating a useful level of activity against aerobic Gram-negative organisms such as Haemophilus influenza and Moraxella catarrhalis have also been described. For example, antibacterial oxazolidinones and methods for their preparation are described in the U.S. Pat. Nos. 5,225,565; 5,182,403; 5,164,510; 5,247,090; 5,231,188; 5,565,571; 5,668,286; 5,547,950; 5,952,324; 5,968,962; 5,688,792; 6,069,160; 6,239,152; 5,792,765; 4,705,799; 5,043,443; 5,652,238; 5,827,857; 5,529,998; 5,684,023; 5,627,181; 5,698,574; 6,166,056; 6,051,716; 6,255,304; 6,043,266; 6,313,307; and 5,523,403 as well as in the PCT Applications WO94/0110, WO95/07271, WO95/25106, WO96/13502, WO96/35691, WO97/09328, WO97/09328, WO97/10235, WO97/10223, WO97/19089, WO97/21708, WO97/30981, WO96/15130, WO96/23788, WO98/54161, WO99/29688, WO97/30995, WO97/09328, WO95/07271, WO00/21960, WO01/40236, WO99/64417, and WO01/81350. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 203

•

Psychonutracological method for craving reduction in humans Inventor(s): Scott, Nick; (Santa Barbara, CA) Correspondence: Nick Scott; 201 Bath #2; Santa Barbara; CA; 93101; US Patent Application Number: 20020150632 Date filed: March 12, 2002 Abstract: A method for reducing or eliminating cravings associated with habitual substance abuse by administering to a human a synergistic composition containing an effective amount of each of Glutamine, gamma aminobutyric acid, tyrosine, taurine, theanine, 5-hydroxtryptamine, phenylethylamine, phosphatidyl serine, phosphatidyl choline, inositol, thiamin, riboflavin, niacin, pyridoxin, folic acid, biotin, pantothenic acid, cyanocobalamin, chromium polynicotinate magnesium, and decosahexaenoic acid. The pharmaceutical composition can be administered after complete cessation of a given habit forming substance, or to nullify cravings and to reduce abuse of a given habit forming substance, without total and complete remittance prior to administration of the composition. Worthy of note, all constituents found in this composition may be derived by synthetic means, or from natural sources. Excerpt(s): The present invention relates to a composition that is useful for drug craving reduction in humans and as a treatment for addiction or habitual use to a variety of substances. More specifically the invention is directed toward a composition containing 4 subgroups of nutrients, each grouping implicating it's distinctive role in craving reduction and overall recovery from physical addiction. Furthermore the invention is a composition containing a B-vitamin complex, neurologically active amino acids, and specific lipids that synergistically elicit reduced withdrawal symptoms, and normalize the neurochemical imbalance caused by chronic, habitual use of a physically detrimental substance. Substance abuse and addiction is an age-old dilemma that has plagued many societies. Many, many methods have been contrived to help people stop the cycle of abuse. These methods include everything from psychotherapy, to group congregations, to replacement drug treatment, and other varying nutritional practices. These methods have varying degrees of efficacy and no one method is right for every individual. Frequently, more than one method should be simultaneously administered. There is continuing research for the biological, environmental, and evolutional roots of substance abuse, and they cannot be separated into different entities, because of their high correlation factor. Substance abuse is a broad and widely encompassing term, and within this patent document the term may be used to describe the habitual use of a variety of chemical compounds, some very common and fairly benign, and others highly dangerous, and relatively uncommon. The composition may be used to nullify cravings for such chemical substances consumed by humans such as refined sugar, caffeine, alcohol, nicotine, ephedrine, meth-amphetamines, opiates, and cocaine. It has been suggested that genetics play a role in substance abuse, and that certain individuals have a propensity towards chronic, frequent use where others are only prone to experimental or sporadic use. Propensity towards addiction can be considered a weak link in genetics, but it can also be attributed to environmental stimuli, such as societal images, peer pressure, behavioral stereotypes of different age groups, and ethnic cultural background. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

204 Folic Acid

•

Structured particulate systems Inventor(s): Cain, Frederick William; (Wormerveer, NL), McNeill, Gerald Patrick; (Channahon, IL), Tongue, Thomas M. JR.; (Channahon, IL) Correspondence: Morgan Lewis & Bockius Llp; 1111 Pennsylvania Avenue NW; Washington; DC; 20004; US Patent Application Number: 20020192353 Date filed: March 26, 2001 Abstract: Structured particulate systems of active solid organic components in a matrix in a weight ratio of 99:1 to 1:99 and a mean weight diameter of 25 to 500 microns wherein the active organic component is selected from the group consisting of oleanoic acid, ursolic acid, folic acid, policosanol, phytosterols, or derivatives or salts thereof are novel and can be used to improve the oral properties and/or the homogeneity of the organic, solid, active component in a food product. Excerpt(s): The use of solid organic active components in foods and in particular in health foods is well known nowadays. Examples of active organic components that are applied herefore are e.g. folic acid, ursolic acid, phytosterols, oleanolic acid and policosanol or derivatives or salts thereof. These components are added to the food as small particles (e.g. with a size of 2 to 250 microns) or as a solution after being dissolved in a solvent. Neither of these delivery forms have been found to be satisfactory because the addition as small particles led to problems with oral mouthfeel and to problems with the bioavailability of the components, while also the homogeneity of the food product was poor due to a limited dispersability of the components in the food products. Delivery in the form of a solution in a solvent also led to problems with mouthfeel and bioavailabilty. Moreover this delivery form introduced a solvent in the food product that had to be food grade and which is not always easily available for the type of component that needs to be introduced, while the solvent also easily could affect the texture of the food product in a negative sense. Further the presence of a solvent diluted the amount of active component in the food product. We studied whether we could find a solution for above problems and this study resulted in the finding of a new delivery form for the solid organic active components. Therefore our invention concerns in the first instance novel structured particulate systems comprising active, organic, solid component(s) in a matrix in a weight ratio of 1:99 to 99:1, preferably 5:95 to 95:5, more preferably 15:85 to 85:15 and wherein the active, organic, solid component(s) preferably is selected from one or more of the components from the group consisting of oleanoic acid, ursolic acid, folic acid, policosanol, phytosterols, or derivatives or salts thereof and wherein the mean weight diameter of the particles of the structured particulate system ranges from 25 to 1500 microns. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Treatment of pathological conditions characterized by an increased IL-1 level Inventor(s): Charbit, Suzy; (Creteil, FR), Pellctier, Jean-Pierre; (Saint-Lambert, CA), Schutze, Francois; (St-Nom-La-Breteche, FR), Taccoen, Alain; (Le Chesnay, FR) Correspondence: I.P. Docketing; Paterson, Belknap, Webb &tyler; 1133 Avenue TO The Americas; New York; NY; 10036; US Patent Application Number: 20020128317 Date filed: January 23, 2001

Patents 205

Abstract: An enteral food composition for clinical or dietary use, comprises, in addition to carbohydrates and proteins or their hydrolysates the following components or their nutritional equivalents, per daily dosage: methionine (0.6-7 g), cysteine (0.5-2.5 g), folic acid (0.4-8 mg), pyridoxal (vitamin B 6) (3-20 mg), zinc (18-120 mg) and at least 400 kcal energy in the form of carbohydrates. These amounts are well above the Recommended Daily Allowance (RDA) values. Further preferred components include lecithin, cvanocobalamine, betaine and magnesium, as well as transsulfuration metabolites, ATP enhancers and antioxidants. Excerpt(s): The invention specifically resides in a method for treatment of pathological conditions characterized by an increased IL-1 and/or TNF-.alpha. level, such as rheumatoid arthritis, psoriatic arthritis, Wegener's disease, granulomatosis, asthma, pulmonary emphysema, Paget's disease, osteoporosis. bone metastases and atherosclerosis, by administering an effective amount of diacerein or rhein The invention also comprehends the treatment of certain conditions or disorders associated with the process of formation and development of the various types of blood cells and other formed elements by the hemopoietic tissues such as myeloma and myeloid leukemia. The pathological conditions contemplated herein as benefiting from treatment with diacerein or rhein broadly encompass the inflammatory and autoimmune diseases. The significance of the mechanism of action of diacerein as an inhibitor of IL-1 in connection with cartilage in osteoarthritis suggested to the inventors the invention herein, namely the use of diacerein and rhein in the treatment of inflammatory and autoimmune diseases including, without limitation, chronic heart failure, psoriatic arthritis, Wegener's disease, granulomatosis, endometriosis, asthma, Paget's disease, osteoporosis, bone metastasis, atherosclerosis, and hematopoietic disorders such as myeloma and myeloid leukemia. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

TREATMENT OF PATIENTS AT ELEVATED CARDIOVASCULAR RISK WITH A COMBINATION OF A CHOLESTEROL-LOWERING AGENT, AN INHIBITOR OF THE RENIN-ANGIOTENSIN SYSTEM, AND ASPIRIN Inventor(s): Liang, Matthew H.; (Boston, MA), Manson, JoAnn E.; (Beverly, MA) Correspondence: Reed & Associates; 800 Menlo Avenue; Suite 210; Menlo Park; CA; 94025; US Patent Application Number: 20030049314 Date filed: August 28, 2001 Abstract: Methods and compositions are provided for reducing the risk of cardiovascular events in individuals who are at elevated cardiovascular risk, including individuals who have systemic lupus erythematosus. The methods comprise administering a combination of: a cholesterol-lowering agent, such as an HMG CoA reductase inhibitor; an inhibitor of the renin-angiotensin system, such as an ACE inhibitor; aspirin; and optionally one or more of vitamin B.sub.6, vitamin B.sub.12, and folic acid. Pharmaceutical formulations combining all the active agents in unit-dose form for once-daily dosing are provided. Excerpt(s): This invention relates generally to methods and pharmaceutical formulations for treating patients at elevated cardiovascular risk, and more particularly relates to treatment of such patients with a combination of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin. Many individuals are at an

206 Folic Acid

elevated risk of suffering serious to life-threatening cardiovascular events, such as myocardial infarction (heart attack), cardiac arrest, congestive heart failure, stroke, peripheral vascular disease and/or claudication. The risk factors are numerous and widespread throughout the world population. They include cigarette smoking, diabetes, hypercholesterolemia (high serum cholesterol), hypertension, angina, systemic lupus erythematosus, prior heart attacks or strokes, hemodialysis, hyperhomocysteine levels, obesity, sedentary lifestyle, receiving an organ transplant, and others. Many of these risk factors are mediated through atherosclerosis. There is a need for a safe and convenient pharmaceutical formulation that would effectively reduce the risk of incurring a cardiovascular event in individuals who have these risk factors. Olukotun et al., in U.S. Pat. No. 5,622,985, disclose that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (cholesterol-lowering drugs), particularly pravastatin, when used alone or with an angiotensin converting enzyme (ACE) inhibitor, decrease the risk of a second heart attack in a patient who has a substantially normal cholesterol level. The combination with an ACE inhibitor is optional, and no mention is made of combining HMG CoA reductase inhibitors with other inhibitors of the renin-angiotensin system or with aspirin. In addition, the prevention of cardiovascular events other than second heart attacks is not considered. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of bioquinones for producing cosmetic or dermatological preparations for treating the hair and scalp Inventor(s): Hoppe, Udo; (Heidmuhlen, DE), Pollet, Dieter; (Hamburg, DE), Sauermann, Gerhard; (Weimersdorf, DE) Correspondence: Nixon & Vanderhye, PC; 1100 N Glebe Road; 8th Floor; Arlington; VA; 22201-4714; US Patent Application Number: 20030180277 Date filed: January 28, 2003 Abstract: The invention relates to the use of one or more compounds from the bioquinone group for producing cosmetic or dermatological preparations for treating the scalp and the hair, in order to prolong the anagen phase and/or to treat and prevent seborrhoeic outbreaks, optionally with the additional use of one or more compounds from the group formed by carnitine, arginine, succinic acid, folic acid, conjugated fatty acids and their respective derivatives, in addition to antioxidants. Excerpt(s): The subject of the invention is the use of bioquinones for producing cosmetic or dermatological preparations for treating the hair and the scalp, which bring about a prolongation of the anagenic phase of the hair growth cycle, or are also effective against dandruff. It is known that hair growth corresponds to a cycle. Papillary hair is the name given to hair in the growth period, which is also known as the anagenic phase or anagen phase. In this phase the hair is anchored with its papilla in the skin. Approximately 80% of head hair is in the anagen phase for approximately 3 to 5 years. In a subsequent transitional phase (catagen phase) the hair migrates for approximately 2 weeks to the epidermis and remains there for approximately 3 to 4 months in a resting stage (telogen phase) until it finally falls out. Hair loss over and above the norm is generally regarded as a serious cosmetic disorder, as are other hair growth disorders. Many agents have therefore already been proposed for the treatment of hair loss and balding, as well as hair growth agents which are intended to achieve or encourage hair growth.

Patents 207

Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of folic acid and/or derivatives thereof for the preparation of cosmetic or dermatological preparations for the prophylaxis of damage to DNA intrinsic to the skin and/or for the repair of existing damage to DNA intrinsic to the skin Inventor(s): Hargens, Birgit; (Hamburg, DE), Max, Heiner; (Hamburg, DE), Raschke, Thomas; (Hamburg, DE), Schimpf, Ralph; (Bonningstedt, DE), Will, Katriu; (Hamburg, DE) Correspondence: Kurt Briscoe; Norris, Mclaughlin & Marcus, P.A.; 220 East 42nd Street, 30th Floor; New York; NY; 10017; US Patent Application Number: 20020150601 Date filed: December 12, 2001 Abstract: Use of folic acid and/or derivatives thereof for the preparation of cosmetic or dermatological preparations for the prophylaxis of damage to DNA intrinsic to the skin and/or for the repair of existing damage to DNa intrinsic to the skin. Excerpt(s): The present invention relates to the use of folic acid and/or derivatives thereof for the preparation of cosmetic or dermatological preparations for the prophylaxis of damage to DNA intrinsic to the skin and/or for the repair of existing damage to DNA intrinsic to the skin. The skin is exposed to a large number of environmental influences which can lead to damage. As well as lipids and proteins, the DNA in particular can be affected. The harmful effect of the ultraviolet part of solar radiation on the skin is generally known. Whereas rays with a wavelength below 290 nm (the UVC region) are absorbed by the ozone layer in the earth's atmosphere, rays in the range between 290 nm and 320 nm, the UVB region, cause erythema, simple sunburn or even burns of greater or lesser severity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Vitamin supplement composition Inventor(s): Herbert, Victor D.; (New York, NY) Correspondence: Kagan Binder, Pllc; Intellectual Property Attorneys; Maple Island Building, Suite 200; 221 Main Street North; Stillwater; MN; 55082; US Patent Application Number: 20020193341 Date filed: August 9, 2002 Abstract: A vitamin B.sub.12 supplement composition comprising vitamin B.sub.12 with and/or without added folic acid that is essentially free of antioxidants, such as vitamin C, as well as iron is disclosed. Also disclosed are methods of using this vitamin composition to prevent brain and nervous system damage, such as peripheral nerve damage, as well as pernicious anemia, such as where such anemia is caused by a deficiency of vitamin B.sub.12 deficiency. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 09/291,372, filed Apr. 14, 1999, which was a divisional of U.S. application Ser. No. 08/544,330, filed Oct. 17, 1995, now U.S. Pat. No. 5,932,624, issued Aug. 3, 1999, the disclosures of which are hereby incorporated by reference in their entirety. Homocystinuria is characterized by high serum homocysteine levels and leads to blood

208 Folic Acid

vessel damage, excretion of homocysteine in the urine, mental retardation, ectopia lentis, sparse blonde hair, convulsive tendency, thromboembolic episodes, and fatty changes of liver and is associated with defective formation of cystathionine synthetase. Homocysteine is a homolog of cysteine and is produced by the demethylation of methionine, and is an intermediate in the biosynthesis of cysteine from methionine via cystathionine by cystathioninase. 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 folic acid, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “folic acid” (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 folic acid. You can also use this procedure to view pending patent applications concerning folic acid. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

209

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

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

Cleft Lip and Palate: From Origin to Treatment Source: New York, NY: Oxford University Press, Inc. 2002. 536 p. Contact: Available from Oxford University Press. Customer Service Department, 2001 Evans Road, Cary, NC 27513. (800) 445-9714. Fax (919) 677-1303. E-mail: [email protected]. Website: www.oup-usa.org. PRICE: $125.00 plus shipping and handling. ISBN: 0195139062. Summary: Cleft lip with or without cleft palate and isolated cleft palate, collectively termed oral clefts, are the second most common birth defects among newborns. This textbook on cleft lip and palate covers a broach range of theoretical, experimental, and clinical topics and is written by experts in the fields of craniofacial development, biomedical sciences, genetics, epidemiology, and public health. The text includes 42 chapters in six sections: basic embryology, clinical features, epidemiology, genetics, treatment, and public health issues. Specific topics include the orofacial examination,

210 Folic Acid

classification, syndromes with orofacial clefting, epidemiology, birth defects surveillance systems, international perspective on oral clefts, maternal nutrition, environmental risk factors, the Human Genome Project, twin studies, patient care team, infant feeding, stage of cleft lip and palate reconstruction, evaluation and management of speech and language disorders, pediatric dental care, the role of the orthodontist, genetic counseling, psychological care of children with cleft lip and palate in the family, international surgical missions, prevention of oral clefts (folic acid and multivitamin supplements), personal and societal implications of oral clefts, insurance and coverage of care, ethical issues, and translating research findings into public health action. Each chapter concludes with a list of references and the text concludes with a directory of Internet resources, a glossary of terms, and a subject index. •

101 Tips for Staying Healthy with Diabetes (and Avoiding Complications). 2nd ed Source: Alexandria, VA: American Diabetes Association. 1999. 127 p. 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: $14.95 plus shipping and handling. ISBN: 1580400078. Summary: This book presents a collection of tips, techniques, and strategies for preventing and treating diabetes complications. One question appears on each page, with the answer immediately below. Questions in chapter one provide general information about diabetes and diabetes complications. Chapter two focuses on glucose control. The third chapter answers questions about various foods and nutrients, including chromium, fiber, fructose, ginseng, folic acid, magnesium, and melatonin. Questions in chapter four provide general information about nutrition, meal planning, and weight management. This is followed by a chapter that describes small blood vessel complications, including eye and kidney disease, diabetic gastroparesis, and foot problems. Chapter six answers questions about large blood vessel complications, including heart disease, erectile dysfunction, and bladder problems. The next two chapters answer miscellaneous questions and offer new tips. The final chapter lists the name, address, and telephone number of helpful organizations. The book also includes an index.

•

NutriBase Nutrition Facts Desk Reference Source: Garden City Park, NY: Avery Publishing Group. 1995. 789 p. Contact: Available from Avery Publishing Group. 120 Old Broadway, Garden City Park, NY 11040. (800) 548-5757, ext. 123. Fax (516) 742-1892. PRICE: $17.95. ISBN: 0895296233. Summary: This book provides comprehensive nutritional information about a wide range of foods, both generic and brand name, raw and prepared. Part One is an A to Z reference to the general nutrients provided by foods. In this section are listed the amount of calories, protein, carbohydrates, sodium, fiber, fat, saturated fat, and cholesterol, as well as the percentage of calories that come from fat. Part Two is an A to Z reference to the vitamins and minerals provided by foods. This section states the amount of vitamin A, thiamine, riboflavin, niacin, vitamin B6, folic acid, vitamin B12, vitamin C, calcium, iron, magnesium, potassium, and zinc. Part Three is an A to Z reference to the nutrient values of various types of fast food. In this section, foods are listed alphabetically under the name of the restaurant chain, and each food item is accompanied by the amounts of the general nutrients found in that item. All of the foods are listed alphabetically, and for convenience similar foods have been grouped together

Books

211

in categories, such as Baby Foods, Breads, Candies, Cereals, Cheese, Cookies, Pasta, and Sauces. The book includes an introduction to dietary health and food guidelines; a list of abbreviations is also provided. •

Low-Fat Living for Real People. 2nd ed Source: New York, NY: Lake Isle Press, Inc. 1998. 252 p. Contact: Available from Lake Isle Press, Inc. 2095 Broadway, Suite 404, New York, NY 10023. (800)462-6420 or (212) 769-2361. PRICE: $14.95. ISBN: 096274039X. Summary: This book, written by a humorist and a registered dietitian, is designed to help readers adjust to eating foods that are lower in fat. Nine chapters provide practical information about fat intake, carbohydrates, protein, snacks, exercise, eating out, and coping with family rebellion. Chapter 10 addresses phytochemicals, folic acid, fiber, soybeans, garlic, nuts, vitamin E, and LDL cholesterol. Chapters 11 and 12 provide answers to frequently asked questions and information about using food labels to select foods low in fat. The last chapter includes easy to prepare recipes in seven categories: rice, pasta, potatoes, barley, and beans; vegetables; soups and salads; appetizers, dressings, and sauces; chicken and turkey; fish; and desserts. All recipes include serving sizes and nutritional analyses noting calories, fat, carbohydrate, protein, and sodium. Pen and ink illustrations appear throughout the book. A subject index and a list of resources to consult for further information conclude the book. 43 endnotes. (AA-M).

•

Pregnancy After a Loss: A Guide to Pregnancy After a Miscarriage, Stillbirth, or Infant Death Source: New York, NY: Berkley Books/Penguin Putnam, Inc. 1999. 391 p. Contact: Available from Berkley Books/Penguin Putnam, Inc., 375 Hudson Street, New York, NY 10014. (800) 788-6262 (orders), (800) 631-8571 (customer service hotline), (800) 227-9604 (Fax), [email protected] (E-mail), http://www.penguinputnam.com (Web Site). $14.95. ISBN 0-425-17047-0. Summary: This book, written by a woman who lost her son, Patrick, to an umbilical cord problem on her due date, is designed to give hope and practical information to other women who have suffered a pregnancy loss. The author interviewed nearly 100 women while writing this book, all of whom made it through pregnancy after a loss and now have one or more healthy babies. The book focuses on the feelings that are unique to women who have suffered a pregnancy loss, and provides advice on reducing anxiety. Medical aspects of pregnancy loss are described in simple, straightforward language. Chapter 1 takes readers down the road that a bereaved mother would travel to find out why her baby died. This chapter covers the followup visit with the obstetrician, which is when the parents discuss the autopsy and any genetic testing that was done on the baby. If these do not provide an answer, the doctor may suggest that the mother be tested for autoimmune disorders, uterine abnormalities, genetic disorders, viral and bacterial infections, and hormone imbalances. Other common reasons for pregnancy loss are described (i.e., neural tube defects, placental problems, umbilical cord problems, incompetent cervix, and maternal illness) as are common reasons for early infant death: congenital problems, streptococcus infection, and sudden infant death syndrome. Chapter 2 discusses the subject of getting ready to get pregnant again, both physically and emotionally. This chapter covers the advantages and disadvantages of getting pregnant right away, factors that will affect one's decision to get pregnant, when partners disagree on the timing of another pregnancy, and where to find support and guidance during the decision-making process. Even if a woman has waited 6 months or

212 Folic Acid

a year to get pregnant again, there are certain things she should do to prepare for the pregnancy. Mothers to be should get a thorough physical exam; get into shape; take folic acid; keep track of her periods; and avoid drugs, alcohol, and cigarettes. This chapter also covers the pros and cons of choosing a new doctor or staying with the old one, questions one should ask each doctor under consideration, the stress of not getting pregnant right away, infertility problems and treatment, and when the pregnancy is a surprise. Chapter 4 focuses on the first trimester of a new pregnancy, including concerns over telling others about the pregnancy, suggestions for alleviating the anxiety, what to expect during the prenatal visits, tests one can have done at this time, and the signs of an impending miscarriage. Chapter 5 focuses on the second trimester, including concerns about answering awkward questions, the gender of the baby, delivering too early, exercising, and sexual intercourse. Feelings that may be common during this trimester are panic over the baby's movements, reluctance to bond with the baby, anxiety about surpassing the anniversary of the previous baby's death, superstitions about the pregnancy, and fear. Prenatal tests that can be offered at this time and symptoms that are not normal during the second trimester also are covered. Chapter 6 examines the concerns mothers are likely to have during the third trimester regarding early delivery, setting up the nursery, baby shower offers, choosing a name, and excessive weight gain. Feelings that may be common during this time include obsession over the baby's movements, constant worry, and being annoyed by unsolicited advice. Tips for alleviating the anxiety include taking a prepared childbirth class, writing a birth plan, getting a doula, calling the doctor frequently, insisting on frequent prenatal visits, eliminating unnecessary stress, and practicing relaxation techniques. The nature of prenatal visits during the third trimester, tests that are usually done at this time, monitoring the baby's kicks, and danger signals in late pregnancy also are discussed. Chapter 7 deals with the truly high-risk pregnancy. Common reasons for high-risk status are a history of preterm labor or delivery, incompetent cervix, impending multiple birth, history of placental problems, history of two or more miscarriages, genetic problems, chronic medical conditions, and pregnancy after age 35. Bed rest is a commonly prescribed treatment in high-risk pregnancies. This chapter provides suggestions for surviving extended bed rest as well as a chart of activities to help mothers and their OB/GYNs mutually define what she can and can't do. Other topics that are discussed include hospitalization, the impact of that and bed rest on family and career, selective reduction in cases of multiples, feelings that are common among mothers during bed rest, and tips for relieving the anxiety. The signs and treatment of preterm labor also are discussed. Chapter 8 deals with labor and delivery, including fetal monitoring during labor, bonding with the baby, feelings commonly reported after birth, what to expect if your baby goes to the NICU, and tips for relieving anxiety. Chapter 9 talks about the consequences of pregnancy loss on parenting the subsequent child. It is common for parents to feel anxious and overprotective, but their loss also may make them exceptional parents. There is often continued sadness and introspection and a totally changed outlook on life. This chapter also reviews some of the private and public ways in which parents have chosen to remember their infants who died. Chapter 10 looks at pregnancy after a loss from a father's perspective, including feelings that are common to fathers who are expecting again and ways in which the mother can ease her spouse's anxiety. A list of resources includes support organizations for pregnancy and infant loss, high-risk pregnancy, subsequent pregnancy, infertility, and pregnancy/childbirth; publishers of relevant books; and internet resources.

Books

•

213

Genetic Disorders and Birth Defects: A Compendium of AAP Guidelines and Resources for the Primary Care Practitioner Source: Elk Grove Village, IL: American Academy of Pediatrics (AAP). 1997. 130 p. Contact: Available from American Academy of Pediatrics (AAP). 141 Northwest Point Boulevard, Elk Grove Village, IL 60007-1098. (800) 433-9016 (members) or (888) 227-1773 (nonmembers). Fax (847) 434-8000. Website: www.aap.org. PRICE: $24.95 each (members); $29.95 each (nonmembers); plus shipping and handling. Order Number BMA0097. Summary: This volume provides a compendium of the American Academy of Pediatrics (AAP) guidelines and resources for health care providers who are working with patients who have genetic disorders and birth defects. The compendium serves as a diagnostic and management resource guide for pediatricians and primary care physicians. Although some of the disorders covered are relatively uncommon, it is likely that most pediatricians will encounter and care for a few such patients in their practice panel. The authors emphasize that early intervention services, multidisciplinary care, and developmental assessment and management form a major part of continuing care for many children with genetic conditions. The AAP Policy Statements are provided on folic acid for the prevention of neural tube defects, issues in newborn screening, maternal phenylketonuria, maternal serum alpha-fetoprotein screening, newborn screening for congenital hypothyroidism, newborn screening fact sheets, and prenatal genetic diagnosis for pediatricians. In addition, policy statements are provided for the health supervision of children born with the following conditions: achondroplasia, Down syndrome, fragile X syndrome, Marfan syndrome, neurofibromatosis, sickle cell disease, and Turner syndrome. Each Policy Statement includes references. The compendium includes extensive appendices, covering topics including fetal alcohol syndrome, general principles of care for children and adolescents with genetic and other chronic health conditions, hospital stays, medical homes, preventive pediatric health care, and transition of care provided for adolescents with special health care needs. The compendium also lists the references where the policy statements were first published, the contact information for national and regional genetic organizations, and the members of the AAP Section on Genetics and Birth Defects.

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

Chemistry and Biology of Pteridines, 1986: Pteridines and Folic Acid Derivatives: Proceedings of the Eighth International Symposium on Pteridines A by V.M. Whitehead (Editor), B. A. Cooper (Editor) (1986); ISBN: 3110107716; http://www.amazon.com/exec/obidos/ASIN/3110107716/icongroupinterna

214 Folic Acid

•

Chemistry and Biology of Pteridines, 1989: Pteridines and Folic Acid Derivatives: Proceedings of the 9th International Symposium on Pteridines and by International Symposium on Pteridines and Folic Acid Derivatives: Chem, et al (1990); ISBN: 0899256090; http://www.amazon.com/exec/obidos/ASIN/0899256090/icongroupinterna

•

Chemistry and Biology of Pteridines: Pteridines and Folic Acid Derivatives by John A. Blair (Editor) (1983); ISBN: 3110085607; http://www.amazon.com/exec/obidos/ASIN/3110085607/icongroupinterna

•

Development of Folates and Folic Acid Antagonists in Cancer Chemotherapy: Innisbrook, Tarpon Springs, Florida, January 23-26, 1986 by Natl Cancer Inst. (1985); ISBN: 999903229X; http://www.amazon.com/exec/obidos/ASIN/999903229X/icongroupinterna

•

Folic Acid by Sidney M. Baker; ISBN: 0879836628; http://www.amazon.com/exec/obidos/ASIN/0879836628/icongroupinterna

•

Folic Acid (Pteroylglutamic Acid) in Health, Deficiency & Therapy: Index of New Information With Authors, Subjects & References by Spencer D. Bradshaw (1996); ISBN: 0788313231; http://www.amazon.com/exec/obidos/ASIN/0788313231/icongroupinterna

•

Folic acid : biochemistry and physiology in relation to the human nutrition requirement : proceedings of a Workshop on Human Folate Requirements, Washington, D.C., June 2-3, 1975; ISBN: 0309026059; http://www.amazon.com/exec/obidos/ASIN/0309026059/icongroupinterna

•

Folic Acid and Neural Tube Defects (Evaluation of Publicly Available Scientific Evidence Regarding Certain nutrIent Series) by Daphne A. Roe (1991); ISBN: 9992239794; http://www.amazon.com/exec/obidos/ASIN/9992239794/icongroupinterna

•

Folic Acid and the Amazing B Vitamins: A Question-And-Answer Guide for Women and Men by Glenn S. Rothfeld, Suzanne Levert (2000); ISBN: 0425173690; http://www.amazon.com/exec/obidos/ASIN/0425173690/icongroupinterna

•

FOLIC ACID CAMPAIGN: GUID PURCH by HEA; ISBN: 0752105779; http://www.amazon.com/exec/obidos/ASIN/0752105779/icongroupinterna

•

Folic Acid Education Pack (1998); ISBN: 0752111728; http://www.amazon.com/exec/obidos/ASIN/0752111728/icongroupinterna

•

Folic Acid in Neurology, Psychiatry and Internal Medicine by M.I. Botex, E.H. Reynolds (Editor) (1979); ISBN: 0890043388; http://www.amazon.com/exec/obidos/ASIN/0890043388/icongroupinterna

•

Folic Acid Metabolism in Health and Disease (Contemporary Issues in Clinical Nutrition, Vol 13) by E.L. Robert Stokstad, et al; ISBN: 0471567442; http://www.amazon.com/exec/obidos/ASIN/0471567442/icongroupinterna

•

Folic Acid: Education Guidance Pack; ISBN: 0752110446; http://www.amazon.com/exec/obidos/ASIN/0752110446/icongroupinterna

•

Folic Acid: The Essential B Vitamin That Prevents Birth Defects and Promotes Optimal Health by Allan, M.D. Spreen, Allan N. Spreen (2000); ISBN: 1580540848; http://www.amazon.com/exec/obidos/ASIN/1580540848/icongroupinterna

Books

•

Report on Health and Social Subjects: Folic Acid and the Prevention of Disease (1999); ISBN: 0113223048; http://www.amazon.com/exec/obidos/ASIN/0113223048/icongroupinterna

•

Vitamin B12 and Folic Acid by Ruth Adams, Frank Murray; ISBN: 0915962314; http://www.amazon.com/exec/obidos/ASIN/0915962314/icongroupinterna

215

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 “folic acid” (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 •

Chemistry and biology of pteridines, 1989: pteridines and folic acid derivatives: proceedings of the Ninth International Symposium on Pteridines and Folic Acid Derivatives, Chemical, Biological, and Clinical Aspects, Zurich, Switzerland,September 3-8, 1989 Author: Curtius, H. Ch. (Hans-Christoph); Year: 1990; Berlin; New York: De Gruyter, 1990; ISBN: 3110121999 http://www.amazon.com/exec/obidos/ASIN/3110121999/icongroupinterna

•

Development of folates and folic acid antagonists in cancer chemotherapy: Innisbrook, Tarpon Springs, Florida, January 23-26, 1986 Author: O'Dwyer, Peter J.; Year: 1973; Bethesda, MD: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health, [1987]

•

Experiences with folic acid. Author: Spies, Tom Douglas,; Year: 1947; Chicago, Year book pub. [1947]

•

Folic acid and vitamin B12; their interrelationships, by George H. Schneller and Josephine L. Hutchinson. Author: Schneller, George H.; Year: 1953; New York, Fine Chemicals Division, American Cyanamid Co. [1954]

•

Folic acid content of foods; microbiological assay by standardized methods and compilation of data from the literature, by Edward W. Toepfer [and others]. Author: Toepfer, Edward William,; Year: 1951; Washington, 1951 [i. e. 1952]

•

Folic acid in the megaloblastic anemias, by Richard A. Carey and Josephine L. Hutchinson. Author: Carey, Richard A.; Year: 1975; New York, American Cyanamid Co., Fine Chemicals Division [1956]

•

Folic acid U. S. P. Author: Upjohn Company.; Year: 1956; Kalamazoo, Mich. [c1956]

•

Morphologic changes in folic acid deficiency induced by methotrexate in human bone marrow and blood. Author: Speck, Bruno,; Year: 1963; [Minneapolis, Minn.] 1965

11

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

216 Folic Acid

•

The biochemistry of folic acid and related pteridines. Author: Blakley, Raymond L.; Year: 1950; Amsterdam, North-Holland Pub. Co., 1969

•

The formation of certain folic acid enzymes during the growth of bacteria. Author: Soini, Juhani.; Year: 1969; Helsinki: Suomalainen Tiedeakatemia, 1967

•

The nutrional and clinical significance of folic acid. Author: Lederle Laboratories.; Year: 1954; [New York, c1950]

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

Erythropoietin Therapy in Renal Failure Source: in Stollerman, G.H., et al., eds. Advances in Internal Medicine. Vol 38. St. Louis, MO: Mosby-Year Book, Inc. 1993. p. 223-243. Contact: Available from Mosby Year-Book, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 426-4545. Fax (800) 535-9935. E-mail: [email protected]. PRICE: $72.95. ISBN: 0815183089. ISSN: 00652822. Summary: Although there are many factors contributing to the anemia of uremia, such as blood loss, iron deficiency, and deficiencies of folic acid and vitamin B12, the basic underlying cause of anemia is the failure of the production of the hormone erythropoietin. This chapter covers erythropoietin therapy in renal failure. Genetically engineered erythropoietin is now available for both intramuscular and intravenous administration. The administration of this hormone will correct the anemia of uremia, therefore obviating the need for blood transfusion with all the attendant risks (infection and antigen stimulation). The authors outline the benefits of the drug in correcting the hematologic and hemodynamic profile, as well as its role in improving the patient's sense of well being, exercise tolerance, and cognitive function. The authors note that, where iron overload was previously a major concern in uremic patients receiving multiple transfusions, now iron deficiency is common and, if not corrected, may lead to resistance to erythropoietin therapy. The authors conclude that the judicious use of erythropoietin along with informed dosing practices will lead to an overwhelmingly favorable balance in the risk to benefit ratio of care. 6 figures. 2 tables. 68 references. (AA-M).

•

Anaemia Source: in Scully, C. and Cawson, R.A. Medical Problems in Dentistry. 4th ed. Woburn, MA: Butterworth-Heinemann. 1998. p. 106-122. Contact: Available from Butterworth-Heinemann. 225 Wildwood Avenue, Woburn, MA 01801-2041. (800) 366-2665 or (781) 904-2500. Fax (800) 446-6520 or (781) 933-6333. E-mail: [email protected]. Website: www.bh.com. PRICE: $110.00. ISBN: 0723610568.

Books

217

Summary: Anemia is not a disease in itself but may be a feature of many diseases. The essential feature of anemia is a hemoglobin level below normal for the age and sex of the patient. This chapter on anemia is from a text that covers the general medical and surgical conditions relevant to the oral health care sciences. Topics include the classification of anemias, laboratory investigations, general dental aspects of anemia, iron deficiency anemia, Vitamin B12 (cobalamin) deficiency, pernicious (Addisonian) anemia, folate (folic acid) deficiency, anemia associated with systemic disease, aplastic anemia, hemolytic anemia, sickle cell disease, the thalassemias, erythrocyte membrane defects, erythrocyte metabolic defects, and acquired hemolytic anemia. For each disorder, the authors discuss general aspects, diagnosis and management issues, dental aspects, and patient care strategies. The chapter includes a lengthy summary of the points covered. 1 appendix. 2 figures. 12 tables. 49 references. •

Sprue Syndromes Source: in Brandt, L., et al., eds. Clinical Practice of Gastroenterology. Volume One. Philadelphia, PA: Current Medicine. 1999. p. 484-493. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 545-2522. Fax (800) 874-6418 or (407) 352-3445. Website: www.wbsaunders.com. PRICE: $235.00 plus shipping and handling. ISBN: 0443065209 (two volume set); 0443065217 (volume 1); 0443065225 (volume 2). Summary: Celiac sprue is a disease of the small intestine resulting from a sensitivity to gluten, the water insoluble protein of wheat, and characterized by various degrees of villous atrophy (wasting of the villi of the small intestine) and malabsorption. Tropical sprue is an idiopathic disease of the small intestine that is acquired in tropical regions. Although the clinical and histologic findings superficially may resemble those of celiac sprue, treatment is different. This chapter on sprue syndromes is from a lengthy textbook that brings practitioners up to date on the complexities of gastroenterology practice, focusing on the essentials of patient care. Most patients with celiac sprue improve after withdrawal of gluten from their diets, but a few have a more complex course or develop one or more associated extraintestinal diseases. Celiac disease is characterized by poor food absorption and intolerance to gluten. The clinical features at presentation depend on the severity of disease and the age of the person affected. The small bowel biopsy remains the standard for diagnosis. Treatment requires lifelong abstinence from dietary gluten (removing from the diet all foods that contain wheat, barley, and rye). Within weeks of starting the gluten free diet, most patients respond to a gluten free diet with weight gain and decreased diarrhea. Tropical sprue is an idiopathic disease of chronic malabsorption that causes subtotal villous atrophy of the entire small intestine and ultimately leads to malabsorption and nutritional deficiencies. A careful history is crucial in making the diagnosis. Tropical sprue should be suspected in patients who have been in an endemic area for more than 2 weeks and who present with intestinal symptoms of diarrhea or steatorrhea and weight loss associated with macrocytic anemia; endoscopy is helpful in confirming diagnosis. Tropical sprue patients typically respond rapidly, although temporarily, to folic acid administration and more slowly and permanently to antibiotics. 9 figures. 5 tables. 30 references.

•

Systemic Disease: Oral Manifestations and Effects on Oral Health Source: in Wray, D., et al. Textbook of General and Oral Medicine. Edinburgh, Scotland: Churchill Livingstone. 1999. p. 307-328.

218 Folic Acid

Contact: Available from Harcourt Health Sciences. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 325-4177. Fax (800) 874-6418. Website: www.harcourthealth.com. PRICE: $50.00 plus shipping and handling. ISBN: 0443051895. Summary: Oral lesions and symptoms are usually the result of local disease, but can be the earliest indication of, or in some instances the main features in, patients with systemic disease. Indeed, oral manifestations can sometimes lead to the diagnosis of systemic disease. This chapter on the oral manifestations of systemic disease is from an undergraduate dentistry textbook that covers both general medicine and surgery, and oral medicine, emphasizing the overlap between them. The authors note that there are surprisingly few diseases, or their treatments, that are not capable of causing some oral signs or symptoms or affecting oral health care. Topics include blood disorders, including anemia, the thalassemias, lymphoreticular malignancy, myeloproliferative disorders, plasma cell tumors (myeloma), and porphyria; hemorrhagic diseases, including platelet disorders, Von Willebrand's disease, clotting disorders, and acquired clotting defects; cardiovascular disease, including patients with cardiac pacemakers, and oral reactions to drugs used for heart disease; endocrine (hormone) disorders, including acromegaly, adrenocortical insufficiency, corticosteroid treatment, diabetes mellitus, hyperthyroidism, hypothyroidism, hyperparathyroidism, and hypoparathyroidism; gastrointestinal disorders, including celiac disease (gluten sensitive enteropathy), Crohn's disease, Gardner's syndrome, and pyostomatitis vegetans; granulomatous diseases, including foreign body reactions, midline granuloma syndromes, orofacial granulomatosis, and sarcoidosis; immunological disorders, including allergy that may manifest as angioedema, aphthae, contact cheilitis, erythema multiforme, lichen planus, orofacial granulomatosis, and plasma cell gingivitis; nutritional deficiencies, including vitamin A, riboflavin (vitamin B2), nicotinamide, vitamin B12 and folic acid, vitamin C, and vitamin D; pregnancy; and renal disease. Clinical points to remember are highlighted in text boxes. 16 figures. 31 tables. •

Short-Bowel Syndrome Source: in Brandt, L., et al., eds. Clinical Practice of Gastroenterology. Volume One. Philadelphia, PA: Current Medicine. 1999. p. 507-516. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 545-2522. Fax (800) 874-6418 or (407) 352-3445. Website: www.wbsaunders.com. PRICE: $235.00 plus shipping and handling. ISBN: 0443065209 (two volume set); 0443065217 (volume 1); 0443065225 (volume 2). Summary: The short bowel syndrome (SBS) refers to the clinical sequelae of resection (removal) of a substantial portion of the small intestine. This chapter on SBS is from a lengthy textbook that brings practitioners up to date on the complexities of gastroenterology practice, focusing on the essentials of patient care. The major features of SBS are diarrhea and malabsorption, which may result in hypovolemia (abnormally low blood circulating volume), dehydration, metabolic acidosis, and malnutrition marked by weight loss, hypoalbuminemia (low albumin levels in the blood), and deficiencies of potassium, calcium, zinc, magnesium, copper, fatty acids, fat soluble vitamins, folic acid, and B12. Factors other than the residual length of the intestine affect clinical outcome, including the site and extent of resected intestine; the factors that made resection necessary; whether the remaining intestine is structurally or functionally normal and capable of adapting; the residual function of the stomach, pancreas, biliary tree, and colon; and whether the ileocecal valve has been included in the resected intestine. The comprehensive management of patients with SBS demands detailed attention to meeting their metabolic and nutritional needs. Treatment can include drug

Books

219

therapy, enteral or parenteral nutritional support, or both, and some patients require surgical intervention. 1 figure. 7 tables. 65 references. •

Oral Manifestations of Nutritional Disorders Source: in Bork, K., et al. Diseases of the Oral Mucosa and the Lips. Orlando, FL: W.B. Saunders Company. 1993. p. 355-357. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887-4430. (800) 545-2522 (individuals) or (800) 782-4479 (schools); Fax (800) 874-6418 or (407) 352-3445; http://www.wbsaunders.com. PRICE: $99.00 plus shipping and handling. ISBN: 0721640397. Summary: This brief chapter, from a textbook on diseases of the oral mucosa and the lips, discusses the oral manifestations of nutritional disorders. Disorders covered include deficiencies of vitamin A, vitamin B2 (riboflavin), nicotinic acid, vitamin B6 (pyridoxine), B12, folic acid, and vitamin C; iron deficiency; zinc deficiency; and protein deficiency. For each topic, the authors describe the clinical features. The authors note that the most common causes of vitamin deficiency today include starvation (common in many parts of the world; in the West, it is seen mainly in terminal cancer patients); malnutrition, especially among the poor, elderly, and homeless; and gastrointestinal disease with malabsorption. Treatment for all vitamin deficiencies is obvious: a wellbalanced diet and vitamin supplements. Except for patients with malabsorption, oral supplementation with ordinary multivitamins suffices. 2 references. (AA-M).

•

Nutrition Therapy for Pregnancy and Lactation Source: in Franz, M.J. and Bantle, J.P., eds. American Diabetes Association Guide to Medical Nutrition Therapy for Diabetes. Alexandria, VA: American Diabetes Association. 1999. p. 229-248. 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: $39.95 for members; $49.95 for nonmembers; plus shipping and handling. ISBN: 158040006X. Order number 561601. Summary: This chapter focuses on nutrition issues associated with pregnancy and breastfeeding. Nutrition related concerns during pregnancy include weight gain and caloric requirements, adequate nutrients, and possible need for vitamin and mineral supplements such as iron and folic acid. The problems associated with pregnancy in women with diabetes include an increased risk for fetal birth defects and increased spontaneous abortion rates. Nutrition therapy for women who have prior onset type 1 or type 2 diabetes begins with a prenatal meal plan before attempting conception so that they can attempt to achieve glycemic control and optimal body weight. The goal of medical nutrition therapy (MNT) in a pregnancy with diabetes is to maintain normal blood glucose levels while meeting the nutritional needs of pregnancy. Regular meals and snacks are very important to avoid hypoglycemia during pregnancy. Breastfeeding is recommended for women who have diabetes, and a postpartum meal plan must account for the energy demands of breastfeeding as well as its lowering effects on blood glucose. For women who develop gestational diabetes mellitus (GDM), MNT is used to achieve optimal blood glucose control with adequate nutrition for both mother and fetus. Intensive nutrition therapy, along with daily blood glucose monitoring and an exercise program, may be an alternative to insulin therapy in women who develop GDM. Breastfeeding is also encouraged in women who have GDM. Women should not follow a hypocaloric diet until lactation is terminated. 1 figure. 6 tables. 63 references.

220 Folic Acid

•

Diet and the Aging Gut Source: in Janowitz, H.D. Good Food for Bad Stomachs. New York, NY: Oxford University Press. 1997. p. 175-180. Contact: Available from Oxford University Press. Order Department, 2001 Evans Road, Cary, NC 27513. (800) 451-7556. Fax (919) 677-1303. PRICE: $12.95 plus shipping and handling. ISBN: 0195126556. Summary: This chapter on diet and aging is from a book that presents a detailed look at present knowledge about the role of eating habits in preventing, causing, and treating the many disorders that plague the gastrointestinal tract and its associated digestive glands, the liver, the gallbladder, and the pancreas. The author notes that unlike the central nervous system and the cardiovascular organs, the digestive system is on the whole spared many of the dramatic effects of age although aging does have some effects. The author reviews the changes that occur in the gastrointestinal system with aging, then considers general and specific aspects of nutrition in older people, including the minerals and vitamins recommended for older adults (folic acid, calcium, vitamin D, antioxidants).

•

Nutrition and the Professional Voice User Source: in Sataloff, R.T., ed. Professional Voice: The Science and Art of Clinical Care. 2nd ed. San Diego, CA: Singular Publishing Group, Inc. 1997. p. 337-354. Contact: Available from Singular Publishing Group, Inc. 401 West 'A' Street, Suite 325, San Diego, CA 92101-7904. (800) 521-8545 or (619) 238-6777. Fax (800) 774-8398 or (619) 238-6789. E-mail: [email protected]. Website: www.singpub.com. PRICE: $325.00 plus shipping and handling. ISBN: 1565937287. Summary: This chapter on nutrition and the professional voice user is from a book on the clinical care of the professional voice. Performers must understand why attention to their own nutritional status is important to their lives and livelihoods. Laryngeal and vocal health cannot be separated from general health and longevity. The authors stress that nutritional status is extremely important to the singer or actor who wants to be vital and energetic, maintain appropriate body weight, resist the colds and common maladies that often travel through an entire cast or choir. Stress and fatigue are endemic in performers, due in no small part to grueling audition, rehearsal, and performance schedules, working second and third jobs, intense competition, and self scrutiny. Without proper instruction and attention to nutrition and food choices, a performer's lifestyle demands can result in an unstable, inadequate nutritional status that invites illness. The authors discuss basic nutrition and dietary guidelines, recent research in nutrition, free radical pathology and antioxidant defenses, determining nutritional status, choosing supplements, nutrition fact food labels, food as medicine, vocal longevity and nutrition, and nutritional goals for performers. One extensive table summarizes the functions, RDA levels, and food sources of common nutrients, including fluids, carbohydrates, proteins, fatty acids, vitamins, biotin, folic acid, calcium, other minerals, and trace elements. 2 figures. 1 table. 118 references.

•

Nutrition Basics Source: in Korn, D. Kids with Celiac Disease: A Family Guide to Raising Happy, Healthy, Gluten-Free Children. Bethesda, MD: Woodbine House. 2001. p. 159-182. Contact: Available from Woodbine House. 6510 Bells Mill Road, Bethesda, MD 20817. (800) 843-7323 or (301) 897-3570. Fax (301) 897-5838. E-mail: [email protected].

Books

221

Website: www.woodbinehouse.com. PRICE: $17.95 plus shipping and handling. ISBN: 1890627216. Summary: This chapter on nutrition is from a practical survival guide for families of children and teenagers with celiac disease, a lifelong digestive disorder that affects nearly two million Americans. Celiac disease results from an intolerance of gluten, a protein found in wheat, rye, barley, and oats, and any food made with these grains. Removing gluten from the diet is the only known treatment for this illness. Left untreated, the disease can lead to serious conditions such as damage to the central nervous system, osteoporosis, and cancer. In this chapter, the author helps parents and children achieve a healthy, balanced diet when so many foods are forbidden. In addition, before the child's celiac disease is controlled, he or she can have nutritional deficiencies that need to be addressed and corrected. And, as with any children, parents may encounter special nutritional issues, such as a child who wants to become a vegetarian, or one who goes on food jags, or one who needs additional calories. The author discusses the food guide pyramid, the five food groups used in the pyramid (with specific suggestions offered in each group), nutrient imbalances and deficiencies related to celiac disease (carbohydrates, protein, fat, fat soluble vitamins, calcium, magnesium, zinc, iron, folate or folic acid, vitamin B12, and electrolytes), disaccharide intolerance (including lactose intolerance), making snacks healthy and fun, managing food jags, boosting calories and nutrients in the child's diet, and the importance of working with a dietitian with any additional questions parents may have. The chapter includes black and white photographs of children, and sidebars sharing quotations from parents. •

Therapeutic Expectations: Medical Management of Ulcerative Colitis Source: in Bayless, T.M. and Hanauer, S.B. Advanced Therapy of Inflammatory Bowel Disease. Hamilton, Ontario: B.C. Decker Inc. 2001. p. 111-113. Contact: Available from B.C. Decker Inc. 20 Hughson Street South, P.O. Box 620, L.C.D. 1 Hamilton, Ontario L8N 3K7. (905) 522-7017 or (800) 568-7281. Fax (905) 522-7839. Email: [email protected]. Website: www.bcdecker.com. PRICE: $129.00 plus shipping and handling. ISBN: 1550091220. Summary: This chapter on the medical management of ulcerative colitis is from the second edition of a book devoted to the details of medical, surgical, and supportive management of patients with Crohn's disease (CD) and ulcerative colitis (UC), together known as inflammatory bowel disease (IBD). The author stresses that therapeutic expectations for UC must take into consideration the chronic, medically incurable nature of inflammatory bowel disease (IBD), the varied mucosal extent, potential severity, and disease or therapy related complications. It is most useful to consider the therapeutic expectations with regard to inducing remission, maintaining remission, treating symptoms, and treating or preventing complications. Ulcerative colitis can be complicated by intestinal or extra-intestinal complications. Intestinal complications, such as bleeding and associated anemia, hypoproteinemia, or electrolyte abnormalities require prompt control with inductive therapies. Thereafter, supplementation with iron and folic acid (with sulfasalazine) should treat and prevent further development of anemia during maintenance therapy. Other intestinal complications, such as toxic megacolon or perforation, can be prevented with aggressive inductive therapies, according to the severity of presentation. Patients should be warned against the use of NSAIDs and to alert their physician when primary care physicians or other specialists prescribe antibiotics or other medications, to be certain they do not induce diarrhea (Clostridium difficile) and are compatible with UC therapy. Controlling colonic

222 Folic Acid

inflammation usually prevents extraintestinal complications, such as peripheral arthritis and cutaneous manifestations. In addition, with the advent of pelvic pouch procedures, an additional goal of medical therapy is to treat, and eventually prevent, pouchitis. This chapter serves as an introduction to a section of 12 chapters on UC. 6 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.

•

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 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,

Books

223

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. •

Trace Elements and Vitamins in Renal Disease Source: in Mitch, W.E., and Klahr, S., eds. Nutrition and the Kidney. 2nd ed. Boston, MA: Little, Brown and Company. 1993. p. 114-131. Contact: Available from Lippincott-Raven Publishers. 12107 Insurance Way, Hagerstown, MD 21740. (800) 777-2295. Fax (301) 824-7390. E-mail: [email protected]. Website: http://www.lrpub.com. PRICE: $94.95. ISBN: 0316575003. Summary: This chapter, from a medical textbook on nutrition and the kidney, reviews the metabolism, concentrations, and requirements of trace elements and vitamins in patients with chronic renal failure (CRF) prior to the onset of dialysis and during treatment with either hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Topics include the alteration of trace element metabolism in kidney failure, including aluminum, iron, zinc, copper, selenium, and ultra trace elements; and vitamins, including thiamine (B1), riboflavin (B2), pyridoxine (B6), cobalamin (B12), folic acid, biotin, niacin, pantothenic acid, ascorbic acid (vitamin C), retinol (vitamin A), and tocopherol (vitamin E). The authors briefly discuss recommendations for supplementation. 4 tables. 101 references.

225

CHAPTER 8. MULTIMEDIA ON FOLIC ACID Overview In this chapter, we show you how to keep current on multimedia sources of information on folic acid. 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 Folic Acid 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 folic acid (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 folic acid: •

Folate, folic acid, and health [electronic resource] Source: [produced by Barry Borman]; Year: 1999; Format: Electronic resource; [Wellington, N.Z.: Ministry of Health, 1999?]

•

Folic acid [videorecording]. Year: 1992; Format: Videorecording; Chevy Chase, Md.: Radio TV Reports, [1992?]

•

Folic acid antagonists [videorecording] Source: University of Texas, System Cancer Center, M. D. Anderson Hospital and Tumor Institute; produced by MDA-TV; Year: 1973; Format: Videorecording; Houston: The Center, 1973

•

The role of folic acid in Alzheimer's disease prevention [videorecording]. Year: 2002; Format: Videorecording; Carrollton, TX: HSTN, c2002

227

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

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

Folic acid may not cut risk of heart attack, death Source: Reuters Health eLine Date: June 17, 2003

•

Folic acid does not appear to reduce cardiovascular event recurrence Source: Reuters Industry Breifing Date: June 17, 2003

228 Folic Acid

•

Report questions use of folic acid for sickle cell Source: Reuters Health eLine Date: May 28, 2003

•

Folic acid supplementation may reduce risk of Down's syndrome Source: Reuters Medical News Date: April 21, 2003

•

Folic acid use not linked to multiple births Source: Reuters Medical News Date: January 31, 2003

•

Folic acid not linked to multiple births: study Source: Reuters Health eLine Date: January 31, 2003

•

Folic acid intake tied to colon cancer risk Source: Reuters Health eLine Date: January 09, 2003

•

Fortification of food with folic acid has reduced neural tube defects in Canada Source: Reuters Medical News Date: December 19, 2002

•

Report supports folic acid for heart health Source: Reuters Health eLine Date: November 22, 2002

•

Lowering homocysteine with folic acid decreases cardiovascular disease risk Source: Reuters Medical News Date: November 21, 2002

•

Folic acid supplementation may reduce risk of gestational hypertension Source: Reuters Medical News Date: November 06, 2002

•

Folic acid may help prevent pregnancy complication Source: Reuters Health eLine Date: November 01, 2002

•

Folic acid may lower risk of miscarriage: study Source: Reuters Health eLine Date: October 15, 2002

•

Folic acid and cobalamin aid coronary endothelial function Source: Reuters Medical News Date: September 18, 2002

•

More women getting adequate folic acid: CDC Source: Reuters Health eLine Date: September 12, 2002

•

Extra folic acid cuts birth defect rate in Canada Source: Reuters Health eLine Date: September 09, 2002

•

Folic acid supplementation significantly reduces adverse events after PCI Source: Reuters Industry Breifing Date: August 27, 2002

Periodicals and News

•

Long-term folic acid use improves homocysteine levels, endothelial function Source: Reuters Medical News Date: June 14, 2002

•

Folic acid may help restore artery health Source: Reuters Health eLine Date: May 29, 2002

•

UK agency advises against folic acid fortification Source: Reuters Health eLine Date: May 10, 2002

•

Zinc and folic acid supplementation increases sperm count Source: Reuters Industry Breifing Date: April 01, 2002

•

Zinc, folic acid shown to boost sperm count Source: Reuters Health eLine Date: March 14, 2002

•

Folic acid could shield elderly from heart disease Source: Reuters Health eLine Date: March 06, 2002

•

Elderly need to boost folic acid intake to prevent heart disease Source: Reuters Medical News Date: March 06, 2002

•

Weekly iron, folic acid supplement reduces anemia in high prevalence population Source: Reuters Medical News Date: February 14, 2002

•

UK docs advise adding B12 and folic acid to grains Source: Reuters Health eLine Date: January 18, 2002

•

High-dose folic acid prevents gastric cancer in animals Source: Reuters Industry Breifing Date: December 26, 2001

•

Folic acid prevents stomach cancer: study Source: Reuters Health eLine Date: December 20, 2001

•

UK docs urge caution for folic acid in flour plan Source: Reuters Health eLine Date: November 23, 2001

•

UK physicians urge caution on folic acid fortification of flour Source: Reuters Medical News Date: November 22, 2001

•

Folic acid not linked to miscarriage risk Source: Reuters Health eLine Date: September 07, 2001

•

Folic acid use does not increase risk of miscarriage Source: Reuters Medical News Date: September 06, 2001

229

230 Folic Acid

•

Preconception folic acid can prevent birth defects Source: Reuters Health eLine Date: September 05, 2001

•

Birth defects drop after folic acid added to food Source: Reuters Health eLine Date: June 19, 2001

•

Folic acid reduces plasma homocysteine levels in patients with CAD Source: Reuters Medical News Date: May 31, 2001

•

Folic acid reduces damage to arterial lining Source: Reuters Health eLine Date: May 31, 2001

•

Folic acid fortification making clear difference in Americans' nutritional status Source: Reuters Industry Breifing Date: April 02, 2001

•

FDA scores a win with folic acid fortification Source: Reuters Health eLine Date: April 02, 2001

•

Few women at risk of having child with neural tube defect take folic acid Source: Reuters Medical News Date: March 23, 2001

•

Many women don't know why they need folic acid Source: Reuters Health eLine Date: March 16, 2001

•

Many women still unaware of the importance of folic acid Source: Reuters Medical News Date: March 15, 2001

•

Dietary supplement makers win victory against FDA in folic acid suit Source: Reuters Industry Breifing Date: February 02, 2001

•

Court rules FDA must allow folic acid claim Source: Reuters Health eLine Date: February 02, 2001

•

Supplement makers, FDA clash over folic acid claim Source: Reuters Health eLine Date: December 05, 2000

•

Supplement makers seek preliminary injunction against FDA in folic acid suit Source: Reuters Industry Breifing Date: December 04, 2000

•

Use of folic acid antagonists increases risk of birth defects Source: Reuters Industry Breifing Date: November 29, 2000

•

Folic acid may reduce risk of several birth defects Source: Reuters Health eLine Date: November 29, 2000

Periodicals and News

231

•

Dietary supplement makers sue FDA for right to make folic acid claim Source: Reuters Industry Breifing Date: November 15, 2000

•

FDA prohibits dietary supplement firms from making claims about folic acid, fiber Source: Reuters Industry Breifing Date: October 12, 2000

•

Folic acid supplements have only modest effect on high homocysteine levels Source: Reuters Medical News Date: September 26, 2000 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 “folic acid” (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 “folic acid” (or synonyms). If you know the name of a company that is relevant to folic acid, 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/.

232 Folic Acid

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 “folic acid” (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 “folic acid” (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 folic acid: •

Q Is for Quinoa: Questionable or Not? Source: Gluten-Free Living. p. 3, 6, 8. July-August 1999. Contact: Available from Gluten-Free Living. P.O. Box 105, Hastings-on-Hudson, NY 10706. E-mail: [email protected]. Summary: Gluten, a grain protein, is found primarily in wheat, but also in rye, barley, spelt, kamut, triticale, and possibly oats. People who are genetically predisposed to gluten sensitivity have trouble eating foods that contain gluten. Their small intestine reacts as if the food were poison. The reaction damages the small intestine, causing malabsorption of vital nutrients, including iron, calcium, folic acid, and fat soluble vitamins. This article discusses the use of quinoa on a gluten free diet. Quinoa is a fruit, not a grain (botanically speaking) and has been determined to be gluten free. The author stresses that the variety that alternative grains add to the limited celiac diet is enormous. Quinoa can be prepared as a breakfast cereal, used in place of rice or potato at dinner, or ground into flour for baking or thickening. Quinoa is also used to make a tasty pasta that is not difficult to find on grocery store shelves. The author reviews the history of quinoa use and discusses the processing that quinoa typically undergoes, in an attempt to address the hesitations of some people with celiac disease who are uncertain about using quinoa. The author reviews the producers of quinoa products (imported as well as those farms in the United States) and describes the farming process. The contact information for two companies is provided. One sidebar offers a description of how to cook with quinoa, including a recipe for Lemon Pie in Chocolate Quinoa Crust.

•

A Health Bar of One's Own? Source: University of California, Berkeley, Wellness Letter. 18(6):5. March 2002. Contact: Health Letter Associates. P.O. Box 412, Prince Street Station, New York, NY 10012-0007. www.wellnessletter.com. Summary: Many food products marketed to women were developed to help meet their nutritional requirements. This article provides examples of these 'gender- specific' products, which are often more expensive than their plain counterparts, and a description of the nutrients they contain. Although women and men have some

Periodicals and News

233

different nutritional needs, the article notes that 'nothing can take the place of a varied diet rich in fruits, whole grains, vegetables, and nonfat or low-fat dairy products.' If women need extra calcium, folic acid, iron, or vitamins C or E, supplements are an easy, inexpensive way for women to get these nutrients. •

A Bushel and a Peck of Peppers Source: University of California, Berkeley, Wellness Letter. 17(3):3. December 2000. Contact: Health Letter Associates. P.O. Box 412, Prince Street Station, New York, NY 10012-0007. www.wellnessletter.com. Summary: Peppers, whether hot or sweet, are a diverse and nutritious food. Peppers contain vitamin C, beta carotene, potassium, folic acid, calcium, and fiber, along with other phytochemicals. Most peppers start out green; as they ripen and become more vivid in color, they contain more nutrients. The hotness of hot peppers comes from a phytochemical called capsaicin. Capsaicin is used as a component of ointments for relieving arthritis pain, cluster headaches, and other health problems, and may also have other pharmacological uses.

•

ABC's of Vitamins Source: PKD Progress. 17(4): 14. Winter 2002. Contact: Available from PKD Foundation. 4901 Main Street, Suite 200, Kansas City, MO 64112-2634. (800) 753-2873. E-mail: [email protected]. Summary: This brief newsletter article helps readers with polycystic kidney disease (PKD) understand the role of vitamins and vitamin supplements. The article stresses that vitamins are an important source of energy, and 13 have been established as essential compounds in the diet (because the human body cannot manufacture them). The article focuses on vitamin C and the problems with excess intake, and vitamin A, also problematic in too-high doses. The article concludes by discussing water soluble vitamins (including folic acid and the B vitamins) that are lost during the process of both hemodialysis and peritoneal dialysis and should be replaced.

•

Gluten-Free Eating the Food Guide Pyramid Way Source: Lifeline. 19(1): 8-9. Winter 2000. Contact: Available from Celiac Sprue Association-United States of America, Inc. P.O. Box 31700, Omaha, NE 68131. (402) 558-0600. Website: www.csaceliacs.org. Summary: This newsletter article helps readers with celiac disease understand how they can use the guidelines of the Food Guide Pyramid while still following a gluten free diet. The broad base of the Food Guide is the grain group, which might seem discouraging to patients with celiac disease who must avoid bread and cereal products containing gluten. Gluten and its damaging fraction, gliadin, are used widely in the baking industry to impart dough strength, gas retention, and water absorption properties to breads and cakes, as a binder and filler in processed foods, as a carrier in spices, and as a tableting aid in the pharmaceutical industry. People with celiac disease must avoid all foods containing gluten because of its adverse effects on their intestines and their utilization of nutrients. The author reviews each portion of the Food Guide Pyramid, offering strategies for people with celiac disease. The use of rice in the grain group, as well as the purchase of specialty items for bread and other items in this group, is recommended. The fruits and vegetables and dairy groups present fewer problems for

234 Folic Acid

people with celiac disease, although some patients may also have to deal with lactose intolerance (lactose is milk sugar). In the meats group, the author notes that while unprocessed meats contain no gluten, some types of processed meats (bologna, luncheon meats, etc.) may contain gluten as a binder or filler. Beans are an economical, low fat source of protein, folic acid, soluble fiber, iron, magnesium, and calcium. Nuts and seeds provide protein, B vitamins, and iron. These foods are typically higher in fat, but the fat is primarily unsaturated; these foods can provide additional variety and nutrients for the person with celiac disease. The author concludes that variety, moderation, and balance are the keys to healthful eating. The Food Guide Pyramid can be adapted for those with special dietary concerns, including those who are following a gluten free diet. 1 figure. 3 references.

Academic Periodicals covering Folic Acid Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to folic acid. In addition to these sources, you can search for articles covering folic acid 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.”

235

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 folic acid. 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 non-profit 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 folic acid. 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

236 Folic Acid

following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to folic acid: Betaine •

Systemic - U.S. Brands: Cystadane http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203077.html

Folic Acid (Vitamin B 9 ) •

Systemic - U.S. Brands: Folvite http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202250.html

Leucovorin •

Systemic - U.S. Brands: Wellcovorin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202321.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.

237

APPENDICES

239

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.

240 Folic Acid

•

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

Physician Resources

241

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.

242 Folic Acid

•

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 Combined Health Information Database

A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “folic acid” using the “Detailed Search” option. Go directly to the following hyperlink: 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 the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “folic acid” (or synonyms) into the “For these words:” box. The following is a sample result: •

Folic acid and the prevention of birth defects: A national survey of pre-pregnancy awareness and behavior among women of childbearing age 1995-20__ Source: New York, NY: March of Dimes. 2000-. annual. Contact: Available from Greater New York March of Dimes, 233 Park Avenue South, New York, NY 10211-0300. Telephone: (800) 367-6630. 2000-$9.00; 2001-$4.50. Summary: These reports provide data from a series of surveys of women of childbearing age to assess their knowledge and behaviors relative to daily consumption of folic acid and other pre-pregnancy health issues. The first survey was made in 1995, and has been repeated every one or two years. Survey topics include vitamin use; folic acid benefits and sources; reducing the risk of birth defects, and prepregnancy and pregnancy health information. The reports conclude with a technical appendix containing survey information such as sampling tolerances, response rate, and region identification.

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 “folic acid” (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.

15 16

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

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).

Physician Resources

243

Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 23198 242 601 56 3 24100

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 “folic acid” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

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/.

17

Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html.

18

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

19

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. 20 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 21 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.

244 Folic Acid

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 Folic Acid In the following section, we will discuss databases and references which relate to the Genome Project and folic acid. 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. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “folic acid” (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 folic acid: •

Folic Acid, Transport Defect Involving Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?229050

•

Fragile Site, Folic Acid Type, Rare, Fra(12)(q13.1) Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?136630

•

Fragile Site, Folic Acid Type, Rare, Fra(x)(q28) Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?309548 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 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.

Physician Resources

245

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, 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

246 Folic Acid

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

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 “folic acid” (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.

24

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html.

Physician Resources

247

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 “folic acid” (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).

25

Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

249

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 folic acid 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 folic acid. 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 folic acid. 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 “folic acid”:

250 Folic Acid

•

Other guides Neural Tube Defects http://www.nlm.nih.gov/medlineplus/neuraltubedefects.html Prenatal Care http://www.nlm.nih.gov/medlineplus/prenatalcare.html Spina Bifida http://www.nlm.nih.gov/medlineplus/spinabifida.html

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

General/Overviews Folic Acid Source: March of Dimes Birth Defects Foundation http://www.marchofdimes.com/pnhec/173_769.asp Folic Acid Frequently Asked Questions (FAQs) Source: National Center on Birth Defects and Developmental Disabilities http://www.cdc.gov/ncbddd/folicacid/folicfaqs.htm

•

Nutrition Cereals That Contain 100% of the Daily Value (DV) of Folic Acid Source: Centers for Disease Control and Prevention http://www.cdc.gov/ncbddd/folicacid/cereal.htm

•

Specific Conditions/Aspects Folate Source: National Institutes of Health, Office of Dietary Supplements http://www.cc.nih.gov/ccc/supplements/folate.html Folate vs. Folic Acid: What's the Difference? Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HQ00703 Folic Acid Source: American Cancer Society http://www.cancer.org/docroot/eto/content/eto_5_3x_folic_acid.asp?sitearea=eto Folic Acid Use Does Not Increase the Risk for Miscarriage Source: Centers for Disease Control and Prevention http://www.cdc.gov/od/oc/media/pressrel/r010906.htm Latest Study Confirms Folate Lowers Colorectal Cancer Risk Source: American Cancer Society http://www.cancer.org/docroot/nws/content/nws_2_1x_latest_study_confirms_f olate_lowers_colorectal_cancer_risk.asp Taking Folic Acid During Pregnancy May Protect Kids from Childhood Leukemia Source: Nemours Foundation http://kidshealth.org/research/folate_all.html

Patient Resources

251

What You Should Know About Folic Acid Source: National Center on Birth Defects and Developmental Disabilities http://www.cdc.gov/ncbddd/folicacid/whatknow/wsk1.htm •

From the National Institutes of Health Folic Acid Source: Center for the Evaluation of Risks to Human Reproduction http://cerhr.niehs.nih.gov/genpub/topics/folic_acid-ccae.html

•

Men Folic Acid http://www.4woman.gov/faq/easyread/folic-etr.htm

•

Organizations Center for the Evaluation of Risks to Human Reproduction (CERHR) Source: Center for the Evaluation of Risks to Human Reproduction http://cerhr.niehs.nih.gov/ National Center on Birth Defects and Developmental Disabilities Source: Centers for Disease Control and Prevention http://www.cdc.gov/ncbddd/default.htm

•

Prevention/Screening Folic Acid and Pregnancy Source: Nemours Foundation http://kidshealth.org/parent/pregnancy_newborn/pregnancy/folic_acid.html

•

Research Folate Deficiency Associated with Higher Early Miscarriage Risk Source: National Institute of Child Health and Human Development http://www.nih.gov/news/pr/oct2002/nichd-15.htm Folate Lowers Breast Cancer Risk in Women Who Consume Alcohol Source: American Cancer Society http://www.cancer.org/docroot/nws/content/nws_2_1xu_folate_lowers_breast_c ancer_risk_in_women_who_consume_alcohol_.asp Folic Acid Possibly a Key Factor in Alzheimer's Disease Prevention Source: National Institute on Aging http://www.nih.gov/news/pr/mar2002/nia-01.htm Foods Rich in Folate May Reduce Risk of Stroke Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3002589 Mouse Experiments Link Folic Acid Deficiency to Parkinson's Disease Source: National Institute on Aging http://www.nia.nih.gov/news/pr/2002/0114.htm

252 Folic Acid

Possible New Role for Folate: Breast Cancer Prevention Source: American Cancer Society http://www.cancer.org/docroot/nws/content/nws_1_1x_possible_new_role_for_f olate_breast_cancer_prevention.asp •

Women Folic Acid http://www.4woman.gov/faq/easyread/folic-etr.htm

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

What you should know about folic acid: For parents who have lost a pregnancy or had a child with spina bifida, anencephaly, or encephalocele Source: [Akron, OH?]: Children's Hospital Medical Center of Akron. 1997. 6 pp. Contact: Available from National Maternal and Child Health Clearinghouse, 2070 Chain Bridge Road, Suite 450, Vienna, VA 22182-2536. Telephone: (703) 356-1964 or (888) 4344MCH / fax: (703) 821-2098 / e-mail: [email protected] / Web site: http://www.nmchc.org. Available at no charge. Summary: This brochure explains neural tube defects and how they can be lessened by folic acid intake. The brochure is available in English and Spanish. [Funded by the Maternal and Child Health Bureau].

•

Folic acid: Eating for a healthier future: The complete trainer's guide on the role of folic acid in preconceptional nutrition Source: New Port Richey, FL: Pasco County Public Health Department. [1997?]. 36 pp., 20 slides, 4 other items. Contact: Available from Pasco County Public Health Department, 10841 Little Road, New Port Richey, FL 34654. Summary: This information package gives a health educator a variety of information and presentation materials for a lecture on folic acid and the prevention of neural tube defects. One section contains a set of 20 color slides, a script with suggested text to accompany the slide presentation, cards for attendees on cooking and storage tips to

Patient Resources

253

preserve food folate content, a color brochure on folic acid and eating for a healthier future, and a food folic acid content counter. A second section contains handout masters for reproduction on food sources of folate, questions and answers about folate, and cooking and storage tips to preserve food folate, plus a public resource list, sample menus, and a sample nutrition facts label. A third section contains a professional reading and resource list, additional handout masters, sample press releases, and a participant evaluation form. •

Teens and folic acid: A woman's decision for herself, for her future Source: Boston, MA: Adolescent Health Training Program, Children's Hospital. 1994. 4 pp. Contact: Available from Children's Hospital, Adolescent Health Training Program, 300 Longwood Avenue, Boston, MA 02115. Telephone: (617) 735- 7170 / fax: (617) 730-0442. Summary: This pamphlet describes the relationship between folic acid and the prevention of neural tube defects. The pamphlet, which is designed for use by female adolescents, encourages them to increase their intake of folic acid by modifying their daily diet or by using vitamin supplements. The folic acid content of common foods and vitamin supplements is indicated. [Funded by the Maternal and Child Health Bureau].

•

Are you a woman between the ages of 13 and 45? Do you know what folic acid is? Source: Concord, NH: Bureau of Maternal and Child Health, and Bureau of Health Promotion, New Hampshire Department of Health and Human Services. 1996. 2 pp. Contact: Available from March of Dimes, New Hampshire Chapter, 22 Bridge Street, Concord, NH 03301. Telephone: (603) 271-4517 / fax: (603) 228-0318. $15.00/packet of 50. Summary: This pamphlet, aimed at women of childbearing age, gives the recommended daily amount of folic acid intake, why folic acid is important, and the folate content of common foods. The format includes information about foods, about neural tube defects, a folate intake self-test, and the food pyramid with annotations. The National Guideline Clearinghouse™

The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “folic acid” (or synonyms). The following was recently posted: •

Folic acid for the prevention of neural tube defects Source: American Academy of Pediatrics - Medical Specialty Society; 1999 August; 3 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2774&nbr=2000&a mp;string=folic+AND+acid Healthfinder™

Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is

254 Folic Acid

located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

FAQ - Why Folic Acid Is So Important Summary: The National Center for Environmental Health (NCEH) answers questions on the causes and prevention of the birth defects spina bifida and anencephaly. Discusses the dietary supplement foloic acid. Source: National Center for Environmental Health, Centers for Disease Control and Prevention http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=1227

•

Folic Acid Now Source: National Center on Birth Defects and Developmental Disabilities http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=4469

•

Folic Acid Now: Before You Know You’re Pregnant Source: National Center on Birth Defects and Developmental Disabilities http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=5429

•

Preventing Neural Tube Birth Defects: A Prevention Model and Resource Guide Summary: This resource manual has been produced by the Centers for Disease Control and Prevention (CDC) to assist in the development and implementation of folic acid promotion/NTD prevention campaigns. Source: National Center for Environmental Health, Centers for Disease Control and Prevention http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=3898

•

The Folic Acid National Campaign Summary: The CDC, the March of Dimes, and the National Council on Folic Acid have organized the National Folic Acid Campaign to promote the use of folic acid to prevent the serious birth defects spina bifida Source: National Center on Birth Defects and Developmental Disabilities http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=4470 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 folic acid. 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

Patient Resources

255

specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

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

•

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

•

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

•

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

•

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

•

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

•

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

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to folic acid. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with folic acid. 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 folic acid. 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 “folic acid” (or a synonym), and you will receive information on all relevant organizations listed in the database.

256 Folic Acid

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 “folic acid”. 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 “folic acid” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “folic acid” (or a synonym) into the search box, and click “Submit Query.”

257

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.

258 Folic Acid

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.

Finding Medical Libraries

259

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

260 Folic Acid

•

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/

Finding Medical Libraries

261

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

262 Folic Acid

•

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

263

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 folic acid: •

Basic Guidelines for Folic Acid Folic acid - test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003686.htm Folic acid (folate) Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002408.htm Folic acid and birth defect prevention Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002092.htm

•

Signs & Symptoms for Folic Acid Anemias Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000560.htm Diarrhea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003126.htm

264 Folic Acid

Fainting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003092.htm Menstrual problems Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003263.htm •

Diagnostics and Tests for Folic Acid Blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003398.htm Venipuncture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003423.htm

•

Nutrition for Folic Acid Balanced diet Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002449.htm Folate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002408.htm Folic acid Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002408.htm Proteins Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm Vitamin B-12 Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002403.htm Vitamin C Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002404.htm Vitamins Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002399.htm

•

Background Topics for Folic Acid Adolescent test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002054.htm Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm Food guide pyramid Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002093.htm Infant test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002055.htm

Online Glossaries 265

Metabolism Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002257.htm Preschooler test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002057.htm Schoolage test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002058.htm Shellfish Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002851.htm Toddler test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002056.htm

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

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

•

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

267

FOLIC ACID DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 5-Hydroxytryptophan: Precursor of serotonin used as antiepileptic and antidepressant. [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] Abscess: Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. [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] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] 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] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Acne Vulgaris: A chronic disorder of the pilosebaceous apparatus associated with an increase in sebum secretion. It is characterized by open comedones (blackheads), closed comedones (whiteheads), and pustular nodules. The cause is unknown, but heredity and age are predisposing factors. [NIH] Acoustic: Having to do with sound or hearing. [NIH] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH]

268 Folic Acid

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] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenoma: A benign 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] Adenosine Deaminase: An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Since there are wide tissue and species variations in the enzyme, it has been used as a tool in the study of human and animal genetics and in medical diagnosis. EC 3.5.4.4. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] 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] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] 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] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [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] Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and

Dictionary 269

older (aged, 80 and over). [NIH] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Aged, 80 and Over: A person 80 years of age and older. [NIH] Ageing: A physiological or morphological change in the life of an organism or its parts, generally irreversible and typically associated with a decline in growth and reproductive vigor. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Alfalfa: A deep-rooted European leguminous plant (Medicago sativa) widely grown for hay and forage. [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] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]

Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Aloe: A genus of the family Liliaceae containing anthraquinone glycosides such as aloinemodin or aloe-emodin (emodin). [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-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

270 Folic Acid

standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Aluminum: A metallic element that has the atomic number 13, atomic symbol Al, and atomic weight 26.98. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Amblyopia: A nonspecific term referring to impaired vision. Major subcategories include stimulus deprivation-induced amblyopia and toxic amblyopia. Stimulus deprivationinduced amblopia is a developmental disorder of the visual cortex. A discrepancy between visual information received by the visual cortex from each eye results in abnormal cortical development. Strabismus and refractive errors may cause this condition. Toxic amblyopia is a disorder of the optic nerve which is associated with alcoholism, tobacco smoking, and other toxins and as an adverse effect of the use of some medications. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Aminoimidazole Carboxamide: An imidazole derivative which is a metabolite of the antineoplastic agents BIC and DIC. By itself, or as the ribonucleotide, it is used as a condensation agent in the preparation of nucleosides and nucleotides. Compounded with orotic acid, it is used to treat liver diseases. [NIH] Aminopterin: N-(4-(((2,4-Diamino-6-pteridinyl)methyl)amino)benzoyl)-L-glutamic acid. A folic acid derivative used as a rodenticide that has been shown to be teratogenic. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amphetamine: A powerful central nervous system stimulant and sympathomimetic. Amphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulation of release of monamines, and inhibiting monoamine oxidase. Amphetamine is also a drug of abuse and a psychotomimetic. The l- and the d,l-forms are included here. The l-form has less central nervous system activity but stronger cardiovascular effects. The d-form is dextroamphetamine. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Amylase: An enzyme that helps the body digest starches. [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]

Dictionary 271

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] Anaemia: A reduction below normal in the number of erythrocytes per cu. mm., in the quantity of haemoglobin, or in the volume of packed red cells per 100 ml. of blood which occurs when the equilibrium between blood loss (through bleeding or destruction) and blood production is disturbed. [EU] 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] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylactic: Pertaining to anaphylaxis. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] 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] Anemia, Sickle Cell: A disease characterized by chronic hemolytic anemia, episodic painful crises, and pathologic involvement of many organs. It is the clinical expression of homozygosity for hemoglobin S. [NIH] Anemic: Hypoxia due to reduction of the oxygen-carrying capacity of the blood as a result of a decrease in the total hemoglobin or an alteration of the hemoglobin constituents. [NIH] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia

272 Folic Acid

usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Angina, Unstable: Precordial pain at rest, which may precede a myocardial infarction. [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] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Anisotropy: A physical property showing different values in relation to the direction in or along which the measurement is made. The physical property may be with regard to thermal or electric conductivity or light refraction. In crystallography, it describes crystals whose index of refraction varies with the direction of the incident light. It is also called acolotropy and colotropy. The opposite of anisotropy is isotropy wherein the same values characterize the object when measured along axes in all directions. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Anterior Cerebral Artery: Artery formed by the bifurcation of the internal carotid artery. Branches of the anterior cerebral artery supply the caudate nucleus, internal capsule, putamen, septal nuclei, gyrus cinguli, and surfaces of the frontal lobe and parietal lobe. [NIH] Anterior chamber: The space in front of the iris and behind the cornea. [NIH] Anthracycline: A member of a family of anticancer drugs that are also antibiotics. [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

Dictionary 273

for white blood cells to destroy the antigen. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Anticonvulsive: An agent that prevents or relieves convulsions. [NIH] Antidepressant: A drug used to treat depression. [NIH] Antidote: A remedy for counteracting a poison. [EU] Antiepileptic: An agent that combats epilepsy. [EU] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-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-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]

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] Antiparasitic Agents: Drugs used to treat or prevent parasitic infections. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH] Antitumour: Counteracting tumour formation. [EU] Antitussive: An agent that relieves or prevents cough. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH]

274 Folic Acid

Aorta: The main trunk of the systemic arteries. [NIH] Aortic Aneurysm: Aneurysm of the aorta. [NIH] Aortic Valve: The valve between the left ventricle and the ascending aorta which prevents backflow into the left ventricle. [NIH] Apathy: Lack of feeling or emotion; indifference. [EU] Aphthous Stomatitis: Inflammation of the mucous membrane of the mouth. [NIH] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [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] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatic: Having a spicy odour. [EU] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriography: A procedure to x-ray arteries. The arteries can be seen because of an injection of a dye that outlines the vessels on an x-ray. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Articular: Of or pertaining to a joint. [EU] Asbestos: Fibrous incombustible mineral composed of magnesium and calcium silicates with or without other elements. It is relatively inert chemically and used in thermal insulation and fireproofing. Inhalation of dust causes asbestosis and later lung and gastrointestinal neoplasms. [NIH] 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] Aspartate: A synthetic amino acid. [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

Dictionary 275

biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] 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] Atherogenic: Causing the formation of plaque in the lining of the arteries. [NIH] Atresia: Lack of a normal opening from the esophagus, intestines, or anus. [NIH] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Audition: The sense of hearing. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autopsy: Postmortem examination of the body. [NIH] Avidity: The strength of the interaction of an antiserum with a multivalent antigen. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]

Axillary Artery: The continuation of the subclavian artery; it distributes over the upper limb, axilla, chest and shoulder. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Bacteroides: A genus of gram-negative, anaerobic, rod-shaped bacteria. Its organisms are normal inhabitants of the oral, respiratory, intestinal, and urogenital cavities of humans,

276 Folic Acid

animals, and insects. Some species may be pathogenic. [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] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Bed Rest: Confinement of an individual to bed for therapeutic or experimental reasons. [NIH] Beer: An alcoholic beverage usually made from malted cereal grain (as barley), flavored with hops, and brewed by slow fermentation. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Benzoates: Salts and esters of benzoic acid that possess antibacterial and antifungal properties. They are used as preservatives in pharmaceutical formulations including oral preparations, cosmetics, and food. [NIH] Benzoic Acid: A fungistatic compound that is widely used as a food preservative. It is conjugated to glycine in the liver and excreted as hippuric acid. [NIH] Beta carotene: A vitamin A precursor. Beta carotene belongs to the family of fat-soluble vitamins called carotenoids. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Bifida: A defect in development of the vertebral column in which there is a central deficiency of the vertebral lamina. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of

Dictionary 277

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] Bile Ducts: Tubes that carry bile from the liver to the gallbladder for storage and to the small intestine for use in digestion. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] 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] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biochemical reactions: In living cells, chemical reactions that help sustain life and allow cells to grow. [NIH] Biological Markers: Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. [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] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning

278 Folic Acid

technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Birth Certificates: Official certifications by a physician recording the individual's birth date, place of birth, parentage and other required identifying data which are filed with the local registrar of vital statistics. [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] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [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 an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [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 Viscosity: The internal resistance of the blood to shear forces. The in vitro measure of whole blood viscosity is of limited clinical utility because it bears little relationship to the actual viscosity within the circulation, but an increase in the viscosity of circulating blood can contribute to morbidity in patients suffering from disorders such as sickle cell anemia and polycythemia. [NIH] Blood Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bone Development: Gross development of bones from fetus to adult. It includes osteogenesis, which is restricted to formation and development of bone from the undifferentiated cells of the germ layers of the embryo. It does not include osseointegration. [NIH]

Dictionary 279

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 metastases: Cancer that has spread from the original (primary) tumor to the bone. [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 Compounds: Inorganic or organic compounds that contain boron as an integral part of the molecule. [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] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Artery: The continuation of the axillary artery; it branches into the radial and ulnar arteries. [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] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchoconstriction: Diminution of the caliber of a bronchus physiologically or as a result of pharmacological intervention. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge of electricity. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central

280 Folic Acid

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] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Calorimeter: Measures the amounts of heat absorbed or given off by a solid, a liquid, or a gas. [NIH] Capsaicin: Cytotoxic alkaloid from various species of Capsicum (pepper, paprika), of the Solanaceae. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbamazepine: An anticonvulsant used to control grand mal and psychomotor or focal seizures. Its mode of action is not fully understood, but some of its actions resemble those of phenytoin; although there is little chemical resemblance between the two compounds, their three-dimensional structure is similar. [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] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiac arrest: A sudden stop of heart function. [NIH] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiopulmonary Bypass: Diversion of the flow of blood from the entrance of the right atrium directly to the aorta (or femoral artery) via an oxygenator thus bypassing both the heart and lungs. [NIH] Cardioselective: Having greater activity on heart tissue than on other tissue. [EU] 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

Dictionary 281

blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carotenoids: Substance found in yellow and orange fruits and vegetables and in dark green, leafy vegetables. May reduce the risk of developing cancer. [NIH] 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] Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Castor Oil: Oil obtained from seeds of Ricinus communis that is used as a cathartic and as a plasticizer. [NIH] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cecum: The beginning of the large intestine. The cecum is connected to the lower part of the small intestine, called the ileum. [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

282 Folic Acid

made up of one or more cells. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell 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 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] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU]

Dictionary 283

Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Cheilitis: Inflammation of the lips. It is of various etiologies and degrees of pathology. [NIH] Chemoprevention: The use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the development or recurrence of, cancer. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] 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] 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] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholecalciferol: An antirachitic oil-soluble vitamin. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially 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] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chorioretinitis: Inflammation of the choroid in which the sensory retina becomes edematous and opaque. The inflammatory cells and exudate may burst through the sensory retina to cloud the vitreous body. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Choroid Plexus: A villous structure of tangled masses of blood vessels contained within the third, lateral, and fourth ventricles of the brain. It regulates part of the production and composition of cerebrospinal fluid. [NIH]

284 Folic Acid

Choroid plexus tumor: A rare type of cancer that occurs in the ventricles of the brain. It usually occurs in children younger than 2 years. [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] 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] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic 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] Chymopapain: A cysteine endopeptidase isolated from papaya latex. Preferential cleavage at glutamic and aspartic acid residues. EC 3.4.22.6. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] Citric Acid: A key intermediate in metabolism. It is an acid compound found in citrus fruits. The salts of citric acid (citrates) can be used as anticoagulants due to their calcium chelating ability. [NIH] Citrus: Any tree or shrub of the Rue family or the fruit of these plants. [NIH] Claudication: Limping or lameness. [EU] Claviceps: A genus of ascomycetous fungi, family Clavicipitaceae, order Hypocreales, parasitic on various grasses. The sclerotia contain several toxic alkaloids. Claviceps purpurea on rye causes ergotism. [NIH] Cleft Palate: Congenital fissure of the soft and/or hard palate, due to faulty fusion. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH]

Dictionary 285

Clitoral: Pertaining to the clitoris. [EU] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] 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] Cobalt: A trace element that is a component of vitamin B12. It has the atomic symbol Co, atomic number 27, and atomic weight 58.93. It is used in nuclear weapons, alloys, and pigments. Deficiency in animals leads to anemia; its excess in humans can lead to erythrocytosis. [NIH] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] Codeine: An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. [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] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [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] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU]

286 Folic Acid

Colloidal: Of the nature of a colloid. [EU] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Colorectal Neoplasms: Tumors or cancer of the either the colon or rectum or both. The most frequent malignant tumor in the United States. Etiological factors which increase the risk of colorectal cancer include chronic ulcerative colitis, familial polyposis of the colon, exposure to asbestos, irradiation of the cervix. [NIH] Communis: Common tendon of the rectus group of muscles that surrounds the optic foramen and a portion of the superior orbital fissure, to the anterior margin of which it is attached at the spina recti lateralis. [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] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH]

Dictionary 287

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] Conditioned stimulus: A situation in which one signal, or stimulus, is given just before another signal. After this happens several times, the first signal alone can cause the response that would usually need the second signal. [NIH] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] 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] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [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]

288 Folic Acid

Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [NIH] 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] Convulsive: Relating or referring to spasm; affected with spasm; characterized by a spasm or spasms. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary Disease: Disorder of cardiac function due to an imbalance between myocardial function and the capacity of the coronary vessels to supply sufficient flow for normal function. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Coronary Vessels: The veins and arteries of the heart. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Corpuscle: A small mass or body; a sensory nerve end bulb; a cell, especially that of the blood or the lymph. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the

Dictionary 289

internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [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] Coumarin: A fluorescent dye. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Creatinine clearance: A test that measures how efficiently the kidneys remove creatinine and other wastes from the blood. Low creatinine clearance indicates impaired kidney function. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Cruciferous vegetables: A family of vegetables that includes kale, collard greens, broccoli, cauliflower, cabbage, brussels sprouts, and turnip. These vegetables contain substances that may protect against cancer. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Curcumin: A dye obtained from tumeric, the powdered root of Curcuma longa Linn. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. [NIH] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cystathionine beta-Synthase: A multifunctional pyridoxal phosphate enzyme. In the second stage of cysteine biosynthesis it catalyzes the reaction of homocysteine with serine to form cystathionine with the elimination of water. Deficiency of this enzyme leads to hyperhomocysteinemia and homocystinuria. EC 4.2.1.22. [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

290 Folic Acid

cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

Cytarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytokinesis: Division of the rest of cell. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytomegalovirus Infections: Infection with Cytomegalovirus, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] 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] Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [NIH]

De novo: In cancer, the first occurrence of cancer in the body. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] 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] 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

Dictionary 291

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] Demethylation: Process that releases substantial amounts of carbon dioxide in the liver. [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 Care: The total of dental diagnostic, preventive, and restorative services provided to meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Dentists: Individuals licensed to practice dentistry. [NIH] Deoxyguanosine: A nucleoside consisting of the base guanine and the sugar deoxyribose. [NIH]

Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [NIH] Deoxyuridine: 2'-Deoxyuridine. An antimetabolite that is converted to deoxyuridine triphosphate during DNA synthesis. Laboratory suppression of deoxyuridine is used to diagnose megaloblastic anemias due to vitamin B12 and folate deficiencies. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermal: Pertaining to or coming from the skin. [NIH] Dermatology: A medical specialty concerned with the skin, its structure, functions, diseases, and treatment. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [NIH] Dextroamphetamine: The d-form of amphetamine. It is a central nervous system stimulant and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. [NIH]

292 Folic Acid

Dextromethorphan: The d-isomer of the codeine analog of levorphanol. Dextromethorphan shows high affinity binding to several regions of the brain, including the medullary cough center. This compound is a NMDA receptor antagonist (receptors, N-methyl-D-aspartate) and acts as a non-competitive channel blocker. It is used widely as an antitussive agent, and is also used to study the involvement of glutamate receptors in neurotoxicity. [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] Diaphragm: The musculofibrous partition that separates the thoracic cavity from the abdominal cavity. Contraction of the diaphragm increases the volume of the thoracic cavity aiding inspiration. [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] 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] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilator: A device used to stretch or enlarge an opening. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] 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] Discoid: Shaped like a disk. [EU]

Dictionary 293

Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [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] 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] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Dopa: The racemic or DL form of DOPA, an amino acid found in various legumes. The dextro form has little physiologic activity but the levo form (levodopa) is a very important physiologic mediator and precursor and pharmacological agent. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [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] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH] Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetics. It is a hydroxy derivative of daunorubicin and is used in treatment of both leukemia and solid tumors. [NIH] Drug Carriers: Substances that facilitate time-controlled delivery, organ-specific targeting, protection, prolonged in vivo function, and decrease of toxicity of drugs. Liposomes, albumin microspheres, soluble synthetic polymers, DNA complexes, protein-drug conjugates, and carrier erythrocytes among others have been employed as biodegradable

294 Folic Acid

drug carriers. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Drug Toxicity: Manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning for which specific headings are available. [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] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dyspareunia: Painful sexual intercourse. [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] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]

Ectoderm: The outer of the three germ layers of the embryo. [NIH] Ectopia Lentis: Congenital displacement of the lens resulting from defective zonule formation. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [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] Ego: The conscious portion of the personality structure which serves to mediate between the demands of the primitive instinctual drives, (the id), of internalized parental and social prohibitions or the conscience, (the superego), and of reality. [NIH] Ejaculation: The release of semen through the penis during orgasm. [NIH] Elasticity: Resistance and recovery from distortion of shape. [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

Dictionary 295

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] Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] 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] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Embryology: The study of the development of an organism during the embryonic and fetal stages of life. [NIH] Embryonic Induction: Embryonic cell differentiation in which one group of cells evokes and controls the differentiation of other groups of cells. [NIH] Emodin: Purgative anthraquinone found in several plants, especially Rhamnus frangula. It was formerly used as a laxative, but is now used mainly as tool in toxicity studies. [NIH] Emollient: Softening or soothing; called also malactic. [EU] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]

Encephalocele: Cerebral tissue herniation through a congenital or acquired defect in the skull. The majority of congenital encephaloceles occur in the occipital or frontal regions. Clinical features include a protuberant mass that may be pulsatile. The quantity and location of protruding neural tissue determines the type and degree of neurologic deficit. Visual defects, psychomotor developmental delay, and persistent motor deficits frequently occur. [NIH]

Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]

Endometriosis: A condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH]

296 Folic Acid

Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the body. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] 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] Energetic: Exhibiting energy : strenuous; operating with force, vigour, or effect. [EU] Enhancer: Transcriptional element in the virus genome. [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] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] 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] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Ependymal: It lines the cavities of the brain's ventricles and the spinal cord and slowly

Dictionary 297

divides to create a stem cell. [NIH] Ependymal tumors: A type of brain tumor that usually begins in the central canal of the spinal cord. Ependymomas may also develop in the cells lining the ventricles of the brain, which produce and store the special fluid (cerebrospinal fluid) that protects the brain and spinal cord. Also called ependymomas. [NIH] Ependymomas: Brain tumors that usually begin in the central canal of the spinal cord. Ependymomas may also develop in the cells lining the ventricles of the brain, which produce and store the special fluid (cerebrospinal fluid) that protects the brain and spinal cord. Also called ependymal tumors. [NIH] Ephedrine: An alpha- and beta-adrenergic agonist that may also enhance release of norepinephrine. It has been used in the treatment of several disorders including asthma, heart failure, rhinitis, and urinary incontinence, and for its central nervous system stimulatory effects in the treatment of narcolepsy and depression. It has become less extensively used with the advent of more selective agonists. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [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] Epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] 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

298 Folic Acid

antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Ergot: Cataract due to ergot poisoning caused by eating of rye cereals contaminated by a fungus. [NIH] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythema Multiforme: A skin and mucous membrane disease characterized by an eruption of macules, papules, nodules, vesicles, and/or bullae with characteristic "bull's-eye" lesions usually occurring on the dorsal aspect of the hands and forearms. [NIH] Erythrocyte Membrane: The semipermeable outer portion of the red corpuscle. It is known as a 'ghost' after hemolysis. [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] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] 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] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estriol: (16 alpha,17 beta)-Estra-1,3,5(10)-triene-3,16,17-triol. A metabolite of estradiol and usually the predominant estrogenic metabolite in urine. During pregnancy, large amounts of estriol are produced by the placenta. It has also been obtained from plant sources. The 16 beta-isomer has also been isolated from the urine of pregnant women. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Ethical drug: Restricted to sale only on a doctor's prescription. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] 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]

Dictionary 299

Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [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] Excrete: To get rid of waste from the body. [NIH] Exercise Test: Controlled physical activity, more strenuous than at rest, which is performed in order to allow assessment of physiological functions, particularly cardiovascular and pulmonary, but also aerobic capacity. Maximal (most intense) exercise is usually required but submaximal exercise is also used. The intensity of exercise is often graded, using criteria such as rate of work done, oxygen consumption, and heart rate. Physiological data obtained from an exercise test may be used for diagnosis, prognosis, and evaluation of disease severity, and to evaluate therapy. Data may also be used in prescribing exercise by determining a person's exercise capacity. [NIH] Exercise Tolerance: The exercise capacity of an individual as measured by endurance (maximal exercise duration and/or maximal attained work load) during an exercise test. [NIH]

Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] 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] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Facial: Of or pertaining to the face. [EU] Factor V: Heat- and storage-labile plasma glycoprotein which accelerates the conversion of prothrombin to thrombin in blood coagulation. Factor V accomplishes this by forming a complex with factor Xa, phospholipid, and calcium (prothrombinase complex). Deficiency of factor V leads to Owren's disease. [NIH] Faecal: Pertaining to or of the nature of feces. [EU] Fallopian Tubes: Two long muscular tubes that transport ova from the ovaries to the uterus. They extend from the horn of the uterus to the ovaries and consist of an ampulla, an infundibulum, an isthmus, two ostia, and a pars uterina. The walls of the tubes are composed of three layers: mucosal, muscular, and serosal. [NIH] Familial polyposis: An inherited condition in which numerous polyps (tissue masses) develop on the inside walls of the colon and rectum. It increases the risk for colon cancer. [NIH]

300 Folic Acid

Family Health: The health status of the family as a unit including the impact of the health of one member of the family on the family as a unit and on individual family members; also, the impact of family organization or disorganization on the health status of its members. [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] Fathers: Male parents, human or animal. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Fenbendazole: Antinematodal benzimidazole used in veterinary medicine. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fertilizers: Substances or mixtures that are added to the soil to supply nutrients or to make available nutrients already present in the soil, in order to increase plant growth and productivity. [NIH] Fetal Alcohol Syndrome: A disorder occurring in children born to alcoholic women who continue to drink heavily during pregnancy. Common abnormalities are growth deficiency (prenatal and postnatal), altered morphogenesis, mental deficiency, and characteristic facies - small eyes and flattened nasal bridge. Fine motor dysfunction and tremulousness are observed in the newborn. [NIH] Fetal Development: Morphologic and physiologic growth and development of the mammalian embryo or fetus. [NIH] Fetal Monitoring: Physiologic or biochemical monitoring of the fetus. It is usually done during labor and may be performed in conjunction with the monitoring of uterine activity. It may also be performed prenatally as when the mother is undergoing surgery. [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] 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] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including

Dictionary 301

chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filler: An inactive substance used to make a product bigger or easier to handle. For example, fillers are often used to make pills or capsules because the amount of active drug is too small to be handled conveniently. [NIH] Financial Management: The obtaining and management of funds for institutional needs and responsibility for fiscal affairs. [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fistulas: An abnormal passage from one hollow structure of the body to another, or from a hollow structure to the surface, formed by an abscess, disease process, incomplete closure of a wound, or by a congenital anomaly. [NIH] Flatus: Gas passed through the rectum. [NIH] Flexor: Muscles which flex a joint. [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] Fluorescence Polarization: Measurement of the polarization of fluorescent light from solutions or microscopic specimens. It is used to provide information concerning molecular size, shape, and conformation, molecular anisotropy, electronic energy transfer, molecular interaction, including dye and coenzyme binding, and the antigen-antibody reaction. [NIH] Fluorescence Polarization Immunoassay: Fluoroimmunoassay where detection of the hapten-antibody reaction is based on measurement of the increased polarization of fluorescence-labeled hapten when it is combined with antibody. The assay is very useful for the measurement of small haptenic antigens such as drugs at low concentrations. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fourth Ventricle: An irregularly shaped cavity in the rhombencephalon, between the medulla oblongata, the pons, and the isthmus in front, and the cerebellum behind. It is continuous with the central canal of the cord below and with the cerebral aqueduct above,

302 Folic Acid

and through its lateral and median apertures it communicates with the subarachnoid space. [NIH]

Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [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] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Galactosides: Glycosides formed by the reaction of the hydroxyl group on the anomeric carbon atom of galactose with an alcohol to form an acetal. They include both alpha- and beta-galactosides. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma-Glutamyl Hydrolase: Catalyzes the hydrolysis of pteroylpolyglutamic acids in gamma linkage to pterolylmonoglutamic acid and free glutamic acid. EC 3.4.19.9. [NIH] Gamma-Glutamyltransferase: An enzyme that catalyzes reversibly the transfer of a glutamyl group from a glutamyl-peptide and an amino acid to a peptide and a glutamylamino acid. EC 2.3.2.2. [NIH] Ganciclovir: Acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [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] Gastric Emptying: The evacuation of food from the stomach into the duodenum. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Dictionary 303

Gastritis: Inflammation of the stomach. [EU] Gastroenterology: A subspecialty of internal medicine concerned with the study of the physiology and diseases of the digestive system and related structures (esophagus, liver, gallbladder, and pancreas). [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastroparesis: Nerve or muscle damage in the stomach. Causes slow digestion and emptying, vomiting, nausea, or bloating. Also called delayed gastric emptying. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Amplification: A selective increase in the number of copies of a gene coding for a specific protein without a proportional increase in other genes. It occurs naturally via the excision of a copy of the repeating sequence from the chromosome and its extrachromosomal replication in a plasmid, or via the production of an RNA transcript of the entire repeating sequence of ribosomal RNA followed by the reverse transcription of the molecule to produce an additional copy of the original DNA sequence. Laboratory techniques have been introduced for inducing disproportional replication by unequal crossing over, uptake of DNA from lysed cells, or generation of extrachromosomal sequences from rolling circle replication. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Library: A large collection of cloned DNA fragments from a given organism, tissue, organ, or cell type. It may contain complete genomic sequences (genomic library) or complementary DNA sequences, the latter being formed from messenger RNA and lacking intron sequences. [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 Counseling: Advising families of the risks involved pertaining to birth defects, in order that they may make an informed decision on current or future pregnancies. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genomic Library: A form of gene library containing the complete DNA sequences present

304 Folic Acid

in the genome of a given organism. It contrasts with a cDNA library which contains only sequences utilized in protein coding (lacking introns). [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geriatric: Pertaining to the treatment of the aged. [EU] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germ Layers: The three layers of cells comprising the early embryo. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gestational Age: Age of the conceptus. In humans, this may be assessed by medical history, physical examination, early immunologic pregnancy tests, radiography, ultrasonography, and amniotic fluid analysis. [NIH] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. [NIH] Ginger: Deciduous plant rich in volatile oil (oils, volatile). It is used as a flavoring agent and has many other uses both internally and topically. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] 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] Gliadin: Simple protein, one of the prolamines, derived from the gluten of wheat, rye, etc. May be separated into 4 discrete electrophoretic fractions. It is the toxic factor associated with celiac disease. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glucocorticoids: A group of corticosteroids that affect carbohydrate metabolism (gluconeogenesis, liver glycogen deposition, elevation of blood sugar), inhibit corticotropin secretion, and possess pronounced anti-inflammatory activity. They also play a role in fat and protein metabolism, maintenance of arterial blood pressure, alteration of the connective tissue response to injury, reduction in the number of circulating lymphocytes, and functioning of the central nervous system. [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutamine: A non-essential amino acid present abundantly throught the body and is

Dictionary 305

involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] 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 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] Glycosaminoglycan: A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [NIH] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] 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] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Graft Survival: The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host. [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]

306 Folic Acid

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] Gravidity: Pregnancy; the condition of being pregnant, without regard to the outcome. [EU] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth Disorders: Deviations from the average values for a specific age and sex in any or all of the following: height, weight, skeletal proportions, osseous development, or maturation of features. Included here are both acceleration and retardation of growth. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Gynecology: A medical-surgical specialty concerned with the physiology and disorders primarily of the female genital tract, as well as female endocrinology and reproductive physiology. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Haematological: Relating to haematology, that is that branch of medical science which treats of the morphology of the blood and blood-forming tissues. [EU] Haematology: The science of the blood, its nature, functions, and diseases. [NIH] 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] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when 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 Education: Education that increases the awareness and favorably influences the attitudes and knowledge relating to the improvement of health on a personal or community

Dictionary 307

basis. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartbeat: One complete contraction of the heart. [NIH] Hematocrit: Measurement of the volume of packed red cells in a blood specimen by centrifugation. The procedure is performed using a tube with graduated markings or with automated blood cell counters. It is used as an indicator of erythrocyte status in disease. For example, anemia shows a low hematocrit, polycythemia, high values. [NIH] Hematologic Diseases: Disorders of the blood and blood forming tissues. [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] Hemodilution: Reduction of blood viscosity usually by the addition of cell free solutions. Used clinically l) in states of impaired microcirculation, 2) for replacement of intraoperative blood loss without homologous blood transfusion, and 3) in cardiopulmonary bypass and hypothermia. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin C: A commonly occurring abnormal hemoglobin in which lysine replaces a glutamic acid residue at the sixth position of the beta chains. It results in reduced plasticity of erythrocytes. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [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] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Hepatic: Refers to the liver. [NIH]

308 Folic Acid

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] Hepatocyte: A liver cell. [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] 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]

Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Hexosaminidases: Enzymes that catalyze the hydrolysis of N-acylhexosamine residues in N-acylhexosamides. Hexosaminidases also act on glucosides, galactosides, and several oligosaccharides. [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] 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] Homeobox: Distinctive sequence of DNA bases. [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] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of

Dictionary 309

hormone deficiency. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [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] Host: Any animal that receives a transplanted graft. [NIH] Human Development: Continuous sequential changes which occur in the physiological and psychological functions during the individual's life. [NIH] Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is often associated with some types of cancer. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hydrochloric Acid: A strong corrosive acid that is commonly used as a laboratory reagent. It is formed by dissolving hydrogen chloride in water. Gastric acid is the hydrochloric acid component of gastric juice. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]

Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] 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] Hydroxocobalamin: A B12 vitamin. It has been used therapeutically in the treatment and prevention of vitamin B12 deficiency. [NIH] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperhomocysteinemia: An inborn error of methionone metabolism which produces an excess of homocysteine in the blood. It is often caused by a deficiency of cystathionine betasynthase and is a risk factor for coronary vascular disease. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH]

310 Folic Acid

Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertension, Renal: Hypertension due to renal diseases, especially chronic parenchymal disease. Hypertension as a result of compression or obstruction of the renal artery or its branches is hypertension, renovascular. [NIH] Hypertension, Renovascular: Hypertension due to compression or obstruction of the renal artery or its branches. [NIH] Hyperthyroidism: Excessive functional activity of the thyroid gland. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypochlorous Acid: HClO. An oxyacid of chlorine containing monovalent chlorine that acts as an oxidizing or reducing agent. [NIH] Hypoglycemia: Abnormally low blood sugar [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypothermia: Lower than normal body temperature, especially in warm-blooded animals; in man usually accidental or unintentional. [NIH] Hypothyroidism: Deficiency of thyroid activity. In adults, it is most common in women and is characterized by decrease in basal metabolic rate, tiredness and lethargy, sensitivity to cold, and menstrual disturbances. If untreated, it progresses to full-blown myxoedema. In infants, severe hypothyroidism leads to cretinism. In juveniles, the manifestations are intermediate, with less severe mental and developmental retardation and only mild symptoms of the adult form. When due to pituitary deficiency of thyrotropin secretion it is called secondary hypothyroidism. [EU] Hypovitaminosis: A condition due to a deficiency of one or more essential vitamins. [EU] Hypovolemia: An abnormally low volume of blood circulating through the body. It may result in hypovolemic shock. [NIH] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Hysterectomy: Excision of the uterus. [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] Ileal: Related to the ileum, the lowest end of the small intestine. [NIH] Ileocecal Valve: A valve that connects the lower part of the small intestine and the upper part of the large intestine (ileum and cecum). Controls the flow of fluid in the intestines and prevents backflow. [NIH] Ileum: The lower end of the small intestine. [NIH] Iliac Artery: Either of two large arteries originating from the abdominal aorta; they supply blood to the pelvis, abdominal wall and legs. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH]

Dictionary 311

Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immaturity: The state or quality of being unripe or not fully developed. [EU] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunodeficiency syndrome: The inability of the body to produce an immune response. [NIH]

Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Imperforate Anus: A birth defect in which the anal canal fails to develop. The condition is treated with an operation. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH]

312 Folic Acid

Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incontinentia Pigmenti: A genodermatosis occurring mostly in females and characterized by skin changes in three phases - vesiculobullous, verrucous papillomatous, and macular melanodermic. Hyperpigmentation is bizarre and irregular. Sixty percent of patients have abnormalities of eyes, teeth, central nervous system, and skin appendages. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indigestion: Poor digestion. Symptoms include heartburn, nausea, bloating, and gas. Also called dyspepsia. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant Nutrition: Nutrition of children from birth to 2 years of age. [NIH] Infant, Newborn: An infant during the first month after birth. [NIH] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infectious Diarrhea: Diarrhea caused by infection from bacteria, viruses, or parasites. [NIH] Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]

Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [NIH] Ingestion: Taking into the body by mouth [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inosine Monophosphate: Inosine 5'-Monophosphate. A purine nucleotide which has hypoxanthine as the base and one phosphate group esterified to the sugar moiety. [NIH]

Dictionary 313

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] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [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] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] 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] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Introns: Non-coding, intervening sequences of DNA that are transcribed, but are removed from within the primary gene transcript and rapidly degraded during maturation of messenger RNA. Most genes in the nuclei of eukaryotes contain introns, as do mitochondrial and chloroplast genes. [NIH] Introspection: Examination by a person of his own feelings, thoughts, and mental state. [NIH]

Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] 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

314 Folic Acid

properties and is used topically. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Iron Compounds: Inorganic compounds that contain iron as an integral part of the molecule. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Ischemic stroke: A condition in which the blood supply to part of the brain is cut off. Also called "plug-type" strokes. Blocked arteries starve areas of the brain controlling sight, speech, sensation, and movement so that these functions are partially or completely lost. Ischemic stroke is the most common type of stroke, accounting for 80 percent of all strokes. Most ischemic strokes are caused by a blood clot called a thrombus, which blocks blood flow in the arteries feeding the brain, usually the carotid artery in the neck, the major vessel bringing blood to the brain. When it becomes blocked, the risk of stroke is very high. [NIH] Isoflavones: 3-Phenylchromones. Isomeric form of flavones in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position. [NIH] Isotretinoin: A topical dermatologic agent that is used in the treatment of acne vulgaris and several other skin diseases. The drug has teratogenic and other adverse effects. [NIH] Jejunum: That portion of the small intestine which extends from the duodenum to the ileum; called also intestinum jejunum. [EU] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Juniper: A slow growing coniferous evergreen tree or shrub, genus Juniperus. The Juniper is cultivated for its berries, which take up to three years to ripen. The resinous, sweetly flavored berries are borne only by the female juniper, and can be found in various stages of ripeness on the same plant. [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]

Dictionary 315

Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH] Ketosteroids: Steroid derivatives formed by oxidation of a methyl group on the side chain or a methylene group in the ring skeleton to form a ketone. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kidney stone: A stone that develops from crystals that form in urine and build up on the inner surfaces of the kidney, in the renal pelvis, or in the ureters. [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] Lactation: The period of the secretion of milk. [EU] Lactose Intolerance: The disease state resulting from the absence of lactase enzyme in the musocal cells of the gastrointestinal tract, and therefore an inability to break down the disaccharide lactose in milk for absorption from the gastrointestinal tract. It is manifested by indigestion of a mild nature to severe diarrhea. It may be due to inborn defect genetically conditioned or may be acquired. [NIH] Language Disorders: Conditions characterized by deficiencies of comprehension or expression of written and spoken forms of language. These include acquired and developmental disorders. [NIH] 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] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Latent period: A seemingly inactive period, as that between exposure of tissue to an injurious agent and the manifestation of response, or that between the instant of stimulation and the beginning of response. [EU] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

316 Folic Acid

Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Lethargy: Abnormal drowsiness or stupor; a condition of indifference. [EU] Leucovorin: The active metabolite of folic acid. Leucovorin is used principally as its calcium salt as an antidote to folic acid antagonists which block the conversion of folic acid to folinic acid. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukocytosis: A transient increase in the number of leukocytes in a body fluid. [NIH] Levodopa: The naturally occurring form of dopa and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonism and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. [NIH] Levorphanol: A narcotic analgesic that may be habit-forming. It is nearly as effective orally as by injection. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Lichen Planus: An inflammatory, pruritic disease of the skin and mucous membranes, which can be either generalized or localized. It is characterized by distinctive purplish, flattopped papules having a predilection for the trunk and flexor surfaces. The lesions may be discrete or coalesce to form plaques. Histologically, there is a "saw-tooth" pattern of epidermal hyperplasia and vacuolar alteration of the basal layer of the epidermis along with an intense upper dermal inflammatory infiltrate composed predominantly of T-cells. Etiology is unknown. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lip: Either of the two fleshy, full-blooded margins of the mouth. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH]

Dictionary 317

Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Lipoprotein(a): A family of lipoprotein particles varying in density and size depending on the protein-lipid ratio and the protein composition. These particles consist of apolipoprotein B-100 covalently linked to apolipoprotein-a by one or two disulfide bonds. There is a correlation between high plasma levels of this lipoprotein and increased risk for atherosclerotic cardiovascular disease. [NIH] Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution to the tumor site is improved. [NIH]

Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] 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] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Long-Term Potentiation: A persistent increase in synaptic efficacy, usually induced by appropriate activation of the same synapses. The phenomenological properties of long-term potentiation suggest that it may be a cellular mechanism of learning and memory. [NIH] Lovastatin: A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. [NIH]

318 Folic Acid

Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lubricants: Oily or slippery substances. [NIH] Lubrication: The application of a substance to diminish friction between two surfaces. It may refer to oils, greases, and similar substances for the lubrication of medical equipment but it can be used for the application of substances to tissue to reduce friction, such as lotions for skin and vaginal lubricants. [NIH] 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] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphadenopathy: Disease or swelling of the lymph nodes. [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] Lysine: An essential amino acid. It is often added to animal feed. [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]

Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an

Dictionary 319

animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malabsorption syndrome: A group of symptoms such as gas, bloating, abdominal pain, and diarrhea resulting from the body's inability to properly absorb nutrients. [NIH] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] 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 mesothelioma: A rare type of cancer in which malignant cells are found in the sac lining the chest or abdomen. Exposure to airborne asbestos particles increases one's risk of developing malignant mesothelioma. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mannitol: A diuretic and renal diagnostic aid related to sorbitol. It has little significant energy value as it is largely eliminated from the body before any metabolism can take place. It can be used to treat oliguria associated with kidney failure or other manifestations of inadequate renal function and has been used for determination of glomerular filtration rate. Mannitol is also commonly used as a research tool in cell biological studies, usually to control osmolarity. [NIH] Mass Media: Instruments or technological means of communication that reach large numbers of people with a common message: press, radio, television, etc. [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]

Mechlorethamine: A vesicant and necrotizing irritant destructive to mucous membranes. It was formerly used as a war gas. The hydrochloride is used as an antineoplastic in Hodgkin's disease and lymphomas. It causes severe gastrointestinal and bone marrow damage. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU]

320 Folic Acid

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] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Megacolon: Pathological enlargement of the colon. [NIH] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] 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] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental deficiency: A condition of arrested or incomplete development of mind from inherent causes or induced by disease or injury. [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 Health: The state wherein the person is well adjusted. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated

Dictionary 321

during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Mesothelioma: A benign (noncancerous) or malignant (cancerous) tumor affecting the lining of the chest or abdomen. Exposure to asbestos particles in the air increases the risk of developing malignant mesothelioma. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methionine Adenosyltransferase: An enzyme that catalyzes the synthesis of Sadenosylmethionine from methionine and ATP. EC 2.5.1.6. [NIH] Methylcellulose: Methylester of cellulose. Methylcellulose is used as an emulsifying and suspending agent in cosmetics, pharmaceutics and the chemical industry. It is used therapeutically as a bulk laxative. [NIH] Methylmalonic Acid: A malonic acid derivative which is a vital intermediate in the metabolism of fat and protein. Abnormalities in methylmalonic acid metabolism lead to methylmalonic aciduria. This metabolic disease is attributed to a block in the enzymatic conversion of methylmalonyl CoA to succinyl CoA. [NIH] Methylphenidate: A central nervous system stimulant used most commonly in the treatment of attention-deficit disorders in children and for narcolepsy. Its mechanisms appear to be similar to those of dextroamphetamine. [NIH] Methyltransferase: A drug-metabolizing enzyme. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiological: Pertaining to microbiology : the science that deals with microorganisms, including algae, bacteria, fungi, protozoa and viruses. [EU] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH]

322 Folic Acid

Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [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] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]

labeled

with

Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] 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] 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] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the second trimester. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] 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]

Dictionary 323

Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monophosphate: So called second messenger for neurotransmitters and hormones. [NIH] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]

Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] 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] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [NIH] 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] Muscle Relaxation: That phase of a muscle twitch during which a muscle returns to a resting position. [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]

324 Folic Acid

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] Myalgia: Pain in a muscle or muscles. [EU] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myeloproliferative Disorders: Disorders in which one or more stimuli cause proliferation of hemopoietically active tissue or of tissue which has embryonic hemopoietic potential. [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] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Narcolepsy: A condition of unknown cause characterized by a periodic uncontrollable tendency to fall asleep. [NIH] Nasal Mucosa: The mucous membrane lining the nasal cavity. [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] Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatal Screening: The identification of selected parameters in newborn infants by various tests, examinations, or other procedures. Screening may be performed by clinical or

Dictionary 325

laboratory measures. A screening test is designed to sort out healthy neonates from those not well, but the screening test is not intended as a diagnostic device, rather instead as epidemiologic. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Nervousness: Excessive excitability and irritability, with mental and physical unrest. [EU] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural Crest: A strip of specialized ectoderm flanking each side of the embryonal neural plate, which after the closure of the neural tube, forms a column of isolated cells along the dorsal aspect of the neural tube. Most of the cranial and all of the spinal sensory ganglion cells arise by differentiation of neural crest cells. [NIH] 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] Neuroanatomy: Study of the anatomy of the nervous system as a specialty or discipline. [NIH]

Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurofibrils: The delicate interlacing threads, formed by aggregations of neurofilaments and neurotubules, coursing through the cytoplasm of the body of a neuron and extending from one dendrite into another or into the axon. [NIH] Neurofilaments: Bundle of neuronal fibers. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH]

326 Folic Acid

Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]

Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [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] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Night Blindness: Anomaly of vision in which there is a pronounced inadequacy or complete absence of dark-adaptation. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nitroglycerin: A highly volatile organic nitrate that acts as a dilator of arterial and venous smooth muscle and is used in the treatment of angina. It provides relief through improvement of the balance between myocardial oxygen supply and demand. Although total coronary blood flow is not increased, there is redistribution of blood flow in the heart when partial occlusion of coronary circulation is effected. [NIH]

Dictionary 327

Nonmalignant: Not cancerous. [NIH] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] Nonverbal Communication: Transmission of emotions, ideas, and attitudes between individuals in ways other than the spoken language. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] NSAIDs: Nonsteroidal anti-inflammatory drugs. A group of drugs that decrease fever, swelling, pain, and redness. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Obsession: A recurrent, persistent thought, image, or impulse that is unwanted and distressing (ego-dystonic) and comes involuntarily to mind despite attempts to ignore or suppress it. Common obsessions involve thoughts of violence, contamination, and selfdoubt. [EU] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odour: A volatile emanation that is perceived by the sense of smell. [EU] Ofloxacin: An orally administered broad-spectrum quinolone antibacterial drug active against most gram-negative and gram-positive bacteria. [NIH] 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]

328 Folic Acid

Oleanolic Acid: Occurs in leaves of Olea europaea, Viscum album L., and other higher plants. It is also the aglycone component of many saponins. [NIH] Oligosaccharides: Carbohydrates consisting of between two and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Opsin: A visual pigment protein found in the retinal rods. It combines with retinaldehyde to form rhodopsin. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Manifestations: Disorders of the mouth attendant upon non-oral disease or injury. [NIH]

Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] 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] Orgasm: The crisis of sexual excitement in either humans or animals. [NIH] Ornithine: An amino acid produced in the urea cycle by the splitting off of urea from arginine. [NIH] Ornithine Decarboxylase: A pyridoxal-phosphate protein, believed to be the rate-limiting compound in the biosynthesis of polyamines. It catalyzes the decarboxylation of ornithine to form putrescine, which is then linked to a propylamine moiety of decarboxylated Sadenosylmethionine to form spermidine. EC 4.1.1.17. [NIH] Orofacial: Of or relating to the mouth and face. [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] Osseointegration: The growth action of bone tissue, as it assimilates surgically implanted devices or prostheses to be used as either replacement parts (e.g., hip) or as anchors (e.g., endosseous dental implants). [NIH] Osteoarthritis: Degeneration of articular cartilage. Primary osteoarthritis is very common in older persons, especially affecting weight-bearing joints. Articular cartilage becomes soft,

Dictionary 329

frayed and thinned. [NIH] Osteogenesis: The histogenesis of bone including ossification. It occurs continuously but particularly in the embryo and child and during fracture repair. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Ovum Implantation: Endometrial implantation of the blastocyst. [NIH] Oxazolidinones: Derivatives of oxazolidin-2-one. They represent an important class of synthetic antibiotic agents. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Oxytetracycline: An antibiotic substance isolated from the actinomycete Streptomyces rimosus and used in a wide variety of clinical conditions. [NIH] Pacemaker: An object or substance that influences the rate at which a certain phenomenon occurs; often used alone to indicate the natural cardiac pacemaker or an artificial cardiac pacemaker. In biochemistry, a substance whose rate of reaction sets the pace for a series of

330 Folic Acid

interrelated reactions. [EU] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatin: A mammalian pancreatic extract composed of enzymes with protease, amylase and lipase activities. It is used as a digestant in pancreatic malfunction. [NIH] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH] Papain: A proteolytic enzyme obtained from Carica papaya. It is also the name used for a purified mixture of papain and chymopapain that is used as a topical enzymatic debriding agent. EC 3.4.22.2. [NIH] Papilla: A small nipple-shaped elevation. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Paraffin: A mixture of solid hydrocarbons obtained from petroleum. It has a wide range of uses including as a stiffening agent in ointments, as a lubricant, and as a topical antiinflammatory. It is also commonly used as an embedding material in histology. [NIH] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] 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] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parity: The number of offspring a female has borne. It is contrasted with gravidity, which refers to the number of pregnancies, regardless of outcome. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid

Dictionary 331

artery, and the retromandibular vein. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Patient Care Team: Care of patients by a multidisciplinary team usually organized under the leadership of a physician; each member of the team has specific responsibilities and the whole team contributes to the care of the patient. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pedigree: A record of one's ancestors, offspring, siblings, and their offspring that may be used to determine the pattern of certain genes or disease inheritance within a family. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvic inflammatory disease: A bacteriological disease sometimes associated with intrauterine device (IUD) usage. [NIH] Pemoline: A central nervous system stimulant used in fatigue and depressive states and to treat hyperkinetic disorders in children. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: Ulcer that occurs in those portions of the alimentary tract which come into contact with gastric juice containing pepsin and acid. It occurs when the amount of acid and pepsin is sufficient to overcome the gastric mucosal barrier. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU]

332 Folic Acid

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] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [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] Perineal: Pertaining to the perineum. [EU] Perineum: The area between the anus and the sex organs. [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH] Peripheral Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [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] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [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]

Dictionary 333

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] Pharmacists: Those persons legally qualified by education and training to engage in the practice of pharmacy. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] 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] Phosphates: Inorganic salts of phosphoric acid. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorous: Having to do with or containing the element phosphorus. [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] Photodermatitis: Dermatitis caused or elicited by exposure to ultraviolet light, may be phototoxic or photoallergic. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] 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]

334 Folic Acid

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] Plague: An acute infectious disease caused by Yersinia pestis that affects humans, wild rodents, and their ectoparasites. This condition persists due to its firm entrenchment in sylvatic rodent-flea ecosystems throughout the world. Bubonic plague is the most common form. [NIH] 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 fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Platelet Activating Factor: A phospholipid derivative formed by platelets, basophils, neutrophils, monocytes, and macrophages. It is a potent platelet aggregating agent and inducer of systemic anaphylactic symptoms, including hypotension, thrombocytopenia, neutropenia, and bronchoconstriction. [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 Aggregation: The attachment of platelets to one another. This clumping together

Dictionary 335

can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] 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]

Pleura: The thin serous membrane enveloping the lungs and lining the thoracic cavity. [NIH] Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] 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, leukocytosis, and thrombocythemia. Hematopoiesis is also reactive in extramedullary sites (liver and spleen). In time myelofibrosis occurs. [NIH] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]

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] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] 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

336 Folic Acid

pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [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] Postnatal: Occurring after birth, with reference to the newborn. [EU] 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] Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] 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] Pravastatin: An antilipemic fungal metabolite isolated from cultures of Nocardia autotrophica. It acts as a competitive inhibitor of HMG CoA reductase (hydroxymethylglutaryl CoA reductases). [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Preeclampsia: A toxaemia of late pregnancy characterized by hypertension, edema, and proteinuria, when convulsions and coma are associated, it is called eclampsia. [EU] Pregnancy Tests: Tests to determine whether or not an individual is pregnant. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU]

Dictionary 337

Prepuce: A covering fold of skin; often used alone to designate the preputium penis. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection, as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Procarbazine: An antineoplastic agent used primarily in combination with mechlorethamine, vincristine, and prednisone (the MOPP protocol) in the treatment of Hodgkin's disease. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progeny: The offspring produced in any generation. [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] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Propranolol: A widely used non-cardioselective beta-adrenergic antagonist. Propranolol is used in the treatment or prevention of many disorders including acute myocardial infarction, arrhythmias, angina pectoris, hypertension, hypertensive emergencies, hyperthyroidism, migraine, pheochromocytoma, menopause, and anxiety. [NIH] Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed

338 Folic Acid

and unexposed groups. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein 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] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoal: Having to do with the simplest organisms in the animal kingdom. Protozoa are single-cell organisms, such as ameba, and are different from bacteria, which are not members of the animal kingdom. Some protozoa can be seen without a microscope. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pruritic: Pertaining to or characterized by pruritus. [EU] Psoriasis: A common genetically determined, chronic, inflammatory skin disease

Dictionary 339

characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH] Pteroylpolyglutamic Acids: Derivatives of folic acid (pteroylglutamic acid). In gammaglutamyl linkage they are found in many tissues. They are converted to folic acid by the action of pteroylpolyglutamate hydrolase or synthesized from folic acid by the action of folate polyglutamate synthetase. Synthetic pteroylpolyglutamic acids, which are in alphaglutamyl linkage, are active in bacterial growth assays. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] 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 Emphysema: Condition of the lungs characterized by increase beyond normal in the size of air spaces distal to the terminal bronchioles, either from dilatation of the alveoli or from destruction of their walls. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Pupil: The aperture in the iris through which light passes. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Putrescine: A toxic diamine formed by putrefaction from the decarboxylation of arginine and ornithine. [NIH] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH]

340 Folic Acid

Pyridoxal Phosphate: 3-Hydroxy-2-methyl-5-((phosphonooxy)methyl)-4pyridinecarboxaldehyde. An enzyme co-factor vitamin. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radioactive: Giving off radiation. [NIH] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose. [NIH] Raltitrexed: An anticancer drug that inhibits tumor cells from multiplying by interfering with cells' ability to make DNA. Also called ICI D1694. [NIH] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] 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] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU]

Dictionary 341

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] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red 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] Reference point: The midpoint of a line connecting the centers of the two end faces of the acoustic test fixture. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractive Errors: Deviations from the average or standard indices of refraction of the eye through its dioptric or refractive apparatus. [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Reishi: A mushroom, Ganoderma lucidum, of the aphyllophorales order of basidomycetous fungi. It has long been used in traditional Chinese medicine in various forms. Contains sterols, coumarin, mannitol, polysaccharides, and triterpenoids. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Relaxation Techniques: The use of muscular relaxation techniques in treatment. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal Artery: A branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH]

342 Folic Acid

Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Renin-Angiotensin System: A system consisting of renin, angiotensin-converting enzyme, and angiotensin II. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. The converting enzyme contained in the lung acts on angiotensin I in the plasma converting it to angiotensin II, the most powerful directly pressor substance known. It causes contraction of the arteriolar smooth muscle and has other indirect actions mediated through the adrenal cortex. [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Reproductive system: In women, this system includes the ovaries, the fallopian tubes, the uterus (womb), the cervix, and the vagina (birth canal). The reproductive system in men includes the prostate, the testes, and the penis. [NIH] 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] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Resident physician: A physician who lives in a hospital and is constantly available, as an intern. [NIH] Resolving: The ability of the eye or of a lens to make small objects that are close together, separately visible; thus revealing the structure of an object. [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinitis: Inflammation of the retina. It is rarely limited to the retina, but is commonly associated with diseases of the choroid (chorioretinitis) and of the optic nerve

Dictionary 343

(neuroretinitis). The disease may be confined to one eye, but since it is generally dependent on a constitutional factor, it is almost always bilateral. It may be acute in course, but as a rule it lasts many weeks or even several months. [NIH] 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] Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [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] Rhinitis: Inflammation of the mucous membrane of the nose. [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 of the head. Vitamin D and sunlight together with an adequate diet are curative, provided that the parathyroid glands are functioning properly. [EU] Rickettsiae: One of a group of obligate intracellular parasitic microorganisms, once regarded as intermediate in their properties between bacteria and viruses but now classified as bacteria in the order Rickettsiales, which includes 17 genera and 3 families: Rickettsiace. [NIH]

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] Rye: A hardy grain crop, Secale cereale, grown in northern climates. It is the most frequent host to ergot (claviceps), the toxic fungus. Its hybrid with wheat is triticale, another grain. [NIH]

344 Folic Acid

Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of epithelioid and multinucleated giant cells with little necrosis. It usually invades the lungs with fibrosis and may also involve lymph nodes, skin, liver, spleen, eyes, phalangeal bones, and parotid glands. [NIH] Saturated fat: A type of fat found in greatest amounts in foods from animals, such as fatty cuts of meat, poultry with the skin, whole-milk dairy products, lard, and in some vegetable oils, including coconut, palm kernel, and palm oils. Saturated fat raises blood cholesterol more than anything else eaten. On a Step I Diet, no more than 8 to 10 percent of total calories should come from saturated fat, and in the Step II Diet, less than 7 percent of the day's total calories should come from saturated fat. [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] 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] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU]

Dictionary 345

Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedentary: 1. Sitting habitually; of inactive habits. 2. Pertaining to a sitting posture. [EU] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Senility: Old age; the physical and mental deterioration associated with old age. [EU] Sepsis: The presence of bacteria in the bloodstream. [NIH] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [NIH] 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] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Seroconversion: The change of a serologic test from negative to positive, indicating the development of antibodies in response to infection or immunization. [EU] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH]

346 Folic Acid

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]

Short Bowel Syndrome: A malabsorption syndrome resulting from extensive operative resection of small bowel. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Sigmoid: 1. Shaped like the letter S or the letter C. 2. The sigmoid colon. [EU] Sigmoidoscopy: Endoscopic examination, therapy or surgery of the sigmoid flexure. [NIH] 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] Simvastatin: A derivative of lovastatin and potent competitive inhibitor of 3-hydroxy-3methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic LDL receptors, it increases breakdown of LDL-cholesterol (lipoproteins, LDL cholesterol). [NIH] Single-agent: The use of a single drug or other therapy. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Environment: The aggregate of social and cultural institutions, forms, patterns, and

Dictionary 347

processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Benzoate: The sodium salt of benzoic acid. It is used as an antifungal preservative in pharmaceutical preparations and foods. It may also be used as a test for liver function. [NIH]

Sodium Channels: Cell membrane glycoproteins selective for sodium ions. Fast sodium current is associated with the action potential in neural membranes. [NIH] Sodium Selenite: Selenious acid, disodium salt. It is used therapeutically to supply the trace element selenium. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solar radiation: Sunbathing as a therapeutic measure. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. [NIH] Soybean Oil: Oil from soybean or soybean plant. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [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]

348 Folic Acid

Sperm Count: A count of sperm in the ejaculum, expressed as number per milliliter. [NIH] Spermatozoa: Mature male germ cells that develop in the seminiferous tubules of the testes. Each consists of a head, a body, and a tail that provides propulsion. The head consists mainly of chromatin. [NIH] Spermidine: A polyamine formed from putrescine. It is found in almost all tissues in association with nucleic acids. It is found as a cation at all pH values, and is thought to help stabilize some membranes and nucleic acid structures. It is a precursor of spermine. [NIH] Spices: The dried seeds, bark, root, stems, buds, leaves, or fruit of aromatic plants used to season food. [NIH] Spina bifida: A defect in development of the vertebral column in which there is a central deficiency of the vertebral lamina. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinous: Like a spine or thorn in shape; having spines. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sprue: A non febrile tropical disease of uncertain origin. [NIH] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [NIH] Stabilization: The creation of a stable state. [EU] Steatorrhea: A condition in which the body cannot absorb fat. Causes a buildup of fat in the stool and loose, greasy, and foul bowel movements. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this

Dictionary 349

group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Streptococci: A genus of spherical Gram-positive bacteria occurring in chains or pairs. They are widely distributed in nature, being important pathogens but often found as normal commensals in the mouth, skin, and intestine of humans and other animals. [NIH] Streptococcus: A genus of gram-positive, coccoid bacteria whose organisms occur in pairs or chains. No endospores are produced. Many species exist as commensals or parasites on man or animals with some being highly pathogenic. A few species are saprophytes and occur in the natural environment. [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] Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure-activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects. [NIH] Struvite: A type of kidney stone caused by infection. [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] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] 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]

350 Folic Acid

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] Sudden death: Cardiac arrest caused by an irregular heartbeat. The term "death" is somewhat misleading, because some patients survive. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sunburn: An injury to the skin causing erythema, tenderness, and sometimes blistering and resulting from excessive exposure to the sun. The reaction is produced by the ultraviolet radiation in sunlight. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superstitions: A belief or practice which lacks adequate basis for proof; an embodiment of fear of the unknown, magic, and ignorance. [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] 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]

Suspensions: Colloids with liquid continuous phase and solid dispersed phase; the term is used loosely also for solid-in-gas (aerosol) and other colloidal systems; water-insoluble drugs may be given as suspensions. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapses: Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate through direct electrical connections which are sometimes called electrical synapses; these are not included here but rather in gap junctions. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific

Dictionary 351

synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] 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] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Thalassemia: A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely detectable hematologic abnormality to severe and fatal anemia. [NIH] Theophylline: Alkaloid obtained from Thea sinensis (tea) and others. It stimulates the heart and central nervous system, dilates bronchi and blood vessels, and causes diuresis. The drug

352 Folic Acid

is used mainly in bronchial asthma and for myocardial stimulation. Among its more prominent cellular effects are inhibition of cyclic nucleotide phosphodiesterases and antagonism of adenosine receptors. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thiamine: 3-((4-Amino-2-methyl-5-pyrimidinyl)methyl)-5-(2methylthiazolium chloride. [NIH]

hydroxyethyl)-4-

Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] 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] Thymosin: A family of heat-stable, polypeptide hormones secreted by the thymus gland. Their biological activities include lymphocytopoiesis, restoration of immunological competence and enhancement of expression of T-cell characteristics and function. They have therapeutic potential in patients having primary or secondary immunodeficiency diseases, cancer or diseases related to aging. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thymus Gland: A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyrotropin: A peptide hormone secreted by the anterior pituitary. It promotes the growth of the thyroid gland and stimulates the synthesis of thyroid hormones and the release of thyroxine by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] 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 Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of

Dictionary 353

an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] 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] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxaemia: 1. The condition resulting from the spread of bacterial products (toxins) by the bloodstream. 2. A condition resulting from metabolic disturbances, e.g. toxaemia of pregnancy. [EU] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] 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] Translating: Conversion from one language to another language. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual,

354 Folic Acid

between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Trimethoprim-sulfamethoxazole: An antibiotic drug used to treat infection and prevent pneumocystis carinii pneumonia. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]

Trophic: Of or pertaining to nutrition. [EU] Trophoblast: The outer layer of cells of the blastocyst which works its way into the endometrium during ovum implantation and grows rapidly, later combining with mesoderm. [NIH] 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] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor model: A type of animal model which can be used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [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] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] 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] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10 megahertz. [NIH]

Dictionary 355

Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein, which connects the embryo or fetus to the placenta. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethane: Antineoplastic agent that is also used as a veterinary anesthetic. It has also been used as an intermediate in organic synthesis. Urethane is suspected to be a carcinogen. [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] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Valproic Acid: A fatty acid with anticonvulsant properties used in the treatment of epilepsy. The mechanisms of its therapeutic actions are not well understood. It may act by increasing GABA levels in the brain or by altering the properties of voltage dependent sodium channels. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU]

356 Folic Acid

Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Very low-density lipoprotein: The lipoprotein particles that initially leave the liver, carrying cholesterol and lipid. VLDLs contain 10 to 15 percent of the total serum cholesterol along with most of the triglycerides in the fasting serum; VLDLs are precursors of LDL, and some forms of VLDL, particularly VLDL remnants, appear to be atherogenic. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villi: The tiny, fingerlike projections on the surface of the small intestine. Villi help absorb nutrients. [NIH] Villous: Of a surface, covered with villi. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viremia: The presence of viruses in the blood. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visual Cortex: Area of the occipital lobe concerned with vision. [NIH] Vital Statistics: Used for general articles concerning statistics of births, deaths, marriages, etc. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitamin D: The vitamin that mediates intestinal calcium absorption, bone calcium 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] Vitamin U: A vitamin found in green vegetables. It is used in the treatment of peptic ulcers, colitis, and gastritis and has an effect on secretory, acid-forming, and enzymatic functions of the intestinal tract. [NIH]

Dictionary 357

Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Warts: Benign epidermal proliferations or tumors; some are viral in origin. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] Weight-Bearing: The physical state of supporting an applied load. This often refers to the weight-bearing bones or joints that support the body's weight, especially those in the spine, hip, knee, and foot. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xanthine: An urinary calculus. [NIH] Xenobiotics: Chemical substances that are foreign to the biological system. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc. [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] Zinc Compounds: Inorganic compounds that contain zinc as an integral part of the molecule. [NIH] Zygote: The fertilized ovum. [NIH]

359

INDEX 5 5-Hydroxytryptophan, 194, 267 A Abdominal, 49, 159, 161, 267, 292, 310, 319, 321, 330, 332, 341, 354 Abdominal Pain, 267, 319, 354 Abscess, 267, 301 Acanthosis Nigricans, 222, 267 Acatalasia, 267, 281 Acceptor, 172, 267, 316, 329 Acetylcholine, 162, 267, 283, 326 Acidosis, 218, 267 Acne, 201, 267, 314, 343 Acne Vulgaris, 267, 314 Acoustic, 267, 341 Acute myelogenous leukemia, 267 Acute myeloid leukemia, 51, 53, 267 Acute nonlymphocytic leukemia, 267 Acute renal, 268, 307 Adaptability, 268, 282 Adaptation, 268, 326, 334 Adenine, 200, 268, 339 Adenocarcinoma, 151, 268, 327 Adenoma, 21, 43, 149, 170, 191, 268 Adenosine, 33, 38, 268, 280, 310, 333, 352 Adenosine Deaminase, 33, 268 Adjuvant, 33, 176, 268, 303 Adrenal Cortex, 268, 289, 298, 337, 342 Adrenal Glands, 268, 271, 341 Adrenergic, 268, 293, 297, 337, 350 Adverse Effect, 233, 268, 270, 294, 314, 346 Aerobic, 202, 268, 299, 322 Aerosol, 268, 350 Affinity, 19, 32, 42, 49, 51, 53, 57, 164, 190, 268, 269, 275, 292, 347 Age Groups, 203, 268 Age of Onset, 269, 354 Aged, 80 and Over, 269 Ageing, 182, 269 Agonist, 269, 293, 297, 326 Albumin, 80, 133, 218, 269, 293, 334 Alertness, 269, 280 Alfalfa, 174, 269 Algorithms, 269, 278 Alimentary, 182, 269, 330, 331 Alkaline, 164, 165, 267, 269, 270, 280 Alkaloid, 269, 280, 285, 326, 351 Alkylating Agents, 269, 355

Alleles, 38, 269, 308 Allograft, 5, 269 Aloe, 173, 269 Alpha Particles, 269, 340 Alpha-fetoprotein, 213, 269, 300 Alternative medicine, 231, 269 Aluminum, 140, 223, 270 Alveoli, 270, 339 Amblyopia, 93, 270 Ameliorated, 50, 270 Amino Acid Sequence, 270, 272, 303 Aminoimidazole Carboxamide, 33, 270 Aminopterin, 176, 270 Ammonia, 268, 270, 305, 355 Amniotic Fluid, 270, 304 Amphetamine, 270, 291 Amputation, 161, 270 Amylase, 270, 330 Amyloid, 155, 270 Amyloidosis, 222, 271 Anaemia, 61, 65, 70, 174, 216, 271, 320 Anaerobic, 196, 202, 271, 275 Anaesthesia, 271, 312 Anal, 271, 297, 311, 317 Analog, 42, 50, 271, 292, 301, 302 Analogous, 159, 271, 353 Anaphylactic, 271, 334 Anaphylatoxins, 271, 286 Anatomical, 6, 271, 275, 292, 311, 344 Androgens, 268, 271, 289 Anemia, Sickle Cell, 217, 271 Anemic, 69, 271 Aneuploidy, 55, 271 Aneurysm, 271, 274, 355 Angina, 161, 206, 271, 272, 326, 337 Angina Pectoris, 271, 337 Angina, Unstable, 161, 272 Angiogenesis, 41, 272 Angiotensinogen, 272, 342 Animal model, 7, 12, 32, 36, 40, 42, 43, 51, 53, 173, 272, 354 Anions, 269, 272, 314 Anisotropy, 272, 301 Anomalies, 4, 9, 20, 85, 100, 110, 112, 133, 176, 272, 351 Anorexia, 272 Antagonism, 76, 272, 280, 352 Anterior Cerebral Artery, 272, 282

360 Folic Acid

Anterior chamber, 7, 272, 314 Anthracycline, 53, 272, 290 Antiallergic, 272, 289 Antibacterial, 110, 112, 202, 272, 276, 327, 347 Antibiotic, 140, 272, 279, 290, 293, 329, 331, 347, 351, 354 Antibodies, 12, 33, 52, 272, 273, 306, 307, 311, 318, 334, 345 Antibody, 19, 52, 56, 189, 268, 272, 273, 286, 297, 301, 306, 308, 311, 312, 314, 320, 323, 347 Anticonvulsant, 94, 273, 280, 355 Anticonvulsive, 79, 273 Antidepressant, 267, 273 Antidote, 176, 273, 316 Antiepileptic, 267, 273 Antifungal, 273, 276, 347 Antigen, 29, 189, 216, 268, 272, 273, 275, 286, 301, 304, 308, 309, 310, 311, 312, 320 Antigen-Antibody Complex, 273, 286 Anti-infective, 273, 309, 313 Anti-inflammatory, 143, 178, 273, 274, 289, 304, 327, 330, 336 Anti-Inflammatory Agents, 273, 274, 289 Antimetabolite, 273, 291, 301 Antimicrobial, 154, 181, 182, 184, 273 Antineoplastic, 65, 269, 270, 273, 289, 293, 301, 319, 330, 337, 355 Antineoplastic Agents, 269, 270, 273 Antioxidant, 15, 23, 47, 57, 126, 160, 187, 192, 196, 220, 273, 274, 329 Antiparasitic Agents, 176, 273 Antiproliferative, 178, 273 Antiserum, 273, 275 Antitumour, 158, 198, 273 Antitussive, 273, 292 Antiviral, 7, 273, 331 Anuria, 273, 315 Anus, 271, 273, 275, 279, 332, 341 Anxiety, 211, 273, 330, 337 Aorta, 49, 55, 159, 161, 274, 280, 310, 341, 356 Aortic Aneurysm, 161, 274 Aortic Valve, 55, 274 Apathy, 4, 274 Aphthous Stomatitis, 98, 274 Aplastic anemia, 63, 217, 274 Apolipoproteins, 274, 317 Apoptosis, 6, 23, 30, 47, 75, 149, 274, 281 Aqueous, 154, 162, 181, 274, 276, 290, 309, 316, 317

Arginine, 15, 34, 158, 176, 192, 206, 271, 274, 326, 328, 339 Aromatic, 176, 274, 333, 348 Arrhythmia, 174, 274 Arterial, 44, 49, 73, 88, 130, 159, 161, 230, 274, 282, 283, 304, 310, 326, 338, 351 Arteries, 26, 49, 159, 160, 161, 187, 274, 275, 278, 279, 288, 310, 314, 318, 321, 324, 355 Arteriography, 97, 274 Arteriolar, 274, 279, 342 Arterioles, 274, 278, 322, 324 Articular, 274, 328 Asbestos, 274, 286, 319, 321 Ascorbic Acid, 109, 111, 157, 161, 169, 180, 186, 193, 197, 223, 274 Aspartate, 22, 274, 292 Aspirin, 42, 140, 150, 161, 179, 205, 274 Assay, 16, 30, 37, 46, 54, 55, 91, 215, 274, 301 Astrocytes, 36, 275 Ataxia, 171, 245, 275, 351 Atherogenic, 161, 275, 356 Atresia, 55, 275 Atrium, 275, 280, 356 Atrophy, 66, 217, 245, 275 Attenuated, 51, 275, 292 Audition, 220, 275 Autoimmune disease, 176, 205, 275 Autonomic, 267, 275, 327 Autopsy, 12, 211, 275 Avidity, 19, 52, 275 Axillary, 275, 279 Axillary Artery, 275, 279 Axons, 12, 275, 291, 328 B Bacterial Infections, 184, 211, 275 Bactericidal, 275, 298 Bacterium, 275, 287, 307 Bacteroides, 202, 275 Basal Ganglia, 275, 276, 302 Basal Ganglia Diseases, 275, 276 Basal Metabolism, 199, 276 Base, 12, 47, 57, 198, 200, 233, 268, 276, 290, 291, 298, 303, 312, 314, 315, 351 Basement Membrane, 276, 299 Basophils, 276, 306, 316, 334 Bed Rest, 212, 276 Beer, 13, 276 Benign, 203, 268, 276, 302, 306, 321, 325, 357 Benzene, 276, 314

Index 361

Benzoates, 9, 276 Benzoic Acid, 276, 347 Beta carotene, 14, 174, 233, 276 Beta-pleated, 270, 276 Bewilderment, 276, 287 Bifida, 4, 35, 54, 188, 250, 276 Bilateral, 276, 343 Bile, 140, 183, 199, 276, 277, 302, 317, 349, 351 Bile Acids, 276, 277, 349, 351 Bile Acids and Salts, 276, 277 Bile Ducts, 277 Biliary, 218, 277 Bilirubin, 269, 277 Binding Sites, 30, 277 Bioavailability, 7, 34, 35, 54, 65, 102, 157, 165, 186, 204, 277 Bioavailable, 157, 165, 186, 277 Biochemical reactions, 54, 174, 277 Biological Markers, 48, 277 Biological therapy, 277, 306 Biological Transport, 277, 292 Biomarkers, 21, 48, 99, 149, 277 Biopsy, 217, 277, 331 Biosynthesis, 23, 33, 50, 110, 112, 168, 189, 208, 277, 289, 317, 328, 345, 346 Biotechnology, 59, 61, 108, 109, 111, 215, 231, 241, 244, 245, 246, 277 Biotin, 115, 173, 180, 196, 197, 199, 200, 203, 220, 222, 223, 278 Birth Certificates, 37, 278 Bladder, 41, 157, 210, 278, 312, 325, 338, 355 Blastocyst, 278, 287, 329, 334, 354 Bloating, 278, 303, 312, 319 Blood Cell Count, 278, 307, 332 Blood Coagulation, 278, 280, 299 Blood Glucose, 219, 278, 307, 313 Blood Platelets, 278, 345, 352 Blood pressure, 15, 88, 102, 160, 176, 187, 264, 278, 281, 304, 310, 323, 332, 347 Blood transfusion, 216, 278, 307 Blood Viscosity, 278, 307 Blood Volume, 278, 335 Blood-Brain Barrier, 87, 278, 316 Body Fluids, 277, 278, 279, 347, 354 Body Mass Index, 22, 278, 329 Bone Development, 156, 186, 278 Bone Marrow, 215, 267, 274, 276, 279, 298, 311, 318, 319, 323, 324, 335, 347, 349 Bone metastases, 205, 279 Boron, 49, 279, 289

Boron Compounds, 49, 279 Boron Neutron Capture Therapy, 49, 279 Bowel, 15, 138, 161, 217, 218, 221, 271, 279, 292, 312, 313, 315, 325, 332, 346, 348, 349, 354 Bowel Movement, 279, 292, 348, 349 Brachial, 15, 88, 279 Brachial Artery, 15, 88, 279 Bradykinin, 279, 326, 334 Branch, 159, 261, 279, 295, 306, 318, 331, 339, 341, 347, 352 Breakdown, 180, 279, 292, 302, 346 Breeding, 201, 279 Broad-spectrum, 279, 327 Bronchioles, 270, 279, 339 Bronchoconstriction, 279, 334 Buccal, 279, 318 Burns, 199, 207, 279 Burns, Electric, 279 Bypass, 52, 53, 279 C Caffeine, 161, 192, 203, 279, 339 Callus, 280, 295 Calorimeter, 276, 280 Capsaicin, 233, 280 Capsules, 280, 293, 301, 303 Carbamazepine, 74, 75, 280 Carbohydrate, 162, 167, 168, 189, 211, 222, 280, 289, 304, 305, 335, 345 Carbon Dioxide, 280, 290, 291, 334, 356 Carcinogen, 21, 41, 280, 355 Carcinogenesis, 21, 43, 91, 100, 130, 149, 280, 283 Carcinogenic, 183, 269, 276, 280, 312, 337, 349 Carcinoma, 42, 49, 52, 178, 280, 327 Cardiac, 22, 31, 55, 174, 206, 218, 280, 288, 297, 299, 324, 329, 349, 350 Cardiac arrest, 206, 280, 350 Cardiopulmonary, 280, 307 Cardiopulmonary Bypass, 280, 307 Cardioselective, 280, 337 Cardiovascular System, 197, 281 Carnitine, 192, 206, 281 Carotene, 57, 160, 187, 194, 196, 197, 276, 281, 342 Carotenoids, 276, 281 Carrier Proteins, 281, 334 Case report, 70, 281, 284 Case series, 281, 284 Case-Control Studies, 19, 281, 297 Caspase, 30, 281

362 Folic Acid

Castor Oil, 166, 281 Catalase, 196, 267, 281 Catecholamine, 281, 293 Cations, 281, 314 Caudal, 188, 281, 336 Causal, 20, 281, 297, 307 Cause of Death, 14, 34, 48, 160, 161, 170, 183, 184, 187, 197, 281 Cecum, 281, 310, 315 Celiac Disease, 4, 136, 218, 220, 221, 232, 233, 281, 304 Cell, 6, 7, 8, 9, 10, 12, 13, 17, 20, 22, 24, 27, 30, 32, 33, 40, 42, 49, 51, 52, 53, 54, 55, 57, 61, 67, 76, 81, 84, 94, 108, 109, 111, 123, 125, 126, 131, 139, 149, 151, 154, 164, 165, 170, 171, 172, 173, 182, 189, 190, 196, 213, 218, 222, 228, 245, 269, 271, 274, 275, 276, 277, 278, 281, 282, 284, 286, 287, 288, 290, 291, 294, 295, 296, 297, 299, 302, 303, 304, 305, 306, 307, 308, 311, 312, 313, 319, 320, 322, 323, 324, 325, 327, 328, 329, 332, 333, 334, 335, 336, 337, 338, 341, 344, 345, 346, 347, 349, 350, 351, 352, 353, 354, 355, 357 Cell Count, 154, 182, 282 Cell Cycle, 34, 282, 284, 338 Cell Death, 13, 20, 30, 61, 274, 282, 304, 324 Cell Differentiation, 282, 295, 346 Cell Division, 6, 27, 165, 190, 245, 275, 282, 306, 320, 322, 334, 337, 345 Cell membrane, 27, 42, 49, 81, 277, 281, 282, 291, 333, 347 Cell proliferation, 13, 34, 54, 149, 282, 346 Cell Respiration, 282, 322 Cell Survival, 282, 306 Cellobiose, 282 Cellulose, 108, 110, 282, 302, 321, 334 Centrifugation, 282, 307 Cerebellar, 275, 282, 341 Cerebral Infarction, 58, 59, 282 Cerebrospinal, 96, 282, 283, 297 Cerebrospinal fluid, 96, 282, 283, 297 Cerebrovascular, 5, 11, 46, 276, 280, 282, 351 Cerebrum, 282, 283, 354 Cervical, 69, 83, 94, 108, 110, 136, 283 Cervix, 57, 211, 283, 286, 342 Character, 188, 272, 283, 290, 305 Cheilitis, 218, 283 Chemoprevention, 54, 149, 150, 283 Chemopreventive, 42, 283

Chemotactic Factors, 283, 286 Chemotherapy, 10, 50, 52, 104, 141, 151, 164, 176, 214, 215, 283 Chlorine, 199, 283, 310 Chlorophyll, 283, 296, 302 Cholecalciferol, 196, 283 Cholesterol Esters, 283, 317 Choline, 6, 30, 161, 162, 166, 173, 175, 194, 199, 203, 283 Cholinergic, 283, 326 Chorioretinitis, 283, 342 Choroid, 18, 283, 284, 342 Choroid Plexus, 18, 283 Choroid plexus tumor, 18, 284 Chromatin, 274, 284, 296, 326, 348 Chromium, 173, 196, 197, 203, 210, 223, 284 Chromosomal, 43, 51, 271, 284, 334 Chromosome, 13, 51, 99, 271, 284, 287, 303, 306, 316, 323, 345, 354 Chronic renal, 6, 11, 46, 72, 80, 88, 97, 109, 112, 123, 134, 223, 284, 335 Chylomicrons, 284, 317 Chymopapain, 284, 330 CIS, 156, 284, 342 Cisplatin, 10, 156, 284 Citric Acid, 157, 169, 186, 193, 284 Citrus, 274, 284 Claudication, 161, 206, 284 Claviceps, 284, 343 Cleft Palate, 8, 40, 132, 209, 284 Clinical Medicine, 284, 336 Clinical Protocols, 10, 284 Clinical study, 54, 284, 288 Clinical trial, 5, 11, 21, 37, 38, 39, 43, 45, 46, 47, 49, 50, 149, 152, 177, 241, 284, 288, 293, 338, 340 Clitoral, 159, 285 Clone, 23, 285 Cloning, 13, 277, 285 Coagulation, 278, 285, 307, 334, 352 Cobalt, 174, 179, 180, 184, 192, 285 Coca, 285 Cocaine, 203, 285 Codeine, 285, 292 Coenzyme, 162, 163, 174, 177, 192, 201, 206, 274, 285, 301, 317, 326, 346 Cofactor, 171, 173, 176, 195, 285, 338 Cohort Studies, 21, 42, 285, 297 Colitis, 139, 221, 285, 356 Collagen, 276, 285, 301, 303, 335 Collapse, 279, 285

Index 363

Colloidal, 269, 286, 350 Colorectal, 15, 21, 32, 41, 42, 71, 88, 100, 136, 149, 150, 170, 190, 191, 250, 286 Colorectal Cancer, 15, 21, 32, 41, 42, 71, 88, 136, 150, 250, 286 Colorectal Neoplasms, 21, 286 Communis, 281, 286 Complement, 25, 271, 286, 303, 319, 334 Complementary and alternative medicine, 10, 121, 145, 286 Complementary medicine, 121, 286 Complementation, 25, 286 Complete remission, 286, 341 Computational Biology, 241, 244, 287 Conception, 4, 31, 219, 287, 300, 347, 348 Concomitant, 69, 162, 167, 201, 287 Conditioned stimulus, 6, 287 Cones, 287, 342 Confusion, 4, 287, 293, 355 Congestion, 287, 298 Congestive heart failure, 206, 287 Conjugated, 58, 164, 166, 167, 198, 206, 276, 277, 287 Conjugation, 19, 287 Conjunctiva, 287, 312 Connective Tissue, 181, 222, 274, 279, 285, 287, 301, 302, 303, 304, 318, 321, 343, 351 Connective Tissue Cells, 287 Consciousness, 287, 291, 293 Constitutional, 287, 343 Constriction, 287, 314 Contamination, 287, 308, 327 Contraindications, ii, 288 Control group, 55, 288, 337, 340 Controlled clinical trial, 5, 11, 14, 59, 288 Controlled study, 69, 122, 127, 288 Conventional therapy, 288 Conventional treatment, 179, 185, 288 Convulsions, 273, 288, 294, 336 Convulsive, 168, 208, 288 Coordination, 4, 288 Cornea, 272, 288, 305, 344 Corneum, 288, 297 Coronary Arteriosclerosis, 288, 324 Coronary Disease, 31, 183, 288 Coronary heart disease, 6, 11, 14, 16, 22, 45, 48, 58, 59, 72, 108, 111, 183, 280, 288 Coronary Thrombosis, 288, 321, 324 Coronary Vessels, 288 Corpus, 159, 288, 331, 337 Corpus Luteum, 288, 337 Corpuscle, 288, 298

Cortex, 270, 275, 288, 289, 296, 301, 341 Cortical, 13, 270, 289, 299, 345, 351 Corticosteroid, 218, 289 Cortisol, 269, 289 Coumarin, 289, 341 Cranial, 289, 306, 325, 328 Creatinine, 5, 289, 315 Creatinine clearance, 5, 289 Crossing-over, 289, 341 Cross-Sectional Studies, 289, 297 Cruciferous vegetables, 41, 289 Curative, 289, 326, 343, 352 Curcumin, 177, 178, 289 Cutaneous, 222, 289, 318 Cyclic, 158, 280, 289, 306, 326, 333, 336, 344, 352 Cystathionine beta-Synthase, 8, 23, 289, 309 Cysteine, 23, 34, 73, 160, 168, 171, 172, 187, 195, 196, 205, 208, 284, 289, 290, 350 Cystine, 289 Cytarabine, 68, 290 Cytokine, 40, 290 Cytokinesis, 91, 290 Cytomegalovirus, 7, 290, 302 Cytomegalovirus Infections, 290, 302 Cytoplasm, 196, 274, 276, 282, 290, 296, 306, 323, 325, 326, 343 Cytosine, 200, 290 Cytotoxic, 56, 58, 154, 280, 290, 346 Cytotoxicity, 7, 51, 53, 284, 290 D Dairy Products, 14, 167, 233, 290, 344 Databases, Bibliographic, 241, 290 Daunorubicin, 53, 290, 293 De novo, 5, 11, 15, 32, 50, 56, 158, 198, 200, 290 Deamination, 290, 355 Decarboxylation, 290, 308, 328, 339 Decidua, 290, 334 Degenerative, 290, 308 Dehydration, 179, 218, 290 Deletion, 35, 43, 274, 290 Dementia, 12, 29, 36, 46, 77, 128, 155, 290 Demethylation, 168, 208, 291 Dendrites, 12, 291, 325 Density, 14, 25, 58, 59, 190, 278, 282, 291, 317, 328, 335 Dental Care, 4, 210, 291 Dentate Gyrus, 291, 308 Dentists, 4, 291 Deoxyguanosine, 15, 291

364 Folic Acid

Deoxyribonucleic, 189, 291 Deoxyribonucleic acid, 189, 291 Deoxyribonucleotides, 291 Deoxyuridine, 56, 291 Depolarization, 291, 346 Deprivation, 270, 291 Dermal, 291, 316 Dermatology, 68, 98, 99, 291 Deuterium, 86, 291, 309 Developing Countries, 127, 157, 186, 291 Dextroamphetamine, 270, 291, 321 Dextromethorphan, 160, 187, 292 Diabetes Mellitus, 137, 161, 218, 219, 292, 304, 307 Diagnostic procedure, 153, 231, 292 Dialyzer, 292, 307 Diaphragm, 292, 335 Diarrhea, 137, 179, 217, 218, 221, 263, 292, 312, 315, 319 Diarrhoea, 128, 292 Diastolic, 292, 310 Dietitian, 211, 221, 292 Diffusion, 24, 277, 292, 306 Digestion, 62, 174, 269, 276, 277, 279, 292, 303, 312, 313, 316, 317, 331, 349, 355 Digestive system, 152, 183, 220, 292, 303 Digestive tract, 292, 346, 348 Dihydrotestosterone, 292, 341 Dihydroxy, 200, 292 Dilatation, 271, 292, 337, 339, 355 Dilatation, Pathologic, 292, 355 Dilation, 31, 159, 279, 292, 355 Dilator, 292, 326 Dilution, 8, 292 Dimethyl, 34, 292 Diploid, 271, 286, 292, 323, 334, 354 Direct, iii, 9, 15, 22, 30, 57, 155, 235, 284, 292, 293, 341, 350 Discoid, 183, 292 Disinfectant, 293, 298 Disorientation, 287, 293 Dissociation, 268, 293 Distal, 21, 159, 293, 332, 338, 339 Diuresis, 280, 293, 351 Domesticated, 185, 293 Dopa, 293, 316 Dopamine, 162, 176, 270, 285, 291, 293, 316, 333 Dorsal, 159, 293, 298, 325, 336 Dorsum, 159, 293, 302 Dosage Forms, 155, 189, 190, 293 Double-blinded, 44, 58, 293

Doxorubicin, 51, 53, 293 Drug Carriers, 164, 293 Drug Interactions, 236, 294 Drug Tolerance, 294, 353 Drug Toxicity, 151, 164, 294 Duodenum, 276, 294, 302, 314, 349 Dyes, 270, 276, 294, 326 Dyskinesia, 160, 187, 294 Dyspareunia, 159, 294 Dysplasia, 13, 69, 83, 94, 108, 110, 136, 245, 294 Dystrophy, 245, 294 E Eclampsia, 294, 336 Ectoderm, 294, 325 Ectopia Lentis, 168, 208, 294 Edema, 294, 336 Effector, 267, 286, 294, 326, 333 Effector cell, 294, 326 Efficacy, 7, 27, 33, 38, 44, 47, 50, 51, 53, 58, 91, 124, 150, 193, 203, 294, 317 Ego, 294, 327 Ejaculation, 294, 345 Elasticity, 156, 288, 294 Electrolyte, 88, 221, 289, 294, 315, 322, 336, 347 Electrons, 273, 276, 294, 314, 329, 340 Electrophysiological, 6, 295 Embolism, 161, 295 Embolus, 295, 312 Embryo, 9, 19, 20, 123, 173, 278, 282, 294, 295, 300, 304, 312, 321, 329, 348, 355 Embryogenesis, 6, 295 Embryology, 20, 209, 295 Embryonic Induction, 9, 295 Emodin, 269, 295 Emollient, 295, 305, 327 Encapsulated, 295, 317 Encephalocele, 25, 188, 252, 295, 325 Endemic, 217, 220, 295, 319, 348 Endocrine System, 295, 325 Endocrinology, 82, 295, 306 Endocytosis, 49, 164, 295 Endometrial, 54, 124, 295, 329 Endometriosis, 205, 295 Endometrium, 57, 290, 295, 320, 354 Endoscopy, 217, 296 Endothelial cell, 7, 278, 296, 301 Endothelium, 88, 296, 326 Endothelium, Lymphatic, 296 Endothelium, Vascular, 296 Endothelium-derived, 296, 326

Index 365

Endotoxic, 296, 316 Endotoxins, 286, 296, 315 End-stage renal, 6, 284, 296, 335 Energetic, 220, 296 Enhancer, 34, 296 Enteric bacteria, 128, 296 Entorhinal Cortex, 296, 308 Environmental Exposure, 39, 201, 277, 296, 328 Environmental Health, 240, 242, 254, 296 Enzymatic, 7, 21, 29, 33, 34, 46, 171, 195, 280, 281, 286, 296, 308, 321, 330, 342, 356 Enzyme Inhibitors, 296, 334 Eosinophils, 296, 306, 316 Ependymal, 296, 297 Ependymal tumors, 297 Ependymomas, 18, 297 Ephedrine, 203, 297 Epidemic, 4, 101, 133, 297, 348 Epidemiologic Studies, 21, 277, 297 Epidemiological, 20, 36, 48, 297 Epidermal, 189, 297, 316, 320, 357 Epidermal Growth Factor, 189, 297 Epidermis, 206, 288, 297, 309, 316 Epidermoid carcinoma, 297, 348 Epigastric, 297, 330 Epinephrine, 268, 293, 297, 327, 354 Epithelial, 12, 52, 57, 163, 268, 277, 290, 297 Epithelial Cells, 52, 297 Epithelium, 276, 296, 297, 314, 330 Epitope, 52, 297 Erectile, 158, 159, 210, 298, 331 Erection, 159, 298 Ergot, 298, 343 Erythema, 207, 218, 298, 350 Erythema Multiforme, 218, 298 Erythrocyte Membrane, 217, 298 Erythrocytes, 16, 105, 271, 278, 279, 293, 298, 307, 341 Erythropoiesis, 165, 298 Erythropoietin, 216, 298 Esophagus, 275, 292, 298, 303, 333, 349 Essential Tremor, 245, 298 Estradiol, 192, 298 Estriol, 192, 298 Estrogen, 15, 192, 197, 298 Estrogen receptor, 15, 298 Ethanol, 47, 84, 298, 300 Ether, 38, 298 Ethical drug, 194, 298 Ethnic Groups, 17, 38, 298

Excipients, 175, 298 Excitability, 299, 325 Excitation, 299 Excitatory, 299, 304 Excrete, 273, 299, 315 Exercise Test, 299 Exercise Tolerance, 216, 299 Exhaustion, 272, 299, 319 Exocrine, 299, 330 Exogenous, 23, 24, 299, 338, 354 Extensor, 299, 339 Extracellular, 24, 55, 270, 275, 287, 295, 299, 301, 322, 347 Extracellular Matrix, 55, 287, 299, 301 Extracellular Space, 299, 322 Extraction, 25, 299 Extrapyramidal, 293, 299 F Facial, 25, 299, 330 Factor V, 299, 340 Faecal, 292, 299 Fallopian Tubes, 299, 342 Familial polyposis, 286, 299 Family Health, 9, 300 Family Planning, 241, 300 Fat, 14, 40, 160, 187, 210, 211, 218, 221, 222, 232, 233, 234, 276, 277, 279, 281, 288, 289, 295, 300, 304, 316, 317, 321, 329, 335, 343, 344, 347, 348, 350, 352, 354 Fathers, 35, 37, 212, 300 Fatigue, 4, 174, 220, 300, 307, 331 Fatty acids, 15, 165, 194, 206, 218, 220, 269, 300, 305 Febrile, 300, 319, 348 Feces, 16, 299, 300, 349 Fenbendazole, 180, 300 Fermentation, 276, 300 Ferritin, 98, 104, 300 Fertilizers, 162, 300 Fetal Alcohol Syndrome, 213, 300 Fetal Development, 300, 325 Fetal Monitoring, 212, 300 Fetoprotein, 300 Fetus, 35, 55, 219, 269, 278, 298, 300, 334, 336, 348, 355 Fibrinogen, 80, 300, 334, 352 Fibroblast Growth Factor, 189, 300 Fibroblasts, 34, 44, 287, 301 Fibrosis, 200, 245, 301, 344 Filler, 233, 301 Financial Management, 12, 301 Fissure, 284, 286, 291, 301

366 Folic Acid

Fistulas, 26, 301 Flatus, 301, 302 Flexor, 299, 301, 316 Fluorescence, 46, 301 Fluorescence Polarization, 46, 301 Fluorescence Polarization Immunoassay, 46, 301 Fluorouracil, 28, 56, 301 Fold, 27, 30, 44, 50, 301, 321, 337 Foramen, 286, 301, 332 Forearm, 278, 301 Fourth Ventricle, 283, 301 Friction, 302, 318 Frontal Lobe, 272, 282, 302 Fructose, 210, 302 Fungi, 273, 284, 287, 302, 306, 321, 322, 341, 357 Fungus, 298, 302, 343 G Galactosides, 302, 308 Gallbladder, 220, 267, 277, 292, 302, 303 Gamma-Glutamyl Hydrolase, 27, 302 Gamma-Glutamyltransferase, 83, 302 Ganciclovir, 7, 302 Ganglia, 267, 276, 302, 325 Ganglion, 302, 325, 328 Gangrene, 161, 267, 302 Gas, 233, 270, 280, 283, 292, 301, 302, 309, 312, 319, 326, 350, 356 Gastric, 97, 130, 144, 190, 229, 281, 293, 297, 302, 303, 308, 309, 331 Gastric Emptying, 302, 303 Gastrin, 302, 308 Gastritis, 303, 356 Gastroenterology, 97, 217, 218, 303 Gastrointestinal, 100, 168, 218, 219, 220, 222, 274, 279, 297, 298, 303, 315, 319, 345, 349, 354 Gastrointestinal tract, 220, 298, 303, 315, 345, 354 Gastroparesis, 210, 303 Gelatin, 303, 305, 352 Gene Amplification, 44, 303 Gene Expression, 6, 13, 24, 34, 40, 189, 246, 303 Gene Library, 303 Genetic Code, 303, 327 Genetic Counseling, 210, 303 Genetic Engineering, 277, 285, 303 Genetic Markers, 37, 303 Genetic testing, 211, 303

Genetics, 40, 43, 50, 60, 68, 76, 89, 91, 94, 127, 203, 209, 213, 268, 287, 303 Genital, 159, 303, 306, 355 Genomic Library, 25, 303 Genotype, 12, 17, 19, 34, 43, 91, 93, 121, 130, 131, 304, 333 Geriatric, 63, 77, 128, 170, 191, 304 Germ Cells, 304, 320, 329, 347, 348, 351 Germ Layers, 278, 294, 304 Gestation, 121, 304, 332, 334, 348 Gestational, 35, 98, 132, 168, 219, 228, 304 Gestational Age, 35, 168, 304 Giant Cells, 304, 344 Ginger, 173, 304 Ginseng, 158, 194, 210, 304 Gland, 268, 304, 318, 330, 334, 338, 344, 349, 352 Gliadin, 233, 304 Glomerular, 304, 315, 319, 341 Glucocorticoids, 268, 289, 304 Glucose, 22, 210, 219, 245, 274, 278, 282, 284, 292, 304, 307, 313, 344 Glucose Intolerance, 292, 304 Glutamate, 7, 27, 292, 304 Glutamic Acid, 29, 165, 270, 301, 302, 304, 305, 307 Glutamine, 200, 203, 304 Glutathione Peroxidase, 196, 305, 345 Gluten, 217, 218, 220, 221, 232, 233, 281, 304, 305 Glycerol, 305, 333 Glycerophospholipids, 305, 333 Glycine, 17, 23, 123, 162, 163, 276, 277, 305, 345 Glycoprotein, 52, 53, 298, 299, 300, 304, 305 Glycosaminoglycan, 181, 305 Glycosidic, 200, 282, 305, 328 Goats, 184, 290, 305 Governing Board, 305, 336 Gp120, 305, 331 Grade, 45, 204, 305 Graft, 26, 46, 305, 309, 311 Graft Rejection, 305, 311 Graft Survival, 26, 305 Gram-negative, 202, 275, 296, 305, 327 Gram-positive, 202, 305, 327, 349 Granulocytes, 306, 346, 357 Granuloma, 218, 222, 306 Grasses, 284, 301, 306 Gravidity, 306, 330 Growth Disorders, 206, 306

Index 367

Growth factors, 17, 40, 306 Guanylate Cyclase, 306, 326 Gynecology, 55, 67, 68, 86, 90, 94, 108, 110, 128, 159, 306 H Habitat, 180, 306 Habitual, 203, 283, 306 Haematological, 79, 103, 174, 306 Haematology, 306 Haemodialysis, 71, 81, 93, 124, 306 Haploid, 306, 334 Haplotypes, 38, 306 Haptens, 268, 306 Headache, 138, 280, 306, 312 Health Education, 31, 306 Health Status, 300, 307 Heart attack, 160, 168, 179, 187, 190, 206, 227, 280, 307 Heart failure, 205, 297, 307 Heartbeat, 307, 350 Hematocrit, 171, 278, 307 Hematologic Diseases, 170, 171, 194, 195, 307 Heme, 23, 277, 307, 335, 336 Hemodialysis, 26, 71, 74, 94, 100, 104, 110, 112, 133, 150, 206, 223, 233, 292, 307, 315 Hemodilution, 133, 307 Hemoglobin, 31, 171, 217, 271, 278, 298, 307, 336, 351 Hemoglobin C, 31, 271, 307 Hemoglobinuria, 245, 307 Hemolysis, 298, 307 Hemolytic, 217, 222, 271, 307, 351 Hemorrhage, 182, 306, 307, 349 Hemostasis, 307, 345 Hepatic, 190, 199, 269, 307, 336, 346 Hepatitis, 137, 222, 308 Hepatitis A, 222, 308 Hepatocyte, 43, 308 Hepatovirus, 308 Hereditary, 16, 25, 308, 343, 351 Heredity, 201, 267, 303, 308 Heterogeneity, 268, 308 Heterozygotes, 21, 308 Hexosaminidases, 189, 308 Hippocampus, 6, 291, 308, 349 Histamine, 141, 271, 308 Histidine, 163, 200, 308 Histiocytosis, 222, 308 Histology, 12, 308, 330 Homeobox, 24, 308 Homeostasis, 23, 27, 34, 308

Homologous, 13, 20, 21, 51, 269, 289, 307, 308, 323, 345, 350 Homozygotes, 21, 308 Hormonal, 9, 41, 159, 201, 275, 289, 308, 356 Hormone Replacement Therapy, 54, 192, 197, 308 Horny layer, 297, 309 Horseradish Peroxidase, 81, 309 Host, 50, 51, 158, 198, 305, 309, 311, 343, 356 Human Development, 180, 240, 251, 309 Human papillomavirus, 69, 108, 110, 309 Hybrid, 285, 309, 343 Hybridization, 43, 198, 309 Hydrochloric Acid, 169, 180, 193, 309 Hydrogen, 196, 198, 267, 276, 280, 281, 291, 305, 309, 316, 323, 326, 327, 329, 338 Hydrogen Bonding, 198, 309, 327 Hydrogen Peroxide, 196, 281, 305, 309, 316 Hydrolysis, 268, 282, 284, 302, 308, 309, 333, 335, 338 Hydrophilic, 54, 309 Hydrophobic, 305, 309, 317 Hydroxocobalamin, 174, 309 Hydroxylation, 38, 309 Hypercholesterolemia, 14, 48, 137, 206, 309 Hyperhomocysteinemia, 6, 8, 11, 18, 22, 26, 29, 39, 46, 68, 69, 81, 82, 97, 128, 129, 150, 289, 309 Hyperlipidemia, 14, 309 Hyperplasia, 79, 310, 316 Hypersensitivity, 310, 343 Hypertension, 58, 59, 64, 98, 132, 161, 165, 206, 228, 280, 306, 310, 336, 337 Hypertension, Renal, 161, 310 Hypertension, Renovascular, 310 Hyperthyroidism, 218, 310, 337 Hypertrophy, 310 Hypochlorous Acid, 92, 310 Hypoglycemia, 219, 310 Hypotension, 288, 310, 334 Hypothermia, 307, 310 Hypothyroidism, 213, 218, 310 Hypovitaminosis, 96, 310 Hypovolemia, 218, 310 Hypoxanthine, 200, 310, 312 Hysterectomy, 197, 310

368 Folic Acid

I Id, 113, 134, 165, 250, 253, 255, 260, 262, 294, 310 Idiopathic, 81, 128, 217, 310, 344 Ileal, 103, 310 Ileocecal Valve, 218, 310 Ileum, 281, 310, 314 Iliac Artery, 159, 310, 355 Imaging procedures, 310, 353 Imidazole, 270, 278, 308, 311 Immaturity, 168, 311 Immune function, 15, 174, 199, 311 Immune response, 51, 167, 170, 268, 273, 275, 289, 305, 306, 311, 318, 349, 356 Immune system, 40, 51, 166, 167, 277, 294, 311, 318, 332, 355, 357 Immunity, 51, 311 Immunization, 311, 337, 345 Immunodeficiency, 33, 245, 311, 352 Immunodeficiency syndrome, 33, 311 Immunogenic, 311, 316 Immunoglobulin, 272, 311, 323 Immunohistochemistry, 30, 311 Immunologic, 283, 304, 311, 352 Immunology, 40, 167, 268, 309, 311 Immunosuppressant, 269, 301, 311 Immunosuppressive, 183, 184, 311 Immunosuppressive therapy, 311 Immunotherapy, 29, 53, 58, 277, 311 Impairment, 6, 36, 46, 87, 197, 275, 276, 294, 311, 320, 321 Imperforate Anus, 77, 127, 311 Implantation, 287, 311, 329 Impotence, 159, 298, 311 In situ, 7, 311 In vitro, 7, 39, 42, 44, 49, 52, 61, 83, 91, 99, 110, 112, 164, 278, 311, 353 In vivo, 7, 16, 19, 34, 42, 49, 52, 58, 77, 161, 164, 293, 311, 322, 329 Incision, 311, 313 Incontinence, 197, 297, 312 Incontinentia Pigmenti, 43, 312 Indicative, 170, 171, 194, 195, 213, 312, 331, 355 Indigestion, 312, 315 Induction, 30, 42, 52, 56, 271, 312, 346 Infancy, 70, 312, 343 Infant Nutrition, 199, 312 Infant, Newborn, 268, 312 Infarction, 58, 59, 126, 161, 182, 282, 312, 342 Infectious Diarrhea, 179, 312

Infertility, 51, 212, 312 Inflammation, 33, 47, 181, 199, 222, 267, 269, 273, 274, 283, 285, 301, 303, 308, 312, 326, 334, 342, 343, 351, 354 Inflammatory bowel disease, 221, 312 Influenza, 202, 312 Ingestion, 84, 165, 183, 312, 335 Initiation, 161, 312 Inorganic, 279, 284, 312, 314, 323, 333, 357 Inosine Monophosphate, 33, 312 Inositol, 166, 188, 200, 203, 313, 344 Inotropic, 293, 313 Insecticides, 313, 357 Insight, 15, 34, 313 Insomnia, 4, 174, 313 Insulin, 22, 43, 219, 313, 354 Insulin-dependent diabetes mellitus, 313 Insulin-like, 43, 313 Intermittent, 161, 313, 332 Internal Medicine, 10, 47, 64, 105, 171, 214, 216, 295, 303, 313 Interstitial, 299, 313, 314, 341 Intestinal, 62, 78, 87, 103, 163, 169, 188, 217, 221, 275, 281, 313, 319, 356 Intestine, 217, 218, 232, 277, 279, 286, 313, 315, 349 Intoxication, 200, 313, 357 Intracellular, 7, 27, 44, 171, 172, 198, 280, 312, 313, 326, 336, 341, 343, 344, 345, 346 Intrahepatic, 47, 313 Intramuscular, 216, 313, 330 Intravenous, 34, 42, 100, 102, 110, 112, 133, 160, 187, 216, 313, 330 Intrinsic, 10, 207, 268, 276, 313 Introns, 304, 313 Introspection, 212, 313 Invasive, 42, 311, 313, 318 Involuntary, 276, 298, 313, 324, 347 Iodine, 157, 179, 180, 184, 186, 197, 199, 223, 313 Ion Channels, 275, 314, 326, 351 Ionizing, 269, 296, 314 Ions, 156, 185, 276, 293, 294, 309, 314, 347 Iris, 272, 288, 314, 339 Iron Compounds, 157, 186, 314 Irradiation, 279, 286, 314 Ischemia, 33, 275, 314, 342 Ischemic stroke, 82, 314 Isoflavones, 40, 314 Isotretinoin, 202, 314 J Jejunum, 62, 314

Index 369

Joint, 33, 181, 199, 274, 301, 314, 350, 351 Juniper, 173, 314 K Kb, 240, 314 Keto, 24, 315 Ketosteroids, 38, 315 Kidney Disease, 150, 152, 210, 233, 240, 245, 315 Kidney Failure, 223, 296, 315, 319 Kidney Failure, Acute, 315 Kidney Failure, Chronic, 315 Kidney stone, 315, 349 Kinetic, 16, 34, 86, 314, 315 L Labile, 286, 299, 315 Lactation, 199, 219, 315 Lactose Intolerance, 221, 234, 315 Language Disorders, 210, 315 Large Intestine, 281, 286, 292, 310, 313, 315, 341, 346 Latent, 87, 154, 182, 315, 336 Latent period, 154, 182, 315 Laxative, 295, 315, 321 Lens, 294, 316, 342, 357 Lesion, 25, 55, 306, 316, 317, 351 Lethal, 20, 222, 275, 316 Lethargy, 310, 316 Leucovorin, 44, 158, 176, 197, 236, 316 Leukemia, 52, 53, 138, 205, 222, 245, 250, 293, 316 Leukocytes, 93, 276, 278, 279, 283, 296, 306, 316, 323, 326 Leukocytosis, 316, 335 Levodopa, 64, 122, 293, 316 Levorphanol, 292, 316 Library Services, 260, 316 Lichen Planus, 218, 316 Ligament, 316, 338 Ligands, 56, 316 Ligation, 57, 316 Linkage, 13, 198, 282, 302, 303, 316, 339 Lip, 8, 96, 170, 209, 316 Lipase, 316, 330 Lipid, 14, 28, 40, 47, 74, 124, 134, 274, 283, 305, 313, 315, 316, 317, 329, 354, 356 Lipid A, 74, 124, 316 Lipid Peroxidation, 40, 316, 329 Lipopolysaccharides, 316, 317 Lipoprotein, 15, 58, 59, 80, 305, 317, 318, 356 Lipoprotein(a), 80, 317 Liposomal, 49, 52, 53, 317

Liposome, 51, 317 Liver cancer, 269, 317 Liver Extracts, 199, 317 Lobe, 272, 282, 317, 330, 356 Localization, 9, 33, 311, 317 Localized, 33, 41, 88, 159, 271, 295, 312, 316, 317, 334 Locomotion, 317, 334 Longitudinal Studies, 43, 289, 317 Longitudinal study, 133, 317 Long-Term Potentiation, 6, 317 Lovastatin, 317, 346 Low-density lipoprotein, 58, 59, 317, 318 Lubricants, 318, 332 Lubrication, 159, 318 Lumen, 161, 296, 318 Lupus, 183, 318, 351 Lycopene, 40, 41, 177, 178, 318 Lymph, 128, 154, 182, 275, 283, 288, 296, 318, 344, 349 Lymph node, 128, 275, 283, 318, 344 Lymphadenopathy, 154, 182, 318 Lymphatic, 296, 312, 318, 321, 335, 347, 348, 352 Lymphatic system, 318, 347, 348, 352 Lymphocyte, 17, 91, 154, 167, 273, 318, 320 Lymphoid, 272, 318, 352 Lymphoma, 245, 318 Lysine, 56, 307, 318 M Maculopapular, 318, 334 Magnetic Resonance Imaging, 18, 318 Maintenance therapy, 221, 318 Major Histocompatibility Complex, 306, 318 Malabsorption, 87, 96, 169, 217, 218, 219, 232, 245, 281, 319, 346 Malabsorption syndrome, 96, 319, 346 Malaria, 67, 199, 319 Malaria, Falciparum, 319 Malaria, Vivax, 319 Malignancy, 29, 218, 267, 319, 330 Malignant, 49, 57, 83, 95, 184, 245, 268, 273, 286, 308, 317, 319, 321, 323, 325 Malignant mesothelioma, 319, 321 Malignant tumor, 286, 319, 323 Malnutrition, 199, 218, 219, 269, 275, 319, 323 Mammary, 30, 319 Manifest, 218, 319 Mannitol, 319, 341 Mass Media, 60, 319

370 Folic Acid

Meat, 41, 185, 319, 344 Mechlorethamine, 319, 337 Mediate, 44, 52, 53, 293, 294, 319 Mediator, 293, 320, 345 Medical Records, 320, 343 Medical Staff, 293, 320 MEDLINE, 241, 244, 246, 320 Medullary, 292, 320 Megacolon, 221, 320 Megaloblastic, 70, 163, 174, 176, 215, 291, 301, 320 Meiosis, 320, 323, 350 Melanin, 314, 320, 333, 354 Melanocytes, 320 Melanoma, 245, 279, 320 Melanosis, 267, 320 Memory, 4, 6, 272, 291, 317, 320 Meninges, 282, 320 Menopause, 159, 192, 197, 320, 336, 337 Menstrual Cycle, 320, 337 Menstruation, 290, 320 Mental deficiency, 300, 320 Mental Disorders, 152, 194, 320, 337, 339 Mental Health, iv, 5, 152, 240, 243, 320, 337, 339 Mental Retardation, 12, 43, 168, 208, 246, 320 Mesenchymal, 297, 321 Mesenteric, 128, 321 Mesentery, 321, 332 Mesoderm, 321, 354 Mesothelioma, 95, 319, 321 Meta-Analysis, 60, 321 Metabolite, 170, 171, 188, 194, 195, 270, 292, 298, 316, 317, 321, 336, 337 Metastasis, 205, 321 Metastatic, 42, 151, 189, 321, 344 Methionine Adenosyltransferase, 8, 321 Methylcellulose, 190, 321 Methylmalonic Acid, 8, 170, 171, 194, 195, 321 Methylphenidate, 194, 321 Methyltransferase, 38, 173, 321 MI, 79, 156, 161, 202, 212, 265, 321 Microbe, 154, 181, 321, 353 Microbiological, 215, 321 Microbiology, 268, 321 Microcirculation, 307, 322 Microdialysis, 7, 322 Microgram, 178, 184, 322 Micronutrients, 5, 23, 31, 132, 196, 322 Microorganism, 285, 322, 357

Microscopy, 13, 276, 309, 322 Microspheres, 7, 293, 322 Microtubules, 322, 330 Migration, 13, 22, 55, 322 Milligram, 167, 322 Milliliter, 322, 348 Mineralocorticoids, 268, 289, 322 Miscarriage, 77, 91, 138, 211, 212, 228, 229, 250, 251, 322 Mitochondria, 17, 23, 196, 322, 328 Mitochondrial Swelling, 322, 324 Mitosis, 274, 322 Mitotic, 33, 322 Mobilization, 16, 322 Modeling, 86, 323 Modification, 15, 21, 25, 46, 58, 59, 303, 323, 340 Monitor, 74, 289, 323, 327 Monoclonal, 189, 314, 323 Monocytes, 316, 323, 334 Mononuclear, 306, 323 Monophosphate, 158, 189, 312, 323 Monosomy, 271, 323 Morphogenesis, 9, 13, 300, 323 Morphological, 20, 269, 295, 302, 320, 323 Morphology, 12, 175, 306, 323 Motility, 109, 111, 123, 175, 192, 323, 345 Mucosa, 78, 188, 219, 281, 318, 323 Mucus, 323, 354 Multiple Myeloma, 222, 323 Multivalent, 275, 323 Muscle Fibers, 323 Muscle Relaxation, 323 Muscular Atrophy, 245, 323 Muscular Dystrophies, 294, 323 Mutagenesis, 27, 61, 324 Mutagenic, 183, 269, 324 Mutagens, 324 Myalgia, 312, 324 Mydriatic, 292, 324 Myelin, 8, 12, 324 Myelofibrosis, 324, 335 Myeloma, 205, 218, 324 Myeloproliferative Disorders, 218, 324 Myocardial infarction, 30, 58, 59, 108, 111, 126, 161, 206, 272, 288, 321, 324, 337 Myocardial Ischemia, 31, 271, 288, 324 Myocardium, 272, 321, 324 Myotonic Dystrophy, 245, 324 N Narcolepsy, 291, 297, 321, 324 Nasal Mucosa, 312, 324

Index 371

Nausea, 293, 303, 312, 324, 355 NCI, 1, 21, 37, 151, 152, 184, 239, 284, 324 Necrosis, 47, 75, 274, 282, 312, 321, 324, 342, 344 Neonatal, 9, 35, 64, 324 Neonatal Screening, 35, 324 Neoplasia, 18, 42, 149, 245, 325 Neoplasm, 325, 354 Neoplastic, 42, 50, 189, 318, 325 Nephropathy, 315, 325 Nerve, 168, 207, 268, 275, 288, 291, 302, 303, 320, 325, 328, 330, 332, 336, 344, 349, 353 Nervousness, 4, 325 Neural, 4, 7, 9, 11, 13, 16, 17, 20, 22, 24, 25, 32, 35, 40, 44, 54, 60, 62, 64, 66, 68, 70, 76, 77, 80, 83, 86, 87, 91, 92, 95, 104, 108, 110, 112, 121, 122, 126, 127, 128, 129, 130, 132, 134, 161, 163, 168, 170, 187, 188, 190, 211, 213, 214, 228, 230, 250, 252, 253, 254, 270, 295, 300, 325, 347 Neural Crest, 22, 325 Neuroanatomy, 6, 325 Neuroendocrine, 22, 325 Neurofibrils, 155, 325 Neurofilaments, 325 Neurologic, 8, 154, 171, 295, 325 Neuromuscular, 267, 325 Neuromuscular Junction, 267, 325 Neuronal, 13, 174, 325 Neurons, 12, 36, 162, 285, 291, 299, 302, 316, 325, 326, 350 Neuropathy, 3, 93, 325, 332 Neuropeptide, 29, 325 Neuroretinitis, 326, 343 Neurotoxicity, 292, 326 Neurotransmitters, 8, 161, 162, 174, 176, 323, 325, 326 Neutrons, 269, 279, 314, 326, 340 Neutropenia, 222, 326, 334 Neutrophils, 306, 316, 326, 334 Niacin, 62, 157, 169, 180, 183, 184, 186, 193, 199, 200, 203, 210, 222, 223, 326, 354 Niacinamide, 166, 183, 184, 196, 326 Nicotine, 203, 326 Night Blindness, 4, 326 Nitric Oxide, 30, 34, 36, 77, 159, 175, 176, 326 Nitrogen, 36, 50, 269, 271, 305, 315, 326, 354 Nitroglycerin, 77, 326 Nonmalignant, 57, 327

Non-small cell lung cancer, 151, 327 Nonverbal Communication, 327, 339 Norepinephrine, 268, 293, 297, 327 NSAIDs, 143, 221, 327 Nuclear, 9, 18, 91, 276, 285, 287, 295, 302, 324, 327 Nuclei, 269, 272, 287, 294, 303, 313, 318, 322, 326, 327, 328, 338 Nucleic acid, 170, 190, 191, 198, 290, 303, 309, 310, 324, 326, 327, 339, 348 Nucleic Acid Hybridization, 309, 327 Nucleus, 196, 272, 274, 276, 284, 289, 290, 291, 296, 320, 323, 326, 327, 337, 338, 351 Nutritional Status, 31, 167, 220, 230, 327 O Observational study, 11, 327 Obsession, 212, 327 Ocular, 7, 182, 327 Odour, 274, 327 Ofloxacin, 51, 327 Ointments, 233, 293, 327, 330 Oleanolic Acid, 204, 328 Oligosaccharides, 189, 308, 328 Oliguria, 315, 319, 328 Oncogene, 245, 328 Opacity, 291, 328 Opsin, 328, 342 Optic Nerve, 270, 326, 328, 342, 344 Oral Health, 217, 218, 328 Oral Manifestations, 217, 218, 219, 222, 328 Organ Culture, 328, 353 Organelles, 282, 290, 320, 323, 328 Orgasm, 159, 294, 328 Ornithine, 100, 328, 339 Ornithine Decarboxylase, 100, 328 Orofacial, 4, 19, 20, 36, 72, 209, 218, 328 Osmotic, 269, 322, 328 Osseointegration, 278, 328 Osteoarthritis, 205, 328 Osteogenesis, 278, 329 Osteoporosis, 138, 156, 182, 192, 197, 205, 221, 329 Ovaries, 299, 329, 342 Ovary, 41, 57, 288, 298, 329 Overexpress, 33, 42, 49, 52, 329 Overweight, 98, 113, 329 Ovulation, 192, 329 Ovum, 288, 290, 304, 329, 337, 354, 357 Ovum Implantation, 329, 354 Oxazolidinones, 202, 329 Oxidants, 161, 329

372 Folic Acid

Oxidation, 15, 34, 36, 38, 47, 176, 267, 273, 276, 289, 305, 315, 316, 329 Oxidation-Reduction, 329 Oxidative Stress, 14, 329 Oxygenation, 196, 329 Oxytetracycline, 180, 329 P Pacemaker, 329 Paclitaxel, 151, 330 Palate, 9, 96, 170, 209, 284, 330 Palliative, 330, 352 Pancreas, 41, 199, 218, 220, 267, 277, 278, 292, 303, 313, 316, 330, 354 Pancreatic, 245, 281, 330 Pancreatic cancer, 245, 330 Pancreatin, 173, 330 Panic, 212, 330 Papain, 173, 330 Papilla, 206, 330 Papillomavirus, 330 Paraffin, 16, 330 Parasite, 330 Parasitic, 103, 173, 273, 284, 330, 343 Parenteral, 174, 219, 330 Parenteral Nutrition, 219, 330 Parietal, 272, 330, 332, 335 Parity, 67, 124, 330 Parkinsonism, 316, 330 Parotid, 330, 344 Paroxysmal, 245, 271, 331 Partial remission, 331, 341 Particle, 57, 317, 331, 353 Patch, 331, 353 Pathogenesis, 13, 14, 16, 47, 331 Pathologic, 267, 271, 274, 277, 288, 310, 331, 339 Pathologic Processes, 274, 331 Patient Care Team, 210, 331 Patient Education, 252, 258, 260, 265, 331 Pedigree, 25, 331 Pelvic, 51, 138, 159, 222, 295, 331, 338 Pelvic inflammatory disease, 51, 331 Pemoline, 194, 331 Penicillin, 143, 272, 331 Penis, 159, 294, 331, 337, 342 Pepsin, 173, 331 Peptic, 331, 356 Peptic Ulcer, 331, 356 Peptide, 7, 42, 300, 302, 331, 335, 338, 352 Peptide T, 7, 331 Percutaneous, 73, 331 Perforation, 221, 301, 332

Perfusion, 62, 332 Pericardium, 332, 351 Perinatal, 6, 84, 129, 332 Perineal, 159, 332 Perineum, 332 Peripheral blood, 21, 93, 332 Peripheral Neuropathy, 66, 171, 332 Peripheral Vascular Disease, 5, 11, 138, 170, 190, 206, 332 Peritoneal, 53, 223, 233, 332 Peritoneal Cavity, 53, 332 Peritoneal Dialysis, 223, 233, 332 Peritoneum, 53, 321, 332 Pernicious, 65, 79, 168, 207, 217, 222, 317, 320, 332 Pernicious anemia, 79, 168, 207, 222, 317, 332 Peroxide, 196, 332 Petroleum, 330, 332 Phagocyte, 329, 332 Pharmaceutical Preparations, 176, 282, 298, 303, 332, 347 Pharmaceutical Solutions, 293, 333 Pharmacists, 63, 122, 333 Pharmacokinetic, 52, 53, 333 Pharmacologic, 26, 39, 333, 353 Pharynx, 312, 333 Phenotype, 12, 13, 14, 15, 25, 34, 43, 173, 277, 286, 333 Phenylalanine, 161, 176, 333, 354 Phosphates, 169, 193, 333 Phosphodiesterase, 158, 333 Phospholipases, 333, 346 Phospholipids, 8, 174, 300, 313, 317, 333 Phosphorous, 166, 333 Phosphorus, 180, 197, 199, 223, 280, 333 Phosphorylated, 200, 285, 333 Phosphorylation, 33, 200, 333 Photodermatitis, 183, 333 Physical Examination, 304, 333 Physiologic, 5, 9, 16, 34, 173, 269, 277, 293, 300, 320, 322, 333, 341 Physiology, 28, 31, 109, 111, 156, 186, 214, 268, 277, 295, 303, 306, 333 Pigment, 277, 318, 320, 328, 333 Pilot study, 62, 81, 128, 333 Pituitary Gland, 289, 300, 334 Pityriasis, 222, 334 Pityriasis Rosea, 222, 334 Placenta, 67, 168, 298, 334, 337, 355 Plague, 220, 334 Plant Diseases, 296, 334

Index 373

Plaque, 275, 334 Plasma cells, 272, 323, 324, 334 Plasma protein, 199, 269, 296, 334 Plasmid, 303, 334, 355 Plasticity, 6, 307, 334 Platelet Activating Factor, 15, 334 Platelet Activation, 334, 346 Platelet Aggregation, 271, 326, 334 Platelets, 326, 334, 335, 352 Platinum, 284, 335 Pleura, 335 Pleural, 95, 335 Plexus, 335 Poisoning, 294, 298, 313, 324, 335 Polycystic, 233, 245, 335 Polycythemia Vera, 222, 335 Polyethylene, 49, 335 Polymers, 293, 335, 338 Polymorphic, 37, 291, 335 Polymorphism, 16, 17, 21, 24, 29, 35, 74, 91, 99, 335 Polypeptide, 56, 270, 285, 297, 300, 309, 335, 351, 352 Polyposis, 286, 335 Polysaccharide, 190, 273, 282, 305, 335 Polyunsaturated fat, 176, 335 Porphyria, 218, 335 Porphyrins, 335, 336 Posterior, 188, 271, 275, 283, 293, 314, 330, 336, 344 Postmenopausal, 15, 90, 329, 336 Postnatal, 300, 336, 348 Postsynaptic, 336, 346, 350, 351 Post-translational, 189, 336 Potassium, 115, 156, 166, 180, 185, 186, 199, 210, 218, 233, 322, 336 Potentiating, 162, 336 Potentiation, 317, 336, 346 Practice Guidelines, 243, 253, 336 Pravastatin, 206, 336 Precancerous, 283, 336 Predisposition, 25, 336 Prednisone, 336, 337 Preeclampsia, 64, 138, 336 Pregnancy Tests, 304, 336 Prenatal, 6, 13, 35, 69, 132, 212, 213, 219, 250, 295, 300, 336 Prepuce, 159, 337 Prevalence, 6, 15, 32, 35, 95, 110, 112, 134, 229, 337 Primary endpoint, 26, 34, 58, 337 Primary Prevention, 48, 95, 132, 337

Probe, 7, 42, 322, 337 Procarbazine, 132, 337 Prodrug, 7, 337 Progeny, 287, 337 Progesterone, 192, 337, 349 Progression, 16, 26, 34, 38, 48, 154, 160, 182, 187, 272, 337, 354 Progressive, 161, 282, 284, 291, 294, 306, 315, 323, 324, 334, 337, 341, 354 Promoter, 15, 24, 34, 337 Prone, 13, 203, 337 Prophase, 323, 337, 350 Prophylaxis, 26, 67, 154, 182, 207, 337, 343 Proportional, 44, 303, 337 Propranolol, 63, 337 Prospective Studies, 41, 337 Prospective study, 317, 337 Prostate, 29, 39, 41, 245, 277, 338, 342, 354 Protease, 330, 338 Protein Binding, 158, 198, 338 Protein C, 269, 270, 274, 300, 304, 317, 338, 355 Protein S, 165, 190, 198, 215, 246, 278, 303, 338, 343, 351 Proteinuria, 323, 336, 338 Proteolytic, 143, 286, 300, 330, 338 Protocol, 102, 151, 337, 338 Protons, 269, 309, 314, 338, 340 Proto-Oncogene Proteins, 330, 338 Proto-Oncogene Proteins c-mos, 330, 338 Protozoa, 287, 321, 322, 338 Protozoal, 125, 338 Proximal, 62, 159, 293, 338 Pruritic, 316, 338 Psoriasis, 138, 176, 222, 338, 343 Psychiatric, 155, 174, 277, 320, 339 Psychiatry, 64, 65, 77, 122, 128, 214, 339 Psychic, 339, 345 Psychomotor, 280, 295, 339 Psychotherapy, 203, 339 Pteroylpolyglutamic Acids, 302, 339 Public Policy, 241, 339 Publishing, 60, 210, 220, 339 Pulmonary, 55, 205, 278, 283, 287, 299, 315, 339, 350, 356 Pulmonary Artery, 278, 339, 356 Pulmonary Edema, 283, 315, 339 Pulmonary Emphysema, 205, 339 Pulse, 4, 323, 339 Pupil, 288, 292, 324, 339 Purines, 23, 200, 339, 345 Putrefaction, 302, 339

374 Folic Acid

Putrescine, 328, 339, 348 Pyridoxal, 171, 172, 195, 205, 289, 328, 339, 340 Pyridoxal Phosphate, 171, 195, 289, 340 Q Quality of Life, 3, 10, 340 R Race, 38, 293, 322, 340 Radiation, 184, 272, 296, 301, 314, 340, 350, 357 Radioactive, 16, 309, 311, 314, 327, 340 Radiography, 304, 340 Radioisotope, 340, 353 Radiolabeled, 42, 314, 340 Radiological, 18, 331, 340 Radiopharmaceutical, 42, 340 Raltitrexed, 56, 340 Random Allocation, 340 Randomization, 5, 46, 58, 59, 340 Randomized, 5, 11, 14, 21, 26, 34, 42, 44, 46, 49, 57, 58, 59, 62, 69, 72, 73, 80, 88, 89, 91, 108, 111, 122, 130, 150, 178, 294, 340 Randomized clinical trial, 11, 21, 58, 80, 150, 340 Reactive Oxygen Species, 23, 340 Reagent, 38, 283, 309, 340 Receptors, Serotonin, 341, 345 Recombinant, 13, 44, 47, 341, 355 Recombination, 20, 51, 287, 303, 341 Rectal, 14, 150, 341 Rectum, 41, 273, 279, 286, 292, 299, 301, 302, 312, 315, 338, 341 Recurrence, 20, 24, 39, 42, 149, 150, 227, 283, 341 Red blood cells, 88, 171, 298, 307, 341, 344 Red Nucleus, 275, 341 Refer, 1, 177, 183, 279, 286, 302, 317, 318, 326, 341 Reference point, 16, 341 Refraction, 272, 341, 347 Refractive Errors, 270, 341 Refractory, 52, 341 Regeneration, 301, 341 Regimen, 284, 294, 341 Reishi, 177, 178, 194, 341 Relapse, 41, 341 Relaxation Techniques, 212, 341 Remission, 221, 318, 341 Renal Artery, 310, 341 Renal failure, 8, 28, 72, 161, 216, 341 Renin, 205, 272, 342

Renin-Angiotensin System, 205, 342 Reperfusion, 33, 342 Reperfusion Injury, 342 Reproductive system, 192, 342 Research Design, 19, 23, 342 Resected, 218, 342 Resection, 218, 342, 346 Resident physician, 18, 342 Resolving, 201, 342 Response rate, 242, 342 Restoration, 342, 352, 357 Retina, 7, 93, 283, 287, 316, 326, 328, 342, 343, 357 Retinal, 7, 328, 342 Retinitis, 7, 342 Retinoblastoma, 245, 343 Retinoids, 343, 356 Retinol, 223, 342, 343 Retrospective, 60, 92, 343 Retrospective study, 60, 92, 343 Rheumatism, 125, 343 Rheumatoid, 32, 72, 80, 82, 125, 128, 176, 205, 329, 343 Rheumatoid arthritis, 32, 72, 80, 82, 125, 128, 176, 205, 343 Rhinitis, 297, 343 Riboflavin, 62, 127, 180, 196, 197, 199, 200, 201, 203, 210, 218, 219, 222, 223, 343 Ribose, 199, 200, 268, 343 Ribosome, 343, 353 Rickets, 343, 356 Rickettsiae, 343 Rigidity, 330, 334, 343 Rod, 275, 343 Rye, 217, 221, 232, 284, 298, 304, 343 S Salivary, 290, 292, 330, 344, 349 Salivary glands, 290, 292, 344 Saponins, 328, 344, 349 Sarcoidosis, 218, 344 Saturated fat, 210, 344 Schizoid, 344, 357 Schizophrenia, 139, 344, 357 Schizotypal Personality Disorder, 344, 357 Sclera, 283, 287, 344 Sclerosis, 36, 245, 344 Screening, 5, 19, 25, 42, 47, 58, 59, 213, 284, 324, 344 Second Messenger Systems, 326, 344 Secondary tumor, 321, 344 Secretion, 144, 199, 267, 289, 297, 304, 308, 310, 313, 315, 322, 323, 344, 345, 355

Index 375

Secretory, 345, 350, 356 Sedentary, 206, 345 Segregation, 341, 345 Seizures, 161, 280, 331, 345 Selenium, 41, 166, 167, 174, 177, 180, 192, 194, 196, 197, 223, 345, 347 Sella, 293, 334, 345 Semen, 175, 294, 338, 345 Senile, 329, 345 Senility, 162, 345 Sepsis, 199, 345 Sequence Analysis, 25, 345 Sequence Homology, 331, 345 Sequencing, 13, 38, 345 Serine, 17, 23, 171, 172, 195, 203, 289, 338, 345 Seroconversion, 154, 182, 345 Serologic, 345 Serotonin, 162, 168, 176, 267, 341, 345, 354 Serous, 296, 335, 345 Sex Determination, 245, 345 Sharpness, 197, 346 Shock, 310, 346, 354 Short Bowel Syndrome, 218, 346 Side effect, 29, 38, 51, 53, 151, 158, 160, 174, 187, 194, 197, 202, 235, 268, 277, 346, 353 Sigmoid, 346 Sigmoidoscopy, 15, 346 Signal Transduction, 6, 40, 313, 346 Signs and Symptoms, 341, 346 Simvastatin, 62, 346 Single-agent, 57, 346 Skeletal, 271, 306, 323, 346, 347 Skeleton, 188, 314, 315, 346 Skull, 295, 325, 346, 351 Small cell lung cancer, 151, 346 Small intestine, 183, 188, 217, 218, 232, 277, 281, 284, 294, 308, 310, 313, 314, 346, 356 Smooth muscle, 75, 271, 280, 287, 308, 326, 342, 346, 347, 349 Social Environment, 48, 340, 346 Sodium, 109, 111, 115, 121, 166, 169, 180, 193, 199, 210, 211, 322, 347, 355 Sodium Benzoate, 166, 347 Sodium Channels, 347, 355 Sodium Selenite, 109, 111, 347 Soft tissue, 279, 346, 347 Solar radiation, 207, 347 Solid tumor, 151, 272, 293, 347

Solvent, 154, 181, 204, 276, 298, 305, 328, 333, 347 Soma, 347 Somatic, 14, 295, 320, 322, 332, 347 Somatic mutations, 14, 347 Soybean Oil, 335, 347 Spasm, 288, 347 Specialist, 255, 292, 347 Specificity, 18, 34, 46, 52, 164, 268, 347 Spectrum, 25, 43, 184, 289, 347 Sperm, 175, 192, 229, 271, 284, 347, 348 Sperm Count, 175, 192, 229, 348 Spermatozoa, 345, 348 Spermidine, 328, 348 Spices, 233, 348 Spina bifida, 4, 25, 54, 69, 79, 101, 125, 133, 188, 190, 252, 254, 325, 348 Spinal cord, 25, 275, 279, 282, 283, 296, 297, 302, 320, 325, 348 Spinous, 297, 348 Spleen, 271, 290, 318, 335, 344, 348 Splenomegaly, 335, 348 Spontaneous Abortion, 139, 219, 348 Sporadic, 203, 343, 348 Sprue, 4, 217, 233, 348 Squamous, 49, 151, 297, 327, 348 Squamous cell carcinoma, 49, 297, 327, 348 Squamous cells, 348 Stabilization, 56, 348 Steatorrhea, 217, 348 Stem Cells, 20, 52, 298, 348 Sterile, 154, 181, 348 Sterility, 312, 348 Steroid, 277, 289, 315, 344, 346, 348 Stimulant, 166, 174, 270, 280, 291, 308, 321, 331, 349 Stimulus, 270, 287, 294, 299, 314, 349, 352 Stomach, 100, 218, 229, 267, 292, 298, 302, 303, 308, 324, 331, 332, 333, 346, 348, 349 Stool, 312, 315, 348, 349 Streptococci, 202, 349 Streptococcus, 211, 349 Stress, 15, 22, 31, 36, 44, 123, 177, 201, 212, 220, 281, 289, 324, 329, 336, 343, 349 Stroke, 46, 58, 70, 89, 139, 152, 155, 161, 179, 190, 206, 240, 251, 280, 314, 349 Stromal, 295, 349 Structure-Activity Relationship, 42, 349 Struvite, 169, 193, 349 Subacute, 312, 349 Subclinical, 49, 312, 345, 349

376 Folic Acid

Subcutaneous, 294, 330, 349 Subiculum, 308, 349 Submaxillary, 297, 349 Subspecies, 347, 349 Substance P, 321, 344, 349 Substrate, 7, 26, 30, 33, 296, 350 Substrate Specificity, 7, 33, 350 Sudden death, 161, 350 Sulfur, 180, 321, 350 Sunburn, 207, 350 Superoxide, 176, 196, 350 Superstitions, 212, 350 Suppression, 289, 291, 350 Surfactant, 154, 181, 350 Suspensions, 162, 350 Sympathomimetic, 270, 291, 293, 297, 327, 350 Symphysis, 338, 350 Symptomatic, 154, 182, 350 Synapses, 317, 326, 350 Synapsis, 350 Synaptic, 6, 317, 326, 346, 350 Synaptic Transmission, 326, 350 Synergistic, 160, 187, 203, 351 Systemic, 87, 155, 205, 206, 217, 218, 222, 236, 271, 274, 278, 297, 312, 314, 334, 344, 351 Systemic disease, 217, 218, 222, 351 Systemic lupus erythematosus, 87, 205, 206, 351 Systolic, 310, 351 T Tardive, 160, 187, 351 Taurine, 161, 172, 203, 277, 351 Telangiectasia, 245, 351 Temporal, 9, 13, 108, 111, 123, 308, 351 Teratogen, 40, 55, 351 Teratogenic, 20, 22, 35, 40, 132, 269, 270, 314, 351 Testicular, 157, 351 Testis, 298, 351 Testosterone, 341, 351 Tetracycline, 144, 183, 351 Thalamic, 275, 351 Thalamic Diseases, 275, 351 Thalassemia, 90, 351 Theophylline, 339, 351 Therapeutics, 58, 65, 236, 352 Thiamine, 180, 196, 199, 200, 210, 223, 352 Threonine, 162, 172, 331, 338, 345, 352 Threshold, 299, 310, 352 Thrombin, 299, 300, 335, 338, 352

Thrombocytopenia, 222, 334, 352 Thrombosis, 26, 75, 88, 97, 102, 124, 161, 338, 349, 352 Thrombus, 288, 312, 314, 324, 335, 352 Thymosin, 201, 352 Thymus, 83, 311, 318, 352 Thymus Gland, 352 Thyroid, 310, 313, 352, 354 Thyroid Gland, 310, 352 Thyrotropin, 310, 352 Thyroxine, 269, 333, 352 Tin, 332, 335, 352 Tissue Culture, 44, 352 Tolerance, 73, 77, 163, 194, 268, 304, 353 Tomography, 30, 353 Topical, 182, 183, 201, 298, 309, 314, 330, 353 Torsion, 312, 353 Toxaemia, 336, 353 Toxicity, 18, 38, 50, 176, 196, 293, 294, 295, 353 Toxicology, 76, 102, 109, 111, 242, 353 Toxins, 199, 270, 273, 296, 312, 353 Trace element, 220, 223, 279, 284, 285, 347, 352, 353 Tracer, 16, 42, 309, 353 Transdermal, 192, 353 Transduction, 346, 353 Transfection, 28, 277, 353 Transfusion, 353 Translating, 210, 353 Translation, 44, 353 Translational, 33, 353 Translocation, 33, 128, 353 Transmitter, 267, 275, 293, 314, 320, 327, 350, 353 Transplantation, 10, 71, 73, 81, 93, 125, 150, 284, 311, 315, 318, 353 Trauma, 199, 276, 306, 324, 351, 354 Triglyceride, 166, 354 Trimethoprim-sulfamethoxazole, 176, 354 Trisomy, 271, 354 Trophic, 12, 354 Trophoblast, 67, 278, 354 Tryptophan, 162, 176, 285, 345, 354 Tuberculosis, 202, 287, 318, 354 Tuberous Sclerosis, 245, 354 Tumor marker, 57, 277, 354 Tumor model, 19, 42, 52, 53, 58, 354 Tumor suppressor gene, 15, 354 Tumour, 158, 198, 273, 302, 354 Type 2 diabetes, 82, 219, 354

Index 377

Tyrosine, 142, 162, 176, 194, 203, 293, 354 U Ulcerative colitis, 221, 222, 286, 312, 354 Ultrasonography, 304, 354 Umbilical Arteries, 355 Umbilical Cord, 211, 355 Unconscious, 310, 355 Uracil, 21, 91, 200, 355 Urea, 200, 315, 328, 355 Uremia, 216, 315, 341, 355 Urethane, 40, 355 Urethra, 331, 338, 355 Urinary, 17, 33, 80, 84, 86, 197, 297, 312, 328, 355, 357 Urine, 8, 16, 39, 168, 208, 273, 278, 289, 293, 297, 298, 307, 312, 315, 328, 338, 343, 355 Urogenital, 275, 355 Uterus, 159, 283, 288, 290, 295, 299, 310, 320, 329, 337, 342, 355 V Vaccine, 268, 338, 355 Vacuoles, 295, 328, 355 Vagina, 159, 283, 320, 342, 355 Vaginal, 159, 318, 355 Valproic Acid, 40, 145, 355 Vascular, 10, 11, 15, 26, 28, 31, 34, 39, 45, 46, 49, 71, 74, 75, 83, 88, 97, 102, 128, 150, 160, 161, 170, 171, 174, 183, 187, 194, 195, 199, 283, 296, 309, 312, 322, 326, 334, 352, 355 Vasodilation, 30, 88, 159, 355 Vasodilator, 279, 293, 308, 355 Vector, 51, 353, 355 Vein, 271, 313, 327, 331, 355 Venous, 37, 55, 73, 159, 168, 278, 282, 326, 338, 355, 356 Venous blood, 37, 278, 282, 356 Ventricle, 55, 274, 308, 339, 351, 356 Venules, 278, 296, 322, 356 Vertebrae, 348, 356 Vertebral, 276, 348, 356 Very low-density lipoprotein, 14, 356

Veterinary Medicine, 41, 241, 300, 356 Villi, 217, 356 Villous, 217, 281, 283, 356 Vincristine, 337, 356 Viral, 7, 154, 178, 182, 184, 211, 304, 312, 353, 356, 357 Viremia, 154, 356 Virulence, 275, 353, 356 Virus, 154, 181, 182, 185, 296, 303, 304, 305, 309, 334, 353, 356 Viscera, 321, 347, 356 Visceral, 332, 356 Visual Cortex, 270, 356 Vital Statistics, 278, 356 Vitamin A, 57, 70, 157, 160, 161, 169, 180, 193, 197, 219, 313, 343, 356 Vitamin D, 8, 49, 165, 166, 167, 170, 171, 174, 180, 194, 195, 197, 219, 343, 356 Vitamin K, 27, 197, 356 Vitamin U, 10, 242, 356 Vitreous Body, 283, 342, 357 Vitro, 7, 42, 50, 357 Vivo, 7, 16, 19, 42, 50, 52, 58, 158, 198, 357 W Warts, 139, 309, 357 Weight Gain, 197, 212, 217, 219, 357 Weight-Bearing, 328, 357 White blood cell, 272, 316, 318, 323, 324, 326, 334, 357 Withdrawal, 84, 104, 203, 217, 357 Womb, 342, 355, 357 Wound Healing, 301, 357 X Xanthine, 105, 200, 357 Xenobiotics, 23, 357 Xenograft, 272, 354, 357 X-ray, 28, 274, 301, 314, 327, 357 Y Yeasts, 302, 333, 357 Z Zinc Compounds, 157, 186, 357 Zygote, 173, 287, 357

378 Folic Acid

Index 379

380 Folic Acid