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

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

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

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

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

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on 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.

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

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

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON 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

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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

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with 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

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

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CHAPTER 1. STUDIES ON 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.

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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.

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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.

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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).

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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).

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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

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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

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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

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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

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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

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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,

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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

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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

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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

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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

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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

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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),

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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-

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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.

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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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

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

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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.

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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]

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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

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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

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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

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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

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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

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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

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

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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

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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

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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

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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

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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

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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

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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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/

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

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

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

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

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

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

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

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

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

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

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

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

The following is a specific Web list relating to 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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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

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CHAPTER 5. CLINICAL TRIALS AND 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.

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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

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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

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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

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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.

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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/

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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CHAPTER 6. PATENTS ON 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