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

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

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

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

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Preeclampsia: 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: 0-597-84557-3 1. Preeclampsia-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 preeclampsia. 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 PREECLAMPSIA ......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Preeclampsia ................................................................................. 4 E-Journals: PubMed Central ....................................................................................................... 63 The National Library of Medicine: PubMed ................................................................................ 63 CHAPTER 2. NUTRITION AND PREECLAMPSIA ............................................................................. 109 Overview.................................................................................................................................... 109 Finding Nutrition Studies on Preeclampsia .............................................................................. 109 Federal Resources on Nutrition ................................................................................................. 114 Additional Web Resources ......................................................................................................... 115 CHAPTER 3. DISSERTATIONS ON PREECLAMPSIA ......................................................................... 117 Overview.................................................................................................................................... 117 Dissertations on Preeclampsia ................................................................................................... 117 Keeping Current ........................................................................................................................ 118 CHAPTER 4. CLINICAL TRIALS AND PREECLAMPSIA .................................................................... 119 Overview.................................................................................................................................... 119 Recent Trials on Preeclampsia ................................................................................................... 119 Keeping Current on Clinical Trials ........................................................................................... 120 CHAPTER 5. PATENTS ON PREECLAMPSIA .................................................................................... 123 Overview.................................................................................................................................... 123 Patents on Preeclampsia ............................................................................................................ 123 Patent Applications on Preeclampsia......................................................................................... 147 Keeping Current ........................................................................................................................ 154 CHAPTER 6. BOOKS ON PREECLAMPSIA........................................................................................ 157 Overview.................................................................................................................................... 157 Book Summaries: Online Booksellers......................................................................................... 157 Chapters on Preeclampsia .......................................................................................................... 157 CHAPTER 7. PERIODICALS AND NEWS ON PREECLAMPSIA .......................................................... 159 Overview.................................................................................................................................... 159 News Services and Press Releases.............................................................................................. 159 Newsletter Articles .................................................................................................................... 164 Academic Periodicals covering Preeclampsia............................................................................. 165 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 167 Overview.................................................................................................................................... 167 U.S. Pharmacopeia..................................................................................................................... 167 Commercial Databases ............................................................................................................... 168 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 171 Overview.................................................................................................................................... 171 NIH Guidelines.......................................................................................................................... 171 NIH Databases........................................................................................................................... 173 Other Commercial Databases..................................................................................................... 175 The Genome Project and Preeclampsia ...................................................................................... 175 APPENDIX B. PATIENT RESOURCES ............................................................................................... 179 Overview.................................................................................................................................... 179 Patient Guideline Sources.......................................................................................................... 179 Finding Associations.................................................................................................................. 184 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 187 Overview.................................................................................................................................... 187 Preparation................................................................................................................................. 187

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Finding a Local Medical Library................................................................................................ 187 Medical Libraries in the U.S. and Canada ................................................................................. 187 ONLINE GLOSSARIES................................................................................................................ 193 Online Dictionary Directories ................................................................................................... 197 PREECLAMPSIA DICTIONARY ............................................................................................... 199 INDEX .............................................................................................................................................. 283

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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 preeclampsia 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 preeclampsia, 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 preeclampsia, 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 preeclampsia. 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 preeclampsia, 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 preeclampsia. The Editors

1

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

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

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

Preeclampsia and Postpartum Renal Failure: Examples of Pregnancy-Induced Microangiopathy (editorial) Source: American Journal of Medicine. 99(4): 343-347. October 1995. Summary: In this editorial, the author discusses examples of pregnancy-induced microangiopathy. The author hypothesizes that, since pregnancy predisposes women to microangiopathy, the changes in endothelial cell function associated with pregnancy, as well as the alterations that develop with preeclampsia, might provide insight into potential mechanisms of the disease. Topics include endothelial function in pregnancy and in preeclampsia; the role of uteroplacental ischemia in preeclampsia; the differentiation of preeclampsia from gestational hypertension; and postpartum renal failure. 1 table. 56 references.

4

Preeclampsia

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

Project Title: 2002 MYOGENIC CENTENNIAL CONFERENCE Principal Investigator & Institution: Osol, George J.; Professor; Obstetrics and Gynecology; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2003 Summary: (provided by applicant): The Myogenic Centennial Conference will be held in Burlington, Vermont on September 11-15, 2002. From a historical standpoint, this meeting will commemorate the 100th anniversary of the publication of Sir William Bayliss' classic 1902 paper that first described the vascular myogenic response, a physiologic phenomenon that is integral to the control of basal vascular tone, peripheral resistance, blood pressure and blood flow autoregulation. Defined most simply as the intrinsic ability of vascular smooth muscle to generate force in response to intravascular pressure, the physiological importance of this fundamental property - which has been described in arteries, arterioles, veins and lymphatics is well-established. As such, myogenic behavior has a broad impact on vascular physiology (e.g. developmental and age-related changes, gender differences, pregnancy) and pathology (atherosclerosis, diabetes, hypertension, preeclampsia, stroke) and would be of interest to several institutes, e.g. NINDS, NIGMS, and NHLBI. The format of the conference is detailed in the Research Plan, and will include an opening lecture, 24 oral presentations by established scientists that will serve to highlight current knowledge on key issues, two poster discussion sessions that will parallel the themes of the oral sessions and explore some of the more controversial issues and allow younger investigators to present and articulate their work, and two workshops designed to stimulate discussion about the most intriguing new observations and explore the most puzzling and provocative issues relevant to vascular myogenic behavior. The meeting will attract 100-120 attendees, utilizes a format designed to encourage active participation, and includes ample time for discussion in both the group and individual settings. A process has been set up by which information presented at the meeting will be used as a substrate for identifying areas of controversy and future directions in research, and for generating questions that

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).

Studies

5

will be addressed in the workshops. The principal goals are to bring historical and physiological antecedents together in a unique and forward-looking conference focused on: (1) updating and integrating our knowledge about the vascular myogenic behavior in light of recent advances in molecular genetics and imaging technology, and (2) catalyzing future collaboration and communication between younger investigators and established scientists. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: 20-HETE AND ITS INTERACTION WITH NO IN PREGNANT RATS Principal Investigator & Institution: Wang, Mong-Heng; Pharmacology; New York Medical College Valhalla, Ny 10595 Timing: Fiscal Year 2002; Project Start 19-JUL-2002; Project End 30-NOV-2002 Summary: (provided by applicant): This is a proposal to investigate the mechanisms regulating renal vascular and tubular (medullary thick ascending limb; mTAL) synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) during pregnancy. 20-HETE is a major cytochrome P450 (CYP) 4A-derived eicosanoid in the rat kidney whose potent effects on vascular tone and tubular ion transport implicate it in the regulation of renal function and in the control of blood pressure. Normal pregnancy in humans and rats is associated with increases in the glomerular filtration rate and renal blood flow along with a significant decrease in arterial pressure and total peripheral resistance. The exact mechanisms mediating these physiological changes are not fully understood. Preliminary studies demonstrated distinct patterns of CYP4A isoform expression and 20-HETE synthesis in renal microvessels and mTAL during pregnancy and a transient reduction in systolic blood pressure and urinary sodium excretion following administration of an inhibitor of 20-HETE synthesis in pregnant rats. We hypothesize that renal 20-HETE synthesis is affected during gestation and that 20-HETE is involved in the regulation of renal function and blood pressure during pregnancy. Experiments will be performed in Aim 1 to characterize vascular and mTAL 20-HETE synthesis and CYP4A expression in pregnant rats at different gestational days, and in Aim 2 to determine the consequence of inhibition and over-expression of CYP4A proteins in pregnant rats on renal 20-HETE synthesis, vascular reactivity, mTAL potassium channel activity, urinary electrolyte levels, and blood pressure. It has been shown that nitric oxide (NO) inhibits CYP4A activity and expression; inhibition of its production results in signs similar to preeclampsia. Experiments in Aims 3 and 4 will examine the possibility that NO presents a mechanism that regulates CYP4A expression and 20HETE synthesis during pregnancy. The present proposal sets the basis for understanding mechanisms that regulate 20-HETE synthesis in the kidney during pregnancy. Ultimately, this knowledge can uncover new therapeutic targets and provide novel loci for the control and treatment of pregnancy-induced hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ACTIONS OF ESTROGEN IN UTERINE ARTERY ENDOTHELIUM Principal Investigator & Institution: Chen, Dongbao; Reproductive Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 25-SEP-2001; Project End 31-AUG-2005 Summary: The overall hypothesis of this grant is that acute (less than 120 min) actions of estrogen on UA endothelial cells (UAEC) upon binding to membrane estrogen receptor (ER) lead to eNOS phosphorylation and dissociation from caveolin-1 as well as association with heat shock protein 90 (HSP90) thereby increasing eNOS activity directly

6

Preeclampsia

and/or indirectly via the mitogen- activated protein kinase (MAPK) pathway. Whereas, chronic (greater than 2hr) estrogen actions on UAEC result in down- regulation of UA endothelial caveoln-1 expression, and this is ER-mediated and at least in part through membrane ER-mediated activation of MAPK which translocates into the nucleus to stimulate the AP-1 transcription factors thereby inhibiting caveolin-1 expression. Furthermore, there are direct relationships between changes in caveolin-1 HSP90 associated eNOS and caveolin-1 levels in UA endothelium and rises in UBF during the estrous cycle and ERT and pregnancy. To address this hypothesis, the following specific aims will be studied using sheep UA endothelium as the experimental target. Specific aim 1: to further characterize activation of extracellular signal- regulated kinases (ERK2/1) and other MAPK family members (JNK, p38mapk, and ERK5) by estrogen and to determine the membrane ER- initiated signaling that results in ERK activation in response to estrogen and the membrane impermeable E2b-BSA in UAEC. Specific aim 2: to establish the time- and dose-dependency of estrogen stimulated eNOS activity, NO production, eNOS phosphorylation and dissociation from caveolin-1 as well as association with HSP90 in UAEC. Specific aim 3: to establish if estrogen stimulation of NO production in UAEC is through MAPK phosphorylation of eNOS and eNOS dissociation from caveolin-1 and association with HSP90 via the MAPK pathway. Specific aim 4: to establish in UAEC if estrogen activated MAPK translocates into the nucleus to stimulate the AP-1 (Fos/Jun dimers) transcription factors thereby downregulating caveolin-1 expression, and if down-regulation of caveolin-1 is associated with reduced or lost of caveolae. Specific aim 5: to establish if the amounts of UA endothelial caveolin-1/HSP90 associated eNOS changes in vivo during short- term (0-120 min) ERT, and UA endothelial caveolin-1 expression is altered in vivo during long-term (days) ERT, ovarian cycle, and pregnancy, and if these changes are associated with rises in UBF. UBF increases substantially during pregnancy in order to provide sufficient oxygen and nutrient supply for the development of the growing fetus. Insufficient blood supply during pregnancy can result in IUGR, preeclampsia, and decreased neonatal birthweight, which in turn inversely correlates to neonatal morbidity. Thus, this grant application will provide important clinical implications in perinatal healthcare. It may also have relevant implications in the systemic cardiovascular system since estrogen is believed to be the major reason that young women have lower risk in cardiovascular diseases than men. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTION

ALTITUDE-INDUCED

HYPOXIA,

IUGR

AND

PLACENTAL

Principal Investigator & Institution: Zamudio, Stacy A.; Ob/Gyn & Women's Health; Univ of Med/Dent Nj Newark Newark, Nj 07103 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-MAY-2007 Summary: (provided by applicant): We seek to develop and characterize the world's only in-vivo model of human placentation under conditions of chronic hypoxia. Using the unique model of high altitude human pregnancy, the goal of this project is to examine the pathways by which hypoxia, in the absence of pathology, influences placental development and results in adaptation (i.e. normal growth) or fetal growth restriction. In vitro experiments show that oxygen plays a crucial role in early placental development and that both oxygen tension and the time at which it increases are key factors in determining the success of placentation. This data and clinical observations make it clear that hypoxia plays a major role in those pathologies involving abnormalities of placental development, such as intrauterine growth restriction and

Studies

7

preeclampsia. Unfortunately, hypoxia is inevitably intertwined with under- or overlying pathologies and thus it has not been possible to investigate the role of hypoxia in placental development in vivo in the absence of pathology. We predict that the initial effect of chronic maternal hypoxia due to high altitude residence (3600 m) is reduction in trophoblast invasion of uteroplacental arteries, leading to a reduction in uteroplacental blood flow. Subsequent to this, our preliminary data suggest that there are two primary placental responses. The first is an up regulation of angiogenesis reflected in greater placental capillary density and increased release of angiogenic growth factors. The second is a decrease in placental nutrient transport and a consequent down-regulation of fetal growth and placental nutrient transport capacity. The aims of the project are to investigate these responses by determining whether, in high vs. low altitude pregnancy 1) there are increased circulating and placental markers of hypoxia, correlated with reduced trophoblast invasion and uteroplacental blood flow; 2) an increased angiogenic response, as evidenced by placental morphologic changes and increases in circulating and placental angiogenic growth factors, and 3) decreased nutrient transfer, decreased circulating growth factors and reduced placental nutrient transporter capacity. Gene array is used across all 3 aims to investigate 4 groups of specifically targeted and functionally essential genes 1) hypoxia-responsive genes, 2) gene markers of trophoblast invasion, 3) markers of angiogenesis and 4) nutrient transporters and transport regulators. This model will permit the development of a foundation upon which the etiology of various forms of IUGR can be explored. Such work will aid substantially in elucidating the pathologies that involve placenta hypoxia, e.g., preeclampsia, diabetes and IUGR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANDROGENS, PREGNANCIES

LIPIDS,

INSULIN

AND

HYPERTENSIVE

Principal Investigator & Institution: Thadhani, Ravi I.; Director of Clinical Research in Nephrol; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: Although hypertensive disorders affect 5-10 percent of all pregnancies and lead to significant maternal and neonatal morbidity and mortality, the causes are unclear and preventive and therapeutic strategies have largely been unsuccessful. Recent studies indicate hypertensive disorders of pregnancy are characterized by endothelial cell dysfunction, altered endothelium-dependent relaxation, and atherosclerotic-like lesion. In the non-pregnant state, alterations in serum androgens, lipids, and insulin have been associated with endothelial cell dysfunction, vasoconstriction, andatherosclerosis. Recent work from our group and others suggests that alterations in androgens, lipids, and insulin may also be associated with increased risk hypertensive disorders during pregnancy. Prospective data are sparse, however, and the lack of substantial prospective studies may have hampered development of effective therapies. Therefore, the primary objective of this proposal is to examine prospectively the association between levels of testosterone, specific lipid fractions, and markers on insulin resistance at three time points (at 10 and 28 weeks of gestation and at delivery) and the risk of gestational hypertension and preeclampsia. We will test our hypotheses in an open cohort of women who receive prenatal care at the Massachusetts General Hospital and three affiliated neighborhood health centers. Over the next 5 years, we expect to enroll approximately 9000 women, with 470 cases of gestational hypertension and 405 cases of preeclampsia. Our pilot data on 2289 women show that loss to follow-up and missing data are minimal, women who enroll in the study have

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Preeclampsia

similar characteristics to those who do not enroll, and Hispanic and African-American women comprise approximately 19 percent of all enrolled women. Other advantages of this study include: pilot data demonstrates successful enrollment of approximately 150 women every month; prospective design with supportive preliminary work in a large clinical population; and, dedicated team of investigators with expertise in complementary areas. We believe this proposal has the potential to advance our understanding of the pathogenic mechanisms of hypertensive disorders of pregnancy, improve identification and monitoring of women at highest risk, and uncover potential therapies to reduce the widespread impact of these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANGIOGENIC & PREMEABILITY GROWTH FACTORS IN PREECLAMPSIA Principal Investigator & Institution: Johnson, Donna D.; Obstetrics and Gynecology; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 28-AUG-2001; Project End 30-JUN-2004 Summary: (provided by applicant): Pre-eclampsia is a multisystem disorder that complicates 10 percent of pregnancies. This disease leads to increased morbidity and mortality for both the mother and baby. Although the clinical presentation of the disease is well described, the pathophysiologic mechanisms for the clinical manifestations are not. The overall hypothesis of this application is that vascular endothelial growth factor (VEGF) and placental growth factor (PIGE) are likely mediators of some of the clinical features of preeclampsia and the placenta is the site for the altered production of these growth factors. VEGF and PIGF are specific mitogen for endothelial cells and are potent stimuli for angiogenesis and vascular permeability. The biological activity of these related growth factors is modified depending on the concentration of each. This proposal will examine their relationship to the clinical manifestations of preeclampsia in two specific aims. In specific aim one, the hypothesis to be tested is that maternal serum levels of PIGE and VEGF are altered in preeclamptic patients and these alterations correlate to increased vascular permeability and subsequently clinical manifestations of the disease, such as proteinuria and pulmonary edema. Maternal serum levels of VEGF and PIGE will be measured by enzyme-linked immunosorbent assay (ELISA) in pregnancies complicated by pre-eclampsia and then compared to those found in normal pregnancies. We will follow patients longitudinally to determine if the alterations of VEGF and PIGF change as the disease progresses. PIGF is an important modulator of VEGF activity. We predict that PIGE levels decrease but VEGF levels remain unchanged or increase. As PIGF levels become more depressed, the clinical manifestations of preeclampsia will progress. In specific aim two, the hypothesis to be tested is that alterations in maternal serum levels of PIGF and VEGF will be reflected in the placenta at the level of gene expression. Maternal serum levels of VEGF and PIGE will be measured by ELISA in normal pregnancies and pregnancies complicated by preeclampsia and correlated with the expression VEGF and PIGE mRNA in the placenta determined by Northern blot. The placenta is likely the major source for these growth factors in pregnancy and any changes in the serum levels will be reflected in the placenta. In other words PIGF gene expression will be reduced and VEGF gene expression will be unchanged or increased. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANGIOGENIC PRODUCTION

FACTOR

/SHEAR

STRESS

/PA

Studies

9

/UA

NO

Principal Investigator & Institution: Magness, Ronald R.; Professor; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002 Summary: Normal pregnancy is associated with dramatic increases in uteroplacental and fetoplacental blood flows directly correlating with fetal growth, survival and neonatal birth weights. These increases in placental blood flows result from both neovascularization and vasodilatation. During the third trimers of ovine and human pregnancy, at a time when fetal growth and uteroplacental and feto-placental blood flows increase exponentially, the maternal and fetal compartments produce angiogenic factors such as bFGF and VEGF, as well as Nitric Oxide (NO). Elevations in blood flow also substantially increase the laminar shear stress on the endothelial cells, thus the increase in angiogenesis and NO production are associated with a time of pregnancy when neovascularization and vasodilatation are observed in the uterine angiogenesis and NO production are associated with a time of pregnancy when neovascularization and vasodilatation are observed in the uterine and fetoplacental vasculature and shear stress is increasing. The hypothesis of this proposal is that the placental and uterinederived angiogenic factors, bFGF and VEGF serve to augment or modulate shear stress induced increases in NO production and eNOS expression by placental factors, bFGF and VEGF serve to augment or modulate shear stress induced increases in NO production and eNOS expression by placental and uterine artery endothelium so as to control blood flow at the utero-placental interface. In two Specific Aims we will use endothelial cells grown to confluence on artificial capillary beds in CellMax cartridges, a novel model we have developed recently in our laboratory. Specific Aim 1: Angiogenic growth factor (bFGF or VEGF) interaction with shear stress on NO production, eNOS expression (protein and mRNA) and the rate of de novo mRNA transcription in ovine fetoplacental artery endothelial cells (OFPAEC) and uterine artery endothelial cells (UAEC) from pate pregnant and non-pregnant sheep. We will also evaluate the effects of laminar shear stress on bFGF and VEGF production/expression and the expression of their receptors (FGFR-1/Flg-1, Flk-1/KDR). Effects of Actinomycin D or Cyclohexamide on the synergistic actions of angiogenic growth factors (bFGF or VEGF) and laminar shear stress in OFPAEC and UAEC NO production, eNOS protein and mRNA expression. Specific Aim 2: Effects of inhibition of specific signaling pathways on angiogenic growth factor (bFGF or VEGF)-shear stress induced elevations in NO production and eNOS expression; (2a) Mitogen Activated Protein Kinase (MAPK) signaling pathways (ERK +, p38MAPK) and SAPK/JNK pathway); (2b) Calcium signaling pathway; (2b) Calcium signaling pathway; (2c) Protein kinase C signaling pathway (a possible MEK dependent pathway); (2d)m PI3-Kinase/AKT signaling pathway (a MEK independent pathway). Data derived from these studies will provide the first framework for understanding the role of the local control and interactions between shear stress, angiogenesis, and NO to control blood flow to the placental and uterine vasculature, which are critical for normal fetal growth and development. Furthermore, understanding differences and similarities between the fetal and maternal endothelial cell responses to angiogenic factors also will allow us to understand how both sides of the placental communicate during this important period of fetal growth. The importance of these proposed studies become very evident since the normally dramatic increases in fetoplacental and uteroplacental perfusion are directly linked to fetal growth and that these mechanisms are dysfunctional in pathologic pregnancies such as preeclampsia and IUGR. These mechanisms thus relevant to perinatal medicine since modulation of fetal growth impacts fetal survivability.

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Preeclampsia

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

Project Title: PREGNANCY

ANGIOTENSIN

(1-7)

IN

NORMAL

AND

PREECLAMPTIC

Principal Investigator & Institution: Merrill, David C.; Obstetrics and Gynecology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 24-SEP-2001; Project End 31-AUG-2005 Summary: Preeclampsia is one of the leading causes of maternal and fetal morbidity and mortality. It is estimated to affect 6 percent to 10 percent of all pregnancies in the United States. Despite extensive research, the pathophysiology of preeclampsia is still poorly understood. It is well known that the renin- angiotensin-aldosterone system (RAAS) is stimulated in normal pregnancy. The physiological consequences of the stimulated RAAS in normal pregnancy are incompletely understood; and even less understood is the question of how this system may be altered and contribute to the hypertensive disorder of pregnancy. The cardiovascular consequences of normal pregnancy include an increase in cardiac output by 30-40 percent and plasma volume by 50 percent, which are associated with a decrease in total peripheral resistance (TPR). Thus, blood pressure is normal or reduced by the end of the first trimester and reaches its nadir by the second trimester. The reasons for the reduced TPR are not established, but a number of vasodilator substances have been studied. In preeclampsia, the cardiovascular consequences associated with hypertension include increased TPR, failure to develop the hypervolemia of pregnancy, reduced renal blood flow, and glomerular filtration rate. It has been suggested that preeclampsia may arise not only because of stimulation of vasoactive substances, but because of a defect in the contribution of the vasodilator systems. New data from our laboratory in normal human subjects have indicated that a novel vasodilator of the RAAS, angiotensin-(1-7) [Ang-(1-7)], is increased in pregnancy and reduced in preeclampsia subjects. It is our hypothesis that normal pregnancy is a balance of the RAAS comprising both vasoconstrictor [Ang II] and vasodilator [Ang-(17)] pathways. Preeclampsia shifts the balance of the RAAS by maintaining an elevated vasoconstrictor component in the face of a reduced vasodilator pathway. The hypothesis will be tested by the following Specific Aims: 1) Determine the time course of circulating and urinary profiles of the vasoconstrictor (Ang II) and the vasodilator [Ang-(1-7)] components during normal pregnancy and preeclampsia. Other indices of the RAAS, including plasma total renin, active renin, and prorenin, Ang I, platelet AT1 receptor binding and/or mRNA, serum ACE activity and monocyte ACE mRNA, in normal and preeclampsia pregnant subjects will be measured. 2) Determine the physiological role of the Ang-(1-7) by measuring the blood pressure and systemic (cardiac output and total peripheral resistance) and regional (muscle and skin) hemodynamic changes to the vasodilator Ang-(1-7) and its antagonist D-Ala Ang-(1-7) in normal and preeclampsia subjects. In summary, the ultimate goal of this study is to understand the contribution of both vasodilator and vasoconstrictor components of the RAAS to blood pressure regulation in normal and preeclampsia pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANGIOTENSINOGEN VARIANTS AND ADVERSE PREGNANCY OUTCOMES Principal Investigator & Institution: Ward, Kenneth; Senior Scientist; ObstetricsGynecology; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 20-AUG-1995; Project End 31-JUL-2003

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Summary: (Adapted from Investigator's Abstract) Early in normal gestation, there is a decrease in maternal vascular resistance accompanied by a 20% of 100% expansion of maternal blood volume. At the same time, the uterine arteries undergo profound remodeling and dilation -- termed "physiologic change" -- to provide adequate blood flow to the developing conceptus. Failed volume expansion and failed or abnormal physiologic change are associated with a variety of common pregnancy complications, including preeclampsia, intrauterine growth retardation (IUGR), and preterm labor. Molecular variants of the angiotensinogen gene, which increase angiotensinogen expression in certain local systems, predispose women to develop preeclampsia and related pregnancy complications. This competing renewal proposes to test the hypothesis that disease-associated angiotensinogen alleles promote abnormal spiral artery remodeling and inhibit maternal plasma volume expansion. Three interrelated approaches are proposed: 1) an affected sister-pair linkage analysis of polymorphisms in angiotensinogen and other relevant genes, 2) gene expression and quantitative histology studies of spiral artery remodeling using an existing large collection of human pregnancy tissues, and 3) transgenic mouse and human studies to evaluate the newlydescribed paracrine tubular renin angiotensinogen system's role in maternal blood volume expansion. The investigators state that this work may lead to predictive and diagnostic tests that indicate a woman's increased risk for complications early in pregnancy, allowing improved monitoring, earlier diagnosis, and new opportunities for treatment. They further state that the ultimate goal of this research is the development of improved preventive measures and effective treatments for these common pregnancy disorders. Through an understanding of particular genetic subsets of preeclampsia, they note that they may find that once promising therapies, such as low-dose aspirin, do have a role in some patients. Finally, they note that new biologic pathways may be discovered that suggest novel therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AT 1 RECEPTOR ANTIBODIES IN PREECLAMPSIA Principal Investigator & Institution: Prashner, Healther R.; Pathology and Lab Medicine; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-DEC-2002 Summary: This is the applicant's third year of the first faculty appointment at UT Medical School Houston. She is an Assistant Professor of Pathology with subspecialties in renal and pediatric/perinatal pathology and wishes to pursue the laboratory investigation of preeclampsia using clinical collaborations to provide patient material and data. The experiments focus on the placenta and kidney relating the project to the applicant's clinical expertise. Collaborative study of the renin angiotensin system in pregnancy and preeclampsia began two years ago with the applicant's mentor, Dr. Rodney E. Kellems, Ph.D. The applicant has access to a large obstetric service and to a molecular biology laboratory with ongoing investigations in vascular biology, placental development and implantation, and pregnancy in murine models. The applicant's mentor, Dr. Kellems, Professor and Chairman of Biochemistry and Molecular Biology at the medical school, is a primary investigator with a long record of training doctoral candidates and postdoctoral fellows in molecular genetics and biology. The applicant has two clinical co-mentors providing guidance for the clinical collaborations. The training plan includes two years of clinical research training and formal courses in molecular biology, molecular genetics, and immunology. The laboratory experiments will continue for five years, overlapping in the first two years with a clinical curriculum. Preeclampsia complicates 5-10% of pregnancies. The disorder has been extensively

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studied, but the pathogenesis remains unknown. Initial symptoms, hypertension and proteinuria, may herald seizures or death. Fetal morbidity and mortality are high because treatment, delivery, is often premature. Major target organs are the placenta and kidney. In vitro use of patient serum will provide insight into the effects of circulating factors on these organs. The experiments uniquely focus on trophoblast and kidney glomerular cells. The work specifically investigates the recent claim that agonistic antibodies to the AT1 receptor of angiotensin II (AT1-AA) may have a causal role in the disorder. We will be the first to confirm these antibodies and the first to test the cause and effect relationship between AT1-AA and preeclampsia in a cohort study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BREAST CANCER RISK Principal Investigator & Institution: Terry, Mary B.; Assistant Professor; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Numerous studies have shown associations between markers of fetal growth and important domains of adult health. In particular, several recent studies suggest that high birthweight may be associated with an increased risk of breast cancer later in life. The existing literature on birthweight and breast cancer risk, while intriguing, falls short by its inability to address the following: (1) potential confounding by family factors (e.g. socioeconomic status); (2) the importance of and possible interaction with other measures of fetal growth; (3) the independent effect of maternal characteristics and exposures; (4) potential biological mechanisms; (5) the contribution of postnatal growth: and (6) mediation by adult risk factors. We will address these limitations by use of a novel study design examining the association of early life factors with mammographic density, a strong predictor of future breast cancer risk. Specifically, we will recruit a sibling sample of 500 female pairs (comprising 149 low birthweight (=4000g) females and the other of 178 preeclampsia exposed females. In the combined sibling and single child samples, 15% of the females will have been exposed to their mother?s preeclampsia during pregnancy. All females are offspring of pregnant women enrolled during 1959 to 1967 in two New England sites (Boston and Providence) of the National Collaborative Perinatal Project (NCPP) and in the Childhood Health and Development Study (CHDS). The sibling design will allow us to control for family effects such as socioeconomic status that may influence both birthweight and adult risk factor patterns. Exposure information will be derived from prospectively collected pre and postnatal data on mothers, infants, and childhood growth. Maternal sera collected during the third trimester will be used to measure estrogen (E1, E2, E3), and testosterone. Along with the mammogram, we will also collect adult risk factor data through interview and laboratory assays (including measures of IGF-I, IGFBP-3, androstenedione, testosterone. and SHBG). We hypothesize that high birthweight, high placental weight, high placental/birth weight ratio, high maternal pregnancy weight gain, and high maternal estrogen levels will increase mammographic density in the daughters, and that maternal preeclampsia and higher levels of maternal testosterone will decrease mammographic density in the daughters. We will further examine whether any of these associations are mediated by childhood growth patterns and adult risk factors. This study will advance the literature on early determinants of breast cancer risk by directly addressing tinny of the limitations in the existing literature, allowing a more thorough inspection into what may shape early breast cancer susceptibility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CANCER IN THE JERUSALEM PERINATAL STUDY Principal Investigator & Institution: Harlap, Susan; Research Professor; Epidemiology; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 15-JUN-1999; Project End 31-AUG-2006 Summary: (provided by applicant): The Jerusalem Perinatal Study is a population-based cohort of mothers, fathers and their 92,408 offspring born in 1964-76. Subsets of the cohort may be at risk for cancer through founder mutations in BRCA1, BRCA2, FANCC, ATM, BLM, APC and other genes. During 1998-2002 we traced 98% of the offspring (median age 30) and 94% of their mothers and linked them to Israel's Population Registry and its Cancer Registry. We found 642 first primary malignancies in offspring and 2516 in mothers, including 1065 cases of breast cancer. Jewish women from Morocco showed less breast cancer than expected. Ancestries from Iraq, lran/Afghanistan and other West Asian countries were associated with an increased risk of breast cancers in mothers. Daughters with these ancestries experienced more breast cancer, and a specific birth defect was observed in their families. West Asian ancestry also predicted lymphomas in offspring. Other familial associations were observed for myeloid leukemia in offspring. Preeclampsia was a risk factor for cancers of breast, ovary, stomach, lung/larynx and kidney in mothers, as well as for cardiovascular mortality. We found the wives of elderly fathers more at risk for preeclampsia. These and other findings in the cohort have suggested that this population may be at increased risk for de novo mutation in men's spermatogonia, or defects in meiosis. They raise questions about paternal susceptibility to cancer in relation to their potential for reproduction. In continuing the project for a further five years, we propose to add 40,000 fathers to the study, tracing and ascertaining cancer incidence in them, and updating our knowledge of cancer and mortality in mothers and offspring. We will construct family sets and continue to describe and analyze associations of breast cancer in mothers, common cancers in either parents, pediatric cancers, complications of pregnancy and characteristics of newborns (e.g. birth weight and birth defects), both in individuals and families. Further analyses of breast cancer will focus on countries of origin and attempt to identify interactions with other risk factors that might help elucidate whether the risk in migrants from West Asia is due to a unique genetic component or to special environments experienced by Asian immigrants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CARDIAC RECEPTOR ACTIVITY IN THE PREGNANT RAT Principal Investigator & Institution: Hines, Mary Christina.; Thompson Professor of Research; None; University of Missouri Kansas City Kansas City, Mo 64110 Timing: Fiscal Year 2002; Project Start 01-JUN-1996; Project End 30-APR-2006 Summary: Increased blood volume and decreased blood pressure are early and sustained alterations of pregnancy that are directly correlated with positive outcomes. The chronic maintenance of these cardiovascular adjustments implies a significant change in autonomic regulatory pathways, and it is known that reflex effects mediated by these pathways are attenuated during rat and human pregnancy, and further blunted during diseases, such as preeclampsia. One of our long-term objectives is to characterize alterations in these neural reflex pathways during pregnancy and to elucidate mechanisms involved. Understanding changes in these cardiovascular regulatory systems will improve clinical management of blood volume and pressure during pregnancy. Using the pregnant rat model, which undergoes hemodynamic changes similar to those in humans, we have demonstrated that afferent discharge in the

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autonomic receptors, which regulate blood volume and blood pressure, is attenuated during pregnancy. One explanation for a reduction in cardiac receptor sensitivity is the suggestion that pregnancy actually represents an "underfilled" state, and this concept will be explored in the present proposal. In addition, we are investigating the role of alterations in wall stretch and local paracrine factors in the reduction of afferent receptor firing during pregnancy. Based on our findings in the current funding cycle, three aims are proposed for this competing renewal: Aim #1: we will determine if exogenous blood volume expansion restores cardiac receptor activity in the late-pregnant rat to levels observed in the nonpregnant animal, and if volume expansion has a differential effect in the early-pregnant animal; Aim #2: right atrial pressure/dimension relationships will be measured in late-pregnant and nonpregnant animals to gain a better understanding of the degree of stretch "sensed" by cardiac receptors; Aim #3: we will determine whether nitric oxide and/or endothelin, substances known to decrease baroreceptor firing in nonpregnant animals, mediate the reduction in cardiac and baroreceptor activity we have observed during pregnancy. The proposed research plan stems logically from the investigator's currently funded work on alterations in autonomic regulation of cardiovascular function during pregnancy. Data collected during the current grant period have provided intriguing new information about gestational modulation of autonomic receptor activity in the gravid rat. In this competitive renewal we will focus our efforts on mechanisms involved in these changes of pregnancy. The insights gained from these investigations will extend the understanding cardiovascular control in a heretofore-unstudied component of autonomic regulatory pathways in pregnancy, and will further elucidate physiologic as well and pathologic mechanisms of blood volume and blood pressure control during pregnancy that will broaden our knowledge base for clinical management of the pregnant woman. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARDIOVASCULAR DISEASE FOLLOWING HYPERTENSIVE PREGNANCY Principal Investigator & Institution: Wolf, Myles S.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Candidate: Dr. Myles Wolf received the M.D. degree in 1996 from SUNY-Brooklyn. He completed internal medicine and nephrology training at MGH. In 2002, he received the Master of Medical Sciences degree in clinical physiological investigation from Harvard Medical School through its NIH K30supported Scholars in Clinical Science Program. Mentor: David Nathan, M.D., is a world-renowned clinical investigator who has trained numerous investigators in the areas of diabetes and insulin resistance, a field in which he has published extensively. As Director of the MGH GCRC and as a founding member of the Scholars in Clinical Science Program, Dr. Nathan will ensure the success of Dr. Wolf's research training, project and overall career development. Research: cardiovascular disease (CVD) is the leading cause of mortality among women in the U.S. Reducing its burden requires further understanding of its early mechanisms. Women with hypertensive disorders of pregnancy (HDP), including preeclampsia and gestational hypertension, return to their normotensive baseline soon after delivery, yet they are at increased risk for CVD in later years. Therefore, these women represent in-vivo human models of the pre-CVD state in whom its early mechanisms may be studied. In their first study, they will test the hypothesis that otherwise asymptomatic women with prior HDP display evidence of increased CVD risk relative to those with normal pregnancy as early as one year

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postpartum. In addition to examining traditional CVD risk factors, they will focus on insulin resistance, inflammation and microalbuminuria, factors that are associated with HDP but have been understudied in the postpartum period. In a second physiological study, they will examine vascular reactivity using brachial artery ultrasound, and insulin sensitivity using intravenous glucose tolerance tests. The hypotheses to be tested are that women with HDP display evidence of endothelial dysfunction during the early postpartum period and that this alteration is related to insulin resistance. All subjects will be identified from the MGH Obstetric Maternal Study, the largest pregnancy cohort in Massachusetts, and the source of several important studies during pregnancy. The proposed study is sufficiently powered (>90%), IRB-approved and pilot data support its feasibility. They believe the results will provide critical insight into mechanisms of CVD in women and potentially suggest means to alter their CVD risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR MECHANISMS IN THE INDUCTION OF AROMATASE Principal Investigator & Institution: Mendelson, Carole R.; Professor; Biochemistry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-AUG-1983; Project End 31-JUL-2005 Summary: (Adapted from the Investigator's Abstract): The objective of the proposed research is to define cis-acting elements and transcription factors that mediate CYP19 expression in the appropriate tissue-/cell-specific and developmentally regulated manners. Transgenic mice will be created carrying chimeric reporter gene constructs comprised of DNA flanking placenta-specific exon I.1, ovary/testis-specific exon II, and adipose/fetal liver-specific expression. The molecular basis for 'promoter switching' will be analyzed in transgenic mice bearing endocrine-responsive mammary and liver tumors. Transfected human trophoblasts in primary culture will be used to define the cis-acting elements that are required for syncytiotrophoblast-specific CYP19 promoter I.1 expression. Once gene regulatory elements are defined, they will be used to isolate cDNAs encoding transcription factors that mediate syncytiotrophoblast-specific CYP19 gene expression. It is proposed to continue to characterize transcription factors that mediate syncytiotrophoblast differentiation and its regulation by hypoxia/O2 and to define their expression in preeclampsia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHRONIC HYPOXIA, PREGNANCY & SYSTEMIC VASCULAR CONTROL Principal Investigator & Institution: Moore, Lorna G.; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COOPERATIVE MULTICENTER MATERNAL-FETAL MEDICINE UNITS N* Principal Investigator & Institution: Leveno, Kenneth J.; Professor; Obstetrics and Gynecology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 05-MAY-1996; Project End 31-MAR-2006

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Summary: This application describes the qualifications and experience of the maternalfetal medicine faculty and research team at the University of Texas Southwestern (UT Southwestern) Medical Center and Parkland Hospital and the facilities and patient population available to carry out clinical protocols sponsored by the NICHD MaternalFetal Medicine Units (MFMU) Network. UT Southwestern's Division of Maternal-Fetal Medicine includes 14 full-time faculty physicians, 8 of whom are board certified in maternal-fetal medicine. In 1999, there were 14,647 obstetrical patients delivered at Parkland Hospital and approximately 58% were high-risk. Pregnancy complications of particular interest to the MFMU Network, for example, preterm birth and preeclampsia, are well represented in the obstetrics population at Parkland Hospital. Indeed, for the past 4 1/2 years, UT Southwestern's MFMU Network center has frequently been the first or second leading recruiter for Network protocols. A computerized perinatal database for all births at Parkland Hospital, operational since 1982, continues to be a centerpiece in our center's academic productivity as well as an important component of our center's successful participation in the MFMU Network. The perinatal research team at UT Southwestern has successfully completed randomized clinical trials external to the MFMU Network and examples are cited in this application. Importantly, the maternalfetal medicine physicians at UT Southwestern are philosophically dedicated to rigorous controlled trials intended to objectively evaluate principles of obstetrical care consistent with the mission of the MFMU Network. The perinatal research team described has been actively involved with and committed to the MFMU Network for the past 4 1/2 years and seeks to continue this collaboration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COOPERATIVE MULTICENTER MFMU NETWORK Principal Investigator & Institution: Mercer, Brian M.; Professor of Reproductive Biology; Reproductive Biology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (provided by applicant): The goal of this application is to demonstrate that the Maternal-Fetal Medicine Unit in the Department of Reproductive Biology at Case Western Reserve University (CWRU) is qualified to participate in the NICHD MaternalFetal Medicine Units Network (MFMU Network), and that participation will strengthen the MFMU Network and provide leadership in the development and conduct of collaborative research between the individual MFM Units as well as with neonatal researchers. The proposed investigators have backgrounds in clinical research, including multicenter studies and studies requiring neonatal and long term follow-up. The Unit possesses diverse clinical and research interests including: prediction and prevention of preterm birth, perinatal infection, labor induction, maternal carbohydrate metabolism/diabetes, energy expenditure in pregnancy, pathophysiology and prevention of preeclampsia, prenatal diagnosis and fetal assessment, placental function, and nutrition. While CWRU has not previously participated in the MFMU Network, it has demonstrated evidence of prior and ongoing participation in collaborative and NIH funded multicenter research. The Principal Investigator has a 10-year history of successful collaboration within the MFMU Network as the alternate Principal Investigator for UT-Memphis. During that time he played a role in the development and conduct of MFMU Network trials, and in the Networks? administrative structure. In this proposal, CWRU offers the participation of its two primary teaching affiliates, MetroHealth Medical Center and University Hospitals (including Rainbow Babies & Children?s Hospitals). Inclusion of both hospitals offers a large number of women for

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recruitment, and could allow focused cost/time efficient recruitment of selected subjects from a diverse population. CWRU?s NIH-funded General Clinical Research Center has an established record of successful perinatal research. The CWRU-GCRC?s value is enhanced by having Units located at both MetroHealth Medical Center and at University Hospitals. Both Units are available to support MFMU Network trials, can perform ancillary studies in their core laboratories, and could act as a Central Lab for multicenter studies. Rainbow Babies & Children?s Hospital has participated in the NICHD Neonatal Research Network since its inception, and offers special research expertise in long term follow-up. It offers a potential bridge for collaboration between the MFMU and NICU Networks in addition to follow-up for MFMU Network studies. The proposed CWRU MFMU Unit offers experienced clinicians and researchers, a large diverse patient population, as well as a demonstrated ability to conduct collaborative clinical research. The proposed MFM and Neonatology researchers have demonstrated the ability to collaborate across geographic, Hospital and Departmental boundaries, both outside and inside the NICHD MFMU and NICU Networks. The existing infrastructure at CWRU offers the potential for enhanced and cost-effective research as well as the ability to design and support ancillary studies. The investigators believe that they can successfully contribute to the MFMU Network and that they offer potential leadership as the Network expands its efforts in collaborative, longitudinal studies in the 21st Century. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COPPER/ALBUMIN REDOX-CYCLING IN PREECLAMPSIA Principal Investigator & Institution: Kagan, Valerian E.; Professor; Environ & Occupational Health; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 31-JUL-2004 Summary: (Adapted from the Investigator's Abstract): The central hypothesis is that during preeclampsia increased free fatty acids bound by albumin and/or modification of Cys34 impair normal albumin/copper interactions in such a way that 'loosely-bound" copper is capable of catalyzing redox cycling resulting in the generation of reactive oxygen species. The first goal is to establish that changes in copper/albumin interactions can trigger copper-dependent redox cycling and oxidative stress in preeclampsia. Using plasma obtained from preeclamptic and normal pregnant women, the investigator will 1) establish that preeclamptic plasma contains enhanced potential for generating copperdependent oxidative stress and 2) determine the role for free fatty acids and thiol oxidation/nitrosylation of albumin in mediating this enhancement. The second goal is to use a simple model system utilizing purified human serum albumin to define the molecular mechanisms for free fatty acid and Cys34 modification of copper/albumin interactions and redox cycling. The third goal is to determine whether enhanced redox cycling of copper/albumin can alter the vascular behavior by: 1) demonstrating the potential of preeclamptic plasma to alter vascular function in mesenteric arteries from pregnant mice, and 2) establishing that free fatty acid and Cys34, modification of albumin can result in copper-dependent alterations in vascular reactivity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--DATA AND CLINICAL Principal Investigator & Institution: Ness, Roberta B.; Professor and Chair; MageeWomen's Hospital of Upmc 300 Halket St Pittsburgh, Pa 15213

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Timing: Fiscal Year 2002; Project Start 14-JUN-2002; Project End 31-JAN-2007 Summary: Preeclampsia is a major contributor to maternal and perinatal morbidity and mortality. Prevention and treatment require an understanding of both pathophysiology and clinical characterization. The Data and Clinical Core will centralize recruitment, baseline data collection, data management, and statistical consultation for clinical projects within the Program Project. Specifically, these activities will entail recruiting, over a four-year period, an estimated 1700 nulliparous pregnant women without prior evidence of coronary hear5t disease risk and with singleton gestations from MageeWomens Hospital in Pittsburgh. Baseline clinical and laboratory data will be obtained at or prior to 16 weeks gestation and additional biologic samples will be collected at several time points throughout the pregnancy. Furthermore, 200 preeclamptic 200 normotensive and 200 intrauterine growth restricted (IUGR) pregnancies will be studied cross-sectionally at labor and delivery. Finally, 140 women will be recruited at 6-12 months post-partum. In all cases, the Core staff will be responsible for recruitment, data collection (except for special tests described in specific projects), and quality assurance. The Core will also characterize preeclamptic and IUGR women using a strict set of diagnostic criteria and a jury of clinical experts. Data will be organized and maintained using the expertise within the Department of Epidemiology. Statistical consultation will be provided for all projects in an ongoing fashion. The Core builds on extraordinary current success. To date, in the current Program Project, we have enrolled over 23000 women over about four years and will identify almost 400 preeclamptic women. Therefore, we are confident in our ability to take these activities forward into the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINE REGULATION OF TROPHOBLAST FUNCTION Principal Investigator & Institution: Wolfe, Michael W.; Associate Professor; Physiology; University of Kansas Medical Center Msn 1039 Kansas City, Ks 66160 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2004 Summary: In humans and primates, trophoblast secretion of chononic gonadotropin (CG) serves as the embryonic signal for maternal recognition of pregnancy. CG is a heterodimeric glycoprotein hormone composed of an alpha-subunit and a distinct CGbeta-subunit. Expression of CG occurs a few days subsequent to fertilization following differentiation of placental cytotrophoblasts into syncytiotrophoblasts. Absence of CG results in the initiation of a new menstrual cycle. Cytokines have been reported to play a role in regulating secretion of CG and have been postulated to modulate cytotrophoblast differentiation. Of these cytokines, interleukin- 6 (IL-6) and leukemia inhibitory factor (LIF; members of the same cytokine family) have been shown to have important roles during pregnancy. LIF is produced by the uterus at the time of blastocyst implantation and can stimulate trophectoderm proliferation in vitro. IL-6 is secreted from a number of cell types within and outside the uteroplacental unit including trophoblasts themselves and as such can act in an autocrine manner to induce secretion of CG. Trophoblast production of IL-6 is stimulated by exposure to the proinflammatory cytokine, IL-1. Thus, it is feasible that uterine inflammation would lead to altered secretion of CG. Furthermore, women diagnosed with the pregnancy disorder, preeclampsia, have elevated plasma levels of IL-6 and this is associated with elevated levels of CG in circulation. These and other data implicate IL-6 as being involved in trophoblast physiology as well as pathophysiology. The following specific aims are designed to begin to address the hypothesis that IL-6 regulates trophoblast differentiation and secretion of CG. Specific Aim I: Determine the role of IL-6 in regulating trophoblast proliferation and differentiation. Specific Aim II: Investigate IL-6

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regulation of gene expression in trophoblasts using gene array technology. Jar choriocarcinoma cells and primary cultures of cytotrophoblasts will be used to address these aims. It is anticipated that data obtained from these experiments will establish IL-6 as being a critical regulator of trophoblast function and will begin to shed light on how IL-6 regulates trophoblast differentiation. The long term goal of these studies is to better understand maternal/fetal cytokine regulation of trophoblast function and ultimately how trophoblast secretory products modulate the maternal immune system to maintain pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DECIDUAL-ENDOTHELIAL TISSUE FACTOR AND IUGR Principal Investigator & Institution: Lockwood, Charles J.; Professor and Chair; Obstetrics Gynecology & Reprod Scis; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 11-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): Thrombosis in the uteroplacental circulation with resultant hypoxemia and inflammation are common antecedents to intrauterine growth restriction (IUGR), fetal death, abruption and preeclampsia. These pathological obstetrical conditions are associated with acquired and inherited thrombophilias (e.g. Factor V Leiden). The goal of this application is to elucidate the biochemical mechanisms leading to uteroplacental thrombosis. Our central hypothesis is that thrombin, vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNFa) aberrantly induce the potent procoagulant tissue factor (TF) in human endometrial endothelial cells (HEECs) by acting on distinct but potentially synergistic signal transduction pathways. Three specific aims are proposed to test this hypothesis in which we will: 1) Evaluate the separate and interactive in vitro effects of thrombin, VEGF and TNFa on HEEC TF expression and determine their sites of molecular regulation. Whether adjacent stromal cells are required to mediate hypoxia-induced HEEC TF expression in pathological tissues will be assessed in a unique endothelialstromal cell co-culture system. 2) Employ a murine model of the Factor V Leiden mutation to determine whether Inherited thrombophilia induced uteroplacental thrombosis is associated with induction of decidual endothelial cell TF and whether this is correlated with fetal and placental growth restriction. Furthermore, the pivotal role of aberrantly enhanced TF expression will be confirmed by crossbreeding mice expressing low TF levels with those carrying the Factor V Leiden mutation. 3) Conduct a prospective cohort study to determine whether increased maternal thrombin generation at various time points during human gestation and at 6-12 weeks post gestation predicts the subsequent occurrence of IUGR, abruption, preeclampsia and stillbirth. Additionally, we will correlate maternal plasma levels of two sensitive thrombin markers with the presence of acquired or inherited thrombophilias in the selected patient population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EARLY DETERMINANTS OF ADULT HEALTH Principal Investigator & Institution: Susser, Ezra S.; Professor; Epidemiology; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Tantalizing findings have emerged from epidemiologic studies to suggest that the prenatal period may influence disease risk in

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adult life. Birthweight has received particular attention; low birthweight may increase the risk of cardiovascular and neuropsychiatric diseases, high birthweight may increase risk of breast cancer. While intriguing, the existing literature on birthweight and adult health outcomes has not adequately addressed (1) potential confounding by family factors; (2) the importance of other measures of fetal growth; (3) potential biologic mechanisms; (4) the independent effect of maternal characteristics and exposures; (5) the contribution of postnatal growth; and (6) potential mediation by adult risk factors. The Early Determinants of Adult Health (EDAH) Program Project will address these issues using an integrative approach to investigate early determinants of adult health in three research projects: a cardiovascular risk (CVD) Project, a breast cancer risk (BC) Project, and a neuropsychiatric (NP) Project. We will recruit offspring of pregnant women who were enrolled during 1959 to 1967 in two birth cohorts: a New England cohort (Boston and Providence sites of the Collaborative Perinatal Project) and a California cohort (Child Health and Development Study). The offspring are now 35-43 years old--an ideal age to start measuring intermediate markers and following for adult diseases. The centerpiece of the study is a Sibling sample, which will enable us to control for family factors such as socioeconomic status. The Sibling sample is complemented by two Single Child samples which comprise individuals with high birthweight and with exposure to preeclampsia. The total combined sample is 2538 individuals (Sibling sample, 2000 individuals; high birthweight Single Child sample, 350 individuals; and Preeclampsia Single Child sample, 178 individuals). Exposure information will be derived from prospectively collected pre and postnatal data on mothers, infants, and childhood growth, as well as from serologic analysis of archived maternal prenatal sera. We will combine these pre and postnatal data with the adult interview and clinical data in the three health domains. The EDAH is a collaborative research program which cuts across birth cohorts, academic institutions, and scientific domains. Thus, the Program Project will be conducted as partnership of research teams at Columbia and Harvard Universities, with California investigators also playing a leading role. In addition to the CVD, BC, and NP Projects, it includes four Cores: the Administrative and Scientific Leadership (ASL) Core, the Location and Assessment (LA) Core, the Biostatistics and Data Management (BDM) Core, and the Serology/Hormone (S/H) Core. By bringing together expertise across institutions and scientific disciplines, and combining two large birth cohorts to implement a novel design, the study provides an unparalleled opportunity to answer questions about early antecedents of chronic disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT DEVELOPMENT

OF

CHRONIC

INFECTION

ON

PLACENTAL

Principal Investigator & Institution: Boggess, Kim A.; Obstetrics and Gynecology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 13-MAR-2003; Project End 28-FEB-2006 Summary: (provided by applicant): Periodontal disease is a chronic, polymicrobial oral infection that affects up to 50% of pregnant women. This oral infection has recently been associated with adverse pregnancy outcome. Pregnant women with active chronicoral infection have a three to five-fold increased risk for spontaneous miscarriage, preeclampsia, and small-for-gestational age infants. The mechanisms by which chronic maternal oral infection disrupts normal pregnancy is unknown, although there are animal and human data to demonstrate systemic dissemination of oral pathogens to the maternal and fetal circulation, and to the placenta. Maintenance of normal pregnancy is

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predicated by normal placentation and placental development. This application seeks to study the mechanisms that chronic maternal oral infection could affect pregnancy outcome. The purpose of this investigation is to develop a rabbit model to study the effects of chronic maternal infection with oral pathogens on fetal growth and placental development. The hypothesis of this application is that chronic maternal infection with oral pathogens results in translocation of these pathogens to the utero-placental unit, altering maternal-placental interaction at the time of implantation, thus impairing fetal growth. Redundancy exists at the maternal-fetal interface that protects against maternal complement activation and inflammation, which allows normal embryo attachment and placental invasion. Chronic maternal infection with oral pathogens may alter the balance necessary to allow normal placental development to occur. In Specific Aim 1, a model of chronic maternal infection with oral pathogens, distant from the uterus, will be developed in the rabbit and used to measure the effect on fetal growth. In Specific Aim 2, maternal and fetal protective factors that allow normal implantation will be characterized in the rabbit, and placental inflammation and maternal immune tolerance will be compared between rabbits chronically infected with oral pathogens and those uninfected. The presence or absence of biomarkers of inflammation and immune tolerance within the placenta will be correlated with recovery or oral pathogens from the placenta and newborn weight. Understanding of these mechanisms may assist in the development of interventions to protect the fetus and placenta from damage as a result of chronic maternal infection with oral pathogens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ELEVAT SECOND TRIMESTER SERUM HOMOCYST(E)INE LEVEL & SUBSEQ RISK OF PREECLAMPSIA Principal Investigator & Institution: Sorensen, Tanya; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002 Summary: Elevated plasma homocyst(e)ine is a risk factor for endothelial dysfunction and vascular disease. In late gestation, levels of homocyst(e)ine are higher in preeclamptics, as compared with normotensive pregnant women. Our objective was to determine whether homocyst(e)ine elevations precede the development of preeclampsia. We used a prospective nested case-control study to compare second trimester maternal serum homocyst(e)ine concentrations in 52 patients who developed preeeclampsia (pregnancy-induced hypertension with proteinuria) compared with 56 women who remained normotensive throughout pregnancy. Study subjects were selected from a base population of 3,042 women who provided blood samples at an average gestational age of 16 weeks and later delivered at our center. Serum homocyst(e)ine was measured by high performance liquid chromatography and electrochemical detection. Approximately 29% of preeclamptics, as compared to 13% of controls, had homocyst(e)ine levels ?5.5 umol/L (upper decile of distribution of control values). Adjusted for maternal age, parity, and body mass-index, a second trimester elevation of homocyst(e)ine was associated with a 3.2-fold increased risk of preeclampsia (adjuster OR=3.2; 95% CI 1.1-9.2; p=0.030). There was evidence of an interaction between maternal adiposity (as indicated by her pre-pregnancy body mass index) and parity with second trimester elevations in serum homocyst(e)ine. Nulliparous women with elevated homocyst(e)ine levels experienced a 9.7-fold increased risk of preeclampsia as compared with multiparous women without homocyst(e)ine elevations (95% CI 2.1-14.1; p=0.003). Women with a higher prepregnancy body mass index (?21.4 kg/m2, or upper 50th percentile) and who also had

22

Preeclampsia

elevated homocyst(e)ine levels, as compared with leaner women without homocyst(e)ine elevations, were 6.9 times more likely to later develop preeclampsia (95% CI 1.4-32.1; p=0.016). Our findings are consistent with other indications of vascular dysfunction predating clinical preeclampsia. Studies designed to examine the effect of dietary and/or pharmacological mediators of homocyst(e)ine metabolism in preeclampsia are warranted. FUNDING NIH HD/HL-32562 PUBLICATIONS None Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREECLAMPSIA

ENDOTHELIAL-DEPENDENT

VASODILATATION

IN

Principal Investigator & Institution: Kauma, Scott W.; Professor; Obstetrics and Gynecology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 13-APR-2001; Project End 31-MAR-2006 Summary: (provided by applicant): This candidate is an Associate Professor of Obstetrics and Gynecology (OB/GYN) at Virginia Commonwealth University. He has played a key role in Department of OB/GYN in the research program in preeclampsia. His career goals are: 1) to be a leading scientist in patient- oriented research in preeclampsia, and 2) to train junior clinicians as bio- medical scientists. This application has been written to consolidate his status as a clinical scientist and teacher. During the period of the proposed studies, the candidate will perform research and serve as a mentor to junior faculty, residents, and colleagues. The proposed studies involve a new, multidisciplinary approach to understanding the role of lipid peroxides in the development of hypertension in preeclampsia. Preeclampsia is a health problem of pregnancy that affects approximately 5-8 percent of women and is associated with significant maternal/neonatal morbidity and mortality. It is characterized by hypertension thought to be secondary to vascular endothelial activation and dysfunction. The mechanisms that cause hypertension in preeclampsia are poorly understood but are thought to be mediated by decreased vascular endothelial nitric oxide (NO) production. Studies in our laboratory have shown that lipid peroxides in preeclamptic plasma activates endothelial cells and may reduce eNOS derived NO availability. We hypothesize that increased lipid peroxides in preeclampsia decrease endothelial eNOS generated bioavailable NO resulting in decreased flow-mediated endothelial-dependent vascular relaxation. To test this hypothesis, the following specific aims will be performed: Aim 1) Do patients with preeclampsia have decreased flowmediated endothelial-dependent vascular relaxation? Aim 2) Do lipid peroxides in preeclamptic plasma decrease endothelial cell eNOS generated bioavailable NO? Aim 3) Is flow-mediated endothelial-dependent vascular relaxation decreased during early pregnancy in women who subsequently develop preeclampsia? Aims 4) Will antioxidant therapy improve flow-mediated endothelialdependent vascular relaxation in patient at risk for preeclampsia? The institutional and departmental environment as well as the facilities and resources are excellent for career development in academic medicine. The K24 award will protect this candidates time and help him to mature into a senior investigator in OB/GYN. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXERCISE PREECLAMPSIA

INTERVENTION

TO

REDUCE

RECURRENT

Principal Investigator & Institution: Patrick, Thelma E.; Assistant Professor; MageeWomen's Health Corporation 204 Craft Ave Pittsburgh, Pa 152133180

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Timing: Fiscal Year 2002; Project Start 05-SEP-2000; Project End 31-MAY-2005 Summary: Exercise has positive effects on the cardiovascular, metabolic, endocrine, and immune systems. Preeclampsia, a hypertensive disorder of pregnancy, has many common risk factors, and a common pathway, namely endothelial activation, with cardiovascular disease. For women who experience preeclampsia in more than one pregnancy, there is an increased risk of cardiovascular disease in later life. Similarities in cardiovascular disease and preeclampsia led to the conclusion that exercise would be an effective intervention in reducing the recurrence of preeclampsia. Reduction in recurrence of preeclampsia is the primary outcome of this study. The secondary aims are to examine the effect of a moderate intensity exercise intervention on markers of the metabolic syndrome in sedentary pregnant women, and to explore the usual health behaviors, self-efficacy, and differences in health behaviors adopted during pregnancy. To test these hypotheses, we propose a randomized clinical trial to examine the effects of a moderate intensity exercise during pregnancy. Multiparous women who had preeclampsia in a previous pregnancy will be enrolled and randomized to one of two groups. The control group will receive usual care, and the intervention group will receive an exercise intervention. The exercise intervention will consist of 30 minutes of moderate intensity physical activity performed on 5 days per week, and short bouts of exercise (3-10 minute episodes of walking) will be encouraged. Projection of sample size, 160 women per group, was based on the dichotomous primary outcome, a reduction of recurrence from 20 percent to 10 percent and accounts for 10 percent attrition. Juried diagnosis by a panel of clinical experts based on stringent clinical criteria for preeclampsia will be used to determine pregnancy outcome. Fasting serum and plasma samples will be obtained at baseline (first trimester), and at two subsequent times (once in the second and third trimester). Subjects will complete an interview to recall physical activity over the past 7 days, and will respond to questionnaires about health promoting lifestyle activities and exercise self-efficacy. This study will contribute to a program of research directed at health promoting lifestyle behaviors in women who are at risk for high-risk pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FATTY ACID TRANSPORT & METABOLISM IN PREECLAMPTIC & NORMAL PREGNANCIES Principal Investigator & Institution: Taylor, Robert N.; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002 Summary: Introduction: Preeclampsia is a serious obstetrical syndrome characterized by hypertension, proteinuria, generalized edema and generalized vasospasm, which affects ~7% of pregnant women. Despite its recognition since antiquity, the current treatment of this disorder is not based on an understanding of its pathophysiology but remains empricial: delivery of the fetus and placenta. The high maternal and fetal morbidity and mortality associated with preeclampsia largely result from the iatrogenic preterm interruption of affected pregnancies. The cellular and molecular biology that underlies this syndrome only recently has begun to be elucidated. Abnormalities of trophoblast differentiation and invasion have been discovered by Dr. Fisher and colleagues. Studies in my laboratory have focused on mechanisms of maternal vascular endothelial dysfunction in preeclampsia, with an emphasis on the biochemical pathways involved in abnormal prostanoid production. Data from our laboratory and those of others indicate that a preponderance of vasoconstrictor prostanoids are produced in vessels and tissues frompreeclamptic women. Methods and Results: We

24

Preeclampsia

have selected a bioassay (acute release of human umbilical vein endothelial cell prostaglandins) as a paradigm to identify the placenta- and plasma-derived factors responsible for endothelial cell activation in preeclampsia. Our data indicate that the enzyme responsible for prostaglandin synthesis in activated endothelial cells is a member of the family of phospholipases A2. Assays of enzyme activity and immunoblotting of specific PLA2 isoforms are in progress to characterize the enzyme(s) induced in activated cells. Fatty acid substrate transport in the circulation by albumin isoforms, and ultimately into maternal endothelial cells, also appears to be abnormal in preeclampsia. Using isoelectric focusing we haveshown that plasma concentrations of pI=4.8 albumin, an isoform that is relatively rich in fatty acids, are increased significantly in women with preeclampsia compared to normal pregnant controls. We propose that specific fatty acids bound to plasma albumin are the precursors responsible for increased prostaglandin production. Mass spectroscopy will be used to identify the fatty acids associated with plasma albumin isolated from preeclamptic and normal pregnant women. Discussion: The proposed studies will characterize the substrates and enzymes which perturb prostaglandin biosynthesis in preeclampsia. An understanding of these molecules should provide targets for the future development of novel therapeutic antagonists for the rational treatment and possible prophylaxis of preeclampsia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FETAL REGULATION OF PLACENTAL BIOLOGY Principal Investigator & Institution: Sahgal, Namita; Pediatrics; University of Kansas Medical Center Msn 1039 Kansas City, Ks 66160 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Appropriate fetal growth and development is dependent upon a multitude of hormonal, genetic, environmental, and nutritional factors. Survival of the fetus is dependent on the ability of the placenta to maintain a balance between the adequate supply of nutrients and simultaneous disposal of waste materials to the maternal circulation. Hence, appropriate and rapid placental responses to insults in either the maternal or fetal compartments will significantly impact the outcome of the pregnancy. Acute fetal insult in the rodent results in changes in placental expression of various nutrient transporters, components of the insulin-like growth factor (IGF) signaling pathway, and the organization of a population of cells termed glycogen cells. Glycogen cells are an important indicator of normal placental development, and are frequently disrupted in pregnancies complicated by diabetes, preeclampsia and intrauterine growth retardation. Both IGF-I and IGF-II are known to have effects on fetal growth. IGF-II in addition has also been shown to play a significant role in placental growth, with IGF-II null animals developing small placentas with a dramatic depletion in glycogen cells. IGFs circulate bound to a family of insulin-like growth factor binding proteins (IGFBPs) which limit/modify their actions, along with displaying IGFindependent effects, unique to each IGFBP. The expression of one of these binding proteins, IGFBP-2 is remarkable, in that it is highly complementary to the expression of IGF-II throughout gestation. In this project we propose to investigate the effects of fetal insult on placental gene expression, and specifically the result of disruptions in the normal IGF-II - IGFBP-2 expression patterns in placental development. In Aim 1 we analyze changes in gene expression following fetal insult/death. Aim 2 focuses on placental development in animals with over expression of IGF-II and IGFBP-2. In Aim 3 the influence of IGF-II on the differentiation of the trophoblast cell lineage is examined. The proposed research utilizes both in vitro and in vivo strategies. Data derived from

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25

these experiments will add to our understanding of the factors involved in placental development, as well as of the role of the fetus in regulating placental metabolism to compensate for adverse fetal and maternal stimuli. This research will contribute to our knowledge of the etiology and pathogenesis of intrauterine growth retardation and perinatal morbidity and mortality. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENERAL CLINICAL RESEARCH CENTER Principal Investigator & Institution: Kelch, Robert P.; Professor and Chairman; Clinical Research Center; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-DEC-1977; Project End 30-NOV-2002 Summary: The objective of the General Clinical Research Center is to provide a high quality physical and intellectual environment in which clinical investigation is conducted with maximum regard for patient welfare and safety. The Center complements and extends the research resources of the College of Medicine, fosters interdisciplinary activity and serve as an educational resource for students, house-staff and faculty. Areas of investigation include women's health, therapy of prostate cancer, bone loss in anorexia, cochlear implants, gene transfer in cystic fibrosis, and homocysteine and atherosclerosis. Neonatal research includes immunologic effects of placental blood transfusions, pharmacokinetics of erythropoietin and the genetics of preeclampsia. The Center also supports multicenter trials evaluating the prevention of type I diabetes, experimental drug therapies in HIV infection, the genetics of alcoholism, treatment of ocular melanoma and medical therapy of prostatic hypertrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: OUTCOMES

GESTATIONAL

DIABETES:

DIAGNOSTIC

CRITERIA

AND

Principal Investigator & Institution: Ferrara, Assiamira; Research Scientist Ii; Kaiser Foundation Research Institute 1800 Harrison St, 16Th Fl Oakland, Ca 946123433 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: (Adapted from Investigator's Abstract) Gestational diabetes mellitus (GDM) is associated with increased risk of several adverse infant and maternal outcomes and its clinical recognition can reduce these risks. There is concern that the current criteria for GDM may be to restrictive and that residual excess risk of perinatal complications exists below present cutoff values. The proposed study will evaluate whether among women without GDM (as defined by current criteria), increasing levels of maternal glycemia are associated with increased risk of selected perinatal complications: infant severe macrosomia, severe hyperbilirubinemia, hypoglycemia, respiratory distress syndrome, and maternal preeclampsia/eclampsia. To accomplish this, the investigators propose to conduct five nested case-control studies, one for each of the complications of interest, within a large multiethnic cohort of approximately 74,000 women who were screened at 24 to 28 weeks of gestation at Kaiser Permanente, Northern California between 1995 and 1998. In this setting nearly 94 percent of the pregnant women are screened for GDM by a 50 gm., 1 hr. oral glucose tolerance test (50 g, 1-h OGTT) and approximately 15 percent have are abnormal screening and go on to receive the diagnostic (100-g, 3-h OGTT) test. Potential cases of each type of complication will be identified by searching computerized hospitalization and laboratory databases. For each of the infant complications, 500 cases will be randomly selected without knowledge of the maternal glucose values. A single control group for the infant complication case groups will be

26

Preeclampsia

1,000 infants randomly selected from all births and frequency matched on gestational age to the distribution of the combined case group. Five hundred women with either preeclampsia or eclampsia and 500 age-matched controls will be randomly selected. The medical records of the 3,000 mother-infant pairs in the four case-control studies on infant complications, and 1,000 women for the case-control study of preeclampsia/eclampsia, will be abstracted to confirm eligibility, and, if so, to ascertain data on possible maternal and infant covariates. Logistic regression will be used to estimate the odds ratios associated with several levels of pregnancy glycemia and perinatal complications. The investigators state that the proposed study will provide important knowledge about the magnitude of the risk of severe perinatal complications associated with degrees of maternal hyperglycemia below the glucose cutpoints currently used to diagnose GDM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GLOBAL NETWORK FOR WOMEN'S & CHILDREN'S HEALTH RESEARCH Principal Investigator & Institution: Spinnato, Joseph A.; Obstetrics and Gynecology; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 17-SEP-2001; Project End 30-APR-2006 Summary: (Provided by applicant): The maternal, perinatal and neonatal morbidity and mortality rates for Brazil are five to ten-fold higher that that reported for developed countries. In Sao Paulo for the year 1998, 127 matemal deaths were recorded. The maternal death rate was 57 per 100,000 live births. Twenty-four of these deaths were directly attributable to complications of eclampsia and preeclampsia. An additional four deaths were related to chronic hypertension. Overall hypertensive complications of pregnancy were associated with 28 maternal deaths and ranked as the number one cause of maternal death (22%). As high as the Sao Paulo maternal mortality rate was, in Brazil for the same year the rate was 140 per 100,000. Complications of hypertensive disease were the most common cause of death (28.5%). The infrastructure and monies to train health professionals in the techniques of clinical research is inadequate in Brazil. As a result, outcomes-based research that might identify methods to eliminate the causes of morbidity and mortality that are specific to Brazil are not performed, or when performed, are likely to be flawed in one way or another, so that accurate conclusions cannot be made. By providing mentored experience in all phases of clinical research to Brazilian health professionals, well designed outcome-based research can be accomplished that will direct changes in clinical management and public policy that will reduce maternal and perinatal morbidity and mortality rates. The aims of this proposal are to: 1) study the efficacy of antioxidant therapy initiated at or before 20 weeks of gestation to reduce the incidence and severity of preeclampsia in a high risk obstetric population in Sao Paulo Brazil; 2) integrate this research effort with the training of a Brazilian scientist (concurrent application to the International Women?s and Children?s Health Research Training Grant TW-00-007); and 3) stimulate and facilitate international collaborative women?s and children?s health research that will reduce morbidity and mortality from conditions affecting women and children in developing countries. Obstetric patients with chronic hypertension, or preeclampsia in a prior pregnancy, presenting for care at or before 20 weeks of gestation will be randomized, in a masked, double-blinded fashion, to receive either Vitamin E (400 IU) and Vitamin C (1,000 mg) or placebo. The primary outcome assessed will be the incidence of preeclampsia. The Research Committee of the Department of Obstetrics and Gynecology, University of Sao Paulo, and the U.S. investigators will assess the long-term impact of this program on

Studies

27

women?s and children?s health research, health care in Brazil, and international research collaboration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOMOCYSTEINE, PREECLAMPSIA

BETA-OXIDATION

AND

RISK

OF

Principal Investigator & Institution: Powers, Robert W.; Magee-Women's Hospital of Upmc 300 Halket St Pittsburgh, Pa 15213 Timing: Fiscal Year 2002; Project Start 01-MAY-2001; Project End 30-APR-2003 Summary: (Adapted from applicant's description): Preeclampsia is the leading cause of maternal mortality in developed nations and increases perinatal mortality five fold. Many risk factors for preeclampsia (obesity, hypertension, insulin resistance, etc.) are similar to those for atherosclerosis. Another risk factor for atherosclerosis, homocysteine, has also been found to be increased in the blood of women with preeclampsia. The mechanism(s) by which homocysteine increases the risk of vascular disease and preeclampsia is largely unknown. Recent studies have demonstrated a strong association between increased plasma homocysteine and insulin resistance. This inter-relatedness of homocysteine and preeclampsia, atherosclerosis and insulin resistance prompted a search for a common mechanism that may be at work in each of these diseases. Insulin resistance affects lipid metabolism and beta-oxidation in critical ways that promote an atherogenic lipid profile, is associated with decreased endothelium-dependent vasorelaxation, and increases the risk of coronary and peripheral vascular disease. These same effects have been described in preeclampsia and likely contribute to the pathology of the disease. Furthermore, genetic studies indicate that disruption of beta-oxidation significantly increases the risk of preeclampsia. Therefore, we speculate that decreased beta-oxidation may be a common mechanism among these diseases, and homocysteine's effect on beta-oxidation will play a major role in the pathology of preeclampsia. We hypothesize that: 1) Hyperhomocysteinemia predisposes toward decreased beta-oxidation, and this effect will be exacerbated in pregnancy and 2) Decreased beta-oxidation during pregnancy will predispose women toward vascular complications associated with preeclampsia. The investigators will test these hypotheses by testing preeclamptic patients for markers of decreased beta-oxidation and relate this to patient's homocysteine concentration. They will investigate if hyperhomocysteinemia in a mouse model will affect betaoxidation in both pregnant and nonpregnant animals. Lastly, the investigators will investigate the effect of pharmacologically induced decreased beta-oxidation on vasculature function in a nonpregnant and pregnant mouse model. These studies may lead to a greater understanding of the mechanism(s) by which hyperhomocysteinemia increases the risk of preeclampsia and to a more general understanding of the pathophysiology of preeclampsia suggesting novel therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HUMAN FETOPLACENTAL VASCULATURE AND CGRP Principal Investigator & Institution: Dong, Yuan-Lin; Obstetrics and Gynecology; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 30-JUN-2006 Summary: (provided by applicant): The maintenance of adequate blood flow to the placenta is essential for a successful pregnancy. Increased fetoplacental vascular resistance and reduced blood flow seen in intrauterine growth restriction (IUGR)

28

Preeclampsia

and/or preeclampsia is associated with increased fetal and neonatal morbidity and mortality. Calcitonin gene-related peptide (CGRP) has been demonstrated to be involved in the regulation of blood pressure and myometrial contractility during pregnancy via its potent smooth muscle relaxant property, but its role as a vasodilator in physiological and pathological fetoplacental circulation is poorly understood. We have new evidence that CGRP receptors are present in the rat placenta and progressively increase as gestation advances. In addition, CGRP peptide is present in fetal plasma at a higher concentration than that in maternal circulation in late pregnancies. CGRP mRNA is abundantly expressed in the fetal dorsal root ganglia (DRG) and progressively enhanced at term. In humans, CGRP relaxes umbilical, chorionic, and stem villous arteries in a dose-dependent fashion indicating that endogenous CGRP may help maintain low fetoplacental vascular tone during pregnancy. To assess the role of CGRP in the control of human fetoplacental vascular tone, we have proposed the following Specific Aims: Specific Aim 1: To characterize CGRP receptors in the human fetoplacental vasculature. We will identify the cellular location and distribution of CGRP receptor component CRLR and RAMP1 in fetoplacental vessels, and assess radio ligand CGRP binding affinities and capacities. Specific Aim 2: To assess the vasodilatory effects of CGRP on fetoplacental vessels, and determine if they are altered with advancing gestation and modulated by steroid hormones. Specific Aim 3: To determine the post-receptor signaling pathway of CGRP-induced fetoplacental vascular relaxation. Specific Aim 4: To determine the role of CGRP in altered fetoplacental vascular reactivity in IUGR and/or preeclampsia, and evaluate whether insufficient CGRPrelated vasodilator mechanisms were involved in the pathophysiology of IUGR and/or preeclampsia. Our long-term goal is to define the role of CGRP in the regulation of fetoplacental circulation and vascular adaptation during pregnancy. This proposal will have important basic science and clinical implications. Our results may indicate that CGRP has vasodilatory effects on human fetoplacental vasculature and is regulated by sex steroid hormones, as well as elucidate the role of CGRP in IUGR and/or preeclampsia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYPOXIA PREECLAMPSIA

INDUCIBLE

TRANSCRIPTION

FACTORS

AND

Principal Investigator & Institution: Conrad, Kirk P.; Professor; Magee-Women's Health Corporation 204 Craft Ave Pittsburgh, Pa 152133180 Timing: Fiscal Year 2002; Project Start 14-JUN-2002; Project End 31-JAN-2007 Summary: Hypoxia plays an important role in normal placental development and its pathological processes. Cellular hypoxia leads to the expression of specific transcription factors including hypoxia inducible factor HIF- 1alpha and -2alpha which heterodimerized with constitutively expressed HIF-1beta and bind to the hypoxia response element of many genes. Recently, we documented the expression and ontogeny of HIF-1alpha and -2alpha mRNA, protein and DNA binding activity in placental villi. We showed regulation by hypoxia at the level fo protein, but not mRNA, as well as widespread and overlapping cellular distribution of HIF- 1alpha and -2alpha consistent with the physiological with the physiological hypoxia at that gestational stage. The main regulation of HIF-1alpha and -2alpha protein turnover has recently been shown to be through ubiquitin-proteasomal mediated degradation. Thus, we have begun investigating this pathway in the human placenta. Our preliminary data suggest impaired oxygen-dependent degradation of HIF-1alpha and -2alpha in villous explants from preeclamptic placentas. Thus, deficient degradation of HIF-1alpha and -2alpha

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29

contributes to exaggerated expression in preeclamptic placenta. Based on these findings five general hypotheses are proposed. Hypothesis 1 Proteasomal degradation of HIF1alpha and -2alpha proteins is impaired in placental villi from women with preeclampsia, thereby contributing to deficient oxygen- dependent degradation and exaggerated placental expression. Hypothesis 2 Impaired uqiquitinylation of HIF-1alpha and -2alpha contributes to deficient proteasomal degradation of these transcription factors in placental villi of women with preeclampsia. Hypothesis 3 HIF-1alpha and 2alpha proteins are over-expressed by extravilous trophoblasts in the placental bed of women with preeclampsia. Hypothesis 4 HIF-1alpha and -2alpha regulated the expression of specific genes in the human placenta that are likewise inappropriately regulated in preeclampsia. Hypothesis 5 Deficient ubiquitin-proteasomal degradation of HIF-1alpha and-2alpha is a widespread abnormality occurring in other tissues of preeclamptic women and in their offspring. In summary, we propose to investigate the molecular mechanisms and consequences of HIF-1alpha and -2alpha over-expression in the preeclamptic placenta. These studies will likely advance our understanding of the placental contribution to the pathophysiology of preeclampsia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNE ACCEPTANCE OF PREGNANCY Principal Investigator & Institution: Mor, Gil G.; Associate Professor; Obstetrics Gynecology & Reprod Scis; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2003 Summary: The underlying hypothesis of this proposal is that the trophoblast induces a transient, specific tolerance to paternal alloantigens by clonal deletion (apoptosis of cytotoxic T cells) and that this process is mediated by the Fas-FasLigand system. This hypothesis rests on the fact that during implantation the maternal immune system is not indifferent to the presence of paternal alloantigens in the fetus. Implantation is known to be followed by local immune response characterized by the presence of a large population of T cells, many of which express surface markers characteristic of activated T cells and recognize paternal alloantigens. The mechanism preventing any rejection of the fetus is still unknown. The Fas-FasLigand system is involved in the turnover of activated mature T cells and/or clonal deletion of autoreactive T cells in the periphery. FasL, a membrane bound protein, delivers an apoptotic signal and induces cell death by binding to its receptor Fas. FasL is expressed in activated T cells and in immune privileged sites such as the testis and eye. The trophoblast constitutes the outer most border between maternal and fetal circulation in contrast to the old concept of a barrier in the mechanical sense. The trophoblast acts as an active and selective barrier especially to activated T cells. In this setting, activated T cells recognizing placental alloantigens express Fas, bind to the FasL expressed by the trophoblast and thereafter undergo apoptosis. This transient tolerance makes the place of implantation an immunologically privileged site. Since the expression of the FasL by the trophoblast is what confers the immuno privileged properties to the implantation site, the investigators plan to focus their attention mostly on the regulation of FasL expression. To prove the validity of this hypothesis, the investigator proposes a three year plan to: 1) study FasL expression in normal and pathologic human pregnancies; 2) investigate in vitro the regulators of FasL expression; and 3) develop an in vivo animal model to test the hypothesis. If the hypothesis is correct, an imbalance in the Fas-FasL system may cause implantation failure, recurrent pregnancy loss, or preeclampsia. The significance of this proposal is not limited to reproductive problems. It is anticipated that these studies will lead to a

30

Preeclampsia

better understanding of tumor behavior, actions of chemotherapeutic agents and transplant physiology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PLACENTA

IMMUNOMODULATORY

B7

FAMILY

PROTEINS

IN

THE

Principal Investigator & Institution: Petroff, Margaret G.; Anatomy and Cell Biology; University of Kansas Medical Center Msn 1039 Kansas City, Ks 66160 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2008 Summary: (provided by applicant): A breakdown in the immunotolerogenic function of the placenta may result in a failure of the placenta to adequately protect the fetus against possible harmful effects of the maternal immune system. This could in turn contribute to certain pathologies of the placenta such as intrauterine growth retardation and preeclampsia, complications that not only put the mother' s health at risk, but also may have long-term effects on the health of the child. Recent studies have unveiled the existence of multiple cell surface-associated proteins belonging to the B7 and CD28 families that are of fundamental importance in immunological tolerance. Our preliminary studies have shown that these molecules are strong candidates for modulation of the maternal immune system by fetal trophoblast cells. In AIM 1 of this proposal, we will map the cellular sources of (a) the B7 family ligands, B7-DC and B7H2, and (b) their CD28 receptors, PD-1 and ICOS, at the human maternal-fetal interface. Placental tissues and subpopulations of cells of the maternal-fetal interface will be examined for B7 and CD28 family member expression using molecular and histological techniques. In AIM 2, we will elucidate the mechanisms of regulation of BT-H1 and BTH2 in trophoblast cells. This aim will determine the molecular and cellular mechanisms by which these molecules are regulated. AIM 3 will be to determine the functional effects of B7-H1 and B7-H2 on lymphocyte death, proliferation, and cytokine production. In these studies, human trophoblast cell culture models will be used to dissect the molecular and cellular consequences of signaling from trophoblast B7-H1 and B7-H2 to lymphocytes. Lastly, AIM 4 will evaluate the consequences of disruption of B7-H1 and B7-H2 signaling on cytokine production, leukocyte infiltration, and fetal viability in pregnant mice. In this aim, post-implantation pregnant mice will be treated with neutralizing antibodies and will be evaluated for these reproductive parameters. These studies are expected to yield a wealth of insight on the mechanisms by which successful pregnancy is permitted despite the allogeneic incompatibility between mother and fetus. Further, these studies will advance our knowledge in developing therapies for infertility and a wide range of other ailments such as cancer and autoimmune disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPACT OF ENDOTHELIN IN INTRAUTERINE GROWTH RESTRICTION Principal Investigator & Institution: Thaete, Larry G.; Evanston Northwestern Healthcare Evanston, Il 60201 Timing: Fiscal Year 2002; Project Start 18-JUN-2001; Project End 31-MAY-2006 Summary: (Adapted from applicant's description): Intrauterine growth restriction (IUGR) occurs in 4 to 7% of all infants delivered in developed countries, and is a major contributor to perinatal morbidity and mortality. Inadequate uteroplacental perfusion is fundamental to most cases of IUGR in humans. Endothelin-1 (ET-1) and nitric oxide

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(NO) are vascular mediators which are important for the regulation of uterine and placental vascular tone. The investigators hypothesize that increased endogenous ET-1, a locally active vasoconstrictor, is critically important in the pathophysiology of IUGR. They will evaluate the molecular mechanisms regulating the activities of both ET-1 and NO in uteroplacental perfusion and IUGR. They also will evaluate the role of endogenous ET-1 in the pathophysiology of IUGR, using ET-1 receptor antagonists. The investigators will use two different animal models of IUGR which were selected because of the opportunity they provide to study the roles of these two mediators. 1) Chronic maternal hypoxia is a model of IUGR which is associated with increased endogenous ET-1 as well as decreased nitric oxide synthase (NOS) activity. This model will be used to evaluate the efficacy of ET-1 antagonists to improve uteroplacental perfusion and prevent IUGR. 2) Chronic NOS inhibition is another established model of IUGR which also is associated with increased circulating endogenous ET-1. Additionally, NOS inhibition in the rat mimics human preeclampsia, a condition commonly associated with IUGR. The investigators will use this model to evaluate whether ET-1 antagonism prevents the preeclampsia-like state, as well as IUGR, caused by chronic NOS inhibition. In each of these models, they will evaluate the molecular mechanisms which regulate ET-1 activity. Additionally, in the hypoxia model the investigators will evaluate the molecular mechanisms regulating NO activity. The goal is to better understand the regulation of uteroplacental perfusion, to delineate the molecular mechanisms regulating the synthesis and activity of ET-1 and NO, and, using ET-1 antagonists, to evaluate the specific role of ET-1 in the pathophysiology of IUGR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEPTIN PREECLAMPSIA

IN

PREGNANCY

METABOLIC

ADAPTATION

&

Principal Investigator & Institution: Teppa, Roberto; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002 Summary: In this project we tested the biological relevance of increased circulating leptin and whether pregnancy might permanently alter circulating leptin. We tested the following hypothesis; free leptin is increased in normal pregnancy, free leptin concentration returns to prepregnancy concentration after normal and preeclamptic pregnancy, free leptin concentrations are not different after pregnancy in women who have had normal or preeclamptic pregnancies. These hypothesis were tested by the following specific aims: We measured free and bound leptin in preeclamptic and normal pregnant patients during pregnancy. We measured leptin fractions in nulligravid patients to have a baseline to compare our data during the pregnancy period. Free leptin is increased in obese individuals and it is the fraction which is altered by perturbations (e.g., feeding and fasting) known to alter circulating leptin concentration. During human pregnancy the total concentration of many hormones in blood is increased with minimal changes in the free active hormone because of an increase in binding proteins. We determined that the increased plasma leptin of normal pregnancy and the further increase in preeclampsia are not simply due to this phenomenon. We compared serum leptin concentration in serum samples obtained from 18 nulligravid women. Two ml serum were loaded into a column packed with Sephadex G-100 at 4 C in order to separate free from bound leptin. Leptin concentration in the fractions were assayed by RIA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIPID METABOLISM IN PREGNANCY AND WITH PREECLAMPSIA Principal Investigator & Institution: Kelley, David E.; Professor of Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: The specific aim of this project is to examine lipid metabolism in women with healthy and preeclamptic pregnancies and test the hypothesis that women who develop preeclampsia have an accentuation of hypertriglyceridemia and free fatty acids during fasting and postpradial conditions, which are above the physiologic elevations normally found in pregnancy. Pregnancy has a pronounced effect on maternal lipid metabolism. Plasma lipoprotein levels increase markedly during pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIPOPROTEIN LIPASE AND PREECLAMPSIA Principal Investigator & Institution: Hubel, Carl A.; Associate Professor; MageeWomen's Health Corporation 204 Craft Ave Pittsburgh, Pa 152133180 Timing: Fiscal Year 2002; Project Start 15-FEB-2000; Project End 31-JAN-2005 Summary: Preeclampsia is a leading cause of maternal death and increases perinatal death five-fold. There is compelling evidence that maternal endothelial dysfunction contributes to the pathogenesis of preeclampsia. Hypertriglyceridemia, decreases in high density lipoprotein (HDL) cholesterol, and abnormally small-sized low density lipoprotein (LDL) particles are characteristic features of preeclampsia. We have proposed that these lipid abnormalities promote endothelial dysfunction in preeclampsia through the generation of oxidative stress. Lipoprotein lipase (LPL) plays a vital role in the clearance of triglycerides from the circulation. The importance of LPL defects in the development of cardiovascular disease is increasingly recognized. Several common variations in the LPL gene promote the triad of increased triglyceride, decreased HDL cholesterol, and small-sized LDL. The dyslipidemic effects of these functional variants are accentuated by pregnancy. In our Caucasian population, a sum total of 18.8% of preeclamptics are heterozygous for either the N291S or D9N coding sequence variants of the LPL gene, compared with 4.6% of normal pregnancy controls. Accordingly, Aim 1 is to test whether these observations can be generalized to other populations. We will compare the prevalence of the four most common, functional variants in the LPL gene in Caucasians and African-Americans from western Pennsylvania, and in Icelandic women. Aim 2 is to sequence the coding and promoter regions of the LPL gene to identify other functional variants, which will then be genotyped in cases and controls. We posit that variations in the LPL gene the predispose to dyslipidemia are over-represented in women with preeclampsia. Aim 3 is to compare plasma lipids, lipid peroxidation products, and markers of endothelial dysfunction in women with preeclampsia stratified by genotype. We hypothesize that, among women with preeclampsia, those carrying LPL variants with reduced enzymatic activity will display an especially adverse blood profile. In Aim 4, we will measure plasma LPL enzyme activity in women 12 weeks postpartum to further test the hypothesis that a constitutional deficiency in LPL (hormonally and/or genetically mediated) is associated with preeclampsia. In Aim 5, we will explore the effects of heterozygous LPL deficiency on endothelial regulation of vascular function during pregnancy, using the LPL knockout mouse. This systematic approach will help to clarify the link between dyslipidemia and the pathogenesis of preeclampsia and could provide clues to prevention or treatment of the disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MAGNESIUM'S ANTIHYPERTENSIVE EFFECTS IN PREECLAMPSIA Principal Investigator & Institution: Standley, Cynthia A.; Physiology; Midwestern University 555 31St St Downers Grove, Il 60515 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Preeclampsia consists of hypertension and proteinuria in pregnancy and is the most common cause of maternal mortality if left untreated. Hypertension in preeclampsia is implicated in the constellation of symptoms including seizures, glomerular damage and intrauterine growth retardation. Inhibition of nitric oxide synthase (NOS) in pregnant rats is an established model of preeclampsia, as it replicates these symptoms. Magnesium sulfate is the standard treatment for preeclampsia. However, magnesium's anti-hypertensive effects remain poorly understood. Magnesium acts as a vasodilator, an action customarily attributed to its ability to antagonize calcium entry into vascular smooth muscle cells (VSMC). Emerging evidence suggests that magnesium may also regulate vascular nitric oxide (NO). Therefore, magnesium may mediate vascular relaxation and reduction of blood pressure by activating the vascular NO/cGMP/protein kinase G (PKG) signaling pathway. We hypothesize that magnesium and NO act synergistically at the level of the vasculature to cause vasodilation and a reduction in blood pressure. Specifically, magnesium's ability to reduce blood pressure in the nitric oxide-inhibited animal model of preeclampsia is due to its ability to upregulate vascular NO/cGMP/PKG signaling, effectively reducing total vascular resistance and consequently blood pressure. To test this hypothesis, we will use the NOS inhibitor, NGnitro-L-arginine methyl ester (L-NAME), to induce hypertension in pregnant rats. Then, graded doses of magnesium sulfate via chronic infusions in vivo, and acute treatment of vascular tissues ex vivo, will be used to address the following specific aims: 1) Determine if magnesium predictably reduces blood pressure and proteinuria and alters plasma/urinary NOS signaling metabolite levels, and whether these measures can be used therapeutically to predict and track hypertension; 2) Determine magnesium's effects on vascular inducible NOS (iNOS) and endothelial NOS (eNOS) expression; 3) Investigate magnesium's effects on vascular NOS signaling such as NOS activity, NO-mediated guanylate cyclase activity and PKG expression, and 4) Investigate magnesium's ability to regulate vascular reactivity in response to NO-generating stimuli. Data derived from these experiments will elucidate the anti-hypertensive effects of magnesium, its mode of action and the roles of NO and magnesium in preeclampsia and pregnancy-induced hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MATERNAL BRAIN BLOOD FLOW IN NORMAL PREGNANCY AND PREECLAMPSIS Principal Investigator & Institution: Herd, James A.; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HOMEOSTASIS

MATERNAL

DEHYDRATION--FETAL/AMNIOTIC

FLUID

Principal Investigator & Institution: Ross, Michael G.; Professor and Chair; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 905022052

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Preeclampsia

Timing: Fiscal Year 2002; Project Start 01-APR-1989; Project End 31-MAR-2004 Summary: Amniotic fluid (AF) is an essential accompaniment of normal pregnancy, necessary for fetal movement, growth and development. Oligohydramnios, or reduced AF volume, occurs in 8 to 38 percent of all pregnancies. The majority of oligohydramnios patients have no identifiable medical or antepartum complication and only 7 percent of cases have associated fetal malformations. However, oligohydramnios is often associated with conditions of chronic fetal stress, such as intrauterine growth retardation, preeclampsia and postterm pregnancy. These conditions, together with the direct effect of reduced AF volume, results in significant perinatal morbidity and mortality. Increasing AF volume in laboring patients with oligohydramnios improves fetal outcome, though this generally requires rupture of fetal membranes. However, our studies demonstrate that modulation of AF production (fetal urine flow) and AF resorption (fetal swallowing and intramembranous flow) may be utilized to increase AF volume in patients with intact membranes. We have developed a novel model to increase AF volume utilizing maternal administration of the arginine vasopressin (AVP) antidiuretic agonist [desamino, D-Arg8]-AVP (DDAVP). Our studies in the ovine model indicate that maternal hydration and DDAVP induces maternal and fetal plasma hyponatremia, marked increases in fetal urine flow, reduced fetal swallowing and expansion of AF volume. Our human studies have supported the clinical utility of these interventions. Despite these promising results, critical issues of efficacy and safety of DDAVP therapy for both the mother and fetus must be resolved prior to clinical use. Firstly, in studies of efficacy, we will determine the minimum level of maternal hyponatremia which induces and maintains fetal fluid responses, and examine the effects of alterations in placental osmolality gradients. Long term studies will examine the effects of hyponatremia on ovine AF volume, maternal plasma volume and umbilical and uterine blood flows in both normal and oligohydramnios ovine pregnancies. Secondly, in studies of fetal safety, we will determine if fetal brain edema and/or loss of brain electrolytes are induced by hyponatremia. As AVP has important fetal fluid and cardiovascular regulatory roles, we will determine the effect of hyponatremia on fetal osmotic and non- osmotic stimulated AVP secretion. Finally, as permanent imprinting of AVP synthesis and secretion regulatory systems may occur in response chronic tonicity alterations in newborn rats, we will examine the effects of chronic tonicity alterations on fetal AVP transcription and translation. Physiologic assessments will focus on measurements of fetal fluid exchange and fetal plasma and AF volume and composition. Endocrine and molecular assessments will include determination of fluid regulatory hormones and hypothalamic AVP mRNA and pituitary AVP contents, utilizing our newly developed ovine 130 bp cDNA probe and solution and in situ hybridization techniques. The goal of this project is to determine critical efficacy and fetal safety issues central to maternal DDAVP treatment, prior to widespread clinical use in human pregnancies with oligohydramnios. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MATERNAL COORDINATING CTR

FETAL

RESEARCH

NETWORK:

DATA

Principal Investigator & Institution: Thom, Elizabeth A.; Associate Research Professor of Statisti; Statistics; George Washington University 2121 I St Nw Washington, Dc 20052 Timing: Fiscal Year 2002; Project Start 15-APR-1998; Project End 31-MAR-2003 Summary: (Adapted from Applicant s Description): In 1986, the National Institute of Child Health and Human Development created two multicenter perinatal research networks, the Neonatal Research Network and the Maternal Fetal Medicine Units

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(MFMU) Network, each consisting of a number of major academic clinical centers, a data coordinating center, and the Institute, itself. The purpose of both Networks was to conduct clinical research aimed at reducing the risk of adverse pregnancy and infant outcome with the ultimate purpose of contributing to the body of well-conducted studies on which to base medical decisions in obstetrics and neonatology. At present, the MFMU Network is planning, conducting and analyzing multiple randomized clinical trials and observational studies in various aspects of perinatal medicine such as preterm birth prevention, preterm labor suppression, prevention of preeclampsia, and the effects of drugs in pregnancy. The George Washington University Biostatistics Center has been the Data Coordinating Center for both Networks since its inception. This applicant continues to serve as such for the MFMU Network. The purpose is to provide expertise and support in study design, study conduct and statistical analysis. The investigators will provide statistical leadership in the design of the study, prepare interim analyses, and perform final analyses in an expeditious and timely manner. They will prepare study documents, including protocols, manuals of operations and case report forms, and will continue to provide a comprehensive data processing system including distributed and central data entry, data base management and data quality control. They will assist investigators in preparation of manuscripts and abstracts from study results and will archive the data for public access. They will also provide administrative support such as: arrangement of logistical services for provision of study drugs and laboratory assays, coordination of meetings, training sessions and outcome reviews. They will manage resources effectively, so that they can start new studies in a timely manner. In summary, they will participate as full members of the Network, with the common goal of understanding and improving the course of pregnancy and neonatal outcome Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MATERNAL-FETAL HLA SHARING AND RISK OF PREECLAMPSIA Principal Investigator & Institution: Saftlas, Audrey Frieda.; Associate Professor; Epidemiology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-SEP-1995; Project End 31-MAR-2005 Summary: An accumulating body of epidemiological evidence points coherently toward an immune-based etiology for preeclampsia. Several recent studies, as well as a collection of other studies conducted over the past 25 years, suggest that exposure to paternal, fetal; or foreign antigens is protective against subsequent risk preeclampsia; and that paternal/fetal factors may be as important as maternal factors in the etiology of preeclampsia. Consistent this evidence, HLA-sharing between mother and fetus has been positively associated with risk of preeclampsia. We hypothesize that histocompatibility between mother and fetus may have a detrimental effect on pregnancy by impairing maternal recognition of the fetal allograft as a gestation, thereby compromising development of maternal immune tolerance and effective implantation of the placenta. To evaluate this hypothesis, we propose to conduct a case-control study to determine if nulliparous women who develop preeclampsia are more likely to share HLA antigens with their infants than women who have normotensive gestations. Specifically, we will examine sharing at each of five HLA loci (A, B, C, DR, and DQ), as well as generalized sharing across loci. In addition, we will evaluate selected epidemiologic factors indicative of exposure to paternal/fetal antigens (e.g., duration of sexual cohabitation, coital frequency, and use of barrier contraception with baby's father prior to conception). We will also test for the presence of gene-environment interactions to determine if effects of maternal-fetal HLA sharing are modified by the primary

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epidemiologic exposures under study. The study population (N=250 cases; N=250 controls), identified from Iowa and Connecticut live birth files, will include residents of four Iowa and two Connecticut counties who deliver between November l, 2001 and October 31, 2003. All participants will be asked to provide buccal cell samples from their babies and themselves for HLA genotyping (N=1,000 samples), and to respond to a 25 minute telephone interview. Medical chart abstractions will be conducted to validate case definition and control criteria. The study was powered to detect a two-fold increased risk of preeclampsia associated with the presence of only one maternal- fetal HLA mismatch across the three loci (HLA-A, B, and DRbeta1) loci, with at least 80 percent power, and an alpha of.05. The proposed study may be the first to examine the effects of maternal-fetal HLA sharing in an adequately powered epidemiological framework. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF UTERINE VASCULAR ADAPTATION IN PREGNANCY Principal Investigator & Institution: Gokina, Natalia I.; Obstetrics and Gynecology; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2003; Project Start 04-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Normal pregnancy is characterized by a remarkable enhancement of uterine blood flow due to vasodilation and growth and remodeling of uterine vasculature that is associated with an increased uterine reactivity to vasoconstrictors. The long-term goal of this proposal is to understand the causes and cellular mechanisms underlying the modulation of uterine vascular contractility during gestation, with a specific focus on the role of ion channels in endothelial and vascular smooth muscle cells. Our central hypothesis is that pregnancy down- regulates the delayed rectifier and Ca2+-activated potassium channels with a resultant increase in Ca 2+ influx and smooth muscle contractility. Enhanced Ca 2+ sensitization of contractile process is a synergistical mechanism. Pregnancy-induced up-regulation of PKC and RhoA is proposed as a common regulatory mechanism for enhanced Ca 2+ sensitization and inhibition of K+ channel function. These adaptive changes are counteracted by increased Ca2+-dependent production of endothelium-derived NO and EDHF. Furthermore, we suggest that the effects of pregnancy are highly localized by the side of placentation and are mediated by estrogen. Specific Aim 1 will determine the mechanisms that regulate a steady state global [Ca2+]_ in smooth muscle of uterine resistance arteries, and their modulation in pregnancy. The role of PKC and RhoA in regulation of Ca 2+ sensitization and ion channel function will be studied. Specific Aim 2 will explore the mechanisms by which NO and EDHF mediates the effects of pregnancy on uterine arterial contractility with a specific focus on the role of endothelial intracellular Ca 2+ and small conductance Ca 2+-activated potassium channels. Specific Aim 3 will test the role of local vs. systemic factors, and of estrogen in mediating the effects of pregnancy on uterine artery function. The three Specific aims will integrate the physiological function (regulation of arterial diameter) with intracellular (Ca 2+ signaling, Ca 2+ sensitivity and ion channel function) and molecular (PKC and RhoA) mechanisms and will be accomplished by direct measurements of arterial diameter, intracellular Ca, membrane potential, expression and distribution of PKC and RhoA, and ion currents in endothelial and smooth muscle cells. The proposed study will provide new insights into cellular and molecular mechanisms mediating the effects of pregnancy and estrogen on uterine blood flow and significantly deepen the

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understanding how these mechanisms are altered in pregnancy-induced hypertension and preeclampsia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OT MATERNAL IMMUNE TOLERENCE Principal Investigator & Institution: Glimcher, Laurie H.; Irene Heins Given Professor of Immuno; Cancer Cell Biology; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-MAY-2007 Description (provided by applicant): How the allogeneic fetus avoids maternal immune rejection during pregnancy is not only one of the outstanding questions in contemporary immunology, but is also now recognized to have major clinical relevance towards diseases such as recurrent spontaneous abortion and preeclampsia, as well as application towards organ transplantation. Although it is generally accepted that the maternal immune system is ?aware? that the fetus and placenta exist, studies to date have only focused on CD8+ T cells and B cells, and thus have not addressed the behavior of potentially reactive CD4+ T helper cells, the lymphocyte subset likely to play the most important role in any form of antigen-specific tolerance induction. Here, we will directly characterize the responses of both maternal CD4+ and CD8+ T cells towards a placentally expressed antigen, taking advantage of transgenic mice we have recently made that express the well-characterized model antigen ovalbumin in placental tissues (Aim 1). The use of this system will also allow us to test whether maternal tolerance towards the fetus and placenta is local or systemic, and whether it involves attenuation of affector or effector arms of the immune response. The nature of antigen presenting cells (APCs) in the pregnant uterus is another area that is virtually unexplored, despite the central role of these cells in regulating tolerance induction. Thus, we will characterize the behavior and antigen-presenting capacity of APCs in the pregnant uterus, focusing on resident dendritic cells, which have been completely uncharacterized in mice (Aim 2). Lastly, we describe the generation of novel transformed murine trophoblast cell lines directly from cultured trophoblast stem cells. Since these transformed trophoblasts are rejected in non-pregnant allogeneic mice following subcutaneous injection, they provide a powerful reagent for dissecting the relative importance of trophoblasts, the uterine environment, and the hormonal state of pregnancy in establishing maternal tolerance (Aim 3). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MEDIATORS OF VASCULAR DYSFUNCTION IN PREECLAMPSIA Principal Investigator & Institution: Gandley, Robin E.; Magee-Women's Health Corporation 204 Craft Ave Pittsburgh, Pa 152133180 Timing: Fiscal Year 2002; Project Start 14-JUN-2002; Project End 31-JAN-2007 Summary: The goal of this project is to investigate potential mechanisms underling the vascular dysfunction that occurs during and after preeclampsia. Inactivation of nitric oxide (NO) by reactive oxygen species, especially superoxide (O2-), is an important mechanism of vascular dysfunction in several diseases. In this context, important links exist between angiotensin II, vascular O2-production and impaired NO-dependent relaxation. Our data has implicated angiotensin AT-1 receptor signaling and increased vascular O2-generation in the increased myogenic response and loss of endotheliumdependent relaxation that results from exposure of resistance arteries to preeclampsia plasma in vitro. Vitamin C (abscorbate) is a key modulator of NO. Plasma ascorbate is

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decreased during preeclampsia. In a strain of rats unable to synthesize ascorbate, we have shown that subnormal ascorbate intake (30-40% plasma reduction) during pregnancy results in a striking increase in vascular 02- output and myogenic reactivity. Therefore, we hypothesize that two phenomena associated with preeclampsia, namely 1) plasma factors interacting with the AT1 receptor, and 2) suboptimal ascorbate reserves operate in tandem to increase the prevalence of oxidative reactions within the vasculature. In turn, this leads to effective deficiency of NO, through oxidative degradation of NO and/or impaired vascular response to NO. Accordingly, we will use our isolated artery bioassay system to examine plasma factors mediated altered NOdependent responsiveness (Aims 1 and 2). Aim 1 is to characterize the functional changes induced by exposure of mesenteric arteries to pregnancy and postpartum plasma and to evaluate the role of candidate factors operating through angiotensin receptor subtypes. Aim 2 is to determine the role and enzyme sources of O2-, effects of exogenous anti-oxidants and alterations in eNOS potentially impacting NO-dependent responsiveness in this model. We will also use our unique rat strain to further explore the role of ascorbate in the vascular adaptation to pregnancy (Aims 3 and 4). Aim 3 test the hypothesis that subnormal ascorbate results in an effective deficiency of NO that is accentuated during pregnancy. Aim 4 is to determine the oxidative mechanisms of decreased NO bioavailability in this model. Aim 4 is to determine the oxidative mechanisms of decreased NO bioavailability in this model. This integrated approach, in combination with Subproject by S. Schroff, will provide important information concerning oxidant/anti-oxidant mediators of vascular hyperresponsiveness during and after preeclampsia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MENTORED DEVELOPMENT AW

PATIENT

ORIENTED

RESEARCH

CAREER

Principal Investigator & Institution: Barry-Carr, Darcy; Obstetrics and Gynecology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: PROPOSAL (Adapted from the applicant's abstract): Pre-eclampsia, a hypertensive disorder unique to pregnancy, is a leading cause of maternal and neonatal morbidity and mortality. Endothelial dysfunction is a central feature in the pathophysiology of pre-eclampsia. Mechanisms that have been suggested to contribute to the endothelial dysfunction of pre-eclampsia include insulin resistance and a hyperdynamic circulation (high cardiac output). Insulin resistance and high cardiac output persist postpartum, suggesting that these women have an underlying disorder. However, it is unclear whether these abnormalities are related and whether insulin resistance has a role in producing hemodynamic alterations and endothelial dysfunction in these women. The investigator hypothesizes that postpartum women who have a history of pre- eclampsia are insulin resistant and have associated alterations in hemodynamics and endothelial function. Furthermore, she hypothesizes that insulin resistance has a causal role in producing these changes. Two specific aims have been identified to address these hypotheses: 1) to determine whether the insulin resistance present in postpartum women with a history of pre-eclampsia is associated with altered hemodynamics and endothelial dysfunction; and 2) to determine whether reversing insulin resistance in women with a history of pre-eclampsia, is associated with improvements in hemodynamics and endothelial function, thus suggesting that insulin resistance is a causative factor in women with these abnormalities. A case-control study will address the first specific aim. A double-blind, placebo-controlled, randomized

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study will address the second specific aim by using an insulin sensitizing agent, rosiglitazone, as an interventional tool. The results of these studies could provide a rationale for future investigations aimed at determining whether treating insulin resistance in women with a history of pre-eclampsia will decrease the risk of recurrent pre- eclampsia in subsequent pregnancies and reduce the prevalence of the long-term metabolic and cardiovascular complications in these women as they age. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MENTORED DEVELOPMENT AW

PATIENT-ORIENTED

RESEARCH

CAREER

Principal Investigator & Institution: Funai, Edmund F.; Obstetrics Gynecology & Reprod Scis; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 30-JUN-2005 Summary: PROPOSAL (Adapted from the applicant's abstract): The aim of this grant application is to test the hypothesis that in normal pregnancy soluble GPx expressed by the placenta and released into the maternal compartment, catalyzes liberation of NO from S-nitrosothiols (SNOs), such as S-nitroso- glutathione (SNO-Glu). This contributes to the decrease in BP seen as a normal pregnancy progresses. The investigators propose that disturbances in placenta GPx expression or release may be responsible for the various manifestations of pre-eclampsia. In addition, a hypoxic environment, as may be found in the intervillous space early in gestation, may contribute to an increase in endothelial nitric oxide synthase (eNOS) expression, mediated through vascular endothelial growth factor (VEGF). Elevated plasma VEGF levels in the first trimester of women destined to develop pre-eclampsia may suggest an early compensatory mechanism to promote both increased angiogenesis and blood flow. They anticipate that the results of this study will extend their understanding of the pathogenesis of preeclampsia and contribute to strategies for early diagnosis and treatment. A comparison of GPx levels in plasma from normal pregnant, pre-eclamptic pregnant and nonpregnant women will indicate whether GPx is secreted by the placenta into the maternal circulation at levels high enough to support a role for placental GPx in the transport and bioavailability of NO. Northern blot analysis and immunoassay will be used to confirm that expression of GPx messenger ribonucleic acid (mRNA) and release of GPx protein is reduced in placentas from term pre-eclamptic pregnancies as compared to normal pregnancies. NO and SNO-Glu levels in blood from nonpregnant, normal pregnant and pre-eclamptic women will indicate whether there is a relative increase in SNO-Glu in pre-eclampsia, at the expense of bioavailable NO. SNO-hemoglobin levels in venous blood from the three groups will be compared, as one would anticipate higher levels in normal pregnant women. Preliminary data suggest that VEGF levels rise significantly in the first trimester in those patients destined to develop pre-eclampsia, and VEGF may serve as an early marker to identify those patients at risk. They will investigate potential relationships between hypoxia and the expression of VEGF, GPx and eNOS. In addition, plasma VEGF levels will be measured serially throughout gestation during normal and pre-eclamptic pregnancies, and the value of VEGF and its inhibitor, Soluble Flt-1 (sFIt1), as early and reproducible markers of preeclampsia will be explored. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR GENETICS BASIS OF MAMMALIAN BIRTH DEFECTS Principal Investigator & Institution: Lossie, Amy C.; Molecular and Human Genetics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030

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Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-SEP-2005 Summary: (provided by applicant): Extraembryonic tissues, which are derived from the trophoblast layer of the blastocyst, are crucial for normal mammalian development, with placental failure linked to Intrauterine Growth Retardation syndrome (IUGR) and Preeclampsia. Mutagenesis experiments spanning the last 50 years have uncovered a potential model system for IUGR and/or Preeclampsia. This locus, 17Rn3, lies within the albino-deletion complex on chromosome 7 and consists of 6 alleles (ml-m6), all of which have defects in extraembryonic development that can be attributed to trophoblast-derived abnormalities. These 6 mutants also have primary mesoderm defects in the embryo, indicating that this locus has pleiotropic functions in development. In addition, maternal transmission of the m6 allele in hemizygotes is lethal, suggesting that genomic imprinting could also be involved. Mutation analysis has identified Odz4, the Drosophila Odd Oz homolog 4, as the gene responsible for the m4 allele of 17Rn3. Odz4 is one of the four mouse homologs of the Drosophila odd oz/tenascin major (odz/Ten-m) gene, and a member of the Teneurin protein family. Teneurins are cell surface signaling molecules that are highly expressed in the developing CNS and may play a role in limb development, somite formation and the patterning of neural connections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR GENETICS OF PREECLAMPSIA/ECLAMPSIA Principal Investigator & Institution: Williamson, Roger A.; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002 Summary: The goals of this study are to elucidate the genetic importance of leading candidate genes in the pathogenesis of preeclampsia/eclampsia, conduct a genomewide search for chromosomal regions that may be linked to preeclampsia, and identify and evaluate candidate genes within the linked chromosomal regions in women who have had a previous pregnancy complicated by preeclampsia or eclampsia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR REGULATION AND ROLE OF PLACENTA GROWTH FACTOR Principal Investigator & Institution: Torry, Donald S.; Associate Professor; Medical Microbiol & Immunology; Southern Illinois University Carbondale 900 S. Normal Carbondale, Il 629014709 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 30-JUN-2004 Summary: Successful development of the placenta requires coordinated trophoblast and endothelial cell interactions. Indeed, preeclampsia and intrauterine growth retardation (IUGR), the leading causes of maternal and fetal morbidity/mortality, are associated with trophoblast and endothelial cell dysfunction. However, the molecular mechanisms responsible for these functional defects are poorly understood. Our recent findings show that trophoblast produce the potent angiogenic growth factor, placenta growth factor (P1GF), and that P1GF expression is severely reduced in preeclampsia. Furthermore, functional P1GF receptors (flt-1) on trophoblast promote proliferation and inhibit apoptosis in first trimester and term trophoblast, respectively. These data support our hypothesis that aberrant trophoblast production of P1GF contributes to the vascular and trophoblast defects commonly associated with preeclampsia and IUGR. However, the molecular mechanisms regulating trophoblast P1GF expression and autocrine cellular

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responses are not known. Accordingly, the following specific aims will be used to define the molecular regulation and function of P1GF in trophoblast: l) characterize mechanisms responsible for temporal differences in trophoblast P1GF expression throughout gestation, 2) determine positive and negative regulation of trophoblast P1GF production by select cytokines present at the maternal-fetal interface, 3) determine the mechanistic defects responsible for aberrant P1GF expression in preeclamptic trophoblast, 4) delineate the key signal transduction responses which regulate P1GF autocrine functions in normal trophoblast and, 5) elucidate the functional role of endogenous P1GF in normal trophoblast. Results from these studies will provide critical information regarding the paracrine ability of trophoblast-derived P1GF to regulate vascular function and will produce novel data concerning P1GF as an autocrine factor which influences trophoblast function. Collectively, these aims provide comprehensive insights into the expression, regulation and function of P1GF at the maternal-fetal interface and will facilitate a better understanding of the vascular and trophoblast dysfunctions that are characteristic of preeclampsia and IUGR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTICENTER NETWORK OF MATERNAL FETAL MEDICINE UNITS Principal Investigator & Institution: Caritis, Steve N.; Magee-Women's Health Corporation 204 Craft Ave Pittsburgh, Pa 152133180 Timing: Fiscal Year 2002; Project Start 01-APR-1991; Project End 31-MAR-2006 Summary: The purpose of this proposal is to demonstrate the capabilities of the University of Pittsburgh in continuing to participate in the Multicenter Network of Maternal-Fetal Medicine Units. Our unit has been an active participant in the Network for the last fourteen years. We have demonstrated our willingness to cooperate with other institutions and the NICHD in the development and implementation of clinical research protocols. We have been active participants in all aspects of Network activities. We have proposed protocols, have served on subcommittees of other protocols and have faithfully attended every Network meeting over the last fourteen years. We have effectively recruited patients for all studies in which we have participated and have provided intellectual input in the development of new projects as well as the implementation of protocols from our center and from others. The data provided by our unit have consistently been of the highest quality based on objective evaluation by the Data Coordinating Center. The Division of Maternal-Fetal Medicine is composed of 12 specialists in Maternal-Fetal Medicine. Each of these individuals has committed in some way to the Network, either in the recruitment of patients or development of protocols. In addition to clinical faculty, there are 6 research nurses and one research technician committed to the recruitment of patients and acquisition of high quality data for research studies. Eight research faculty in the Division are available to provide specialized expertise for Network projects. The obstetrical unit at the University of Pittsburgh is one of the largest private obstetrical service in the United States with 7076 deliveries annually. In 1999, approximately one-third of our patients were considered as high risk prior to labor, including 907 women with delivery less than 36 weeks, 407 with diabetes, 812 women with preeclampsia or hypertension, 645 women with third trimester bleeding, 313 women with cardiac disease, 204 women with severely growth restricted fetuses, and 165 women with multifetal pregnancies. Approximately 1800 women delivering at the University of Pittsburgh are indigent; 1200 are black or Hispanic and 6000 are white, most of which have third party insurance. This wide

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diversity of patients makes our institution particularly well suited for the performance of clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTICENTER NETWORK OF MATERNAL-FETAL MEDICINE UNITS Principal Investigator & Institution: Egerman, Robert S.; Associate Professor; Obstetrics and Gynecology; University of Tennessee Health Sci Ctr Memphis, Tn 38163 Timing: Fiscal Year 2003; Project Start 05-MAY-1996; Project End 31-DEC-2003 Summary: The Department of Obstetrics and Gynecology at the University of Tennessee, Memphis has been part of the Maternal-Fetal Medicine Network since April 1986. With this application, we hope to participate in a large multicenter network designed to develop and conduct clinical trials in the field of Maternal-Fetal Medicine, which could not be undertaken in a single center. In comparison to our previous application, we have recently expanded our resources and facilities to include patients at all major hospitals in the city. The obstetric population will now total approximately 13,000 women of various ethnic and economic groups. We are particularly interested in pursuing trials which require large sample size in order to adequately address specific questions and those regarding rare events of obstetric interest. The Principal Investigator, Dr. Baha Sibai, and the Alternate Principal Investigator, Dr. Brian Mercer, as well as the faculty in the Division of Maternal-Fetal Medicine continue to be active in Network administrative activities, and the design and conduct of protocols. The Principal Investigator currently participates on the Concurrent Research Committee, the Ad Hoc Committee on Preterm Studies, and the "High-Risk" Aspirin Protocol, the Interim Progesterone, and the Preliminary Terbutaline subcommittees. The Alternate Principal Investigator chairs the "Premature Rupture of Membranes" protocol and the Chart Review Subcommittee. He serves on the Capitation Subcommittee, Preterm PROM Pathology Subcommittee, Preterm Prediction Protocol Subcommittee, Obstetrical Determinants of Neonatal Survival Protocol Subcommittee, Neural Tube Defect Protocol Subcommittee and the Preliminary MgSO4 Subcommittee. He has recently submitted for consideration a clinical trial regarding tocolytic, corticosteroid and antimicrobial therapy after PROM. We are applying to continue as a clinical research center within the Network and agree to join protocols in existence and participate in the design of protocols in cooperation with other centers selected by the NICHD. The University of Tennessee, Memphis, and the Department of Obstetrics and Gynecology are committed to collaborative Maternal-Fetal research as documented by listed publications and the enclosed letters of commitment. The Division of Maternal-Fetal Medicine agrees to cooperate with the policy of capitation of research costs for each individual protocol, in addition to a base budget. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MULTICENTER NETWORK OF NEONATAL INTENSIVE CARE UNITS Principal Investigator & Institution: Korones, Sheldon B.; Pediatrics; University of Tennessee Health Sci Ctr Memphis, Tn 38163 Timing: Fiscal Year 2002; Project Start 01-APR-1991; Project End 31-MAR-2003 Summary: We present qualifications in this application to justify continued participation in the Neonatal Network. They are as follow: Size: Few, if any single, nurseries can contribute a larger patient population for study. Expertise: We have an uncommonly

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rich and protracted experience in multicenter trials. Our scientific research and its publications are substantial; the diversity and depth of expert support personnel is noteworthy. Training program: As a division of the Department of pediatrics, Newborn Medicine is taught in accordance with residency requirements. We are approved for fellowship training in Neonatal- perinatal Medicine. Administrative control: This large unit has been favored with considerable intramural control and institutional priority by virtue of its role in community health and its research activities. Facilities: Copious space, ample equipment and intramural control of a clinical laboratory with broad functions provide the wherewithal for effective clinical investigation. Perinatal data system: We have compiled data manually since 1972, by computer since 1979. We have extensive data stored for the past 15 years, describing demographics, diagnoses, outcomes, procedures and therapies. Inborn admissions: Approximately 95% of admissions are inborn and the number of back-transferred outborn infants is negligible, thereby increasing the number of babies available for study. Obstetrical coordination: The Neonatal Division is an official component of the Department of Obstetrics and Gynecology. Historically, our relationship with the obstetricians has been exemplary and productive. Fiscal efficiency: We are adept at budget management; in previous multicenter studies our costs have been lower than most other participants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NITRIC OXIDE AND SUPEROXIDE INTERACTIONS IN THE PLACENTA Principal Investigator & Institution: Myatt, Leslie; Professor; Obstetrics and Gynecology; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2002 Summary: (Adapted from the Investigator's Abstract): The proposed research will test the hypothesis that the local generation and activity of nitric oxide (NO), superoxide and superoxide dismutase (SOD) regulate vascular reactivity and blood flow in the fetalplacental circulation. The rationale is based on evidence that NO is a vasodilator scavenged by superoxide, whereas SOD scavenges superoxide, hence prolonging the bioactivity of NO. Interaction of NO and superoxide produces the peroxynitrite anion, a strong long-lived cytotoxic oxidant which inhibits mitochondrial electron transport and also nitrates tyrosine residues to block tyrosine-mediated signal transduction. It is further proposed that peroxynitrite may damage the vasculature and cause endothelial dysfunction. In this regard, nitrotyrosine residues, a marker of peroxynitrite formation, are found in the fetal-placental vasculature of pregnancies complicated by preeclampsia and/or IUGR, conditions associated with increased vascular resistance as well as fetal and maternal morbidity and mortality. Based upon this evidence, the proposed research will evaluate a second hypothesis that the activity of enzymes synthesizing and metabolizing NO and superoxide is altered in preeclampsia and/or IUGR. Specifically, the investigators will determine the following: 1. The interactions of NO, superoxide, xanthine oxidase and SOD in the perfused placenta cotyledon by adding exogenous substrate, enzymes or inhibitors. 2. The direct effect of peroxynitrite on vascular reactivity in the perfused placenta and its potential to affect responses to other vasoconstrictors or vasodilators, and to compare this to reactivity of placentas from pregnancies complicated by preeclampsia and/or IUGR. 3. The presence and localization of nitrotyrosine residues in placental villous, basal plate and placental bed tissues of pregnancies complicated by preeclampsia and/or IUGR in comparison to control. 4. Formation of superoxide and peroxynitrite by tissue sections of normal and pathologic placentas and activities of xanthine oxidase and SOD enzyme isoforms in

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these tissues. 5. Expression of mRNA and protein for SOD isoforms, xanthine oxidase and the cytochrome b558 subunit of NADPH oxidase in normal and pathologic placental tissues using RT-PCR and immunohistochemistry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OXIDANT STRESS MECHANISMS IN PREECLAMPSIA Principal Investigator & Institution: Walsh, Scott W.; Professor; Obstetrics and Gynecology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2003; Project Start 05-DEC-2002; Project End 30-NOV-2007 Summary: (provided by applicant): Preeclampsia complicates 5-7% of pregnancies, and is a leading cause of fetal growth retardation, premature delivery and maternal death. The cause of preeclampsia is not known. We propose that increased levels of lipid peroxides (LOOH) activate neutrophils, as well as endothelial and vascular smooth muscle cells, resulting in the elaboration of the neutrophil chemokine interleukin-8 (IL8) from the endothelial and smooth muscle cells. Increased concentrations of IL-8 in the intimal space stimulate transendothelial migration of the neutrophils to the intimal space where they release toxic compounds, such as TNFalpha, superoxide (.O2-), and thromboxane (TX) that are mediators of inflammation and cell dysfunction. The following Specific Aims will test three arms of this proposed pathologic interaction. Specific Aim 1 will test the hypothesis that oxidative stress activates neutrophils to elaborate toxic compounds, such as TNFalpha, superoxide and thromboxane, by a pathway involving nuclear factor-kB (NF-kappaB), cyclooxygenase-2 (COX-2) and thromboxane. Specific Aim 2 will test the hypothesis that oxidative stress stimulates the activation of NF- kappaB and the elaboration of IL-8 by human vascular smooth muscle cells by a signaling pathway involving arachidonic acid metabolites. Specific Aim 3 will test the hypothesis that oxidative stress and preeclamptic plasma stimulate transendothelial migration of neutrophils via IL-8. This aim will also determine if there is infiltration of neutrophils into systemic tissue of women with preeclampsia. Antioxidants will be used to verify the role of oxidative stress, IL-8 neutralizing antibody to assess the importance of IL-8, and dietary fatty acids and arachidonic acid pathway inhibitors to assess their role in modifying responses to oxidative stress. These studies will use plasma, neutrophils and fat obtained from nonpregnant women, normal pregnant women and women with preeclampsia, and primary cell cultures of human endothelial cells and vascular smooth muscle cells. Methodologies will include cell transfection of an NF-kappaB luciferase reporter vector and gel shift assay to determine NF-kappaB activation; Western blot for COX-2; EIA for cytokine and eicosanoid levels; spectrophotometric assay of MDA to estimate oxidative stress, and an unique real time assay to determine superoxide generation. A novel transendothelial migration assay will be used to measure the migration of 51Cr-labeled neutrophils across endothelial cells in culture. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PERINATAL AND ADOLESCENT FACTORS IN BREAST CANCER Principal Investigator & Institution: Stuver, Sherri O.; Assistant Professor; Epidemiology; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 16-FEB-2001; Project End 31-JAN-2003 Summary: The epidemiology of breast cancer is complicated and only partially understood, despite a concerted research effort in this area. The primary goal of the

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proposed study is to examine the association between, on the one hand, perinatal factors that exhibit their hypothesized carcinogenic action during early life and, on the other established breast cancer risk factors that operate during the perimenarcheal years. Our objective will be to explore whether certain perinatal factors may share a common biologic mechanism of action with perimenarcheal risk factors, with respect to breast carcinogenesis. The meet this objective, the following specific aims will be addressed to investigate if there is an association between birth size and indicators of sexual maturity during adolescence, particularly age at menarche and breast development; to study the association between birth size and adolescent somatic growth; to examine the association between perinatal complications, such as pregnancy preeclampsia/eclampsia, jaundice, and prematurity, and indicators of sexual maturity and somatic growth during adolescence. To study these relationships, a retrospective cohort study of the association between perinatal and adolescent factors will be conducted among young girls in Nord Trondelag County in Norway. The population based for this study will be the nearly 5,000 girls, 13 to 19 years of age, who were born between 1977 and 1984 and who participated in general health survey for adolescents that took place in 1996 and 1997. Using the unique personal registration number assigned to all Norwegians, linkage will be made between the relevant information collected during the adolescent health survey and birth record information stored in the national Birth Registry. Access to data of such excellent quality will provide an important opportunity to examine the role of perinatal and perimenarcheal factors in the etiology of breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHENOTYPE OF GENETICALLY REDUCED ADM DURING PREGNANCY Principal Investigator & Institution: Caron, Kathleen M.; Pathology and Lab Medicine; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-JAN-2009 Summary: (provided by applicant): The physiological and genetic mechanisms responsible for normal placentation and how their perturbation impairs placental blood flow to cause fetal growth restriction (FGR) remain largely unknown. Adrenomedullin (Adm) is a peptide vasodilator that has significant roles during pregnancy. A genetically deficient Adm mouse line is presented as a genetically-induced model of FGR and phenotyping of this model will elucidate the role of Adm in pregnancy and fetal growth. The Iong term objectives of this grant, to reveal the role of Adm in reproduction and to identify genetic and physiological factors that contribute to mechanisms of FGR will be achieved in three aims. Specific Aim I will test the hypothesis that local concentrations of Adm at the maternal-fetal interface are essential for normal placentation and fetal.qrowth. To distinguish between the maternal and fetal contribution of Adm, a novel approach of.qenetically predetermined blastocyst transfer will be used. Pregnancies will be monitored for physiological and pathological indications of preeclampsia and placentas will be analyzed by 3-Dimensional placental casts, histology, ultrasound Doppler and the molecular phenotyping approach described in Specific Aim 2. Specific Aim 2 will develop and validate a novel method for characterizinq placental defects by quantitaion of surrogate gene expression markers to determine if there are common placental pathways that are disrupted in association with FGR. Validation and application of this high-throughput phenotyping screen will be done in collaboration with the N/H-funded Mouse Mutagenesis Center for

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Deve/opmental Defects at Bay or Col/ege of Medicine. Specific Aim 3 will combine the novel methods of Aims 1 & 2 to ask how maternal chronic diseases, such as hypertension and preeclampsia, exacerbate FGR. Four hypertensive mouse lines, including a genetically-clamped renin transgenic line, a genetically-deficient NPRA line, a genetically-deficient eNOS line and a spontaneously preeclamptic BPH/5 line will be used. Quantitative and comparative evaluation of the phenotypes will identify common genetic mechanisms that underlie the association between maternal hypertension and FGR. Each of the Specific Aims addresses gaps in our current knowledge of the role of Adm in reproduction and the mechanisms underlying FGR. Thus, results from these studies will advance basic science, contribute to better human reproductive health and potentially identify therapeutic interventions that would favorably alter the course of fetal growth in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PLACENTAL FUNCTION IN PREECLAMPSIA Principal Investigator & Institution: Wang, Yuping; Obstetrics and Gynecology; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, La 71103 Timing: Fiscal Year 2002; Project Start 17-MAR-1999; Project End 29-FEB-2004 Summary: Preeclampsia is a multisystem disorder unique to human pregnancy. It is a leading cause of fetal growth retardation, infant morbidity and mortality associated with premature delivery, and maternal death. Several abnormalities, including vascular endothelial cell dysfunction, have been implicated in the pathogenesis of preeclampsia. However, the mechanisms that underlie the endothelial cell function are poorly understood. The studies outlined in this proposal relate the abnormal placental trophoblast function of preeclampsia with neutrophil activation and endothelial cell dysfunction. We also address potential cellular and molecular mechanisms that contribute to the altered endothelial cell function in preeclampsia. Our central hypothesis is that placental trophoblasts experience an oxidative stress that results in the disturbance of neutrophil and endothelial cell function. This process, coupled to alteration of neutrophil-endothelial interactions, leads to the endothelial cell dysfunction. This hypothesis will be tested by experiments outlined under 3 specific aims: 1) To characterize the placental trophoblast dysfunction in preeclampsia; 2) To elucidate the mechanisms of placental factor-mediated activation of neutrophils; 3) To elucidate the cellular and molecular mechanisms of placental factor-mediated endothelial cell dysfunction. In this study, trophoblasts and endothelial cells from both normal and preeclamptic pregnancies will be isolated and used as testing models. Experiments are proposed to assess trophoblast abnormalities in preeclampsia, to character placental factor(s) in mediating neutrophil activation, to examine trophoblastendothelial cell interactions using co-cultures of the two cell types, and to address the role of placental factor(s) in regulating endothelial cell transcription factor and mRNA expression. We believe that the information obtained from this proposed project will extend our knowledge of the pathogenesis of preeclampsia and provide potential avenues for therapeutic intervention in women suffering from this disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PLACENTAL GENE EXPRESSION PROFILE IN PREECLAMPSIA Principal Investigator & Institution: Karumanchi, S Ananth.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 28-FEB-2005

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Summary: (provided by applicant): This application for RO3 award is submitted in response to PAR-01-066, " Small grant program for KO8 recipients" and is linked to NIH KO8 DK02825-03. With the support of the KO8 funding, the applicant has completed his post-doctoral research training and has begun an independent research career. This grant will increase fiscal independence and provide an opportunity to generate data in a relatively new area of research for the applicant that can form the basis for an RO1 application. Preeclampsia (PE) is a disease characterized by severe hypertension, proteinuria and edema and occurs in 5% of all pregnancies. Endothelial dysfunction plays an important role in the pathogenesis of this disorder; however the etiology and mechanisms are still unknown. There is accumulating evidence for a pathogenic model for PE whereby a hypoxic feto-placental unit secretes a factor into the maternal circulation causing generalized endothelial cell dysfunction. In the first half of the proposal the applicant wishes to identify de novo targets in PE using mRNA expression profiling in normal and preeclamptic placentas. The applicant wishes to use bioinformatic tools such as hierarchical clustering and k-means to identify clusters of genes that will predict the occurrence and severity of PE. These studies will lead to identification of biomarkers, which may be used diagnostically and potentially lead to new therapies for this complex disorder. In preliminary experiments using gene expression profile from preeclamptic placentas, the applicant has identified "sflt-1" (soluble fms-like tyrosine kinase) as a factor that is up-regulated in patients with PE. Flt1 is one of the tyrosine kinase receptors for vascular endothelial growth factor (VEGF) and placental growth factor (PGF). Sflt-1, a secreted splice variant of fit-1 (lacking the transmembrane and cytoplasmic domains) is a potent antagonist of VEGF and PGF, by preventing both VEGF and PGF from interacting with its cell-surface receptor. The second half of the proposal will be to define the role of sflt-1 in the pathogenesis of PE. We will test the hypothesis that sflt-1, which is released by preeclamptic placenta, is responsible for some or all of the in vitro and in vivo phenotypes associated with PE. These focused studies form the beginnings of a framework to understand the pathogenesis of PE. The applicant has just begun his career as an independent investigator in July 2001. The applicant is highly motivated and absolutely committed to a career as a physician-scientist. The experience of the applicant in endothelial cell biology, the expertise of various collaborators and the supportive environment at Harvard Medical School provides an ideal forum for the applicant to not only realize the objectives of this proposal but also to become a successful independent investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PLACENTAL COMPLICATIONS

GENOTYPE

/PHENOTYPE:

PE

/OTHER

Principal Investigator & Institution: Fisher, Susan J.; Professor; Magee-Women's Health Corporation 204 Craft Ave Pittsburgh, Pa 152133180 Timing: Fiscal Year 2002; Project Start 14-JUN-2002; Project End 31-JAN-2007 Summary: Many pregnancy complications are associated with specific placental pathologies. Our research has focused on the placenta in preeclampsia (PE), a syndrome that alters maternal vascular function and restricts intrauterine fetal growth (IUGR). In PE, cytotrophoblast (CTP) invasion of the uterus and its vessels is often rudimentary. The consequent reduction in maternal blood flow to the placenta is thought to be an important part of the syndrome's lesions found in PE occur in other pregnancy complications. We recently confirmed that IUGR is sometimes associated with shallow CTB invasion and discovered a similar lesion in patients with chorioamnionitis who give birth prematurely. If other pregnancy complications are also associated with

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shallow CTB invasion, what are the molecular levels. We now propose a comparison of tissue samples of the fetal maternal interface obtained from the three patient groups in which we observe shallow placentation: women with PE, women without PE who give birth to infants who are small for gestational age, and women with chorioamnionitis who deliver prematurely. The control samples matched for gestational age, will be obtained from patients with clinically normal pregnancies and with pregnancy complications in which we find CTB invasion is morphologically normal. The latter group includes women who deliver prematurely for reasons other than chorioamnionitis. The Specific Aims are as follows: First, we will assess the contribution of genetic anomalies. The techniques to be used include fluorescent in situ hybridization and comparative genomic hybridization. Second, we will investigate the rate of apoptosis, before examining the state of CTB differentiation in relationship to hypoxia and expression of molecules with potentially important immune functions by using immunolocalization and in situ hybridization techniques. At the conclusion of these experiments we will have assembled a set of genetic and molecular markers that differentiate the placental lesions that occur in PE from those associated with other pregnancy complications. This information will provide valuable insights into the etiology of PE. In addition, the studies of placental aneuploidy provide an exciting opportunity to correlate genotype with phenotype, an experimental strategy that has yielded a wealth of data in other experimental systems, from yeast to mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PLACENTAL MATRIX PROTEINS AND IUGR Principal Investigator & Institution: Guller, Seth; Assistant Professor; Obstetrics and Gynecology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002; Project Start 05-APR-1995; Project End 30-JUN-2007 Summary: (provided by applicant): For the last several years, our laboratory has investigated the role of glucocorticoid (GC) in the periparturitional regulation of ECM proteins in the placenta and fetal membranes in humans and non-human primates. In this application, we test a novel action of GC, its role in promoting placental damage in pregnancies associated with intrauterine growth restriction and preeclampsia (IUGR/PE). Based on our preliminary results, we hypothesize that GC, induced in response to fetal stress, promotes an antifibrinolytic/promatrix placental state by pathologically enhancing the expression of plasminogen activator inhibitor-i (PAl- 1) in syncytiotrophoblasts (SYNCTs) and ECM proteins in placental mesenchymal cells (PMCs). We postulate that this hypermatrix state in placenta reduces the flow of nutrients between mother and fetus and compromises fetal well-being. To test this hypothesis we will: 1) use primary cultures of SYNCTs to examine the effect of GC treatment on the stability of PAl-1 mRNA and the expression of proteins that bind to the 3'-untranslated region of the PAl- 1 gene and alter mRNA stability; 2) use run-on and zymographic assays to evaluate the mechanism of GC-mediated over-expression of basal laminar and interstitial ECM proteins in primary cultures of PMCs; 3) determine whether fibrinolytic parameters and levels of ECM proteins are coordinately altered in IUGR/PE placentas compared to controls matched for gestational age; 4) use an in vivo baboon model to determine whether a single or a triple dose of betamethasone (BM) alters placental gene expression in a manner that mimics the anti-fibrinolytic/promatrix state that is observed in pregnancies associated with IUGR/PE. These studies will shed light on the mechanism through which fetal stress alters placental gene expression in pregnancies with IUGR/PE. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PREECLAMPSIA: IMPLICATIONS

MECHANISMS

AND

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POST-PREGNANCY

Principal Investigator & Institution: Roberts, James M.; Director, Magee-Womens Research Institut; Magee-Women's Health Corporation 204 Craft Ave Pittsburgh, Pa 152133180 Timing: Fiscal Year 2002; Project Start 01-APR-1993; Project End 31-JAN-2007 Summary: In the past five years we characterized and identified mechanisms of abnormal trophoblast invasion in preeclampsia and supported the involvement of oxidative stress in the linkage of abnormal implantation to the systemic syndrome. This program extends the studies to detailed mechanistic examination and tests their long range significance to mother and baby. Abnormal implantation and reduced placental perfusion are insufficient to explain the syndrome. Apparently similar changes are present with pregnancies complicated by intrauterine growth restriction (IUGR) and one third of preterm pregnancy (PTB). Subproject 9 examines implantation in preeclampsia, IUGR and PTB in detail, proposing that differences in molecular mechanisms could explain why only preeclampsia results in the maternal syndrome. Project III proposes that reduced placental perfusion produces fetal/placental signals (one of which they propose to test is leptin) that alter maternal metabolism to increase nutrient delivery to the fetus. This beneficial metabolic change cannot be tolerated in some women and preeclampsia results. IUGR is the result of a blunting of this signal. Subproject 10 also concerns abnormal implantation, probing cellular mechanism responsible for their finding that the hypoxia inducible transcription factors HIF-1 alpha and HIF-2 alpha are increased in preeclampsia placentas due to slowed degradation and explores downstream products of HIF1a and HIF2a including leptin (Subproject 11) as one such product. They test is this reduced degradation is present in maternal and other fetal tissues. Subprojects 12 and 13 assess vascular functional changes in preeclampsia. Subprojects 12 and 13 propose a failure to increase maternal arterial compliance early in pregnancy predisposes the woman to higher sheer stresses, endothelial activation and increased oxidative stress. Project V measures global arterial compliance in high risk (prior preeclampsia) before during and after pregnancy, exploring the role of NO and activation of NADPH oxidase by components of the angiotensin response cascade including antibodies. Subprojects 122, 12, and 13 posit previously demonstrated reduced endothelial relaxation at this time in women with prior preeclampsia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PRENATAL DIET EFFECTS ON MOTHER AND CHILD Principal Investigator & Institution: Gillman, Matthew W.; Associate Professor; Harvard Pilgrim Health Care, Inc. 93 Worcester St Wellesley, Ma 02481 Timing: Fiscal Year 2002; Project Start 01-JUL-1998; Project End 30-JUN-2004 Summary: (Adapted from Investigator's Abstract) The overall goal of this amended application is to examine the role of prenatal factors, particularly diet (specifically, trans fatty acids, n-3 fatty acids and calcium), in outcomes of pregnancy and infancy. A total of 6,000 women will be enrolled during their first 12 weeks of pregnancy into the Harvard Pilgrim Health Care Cohort and will be followed along with their offspring until six months postpartum. The influence of specific nutrients on pregnancy outcomes, including fetal growth, length of gestation, and incidence of pre-eclampsia will be assessed. In addition, the effects of these same exposures on infant development and cardiovascular risk factors during the first six months of life will be examined. Four hypotheses will be tested: 1) maternal intake of trans fatty acids is inversely associated

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with fetal growth, length of gestation, and infant cognitive development; 2) maternal intake of n-3 fatty acids is directly associated with fetal growth, length of gestation and infant cognitive development; 3) maternal intake of calcium is inversely associated with incidence of pre-eclampsia and blood pressure levels in infancy; and 4) maternal intake and red blood cell level of n-3 fatty acids are inversely associated with incidence of preeclampsia. Blood samples and detailed data on gestational diet at several times during pregnancy will be collected along with sociodemographic variables, health habits, medical and family history, reproductive history and psychosocial conditions. Fetal growth data will be assessed from ultrasound examinations. Birth weight, height and other anthropometric data and blood pressure will be obtained and the offspring will be followed for 6 months to assess growth, cognitive development and blood pressure. There are plans to provide new avenues for the prevention of common adverse conditions of pregnancy, childhood and, perhaps, adulthood with the prospective, longitudinal study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREPREGNANCY PHENOTYPE & PREDISPOSITION TO PREECLAMPSIA Principal Investigator & Institution: Bernstein, Ira M.; Associate Professor; Obstetrics and Gynecology; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Preeclampsia affects 3-5% of pregnancies and contributes significantly to maternal and neonatal morbidity and mortality. We have generated a novel hypothesis regarding the development of pre-eclampsia that postulates that two primary features contribute independently to its development. One feature is a pre-pregnancy phenotype that includes reduced plasma volume, elevated sympathetic tone, reduced utenne blood flow and enhanced platelet activation. This feature has been suggested by the association of a specific genetic polymorphism of angiotensinogen (TT235) with an increased risk for pre-eclampsia. This polymorphism has been linked in our preliminary data to key pathophysiologic features of preeclampsia, previously thought to be exclusive to pregnancy, in women who are examined prior to pregnancy. The second feature is the physiologic volume expansion of pregnancy. We have theorized that the overt clinical manifestations of pre-eclampsia become apparent in late pregnancy as a result of either 1) a normal volume expansion in women unable to tolerate it due to a chronic adaptation to low intravascular volume (abnormal prepregnancy phenotype) or 2) an excessive volume expansion in women with a normal prepregnancy phenotype (i.e. twins, molar pregnancies). In this grant we propose to examine 3 primary specific aims, employing detailed whole body physiologic measurements in women, that will support this pathophysiologic view of the development of preeclampsia; 1) We will confirm that the angiotensinogen genotype that has been linked to preeclampsia in Caucasians and Asians is associated with reduced plasma volume in a nulligravid population and that this plasma volume constriction is associated with elevated sympathetic tone, reduced uterine blood flow and heightened platelet activation prior to pregnancy, 2) As we follow these women into pregnancy we will demonstrate; a) that low prepregnancy plasma volume is associated with elevated sympathetic tone and reduced uterine blood flow in early pregnancy (12 weeks) predisposing to abnormal placentation despite similar plasma volume expansion, and b) that prepregnancy plasma volume is indirectly related to both the change in mean arterial pressure (corrected for plasma volume expansion) and degree of

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platelet activation in the third trimester, 3) Finally, we will demonstrate that pregnancy results in an increase in both post-puerperal plasma volume and arterial compliance Iowering the risk for both preeclampsia in future pregnancies and hypertension in later life. This will be a controlled prospective longitudinal study examining an integrated pathophysiologic mechanism underlying the development of preeclampsia. This study proposes to evaluate a novel hypothesis that synthesizes apparently contradictory data into a single coherent theory. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PULSATILE ARTERIAL LOAD IN PREECLAMPSIA Principal Investigator & Institution: Shroff, Sanjeev G.; Mcginnis Professor of Bioengineering& Me; Magee-Women's Health Corporation 204 Craft Ave Pittsburgh, Pa 152133180 Timing: Fiscal Year 2002; Project Start 14-JUN-2002; Project End 31-JAN-2007 Summary: Changes in pulsatile arterial load (PAL) early in gestation (e.g., increased global arterial compliance, AC) play an important adaptive role in normal pregnancy (e.g., minimize arterial pressure and flow pulsatiles) and preliminary data suggest that aberrant PAL responses may be involved in the pathophysiology of preeclampsia. Working model: AC does not increase early in gestation in subjects destined to develop preeclampsia resulting in increased arterial pressure and flow pulsatiles, and consequently, increased pulsatile (oscillatory) shear stress at vascular endothelium, which is known to cause a sustained activation of endothelial pro-oxidant processes. Over time, this sustained endothelial dysfunction and/or inadequate compensation by anti-oxidant defenses can lead to the hemodynamic milieu commonly seen with the onset of the clinical syndrome of preeclampsia (high blood pressure; high systemic vascular resistance, SVR; and normal-to-low cardiac output). Thus, the focus of the present proposal is to comprehensively examine systemic arterial and left ventricular (LV) properties in primiparous control and prior preeclamptic women, both in the nonpregnant state and throughout the second gestation. Hypotheses: 1) In subjects with a history of preeclampsia, differences in vascular mechanical properties (PAL in particular) and/or endothelial function exist in the non-pregnant state and chronic antioxidant therapy(vitamin C supplementation) can help reduce these differences. 2) In subjects destined to develop preeclampsia, the increase in AC during early gestation, which is seen in normal pregnancy, is significantly attenuated. Two groups of primiparous women will be studied at 6-12 months post- partum (Aim 1a): i) prior preeclamptic subjects (n=70, Group 1) and ii) control subjects (n=70, Group 2). Group 1 subjects will be restudied following an 8-week supplementation with either vitamin C (N=35) or placebo (n=35) (Aim 1b). Finally, a longitudinal study will be conducted in two groups of primiparous women (pre-conception-during second gestation-postpartum) (Aim 2): i) prior preeclamptic subjects (n=70) and ii) control subjects (n=15). Non-invasive measurements will be performed to quantify arterial properties (global: aortic input impedance spectrum, SVR, AC, wave reflection indices; regional: pulse wave velocity, pressure-diameter relationships, indices of vessel wall stiffness), LV properties (size, shape, and mass, indices of myocardial contractility), and endothelial function (forearm blood flow response to mental stress). Blood and urine samples will be analyzed to derive indices of endothelial activation, oxidative stress, and dyslipidemia. Results of these studies are expected to provide insights into the role of pulsatile arterial load in the pathogenesis of preeclampsia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULAR PREECLAMPSIA

EXERCISE

AMONG

WOMEN

AT

RISK

FOR

Principal Investigator & Institution: Yeo, Seonae; None; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 30-APR-2006 Summary: (Applicant's abstract): Preeclampsia, the sudden onset of high blood pressure along with proteinuria during pregnancy, is a serious complication affecting nearly one in every 20 pregnancies. It is the main cause of maternal death worldwide, and affects women of all races and socioeconomic groups. Unfortunately, no definitive preventive treatment is currently available for this ominous disease. Scientists now believe that preeclampsia is a disease of the endothelium, due in part to oxidative stress. As such, regular exercise has emerged as a potential preventive measure. This contrasts to daily low dose aspirin or calcium supplement which have failed to demonstrate a significant effect and may have adverse effects. The purpose of this study is to determine if moderate intensity exercise during pregnancy will reduce the incidence of preeclampsia and to assess the process (involving oxidative stress and antioxidant process) hypothesized to explain the effect of exercise on preeclampsia. This is a randomized clinical trial with a total of 250 pregnant subjects at risk for preeclampsia. Eligible subjects will enter a run-in period (i.e., qualifying period) at 14 to 18 weeks gestation. Baseline data to be obtained include demographic information, health history, daily physical activities, cardiovascular fitness level, blood pressure, blood sample for serum iron, transferrin, low density lipoprotein, malondialdehyde, superoxide dismutase. At 18 weeks, compliant subjects will be randomly assigned to either the exercise (40 min., 70 percent VO2max, 5x/week) or sham exercise (control group; 10 min. stretch exercise, 5x/week) condition. For both groups, all baseline measurements will be repeated at 28 weeks (Outcome I). Subjects will continue the exercise regimen after 28 weeks up to her term and as long as it is safe and comfortable. A blood sample will be collected again during labor (Outcome II). Subjects who undergo cesarean section for obstetrical reasons will provide a small amount of subcutaneous tissue at the time of incision to measure endothelial superoxide dismutase. Medical records will be reviewed for additional outcome data (pregnancy/birth outcomes and diagnosis of preeclampsia). Chi-square tests of association and logistic regression analysis will be applied to address the effect of exercise, prediction of preeclampsia, and other pregnancy outcomes. Repeated Measures ANOVA will be applied to assess the effect of exercise on various biological markers. ANCOVA will be applied to control confounding factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF MASPIN IN PLACENTAL DEVELOPMENT Principal Investigator & Institution: Dokras-Jagasia, Anuja; Obstetrics and Gynecology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Placental invasion is a highly regulated process and impairment results in pathologic obstetric conditions such as preeclampsia and intrauterine growth restriction (IUGR). Further identification of factors that play a role in modifying this invasive ability of cytotrophoblasts will contribute to a better understanding of this unique developmental process. We have demonstrated a specific timeline for the expression of maspin, novel tumor suppressor gene in placental invasion and development. Our findings show that maspin is maximally expressed in the third trimester with low levels of expression in the first trimester of pregnancy. The

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specific aims of this proposal are 1) To measure the biological consequence(s) of maspin up regulation in human cytotrophoblasts with respect to invasion, motility and morphogenesis in vitro 2) Examine the role of hypoxia in regulating maspin expression in cytotrophoblasts 3) Compare the abundance of maspin/manganese superoxide dismutase mRNA and protein in placentas from women with term and preterm deliveries, with and without preeclampsia. The research design will include using adenoviral approach to transfect maspin into primary trophoblast cultures during the first and second testers and examine the effects of this transfection on cell invasion, migration, motility and morphogenesis. Next, the effects of hypoxia on maspin expression and the role of hypoxia-inducible factor in mediating these effects will be examined. Finally, will confirm our hypothesis using an in vivo model of hypoxia and impaired cytotrophoblast invasion namely preeclampsia. Maspin expression will be compared in placentae from women with preeclampsia to those from normal controls using real-time PCR. The long-term objectives of this project are two-fold, first, to understand the significance and mechanism(s) of action of tumor suppressor genes such as maspin in human placental development second, to identify pathological processes during gestation arising from alterations of maspin expression. Information revealed in this study could have profound implications on therapeutic strategies for clinical conditions associated with decreased cytotrophoblast invasion such as preeclampsia and IUGR. In addition, any important new information that may be obtained about the putative role of maspin during embryonic development may help elucidate the biological significance of its loss during tumor progression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESEARCH ON SCOPE & CAUSES OF STILLBIRTH IN THE US Principal Investigator & Institution: Carpenter, Marshall W.; Director, Maternal Fetal Medicine, Assoc; Women and Infants Hospital-Rhode Island 101 Dudley St Providence, Ri 02905 Timing: Fiscal Year 2003; Project Start 26-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Women and Infants Hospital (WIH) has served as the regional resource for tertiary obstetrical and neonatal care for decades for all the communities in Rhode Island and those of Bristol County, MA. This compact, contiguous area, well defined by state and county boundaries, contains a stable, but racially and ethnically heterogeneous population, producing 20,000 total births and more than 100 stillbirths, annually. Births at WlH represent over 70% of those that occur state-wide and nearly half of those in the region, and are highly representative of those from the region's population. As a specialty hospital, WIH has maintained an active outreach program to the region's nurses, physicians and hospitals for the past 26 years. This active engagement has included educational support in the areas of neonatology, obstetrics and pathology. WlH has also maintained an active collaboration with the Rhode Island Department of Health (DOH) in many initiatives regarding reproductive health. This proposal is made with the enthusiastic support of the Departments of Health of both states and the chiefs of obstetrics and pathology and administration of all the region's 14 hospitals with obstetrical services. The Department of Pathology at WIH has maintained an extensive relational database of its autopsy and placental examinations and relevant clinical information since 1975. Paraffin-imbedded standard tissues sections from these examinations also provide for examination of time-trends of stillbirths occurring in a stable population over the past two decades. The Department has sustained an 80% autopsy rate at WIH and stimulated the rising rate among the other region's hospitals, now at 30%. A rising proportion of the stillbirths occurring at

54

Preeclampsia

other hospitals are being referred to WlH for autopsy and placental examination. Consequently, because of the leadership role of WIH in RI and Bristol County, MA, the close proximity of the 14 hospitals serving its population, and the collegial relations among health care providers, this region is well adapted to provide the resources for a population-based study of the causes of stillbirth in a stable, diverse population-based sample of 20,000 annual births. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREGNANCY

ROLE

OF

ANG-(1-7)

IN

NORMAL

AND

HYPERTENSIVE

Principal Investigator & Institution: Brosnihan, K. Bridget.; Professor; Surgical Sciences; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2004 Summary: (provided by applicant): PIH is estimated to affect 7% to 10% of all pregnancies in the United States. Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of PIH are unclear. It is well known that the RAAS is stimulated in normal pregnancy. The physiological consequences of the stimulated RAAS in normal pregnancy are incompletely understood. Initial findings from our group demonstrate that the novel heptapeptide of the RAAS, Ang-(1-7) is increased in pregnancy and reduced in PIH and preeclampsia. Since Ang-(1- 7) has been shown to act as a vasodilator and thus may counter regulate the actions of Ang II, our findings provide a basis for a possibly important physiological role of Aug-( 1- 7) in the course of pregnancy. It is our hypothesis that an appropriate balance of the vasoconstrictor and vasodilator components of the RAAS exerted by Ang II and Ang-(1- 7), respectively, constitute a crucial feature of cardiovascular regulation during an uncomplicated pregnancy. In particular, normal pregnancy may be characterized by vasodilatory actions of Aug-(1-7) that balance the vasoconstrictor effects of Ang II. In contrast, PIH and preeclampsia may result from an unbridled pressor action of Ang II as a consequence of marked reduction of vasodepressor effects of Ang-(1- 7). The hypothesis will be tested by the following Specific Aims. Specific Aim 1 will determine the time course of changes in the circulating and urinary levels of Ang II and Ang-(1- 7) as the principal vasoconstrictor and vasodilator components, respectively, of the RAAS throughout the course pregnancy of pregnancy in rats. Findings obtained in normal pregnant rats will be compared to a rat model of PIH produced by chronic reduction in utero placental perfusion pressure (RUPP). We will also monitor levels of active renin concentration, Ang I, angiotensin converting enzyme (ACE), Angiotensinogen (Aogen), and aldosterone in normal pregnant rats and in rats subjected to RUPP. Specific Aim 2 will demonstrate that long-term blockade of Ang-(1- 7) by chronic infusion of the Ang(1- 7) specific antagonist, ([D-Ala7]-Ang-(1-7) in otherwise normal pregnant rats tips the balance of blood pressure regulation toward hypertension. Also we will determine whether chronic administration of Ang-(1-7) reverses the hypertension of RUPP animals. We also propose to assess the response of mesenteric and uterine resistance arterioles to Ang peptides in normal pregnancy and hypertension caused by RUPP. The major goal of these studies is to understand the contribution of the vasodilator component of the RAAS to blood pressure regulation in normal pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF ANGIOTENSINOGEN IN HUMAN HYPERTENSION Principal Investigator & Institution: Lalouel, Jean-Marc M.; Professor; Human Genetics; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 15-SEP-1990; Project End 30-APR-2005 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: SIGNALING /NO PRODUCTION /MITOGENESIS IN UAEC /OFPAEC Principal Investigator & Institution: Bird, Ian M.; Professor; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002 Summary: During pregnancy (P), the uterine artery (UA) becomes more refractory to vasoconstrictors. There is also a dramatic enhancement of agonist induced NO production and/or angiogenesis by both the UA and placental artery (PA), so leading to a reduction in vascular resistance and coordinated increases in blood flow on both the maternal and fetal side of the placenta which is so necessary to support the growing fetus. We have coordinated increases in blood flow on both the maternal and fetal side of the placenta which is so necessary to support the growing fetus. We have recently shown in both UA endothelial cells (UAEC) and PA endothelial cells (OFPAEC) that both activation of eNOS and mitogenesis may be mediated more through Extracellular signal Regulated Protein Kinase 1 and 2 (ERK-1/2, members of the MAPK family) rather than elevations in Ca2+, but that additional pathways may also be involved. In addition this signaling pathway may be a convergence point of vascular control by both classical growth factors bFGF and VEGF as well as heptahelical receptor agonists such as Angiotensin II (AII). Therefore we propose that a greater understanding of the signaling events by which bFGF and VEGF control UAEC and OFPAEC function would be of value, as would be an understanding of the signaling events by which bFGF and VEGF as well as heptahelical receptor agonists such as Angiotensin II (AII). Therefore we propose that a greater understanding of the signaling events by which bFGF and VEGF control UAEC and OFPAEC function would be of value, as would be an understanding of how these events integrate with the signaling pathways initiated through heptahelical receptors. To this end we propose Specific Aim 1: to establish if the action of bFGF or VEGF, but not AII or ATP on MEK mediated activation of ERK-1/2 occurs via growth factor receptor autophosphorylation and subsequent phosphotyrosine recruitment of adaptor proteins (Shc/Grb2/SOS) leading to Ras/Raf activation of MEK in P-UAEC and OFPAEC and at what level this is uncoupled in NP-UAEC. Specific Aim 2: to establish if AII and ATP mediated activation of MEK occurs through alternative pathways independent of growth factor receptor phosphorylation and adaptor protein recruitment, namely via the Scr/RAF/MEK cascade in P0UAEC and OFPAEC and at what level this is uncoupled in NP-UAEC. Specific Aim 3: to further delineate the changes which occur in cell signaling in progression from the non-pregnant to pregnant state and so further clarify the mechanistic basis for these changes. This will be investigated by: (3A) further comparing the time course of activation of the Shc/Grb2/SOS/Ras/Raf pathway and the Src/Raf/MEK pathway in response to bFGF, VEGF, AII, ATP and phorbol ester (TPA-control) in PO-UAEC vs. NP-UAEC., and (3B) to further investigate possible MEK independent signaling via PI3-kinase/AKT in NPUAEC, P-UAEC vs. NP-UAEC, AND (3B) to further investigate possible MEK independent signaling via PI3-kinase/AKT in NP-UAEC, P-UAEC and OFPAEC. Specific Aim 4: To establish the importance of these signaling intermediates so identified

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in Aims 1-3 at the level of agonist-stimulated NO production in NP-UAEC, P-UAEC and OFPAEC by observing the effects of selective inhibitors on activity of signaling intermediates and relating any such effects to changes in NO production, eNOS phosphorylation and mitogenesis respectively. In this way not only will we address the state hypothesis but also provide additional information necessary for the completion of project 2 as well as a greater mechanistic understanding of the control of mitogenesis through growth factor secretion, as investigated in projects 3 and 4. Specific Aim 5: to relate these observed changes in vitro back to the pregnancy induced changes in vivo. Where signaling pathway intermediates have been shown to be lost or gained at the level of function we will perform western analysis on UA endothelium and Immunohistochemistry on UA secretions from OVEX, follicular phase, luteal phase and pregnant ewes to determine if change in expression occurs in vivo. We believe these studies will provide a significant advice in both the understanding of normal controls and coordination of UA and PA endothelial function and the mechanism underlying pregnancy-induction of increased UA refractoriness to a variety of vasoconstrictors, and may also provide a new model of endothelial cell function on which future studies searching for the maternal and feto-placental vascular dysfunction leading to preeclampsia and IUGR may be based. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SIGNALING PROLIFERATION

PATHWAYS

MEDIATING

TROPHOBLAST

Principal Investigator & Institution: Rappolee, Daniel A.; Obstetrics and Gynecology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): It is important to make a healthy placenta. Insufficient trophoblast proliferation or an imbalance between proliferation and differentiation may lead to pre-edampsia, IUGR or spontaneous abortion early after implantation of the embryo into the uterus, the time when most human conceptuses are lost. Our long term goal is to understand the signal transduction pathways that transduce intercellular signals into the trophoblast and induce proliferation. We have previously found that FGF input is required to produce trophoblast in the implanting embryo. We propose here to define the signal transduction pathways mediating trophoblast proliferation by promoting FGF-induced trophoblast proliferation and then testing several inhibitors of candidate transduction pathways to find which pathway(s) mediate the proliferative signal. In addition, we will block FGF-induced proliferation and then test for which rate-limiting enzyme genes in several signal transduction pathways are sufficient to re-activate the cell cycle. We also intend to define the FGFinduced signaling pathways that lead to proliferation compared with morptiogenetic events/differentiation. Since the first IVF baby, only 300,000 of 1,500,000 IVF attempts have resulted in a successful pregnancy. The majority of loss of human embryos is near the time of implantation. Other later loss of embryo/fetus loss due to preeclampsia and IUGR may also begin early at the time of implantation. Much of the loss is due to improper growth and differentiation of the placenta. Improved IVF requires an understanding of the mechanisms that mediate growth in the trophoblast lineage that enables placental function. The mouse is an excellent model to study implantation in humans. Therefore, the proposed studies should lead to improvement in methods to facilitate placentation and improve IVF and produce protocols for remediation of common defects in pregnancy such as pre-eclampsia and IUGR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SUPERANTIGEN INVOLVEMENT IN PREECLAMPSIA Principal Investigator & Institution: Deloia, Julie A.; Assistant Professor; MageeWomen's Hospital of Upmc 300 Halket St Pittsburgh, Pa 15213 Timing: Fiscal Year 2002; Project Start 01-MAY-2000; Project End 30-APR-2003 Summary: (Adapted from the Investigator's Abstract): The investigators propose to study a large group of women, including women with pregnancy-induced hypertension that do not progress to preeclampsia as a control group. Longitudinal studies will monitor the occurrence and disappearance of T-cell skewing. They will determine if the hallmarks of a superantigen effect occur in preeclampsia: a) a robust activation of primary T cells; b) MHC class II-dependent response; and c) a TCR Vbrestricted response, in this case, Vb4+ T-cells. Studies will be initiated to define the source of the superantigen by challenging normal T-cells with plasma and syncytiotrophoblast microvillous membrane preparations from preeclamptic patients and monitoring T-cell skewing in vitro. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SURFACE EXPRESSION OF SPECIFIC PLATELET MEMBRANE GLYCOPROTEINS IN PREECLAMPSIA Principal Investigator & Institution: Paidus, Michael; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE PREECLAMPSIA

EPIDEMIOLOGY

OF

MARINE

FATTY

ACIDS

AND

Principal Investigator & Institution: Williams, Michelle A.; Professor; Swedish Medical Center, First Hill 747 Broadway Seattle, Wa 98122 Timing: Fiscal Year 2002; Project Start 01-JUN-1996; Project End 28-FEB-2007 Summary: (provided by applicant) The etiology of preeclampsia is unknown. Briefly, results from several studies (typically small studies not controlling for confounding) suggest that an imbalance in maternal antioxidant and pro-oxidant status may be associated with an increased risk of preeclampsia. There is also emerging evidence suggestive of an association between maternal proinflammatory status and increased risk of preeclampsia. In this competing renewal application, we seek to build on this body of work by continuing the prospective study (Epidemiology of Marine Fatty Acids and Preeclampsia: RO 1 HD 32562), and strategically integrating new biological markers that will serve to better characterize the epidemiology of preeclampsia. The study is a cohort study of 1,500 pregnant women enrolled early in pregnancy and followed until delivery. We plan to expand this cohort to include enrolling a total of 4,200 nulliparous women. We will use a nested case-cohort design and multivariate logistic analytical methods to assess the relation between risk of preeclampsia with biological markers of maternal antioxidant (enzymatic and non-enzymatic) status. Additionally, we will assess hypotheses concerning maternal chronic pro-inflammatory status [as measured by high sensitivity C-reactive protein (hs-CRP) and the pro-inflammatory cytokines including tumor necrosis factor-a (TNF-a)] soluble receptors (sTNFp55 and sTNFp75) in relation to preeclampsia risk. Our overall objective is to test whether dietary, immunological, and other lifestyle characteristics are associated with subsequent risk of

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developing preeclampsia. Results from our efforts should provide additional knowledge concerning the mechanistic basis for endothelial dysfunction and preeclampsia risk. Furthermore, our results should provide information that may be used to motivate the development of prevention intervention strategies sufficient for impacting the occurrence of preeclampsia. Results from the proposed study could have practical significance in developing alternative, practical preventative interventions for preeclampsia and other adverse pregnancy outcomes (e.g., fetal growth retardation and preterm delivery). Antioxidants, and trace metals such as zinc and selenium (which are important to the activity of antioxidant enzymes), as well as iron could be easily manipulated in the diet either by supplement use or by specific choice of foods if evidence from this and other studies indicates a benefit. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE DEVELOPNENT

ROLE

OF

ARNT

IN

VASCULAR

AND

CARDIAC

Principal Investigator & Institution: Ramirez-Bergeron, Diana L.; Anatomy; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 09-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The objective of this K01 award is to provide intensive mentoring and research training to the minority principal investigator that will allow for an effective transition into an independent academic researcher. The candidate will receive scientific and career mentorship from well established, highly motivational sponsors and advisory committee members. In the past, the investigator has focused on hematopoietic development. The proposed research will redirect her research to acquisiton of new skills in the areas of cardiovascular development and hypoxic biology. The proposal is based on work from Dr. Simon's laboratory encompassing work in hematopoiesis and vasculogenesis. Mutations in various subunits of the Hypoxia Inducible Factor (HIF) family, an important hypoxic transcriptional mediator, have contributed to the understanding the role 02 tension plays during early embryonic development. Abrogation of the Arnt subunit of the HIF heterodimer resulted in embryonic lethality by 10.5 days postcoitum (dpc) with yolk sac, placental, cardiac, and vascular defects. The goal of this proposal is to characterize the role of 02 in cardiovascular development, particularly on endothelial cells. The specific aims are to 1) determine how hypoxia influences endothelial behavior, 2) examine the hematopoietic and angiogenic potential of intraembryonic tissues of Amt -/- mice, and 3) determine the effect of hypoxia in heart development. Accomplishing these specific aims will provide an understanding of hypoxic signals in mediating biological responses required for the growth and differentiation of the cardiovascular system. Furthermore, the examination of the cellular and molecular responses to hypoxia will provide important insights into various disease states, including tumor growth, diabetic retinopathy, preeclampsia, wound healing, and ischemia. Additionally, the detailed studies of this proposal and the senior guidance of the faculty committee will assist in commanding the investigator into a leader in the field of cardiovascular biology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYNDROME

THERAPY

WITH

ANNEXINS

FOR

ANTIPHOSPHOLIPID

Principal Investigator & Institution: Campos-Naciff, Maria-Begona M.; Molecular and Cellular Physio; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221

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Timing: Fiscal Year 2002; Project Start 08-MAY-2001; Project End 30-APR-2005 Summary: (Scanned from the applicant's description): APS is a disorder characterized by venous and arterial thrombosis, recurrent fetal loss, thrombocytopenia and by the presence of antiphospholipid antibodies. Recurrent pregnancy loss is produced also in APS patients due to thrombosis in the placental vasculature. Patients with APS also have higher risks of other obstetric and postnatal complications like preeclampsia, fetal distress, fetal growth impairment, premature delivery, maternal postpartum thrombosis and postpartum lung syndrome. In vitro, the annexins, a family of calcium dependent membrane binding proteins, are extremely potent inhibitors of blood coagulation. Annexin V has been proposed to regulate thrombosis and homeostasis on the villous trophoblast surface by shielding the anionic phospholipid membrane that may accelerate the coagulation cascade whereas the antiphospholipid antibodies have been proposed to displace the annexin V shield, causing exposure of phospholipid surfaces that produce activation in the coagulation cascade. Therefore, our initial hypothesis is that annexins could act in vivo as potent anticoagulants and could be beneficial in treating APS. In this study, we will evaluate therapeutic potential of wild type annexin V and mutants annexin V in vivo. Our prediction is that annexin mutants with higher affinity for phospholipid membranes may act as better anticoagulants. To test this hypothesis annexin V mutants will be created. The phospholipid binding affinity of wild type annexin and mutated annexin V will be compared with the antiphospholipid antibodies using three distinct approaches. Using a pregnant mice model, we will evaluate the therapeutic potential of these in vivo against the pathological effects of the antiphospholipid antibodies. Mice will be evaluated for fetal viability and size, fetal loss, placental thrombosis in the fetal and in the maternal side. We predict that annexin V may ameliorate the pathological consequences of the infusion of an antiphospholipid antibody. Transgenic mice will be used to evaluate the potential therapeutic of extracellular annexin V in the context of the whole animal. The results obtained with this work will provide useful treatment strategies to ameliorate the symptoms associated with the antiphospholipid syndrome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TNF ALPHA AND OTHER MEDIATORS IN THE PATHOGENESIS & PREDICTION OF PREECLAMPSIA Principal Investigator & Institution: Lee, Men-Jean; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TOTAL IONIZED MAGNESIUM & CALCIUM IN PRETERM LABOR & PREECLAMPSIA Principal Investigator & Institution: Taber, Evan Beth.; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 905022052 Timing: Fiscal Year 2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TROPHOBLAST REGULATION /ANGIOGENESIS /DIABETIC PLACENTA Principal Investigator & Institution: Golos, Thaddeus G.; Associate Professor; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002 Summary: The placenta and uterus conduct an essential dialogue at the maternal- fetal interface for the initiation, maintenance and completion of pregnancy via the coordinated functions of trophoblasts in contact with maternal blood, and the fetal vasculature within the chorionic in the placental vascular system in diabetic pregnancies is incompletely understood. Our overall hypothesis is that the dysregulation of glucose disposition in Type I diabetic pregnancy precipitates changes in angiogenesis impacting the placental villous vasculature, responsible for the pathophysiology of fetal growth and maternal well-being associated with the Type I diabetic pregnancy. We further hypothesize that glucose and oxygen-mediated pathways influence placental (trophoblast) regulation of angiogenesis. In order to test these hypotheses, we have set the following Specific Aims. Specific Aim 1, To define the changes in expression of mRNAs and proteins important for angiogenic and vasodilatory adaptation in normal and Type I diabetic placentas. Expt.1A/B. Angiogenic factors, eNOS, oxidative stress marker expression in viii and placental vessels Expt. 1C Morphometric analysis of placental villous proliferation, structure and vascular density. Expt. 1D Molecular phenotyping of the diabetic placenta Specific Aim 2. Define in vitro the mechanisms by which glucose, NO and hypoxia alter placental angiogenesis. Expt 2B. Effects of diabetes on trophoblast function and glucose-oxygen responsiveness Expt. 2D Evaluate the role of eNOS/NO in mediating glucose effects on trophoblast function Expt. 2D Evaluate the role of oxidative stress in glucose effects on trophoblast function. Reductions in placental vascularity due to the disruption of angiogenesis in Type 1 diabetic pregnancy can lead to decreased placental blood flow and reduction in fetal weight, survivability and health of the neonate. The mother is also at increased risk for development of ketoacidosis, pyelonephritis and preeclampsia. Type I Diabetes during pregnancy may have additional significance in the offspring for the long-term health and risk for adult disease. A better understanding of the intrauterine environment and its regulation will benefit not only maternal and fetal health, but also further the understanding of disease processes in all individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VASCULAR FUNCTION IN NORMOTENSIVE /PREECLAMPTIC PREGNANC Principal Investigator & Institution: Mclaughlin, Margaret; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002 Summary: Epidemiologic studies provide evidence that women with a history of preeclampsia may be at increased risk of hypertension and cardiovascular disease (CVD) later in life. It has been postulated that preeclampsia's characteristic abnormal placental perfusion may result in endothelial cell dysfunction. Subclinical endothelial function (EF may persist postpartum and contribute to increased risk of CVD. We propose to noninvasivel examine vascular function in women 6-12 months after a preeclamptic (20 cases) or nomotensive (20 controls) pregnancy to determine if vascular dysfunction persists in the preeclamptics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VASCULAR HYPERTENSION

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Principal Investigator & Institution: Khalil, Raouf A.; Associate Professor; None; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 30-APR-2006 Summary: (provided by the applicant): Normal pregnancy is associated with reduction in systemic vascular resistance, increased renal blood flow and decreased arterial pressure. In 5 to 10 percent of pregnancies, women develop a condition called preeclampsia characterized-by proteinuria, increased systemic and renal vascular resistance and pregnancy-induced hypertension (PIH); however, the mechanisms underlying this disorder have not yet been clearly identified. Reduction in uteroplacental perfusion and the ensuing placental ischemia during late pregnancy have been proposed to trigger the increases in systemic vascular resistance and PIH; however, the intermediary vascular and cellular mechanisms involved are unclear. The overall objective of this proposal is to test the central hypothesis that localized reduction in uteroplacental perfusion during late pregnancy is associated with generalized decrease in endothelium-dependent vascular relaxation and increase in vascular smooth muscle reactivity leading to generalized vasoconstriction, increased vascular resistance and hypertension. The decreased vascular relaxation occurs as a result of inhibition of the nitric oxide-cGMP and/or the prostacyclin-cAMP relaxation pathway. The increased vascular smooth muscle reactivity occurs as a result of increased sensitivity of vascular smooth muscle to vasoconstrictors leading to increased Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIRAL-INDUCED PLACENTAL IMPAIRMENT Principal Investigator & Institution: Parry, Samuel I.; Obstetrics and Gynecology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2007 Summary: (Provided By Applicant) Shallow invasion by the extravillous trophoblast into the uterine wall reduces placental perfusion and results in placental dysfunction, but the causes of shallow placental invasion are unknown. The hypothesis to be tested is that infection of invasive trophoblast early in gestation by adeno-associated virus (AAV) and other common viruses that help AAV to replicate causes obstetric complications that result from placental dysfunction, including spontaneous miscarriage, fetal growth restriction, and preeclampsia. Previously, AAV was shown to be able to infect undifferentiated and terminally differentiated trophoblast cells. AAV and its helper viruses (i.e., adenovirus, papillomavirus, herpesvirus, and cytomegalovirus) were discovered in trophoblast cells from miscarriages and in amniocytes from women with preterm premature rupture of the membranes. A relationship between placental viral infections and pathologic abnormalities was reported in cases of fetal growth restriction, and AAV DNA was found in placental tissue from cases of preeclampsia (11/35 cases) and spontaneous preterm birth (8/19 cases). Finally, the serum of 90 women during the first trimester of pregnancy was screened for anti-AAV antibodies, and primary AAV infections (the presence of IgM antibodies) were associated with an increased risk of spontaneous miscarriage (P=0.03). In this proposal, case-control studies will be conducted to determine if AAV infection is associated with a spectrum of adverse reproductive outcomes, and in vitro experiments will be performed to test the hypothesis that viral infection induces pathologic lesions which impair placental invasion of the uterine wall. Three specific aims are proposed: 1) to conduct a case-

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control study using PCR-based analyses to compare the incidence of placental viral infection and associated pathologic lesions in women whose pregnancies are complicated by fetal growth restriction and/or severe preeclampsia (cases) and controls; 2) to conduct a nested case-control study in which maternal serum during the first trimester of pregnancy is screened for antibodies against AAV and its helper viruses, to correlate early maternal viral infection with adverse outcomes attributed to placental dysfunction; 3) to determine the ability of AAV and helper viruses to infect extravillous trophoblast cell lines in vitro and define the pathologic effects associated with viral infection of these cells and villous explants. These experiments will provide insights into the role of viral infection in the pathogenesis of placental dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VULNERABILITY OF THE FETAL BRAIN TO HYPOXIC-ISCHEMIA Principal Investigator & Institution: Figueroa, Jorge P.; Associate Professor; Obstetrics and Gynecology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: Hypoxic-ischemic insult during the perinatal period remains a significant cause of morbidity and mortality in both term and preterm newborns. Epidemiological data suggest that chronically hypoxic fetuses have a higher incidence of neurological morbidity. In this proposal we will test the following interrelated hypotheses: 1) Chronic mild hypoxemia increases the expression of Type I Nitric Oxide Synthase in fetal brain; regional differences in Type I NOS expression following hypoxia are determined by differential expression of alternative splice variants. 2) Chronic fetal hypoxia increases the vulnerability of the fetal brain to neuronal damage. 3) The mechanism by which chronic hypoxia increases fetal brain vulnerability is the augmented release of NO secondary to upregulation of Type I NOS. 4) Increased apoptosis is one of the mechanisms by which NO induces neuronal death following a hypoxic-ischemic insult. In this proposal, we will concentrate in areas of the brain prone to hypoxic-ischemic damage and known to express Type I NOS (Sensory-motor cortex, striatum, hippocampus and cerebellum). Specific Aim 1 examines the effects of chronic hypoxia on Type I NOS expression by measuring enzymatic activity and protein mass using the citrulline assay and western blotting in distinct subcellular compartments of selected brain regions. Also, the Type I NOS mRNA response to hypoxia will be evaluated studying the expression of specific alternative splice variants. In particular, variants of exons 1 and 2. Specific Aim 2 examines the effect of hypoxia on brain vulnerability to acute ischemia using cord occlusion to induced neuronal damage. Coronal sections of the fetal brain will be stained with thionin/acid fuchsin to evaluate the proportion of dead neurons 72 hours after the insult. Specific Aim 3 will determine if the increased vulnerability of the chronically hypoxic fetus can be abrogated by a selective Type I NOS inhibitor (LVNIO) administered before the cord occlusion. Specific Aim 4 examines the effect of hypoxia and cord occlusion in the activation of the apoptosis cascade by measuring cytochrome c release, BAX translocation, cyclophilin D binding to the MPT, caspase-3 activation and DNA laddering 24 hours after the insult. In addition, we will evaluate the number of neurons stained with the TUNEL method in brains obtained in Aim 2. Fetal hypoxemia is a common obstetrical complication in pregnancies in which there is placental insufficiency, i.e., IUGR and preeclampsia. Thus, the data to be obtained are important since they will provide experimental evidence to support the epidemiological association of chronic hypoxia and increased neural morbidity. Also, it will be the first work to demonstrate a differential Type I NOS gene upregulation

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response to hypoxia in different regions of the fetal brain and its potential role as a mechanism for increasing fetal brain vulnerability. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

Critical pathways for the management of preeclampsia and severe preeclampsia in institutionalised health care settings. by Perez-Cuevas R, Fraser W, Reyes H, Reinharz D, Daftari A, Heinz CS, Roberts JM.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=270024

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Endogenous Biosynthesis of Arachidonic Acid Epoxides in Humans: Increased Formation in Pregnancy-Induced Hypertension. by Catella F, Lawson JA, Fitzgerald DJ, FitzGerald GA.; 1990 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54435

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Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. by Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA.; 2003 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151901

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Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered? by Luttun A, Carmeliet P.; 2003 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151908

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 3 4

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

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print. 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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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 preeclampsia, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “preeclampsia” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for preeclampsia (hyperlinks lead to article summaries): •

A longitudinal study of biochemical variables in women at risk of preeclampsia. Author(s): Chappell LC, Seed PT, Briley A, Kelly FJ, Hunt BJ, Charnock-Jones DS, Mallet AI, Poston L. Source: American Journal of Obstetrics and Gynecology. 2002 July; 187(1): 127-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12114900

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A long-term transdermal nitric oxide donor improves uteroplacental circulation in women with preeclampsia. Author(s): Nakatsuka M, Takata M, Tada K, Asagiri K, Habara T, Noguchi S, Kudo T. Source: Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine. 2002 August; 21(8): 831-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12164565

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A prospective comparison of total protein/creatinine ratio versus 24-hour urine protein in women with suspected preeclampsia. Author(s): Durnwald C, Mercer B. Source: American Journal of Obstetrics and Gynecology. 2003 September; 189(3): 848-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14526328

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A randomized trial of intrapartum analgesia in women with severe preeclampsia. Author(s): Head BB, Owen J, Vincent RD Jr, Shih G, Chestnut DH, Hauth JC. Source: Obstetrics and Gynecology. 2002 March; 99(3): 452-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11864673

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Abdominal pain and preeclampsia: sonographic findings in the maternal liver. Author(s): Suarez B, Alves K, Senat MV, Fromageot J, Fischer C, Rosenberg P, Ville Y. Source: Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine. 2002 October; 21(10): 1077-83; Quiz 1085-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12369662

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Abnormal iron parameters in the pregnancy syndrome preeclampsia. Author(s): Rayman MP, Barlis J, Evans RW, Redman CW, King LJ. Source: American Journal of Obstetrics and Gynecology. 2002 August; 187(2): 412-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12193935

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Abortion, changed paternity, and risk of preeclampsia in nulliparous women. Author(s): Saftlas AF, Levine RJ, Klebanoff MA, Martz KL, Ewell MG, Morris CD, Sibai BM. Source: American Journal of Epidemiology. 2003 June 15; 157(12): 1108-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796047

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ACOG practice bulletin on diagnosing and managing preeclampsia and eclampsia. American College of Obstetricians and Gynecologists. Author(s): Schroeder BM; American College of Obstetricians and Gynecologists. Source: American Family Physician. 2002 July 15; 66(2): 330-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12152970

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ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. American College of Obstetricians and Gynecologists. Author(s): ACOG Committee on Obstetric Practice. Source: International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics. 2002 April; 77(1): 67-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12094777

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Activated protein C for preeclampsia: tailoring the disease to the therapy. Author(s): Lapinsky SE, Mehta S. Source: Critical Care Medicine. 2002 August; 30(8): 1929-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163831

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Activated protein C in normal human pregnancy and pregnancies complicated by severe preeclampsia: a therapeutic opportunity? Author(s): von Dadelszen P, Magee LA, Lee SK, Stewart SD, Simone C, Koren G, Walley KR, Russell JA. Source: Critical Care Medicine. 2002 August; 30(8): 1883-92. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163810

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Acute complications of preeclampsia. Author(s): Norwitz ER, Hsu CD, Repke JT. Source: Clinical Obstetrics and Gynecology. 2002 June; 45(2): 308-29. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12048392

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Acute renal failure complicating severe preeclampsia requiring admission to an obstetric intensive care unit. Author(s): Drakeley AJ, Le Roux PA, Anthony J, Penny J. Source: American Journal of Obstetrics and Gynecology. 2002 February; 186(2): 253-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11854645

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Adrenomedullin is decreased in preeclampsia because of failed response to epidermal growth factor and impaired syncytialization. Author(s): Li H, Dakour J, Kaufman S, Guilbert LJ, Winkler-Lowen B, Morrish DW. Source: Hypertension. 2003 November; 42(5): 895-900. Epub 2003 September 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14517225

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Agonistic autoantibodies directed against the angiotensin II AT1 receptor in patients with preeclampsia. Author(s): Wallukat G, Neichel D, Nissen E, Homuth V, Luft FC. Source: Canadian Journal of Physiology and Pharmacology. 2003 February; 81(2): 79-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12710518

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Altered sonographic umbilical cord morphometry in early-onset preeclampsia. Author(s): Raio L, Ghezzi F, Di Naro E, Franchi M, Bolla D, Schneider H. Source: Obstetrics and Gynecology. 2002 August; 100(2): 311-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12151155

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Amniotic fluid and maternal serum leptin levels in pregnant women who subsequently develop preeclampsia. Author(s): Chan TF, Su JH, Chung YF, Hsu YH, Yeh YT, Jong SB, Yuan SS. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2003 May 1; 108(1): 50-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12694970

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An association between maternal smoking and preeclampsia in Japanese women. Author(s): Kobashi G, Ohta K, Hata A, Shido K, Yamada H, Fujimoto S, Kondo K. Source: Seminars in Thrombosis and Hemostasis. 2002 December; 28(6): 507-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12536340

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An endothelial nitric oxide synthase gene polymorphism is associated with preeclampsia. Author(s): Tempfer CB, Dorman K, Deter RL, O'Brien WE, Gregg AR. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2001; 20(1): 107-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044319

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Anesthesia and preeclampsia. Author(s): Mandal NG. Source: Jama : the Journal of the American Medical Association. 2002 October 16; 288(15): 1847; Author Reply 1847-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12377078

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Anticardiolipin and anti-beta2-glycoprotein-I antibodies in preeclampsia. Author(s): Lee RM, Brown MA, Branch DW, Ward K, Silver RM. Source: Obstetrics and Gynecology. 2003 August; 102(2): 294-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12907102

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Antioxidant potential and transferrin, ceruloplasmin, and lipid peroxidation levels in women with preeclampsia. Author(s): Aksoy H, Taysi S, Altinkaynak K, Bakan E, Bakan N, Kumtepe Y. Source: Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research. 2003 September; 51(5): 284-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14577518

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Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review. Author(s): Coomarasamy A, Honest H, Papaioannou S, Gee H, Khan KS. Source: Obstetrics and Gynecology. 2003 June; 101(6): 1319-32. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798543

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Aspirin prevents preeclampsia and complications. Author(s): Miller SM. Source: The Journal of Family Practice. 2003 December; 52(12): 923-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14653972

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Association between fetal nuchal translucency thickness in first trimester and subsequent gestational hypertension and preeclampsia. Author(s): Tsai MS, Lee FK, Cheng CC, Hwa KY, Cheong ML, She BQ. Source: Prenatal Diagnosis. 2002 September; 22(9): 747-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12224064

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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12153382

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Association between plasminogen activator inhibitor 1 gene polymorphisms and preeclampsia. Author(s): Fabbro D, D'Elia AV, Spizzo R, Driul L, Barillari G, Di Loreto C, Marchesoni D, Damante G. Source: Gynecologic and Obstetric Investigation. 2003; 56(1): 17-22. Epub 2003 July 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12867763

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Association of preeclampsia with high birth weight for gestational age. Author(s): Jacquemyn Y, Martens G, Ruyssinck G. Source: American Journal of Obstetrics and Gynecology. 2002 May; 186(5): 1105; Author Reply 1106. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12015546

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Atherogenic profile in preeclampsia. Author(s): Var A, Kuscu NK, Koyuncu F, Uyanik BS, Onur E, Yildirim Y, Oruc S. Source: Archives of Gynecology and Obstetrics. 2003 April; 268(1): 45-7. Epub 2002 May 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12673475

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Autoimmune hepatitis: diagnosis after preeclampsia-induced elevated liver enzymes failed to normalize postpartum. Author(s): Carson MP, Smulian JC, Fedorciw B. Source: Obstetrics and Gynecology. 2003 May; 101(5 Pt 2): 1118-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12738122

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Bilateral retinal occlusion progressing to long-lasting blindness in severe preeclampsia. Author(s): Lara-Torre E, Lee MS, Wolf MA, Shah DM. Source: Obstetrics and Gynecology. 2002 November; 100(5 Pt 1): 940-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12423856

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Bioactivity of serum hCG in preeclampsia. Author(s): Casart YC, Camejo MI, Proverbio F, Febres F. Source: Obstetrics and Gynecology. 2001 September; 98(3): 463-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11530130

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Blindness associated with severe preeclampsia/eclampsia. Author(s): Amata AO. Source: Anesthesia and Analgesia. 2001 October; 93(4): 1081. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11574394

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Blood pressure, serum lipids, fasting insulin, and adrenal hormones in 12-year-old children born with maternal preeclampsia. Author(s): Tenhola S, Rahiala E, Martikainen A, Halonen P, Voutilainen R. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 March; 88(3): 121722. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12629109

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C4 deficiency state in antiphospholipid antibody-related recurrent preeclampsia evolving into systemic lupus erythematosus. Author(s): Queiro R, Weruaga A, Riestra JL. Source: Rheumatology International. 2002 July; 22(3): 126-8. Epub 2002 June 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12111090

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Cellular bases for the lipid-related aspects of preeclampsia. Author(s): Coffey CG. Source: Medical Hypotheses. 2003 May; 60(5): 716-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12710909

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Cerebral perfusion pressure, and not cerebral blood flow, may be the critical determinant of intracranial injury in preeclampsia: a new hypothesis. Author(s): Raschke R. Source: American Journal of Obstetrics and Gynecology. 2003 March; 188(3): 860; Author Reply 860-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634682

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Cerebral perfusion pressure, and not cerebral blood flow, may be the critical determinant of intracranial injury in preeclampsia: a new hypothesis. Author(s): Belfort MA, Varner MW, Dizon-Townson DS, Grunewald C, Nisell H. Source: American Journal of Obstetrics and Gynecology. 2002 September; 187(3): 626-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12237639

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Cerebrovascular reactivity in normal pregnancy and preeclampsia. Author(s): Riskin-Mashiah S, Belfort MA, Saade GR, Herd JA. Source: Obstetrics and Gynecology. 2001 November; 98(5 Pt 1): 827-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11704176

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Cervicovaginal fetal fibronectin levels in women with preeclampsia. Author(s): McKenna DS, Costa S, Iams JD, Samuels P. Source: Obstetrics and Gynecology. 2002 August; 100(2): 266-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12151148

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Change in brain size during and after pregnancy: study in healthy women and women with preeclampsia. Author(s): Oatridge A, Holdcroft A, Saeed N, Hajnal JV, Puri BK, Fusi L, Bydder GM. Source: Ajnr. American Journal of Neuroradiology. 2002 January; 23(1): 19-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11827871

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Changes in blood macrophage colony-stimulating factor levels after cesarean section in normotensive pregnancy and preeclampsia. Author(s): Hayashi M, Hoshimoto K, Ohkura T. Source: The American Journal of the Medical Sciences. 2002 July; 324(1): 5-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12120825

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Changes in plasma endothelin-1 after elective cesarean section in women with preeclampsia and the relationship to thrombocytopenia. Author(s): Asakura H, Nakai A, Takeshita T. Source: Journal of Nippon Medical School = Nihon Ika Daigaku Zasshi. 2003 December; 70(6): 480-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14685288

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Changes in urinary excretion of six biochemical parameters in normotensive pregnancy and preeclampsia. Author(s): Hayashi M, Ueda Y, Hoshimoto K, Ota Y, Fukasawa I, Sumori K, Kaneko I, Abe S, Uno M, Ohkura T, Inaba N. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2002 February; 39(2): 392-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11840382

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Chemokines and leukocyte activation in the fetal circulation during preeclampsia. Author(s): Mellembakken JR, Aukrust P, Hestdal K, Ueland T, Abyholm T, Videm V. Source: Hypertension. 2001 September; 38(3): 394-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11566911

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Choroidal vascular abnormalities in preeclampsia. Author(s): Iida T, Kishi S. Source: Archives of Ophthalmology. 2002 October; 120(10): 1406-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12365932

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Circulating angiogenic factors and the risk of preeclampsia. Author(s): Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA. Source: The New England Journal of Medicine. 2004 February 12; 350(7): 672-83. Epub 2004 Feb 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14764923

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Circulating microparticles: a marker of procoagulant state in normal pregnancy and pregnancy complicated by preeclampsia or intrauterine growth restriction. Author(s): Bretelle F, Sabatier F, Desprez D, Camoin L, Grunebaum L, Combes V, D'Ercole C, Dignat-George F. Source: Thrombosis and Haemostasis. 2003 March; 89(3): 486-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12624632

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Circulatory fetal and maternal DNA in pregnancies at risk and those affected by preeclampsia. Author(s): Zhong XY, Holzgreve W, Hahn S. Source: Annals of the New York Academy of Sciences. 2001 September; 945: 138-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11708467

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Classic and novel risk factor parameters in women with a history of preeclampsia. Author(s): Sattar N, Ramsay J, Crawford L, Cheyne H, Greer IA. Source: Hypertension. 2003 July; 42(1): 39-42. Epub 2003 May 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12743016

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Clinical conference: aprotinin use during deep hypothermic circulatory arrest for type A aortic dissection and cesarean section in a woman with preeclampsia. Author(s): Murphy BA, Zvara DA, Nelson LH, Kon ND, Shore-Lesserson L, Milas BL. Source: Journal of Cardiothoracic and Vascular Anesthesia. 2003 April; 17(2): 252-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12698412

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Coagulation index to distinguish severe preeclampsia from normal pregnancy. Author(s): Kobayashi T, Sumimoto K, Tokunaga N, Sugimura M, Nishiguchi T, Kanayama N, Terao T. Source: Seminars in Thrombosis and Hemostasis. 2002 December; 28(6): 495-500. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12536338

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Comparison of the efficacy of continuous furosemide and low-dose dopamine infusion in preeclampsia/eclampsia-related oliguria in the immediate postpartum period. Author(s): Keiseb J, Moodley J, Connolly CA. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2002; 21(3): 225-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12517329

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Concentrations of apolipoproteins E, C2, and C3 and lipid profile in preeclampsia. Author(s): Chalas J, Audibert F, Francoual J, Le Bihan B, Frydman R, Lindenbaum A. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2002; 21(3): 199-204. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12517327

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Concentrations of estrogens in patients with preeclampsia. Author(s): Zeisler H, Jirecek S, Hohlagschwandtner M, Knofler M, Tempfer C, Livingston JC. Source: Wiener Klinische Wochenschrift. 2002 June 28; 114(12): 458-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12422581

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Connexin expression is not altered in omental resistance vessels from women with preeclampsia. Author(s): Umans JG, Lindheimer MD, Hack B, Davidson-Garcia CA. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2001; 20(1): 119-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044320

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Contemporary concepts of the pathogenesis and management of preeclampsia. Author(s): Lain KY, Roberts JM. Source: Jama : the Journal of the American Medical Association. 2002 June 26; 287(24): 3183-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12076198

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Correlation between random urinary protein-to-creatinine ratio and quantitation of 24-hour proteinuria in preeclampsia. Author(s): Yamasmit W, Wongkitisophon K, Charoenvidhya D, Uerpairojkit B, Chaithongwongwatthana S. Source: J Med Assoc Thai. 2003 January; 86(1): 69-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12678141

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Correlation of P-selectin and lipoprotein(a), and other lipid parameters in preeclampsia. Author(s): Aksoy H, Kumtepe Y, Akcay F, Yildirim AK. Source: Clinical and Experimental Medicine. 2002 May; 2(1): 39-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12049188

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Correlation of quantitative protein measurements in 8-, 12-, and 24-hour urine samples for the diagnosis of preeclampsia. Author(s): Adelberg AM, Miller J, Doerzbacher M, Lambers DS. Source: American Journal of Obstetrics and Gynecology. 2001 October; 185(4): 804-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11641655

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Could an infectious trigger explain the differential maternal response to the shared placental pathology of preeclampsia and normotensive intrauterine growth restriction? Author(s): von Dadelszen P, Magee LA. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2002 July; 81(7): 642-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12190839

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Current concepts in the use of antioxidants for the treatment of preeclampsia. Author(s): Bilodeau JF, Hubel CA. Source: J Obstet Gynaecol Can. 2003 September; 25(9): 742-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12970809

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Cytokine expression in peripheral blood lymphocytes indicates a switch to T(HELPER) cells in patients with preeclampsia. Author(s): Rein DT, Schondorf T, Gohring UJ, Kurbacher CM, Pinto I, Breidenbach M, Mallmann P, Kolhagen H, Engel H. Source: Journal of Reproductive Immunology. 2002 March; 54(1-2): 133-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11839400

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Decreased maternal serum leptin in pregnancies complicated by preeclampsia. Author(s): Laml T, Preyer O, Hartmann BW, Ruecklinger E, Soeregi G, Wagenbichler P. Source: Journal of the Society for Gynecologic Investigation. 2001 March-April; 8(2): 8993. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11336879

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Decreased maternal serum placenta growth factor in early second trimester and preeclampsia. Author(s): Su YN, Lee CN, Cheng WF, Shau WY, Chow SN, Hsieh FJ. Source: Obstetrics and Gynecology. 2001 June; 97(6): 898-904. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11384693

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Decreased tryptophan catabolism by placental indoleamine 2,3-dioxygenase in preeclampsia. Author(s): Kudo Y, Boyd CA, Sargent IL, Redman CW. Source: American Journal of Obstetrics and Gynecology. 2003 March; 188(3): 719-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634647

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Diagnosis and management of gestational hypertension and preeclampsia. Author(s): Sibai BM. Source: Obstetrics and Gynecology. 2003 July; 102(1): 181-92. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12850627

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Differences in apoptotic susceptibility of cytotrophoblasts and syncytiotrophoblasts in normal pregnancy to those complicated with preeclampsia and intrauterine growth restriction. Author(s): Crocker IP, Cooper S, Ong SC, Baker PN. Source: American Journal of Pathology. 2003 February; 162(2): 637-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12547721

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Diffusion imaging may predict reversible brain lesions in eclampsia and severe preeclampsia: initial experience. Author(s): Loureiro R, Leite CC, Kahhale S, Freire S, Sousa B, Cardoso EF, Alves EA, Borba P, Cerri GG, Zugaib M. Source: American Journal of Obstetrics and Gynecology. 2003 November; 189(5): 1350-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14634567

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Diffusion-weighted magnetic resonance imaging and the evaluation of cortical blindness in preeclampsia. Author(s): Gregory DG, Pelak VS, Bennett JL. Source: Survey of Ophthalmology. 2003 November-December; 48(6): 647-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14609710

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Do acetylsalicylic acid and other antiplatelet drugs prevent preeclampsia? Author(s): Maharaj R. Source: Can Fam Physician. 2001 December; 47: 2480-2. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11785278

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Does a lean prepregnancy body mass index influence outcome in pregnancies complicated by mild preeclampsia remote from term? Author(s): Barton JR, O'Nan JM, Bergauer NK, Jacques DL, Sibai BM. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2001; 20(3): 283-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044336

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Does antiplatelet therapy prevent preeclampsia and its complications? Author(s): Kruszka S, Kruszka P. Source: The Journal of Family Practice. 2001 May; 50(5): 468. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11350714

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Does thrombin activatable fibrinolysis inhibitor (TAFI) contribute to impairment of fibrinolysis in patients with preeclampsia and/or intrauterine fetal growth retardation? Author(s): Antovic JP, Rafik Hamad R, Antovic A, Blomback M, Bremme K. Source: Thrombosis and Haemostasis. 2002 October; 88(4): 644-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12362237

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Doppler velocimetry: is it useful in preeclampsia? Author(s): Ceres R, Modrono A, Ruiz S. Source: American Journal of Obstetrics and Gynecology. 2001 August; 185(2): 522-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11518921

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Early pregnancy levels of pregnancy-associated plasma protein a and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth. Author(s): Smith GC, Stenhouse EJ, Crossley JA, Aitken DA, Cameron AD, Connor JM. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 April; 87(4): 1762-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11932314

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Effect of preeclampsia in the mother on the leucine metabolism in the newborn infant. Author(s): Saenz De Pipaon Marcos M, Wattimena DJ, Van Beek RH, Lotgering FK, Sauer PJ. Source: Biology of the Neonate. 2002 January; 81(1): 23-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11803173

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Electron microscopy of umbilical cord endothelial cells in preeclampsia. Author(s): Sulbaran TA, Castellano A, Chacin L, Vergel C, Portillo MA, Urbina E, Silva ER, Castejon OJ. Source: J Submicrosc Cytol Pathol. 2002 October; 34(4): 389-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12585229

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Elevated plasma endothelial microparticles in preeclampsia. Author(s): Gonzalez-Quintero VH, Jimenez JJ, Jy W, Mauro LM, Hortman L, O'Sullivan MJ, Ahn Y. Source: American Journal of Obstetrics and Gynecology. 2003 August; 189(2): 589-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14520240

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Elevated plasma homocysteine in early pregnancy: a risk factor for the development of nonsevere preeclampsia. Author(s): Cotter AM, Molloy AM, Scott JM, Daly SF. Source: American Journal of Obstetrics and Gynecology. 2003 August; 189(2): 391-4; Discussion 394-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14520204

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Elevated plasma homocysteine in early pregnancy: a risk factor for the development of severe preeclampsia. Author(s): Levine RJ, England LJ, Sibai BM. Source: American Journal of Obstetrics and Gynecology. 2002 May; 186(5): 1107; Author Reply 1108. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12015548

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Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. Author(s): Koga K, Osuga Y, Yoshino O, Hirota Y, Ruimeng X, Hirata T, Takeda S, Yano T, Tsutsumi O, Taketani Y. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 May; 88(5): 2348-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12727995

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Elevation of serum macrophage colony-stimulating factor before the clinical manifestations of preeclampsia. Author(s): Hayashi M, Ohkura T, Inaba N. Source: American Journal of Obstetrics and Gynecology. 2003 November; 189(5): 135660. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14634568

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Endothelial cells and peripheral blood mononuclear cells are a potential source of extraplacental activin a in preeclampsia. Author(s): Tannetta DS, Muttukrishna S, Groome NP, Redman CW, Sargent IL. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 December; 88(12): 5995-6001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671202

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Endothelial dysfunction in preeclampsia and eclampsia: current etiology and future non-invasive assessment. Author(s): Blum A, Shenhav M, Baruch R, Hoffman M. Source: Isr Med Assoc J. 2003 October; 5(10): 724-6. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14719469

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Endothelial dysfunction in uterine circulation in preeclampsia: can estrogens improve it? Author(s): Svedas E, Nisell H, Vanwijk MJ, Nikas Y, Kublickiene KR. Source: American Journal of Obstetrics and Gynecology. 2002 December; 187(6): 1608-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12501072

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Endothelial junctional protein redistribution and increased monolayer permeability in human umbilical vein endothelial cells isolated during preeclampsia. Author(s): Wang Y, Gu Y, Granger DN, Roberts JM, Alexander JS. Source: American Journal of Obstetrics and Gynecology. 2002 February; 186(2): 214-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11854638

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Endothelial nitric oxide synthase polymorphism in preeclampsia. Author(s): Hakli T, Romppanen EL, Hiltunen M, Helisalmi S, Punnonen K, Heinonen S. Source: Journal of the Society for Gynecologic Investigation. 2003 April; 10(3): 154-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12699878

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Endothelin converting enzyme (ECE) activity in normal pregnancy and preeclampsia. Author(s): Ajne G, Wolff K, Fyhrquist F, Carlstrom K, Hemsen-Mortberg A, Nisell H. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2003; 22(3): 215-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14572358

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Endothelin-mediated preeclampsia at high altitude. Author(s): Angerio AD. Source: Critical Care Nursing Quarterly. 2000 August; 23(2): 73-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11853029

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Enhanced coagulation activation in preeclampsia: the role of APC resistance, microparticles and other plasma constituents. Author(s): VanWijk MJ, Boer K, Berckmans RJ, Meijers JC, van der Post JA, Sturk A, VanBavel E, Nieuwland R. Source: Thrombosis and Haemostasis. 2002 September; 88(3): 415-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12353069

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Evidence for an association of the R485K polymorphism in the coagulation factor V gene with severe preeclampsia from screening 35 polymorphisms in 27 candidate genes. Author(s): Watanabe H, Hamada H, Yamakawa-Kobayashi K, Yoshikawa H, Arinami T. Source: Thrombosis and Haemostasis. 2001 December; 86(6): 1594-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11776341

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Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. Author(s): Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Source: The Journal of Clinical Investigation. 2003 March; 111(5): 649-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12618519

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Expansion of the fraction of Th1 cells in women with preeclampsia: inverse correlation between the percentage of Th1 cells and the plasma level of PAI-2. Author(s): Ohkuchi A, Minakami H, Aoya T, Haga T, Kimura H, Suzuki M, Sato I. Source: American Journal of Reproductive Immunology (New York, N.Y. : 1989). 2001 October; 46(4): 252-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11642673

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Expectant management of severe preeclampsia and preeclampsia superimposed on chronic hypertension between 24 and 34 weeks' gestation. Author(s): Vigil-De Gracia P, Montufar-Rueda C, Ruiz J. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2003 March 26; 107(1): 24-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12593889

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Factor V Leiden and factor II G20210A in preeclampsia and HELLP syndrome. Author(s): Benedetto C, Marozio L, Salton L, Maula V, Chieppa G, Massobrio M. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2002 December; 81(12): 1095-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12519104

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Factor V Leiden mutation and preeclampsia. Author(s): Rigo J Jr, Nagy B, Fintor L. Source: American Journal of Obstetrics and Gynecology. 2002 April; 186(4): 853; Author Reply 853-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11967524

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Familial risk of preeclampsia in Newfoundland: a population-based study. Author(s): Dawson LM, Parfrey PS, Hefferton D, Dicks EL, Cooper MJ, Young D, Marsden PA. Source: Journal of the American Society of Nephrology : Jasn. 2002 July; 13(7): 1901-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12089387

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Family history of hypertension and diabetes in relation to preeclampsia risk in Peruvian women. Author(s): Sanchez SE, Zhang C, Qiu CF, Williams MA. Source: Gynecologic and Obstetric Investigation. 2003; 56(3): 128-32. Epub 2003 September 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14530611

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Family history of hypertension and type 2 diabetes in relation to preeclampsia risk. Author(s): Qiu C, Williams MA, Leisenring WM, Sorensen TK, Frederick IO, Dempsey JC, Luthy DA. Source: Hypertension. 2003 March; 41(3): 408-13. Epub 2003 February 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12623936

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Fas and Fas ligand expression in maternal blood and in umbilical cord blood in preeclampsia. Author(s): Kuntz TB, Christensen RD, Stegner J, Duff P, Koenig JM. Source: Pediatric Research. 2001 December; 50(6): 743-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11726734

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Fatal maternal outcome of a parturient with Eisenmenger's syndrome and severe preeclampsia. Author(s): Phupong V, Ultchaswadi P, Charakorn C, Prammanee K, Prasertsri S, Charuluxananan S. Source: Archives of Gynecology and Obstetrics. 2003 January; 267(3): 163-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12552329

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Fetal betamethasone treatment and neonatal outcome in preeclampsia and intrauterine growth restriction. Author(s): Szabo I, Vizer M, Ertl T. Source: American Journal of Obstetrics and Gynecology. 2003 December; 189(6): 1812-3; Author Reply 1813. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14710131

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Fetal DNA clearance from maternal plasma is impaired in preeclampsia. Author(s): Lau TW, Leung TN, Chan LY, Lau TK, Chan KC, Tam WH, Lo YM. Source: Clinical Chemistry. 2002 December; 48(12): 2141-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12446469

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Fetal DNA quantitation in peripheral blood is not useful as a marker of disease severity in women with preeclampsia. Author(s): Byrne BM, Crowley A, Taulo F, Anthony J, O'Leary JJ, O'Herlihy C. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2003; 22(2): 157-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12909000

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Fetal growth and body proportion in preeclampsia. Author(s): Rasmussen S, Irgens LM. Source: Obstetrics and Gynecology. 2003 March; 101(3): 575-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12636965

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Fibrinogen and factor VII promoter polymorphisms in women with preeclampsia. Author(s): Laasanen J, Hiltunen M, Punnonen K, Mannermaa A, Heinonen S. Source: Obstetrics and Gynecology. 2002 August; 100(2): 317-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12151156

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Fibronectin is a marker for organ involvement and may reflect the severity of preeclampsia. Author(s): Ostlund E, Hansson LO, Bremme K. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2001; 20(1): 79-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044316

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First trimester inhibin-A concentrations and later development of preeclampsia. Author(s): Roes EM, Gaytant MA, Thomas CM, Raijmakers MT, Zusterzeel PL, Peters WH, Steegers EA. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2004 January; 83(1): 117. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14758802

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First trimester insulin resistance and subsequent preeclampsia: a prospective study. Author(s): Wolf M, Sandler L, Munoz K, Hsu K, Ecker JL, Thadhani R. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 April; 87(4): 1563-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11932283

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First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. Author(s): Thadhani R, Mutter WP, Wolf M, Levine RJ, Taylor RN, Sukhatme VP, Ecker J, Karumanchi SA. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 February; 89(2): 770-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14764795

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First-trimester maternal serum levels of placenta growth factor as predictor of preeclampsia and fetal growth restriction. Author(s): Ong CY, Liao AW, Cacho AM, Spencer K, Nicolaides KH. Source: Obstetrics and Gynecology. 2001 October; 98(4): 608-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11576576

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Frequency of factor V, prothrombin and methylenetetrahydrofolate reductase gene variants in preeclampsia. Author(s): D'Elia AV, Driul L, Giacomello R, Colaone R, Fabbro D, Di Leonardo C, Florio P, Petraglia F, Marchesoni D, Damante G. Source: Gynecologic and Obstetric Investigation. 2002; 53(2): 84-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11961379

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Gene analysis of the N-terminal region of the estrogen receptor alpha in preeclampsia. Author(s): Malamitsi-Puchner A, Tziotis J, Evangelopoulos D, Fountas L, Vlachos G, Creatsas G, Sekeris CE, Moutsatsou P. Source: Steroids. 2001 September; 66(9): 695-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11546557

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Genetic and environmental contributions to severe preeclampsia: lack of association with the endothelial nitric oxide synthase Glu298Asp variant in a developing country. Author(s): Yoshimura T, Chowdhury FA, Yoshimura M, Okamura H. Source: Gynecologic and Obstetric Investigation. 2003; 56(1): 10-3. Epub 2003 July 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12867761

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Genetic susceptibility to preeclampsia: roles of cytosineto-thymine substitution at nucleotide 677 of the gene for methylenetetrahydrofolate reductase, 68-base pair insertion at nucleotide 844 of the gene for cystathionine beta-synthase, and factor V Leiden mutation. Author(s): Kim YJ, Williamson RA, Murray JC, Andrews J, Pietscher JJ, Peraud PJ, Merrill DC. Source: American Journal of Obstetrics and Gynecology. 2001 May; 184(6): 1211-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11349190

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Genetics of preeclampsia: what are the challenges? Author(s): Bernard N, Giguere Y. Source: J Obstet Gynaecol Can. 2003 July; 25(7): 578-85. Review. Erratum In: J Obstet Gynaecol Can. 2003 September; 25(9): 717. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12851670

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Heat shock protein 70 is not increased in women with severe preeclampsia. Author(s): Livingston JC, Ahokas R, Haddad B, Sibai BM, Awaads R. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2002; 21(2): 123-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12175440

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Heme oxygenase expression in human placenta and placental bed: reduced expression of placenta endothelial HO-2 in preeclampsia and fetal growth restriction. Author(s): Barber A, Robson SC, Myatt L, Bulmer JN, Lyall F. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2001 May; 15(7): 1158-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11344084

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Hemodynamic monitoring in high-risk obstetrics patients, II. Pregnancy-induced hypertension and preeclampsia. Author(s): Bridges EJ, Womble S, Wallace M, McCartney J. Source: Critical Care Nurse. 2003 October; 23(5): 52-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14606127

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Hemodynamic responses to obstructive respiratory events during sleep are augmented in women with preeclampsia. Author(s): Edwards N, Blyton DM, Kirjavainen TT, Sullivan CE. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2001 November; 14(11 Pt 1): 1090-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11724205

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Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome as a complication of preeclampsia in pregnant women increases the amount of cell-free fetal and maternal DNA in maternal plasma and serum. Author(s): Swinkels DW, de Kok JB, Hendriks JC, Wiegerinck E, Zusterzeel PL, Steegers EA. Source: Clinical Chemistry. 2002; 48(4): 650-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11901066

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High intake of energy, sucrose, and polyunsaturated fatty acids is associated with increased risk of preeclampsia. Author(s): Clausen T, Slott M, Solvoll K, Drevon CA, Vollset SE, Henriksen T. Source: American Journal of Obstetrics and Gynecology. 2001 August; 185(2): 451-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11518908

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History of abortion and subsequent risk of preeclampsia. Author(s): Dempsey JC, Sorensen TK, Qiu CF, Luthy DA, Williams MA. Source: J Reprod Med. 2003 July; 48(7): 509-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12953325

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History of abortion, preterm, term birth, and risk of preeclampsia: a population-based study. Author(s): Xiong X, Fraser WD, Demianczuk NN. Source: American Journal of Obstetrics and Gynecology. 2002 October; 187(4): 1013-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12388998

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Homocysteine and cellular fibronectin are increased in preeclampsia, not transient hypertension of pregnancy. Author(s): Powers RW, Evans RW, Ness RB, Crombleholme WR, Roberts JM. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2001; 20(1): 69-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044315

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Homocysteine and other plasma amino acids in preeclampsia and in pregnancies without complications. Author(s): Lopez-Quesada E, Vilaseca MA, Artuch R, Gomez E, Lailla JM. Source: Clinical Biochemistry. 2003 May; 36(3): 185-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12726926

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Homocysteine plasma concentration levels for the prediction of preeclampsia in women with chronic hypertension. Author(s): Zeeman GG, Alexander JM, McIntire DD, Devaraj S, Leveno KJ. Source: American Journal of Obstetrics and Gynecology. 2003 August; 189(2): 574-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14520237

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Human trophoblast invasion and spiral artery transformation: the role of PECAM-1 in normal pregnancy, preeclampsia, and fetal growth restriction. Author(s): Lyall F, Bulmer JN, Duffie E, Cousins F, Theriault A, Robson SC. Source: American Journal of Pathology. 2001 May; 158(5): 1713-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11337369

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Hyperhomocysteinemia in preeclampsia is associated to higher risk pressure profiles. Author(s): Noto R, Neri S, Noto Z, Cilio D, Abate G, Noto P, Pepi F, Leanza A, Molino G. Source: Eur Rev Med Pharmacol Sci. 2003 May-June; 7(3): 81-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14650644

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Hypertension in pregnancy and preeclampsia. Knowledge and clinical practice among obstetrician-gynecologists. Author(s): Repke JT, Power ML, Holzman GB, Schulkin J. Source: J Reprod Med. 2002 June; 47(6): 472-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12092016

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Hypertension/preeclampsia. Author(s): Odendaal H. Source: Cardiovasc J S Afr. 2002 January-February; 13(1): 5-8. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11875601

84

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Hyperuricemia, oxidative stress in preeclampsia. Author(s): Kharb S, Singh GP. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2001 March; 305(1-2): 201-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11354030

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Hypothesis: preeclampsia as a maternal-fetal conflict. Author(s): Odent M. Source: Medgenmed [electronic Resource] : Medscape General Medicine. 2001 September 5; 3(5): 2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11976604

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Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Author(s): Hung TH, Skepper JN, Charnock-Jones DS, Burton GJ. Source: Circulation Research. 2002 June 28; 90(12): 1274-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12089065

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ICAM-1 in maternal serum and amniotic fluid as an early marker of preeclampsia and IUGR. Author(s): Baviera G, D'Anna R, Corrado F, Ruello A, Buemi M, Jasonni VM. Source: J Reprod Med. 2002 March; 47(3): 191-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11933682

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Impact of preeclampsia and gestational hypertension on birth weight by gestational age. Author(s): Xiong X, Demianczuk NN, Saunders LD, Wang FL, Fraser WD. Source: American Journal of Epidemiology. 2002 February 1; 155(3): 203-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11821244

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Increased endothelial monocyte chemoattractant protein-1 and interleukin-8 in preeclampsia. Author(s): Kauma S, Takacs P, Scordalakes C, Walsh S, Green K, Peng T. Source: Obstetrics and Gynecology. 2002 October; 100(4): 706-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12383538

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Increased endothelial monolayer permeability is induced by serum from women with preeclampsia but not by serum from women with normal pregnancy or that are not pregnant. Author(s): Zhang Y, Gu Y, Li H, Lucas MJ, Wang Y. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2003; 22(1): 99-108. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12648447

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Increased levels of macrophage colony-stimulating factor in the placenta and blood in preeclampsia. Author(s): Hayashi M, Hoshimoto K, Ohkura T, Inaba N. Source: American Journal of Reproductive Immunology (New York, N.Y. : 1989). 2002 January; 47(1): 19-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11883744

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Increased levels of serum macrophage colony-stimulating factor before the onset of preeclampsia. Author(s): Hayashi M, Ohkura T, Inaba N. Source: Hormone and Metabolic Research. Hormon- Und Stoffwechselforschung. Hormones Et Metabolisme. 2003 October; 35(10): 588-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14605992

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Increased placental expression of tissue factor is associated with abnormal uterine and umbilical Doppler waveforms in severe preeclampsia with fetal growth restriction. Author(s): Di Paolo S, Volpe P, Grandaliano G, Stallone G, Schena A, Greco P, Resta L, Selvaggi L, Cincione R, Schena FP, Gesualdo L. Source: Journal of Nephrology. 2003 September-October; 16(5): 650-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14733410

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Increased plasma adenosine concentrations and the severity of preeclampsia. Author(s): Yoneyama Y, Suzuki S, Sawa R, Yoneyama K, Power GG, Araki T. Source: Obstetrics and Gynecology. 2002 December; 100(6): 1266-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12468172

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Increased risk of preeclampsia among nulliparous pregnant women with idiopathic hematuria. Author(s): Stehman-Breen CO, Levine RJ, Qian C, Morris CD, Catalano PM, Curet LB, Sibai BM. Source: American Journal of Obstetrics and Gynecology. 2002 September; 187(3): 703-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12237651

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Increased vascular endothelial cell production of interleukin-6 in severe preeclampsia. Author(s): Takacs P, Green KL, Nikaeo A, Kauma SW. Source: American Journal of Obstetrics and Gynecology. 2003 March; 188(3): 740-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634650

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Induction to delivery time interval in patients with and without preeclampsia: a retrospective analysis. Author(s): Griffiths AN, Hikary N, Sizer AR. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2002 September; 81(9): 867-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12225304

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Influence of maternal preeclampsia on recombinant human granulocyte colonystimulating factor effect in neutropenic neonates with suspected sepsis. Author(s): Zuppa AA, Girlando P, Florio MG, Cota F, Romagnoli C, Tortorolo G. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2002 May 10; 102(2): 131-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11950479

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Inhibin-A and superimposed preeclampsia in women with chronic hypertension. Author(s): Zeeman GG, Alexander JM, McIntire DD, Byrd W, Leveno KJ. Source: Obstetrics and Gynecology. 2003 February; 101(2): 232-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12576244

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Interleukin-18 in the plasma of women with preeclampsia. Author(s): Adams KM, Mandel LS, Guthrie KA, Atkinson MW. Source: American Journal of Obstetrics and Gynecology. 2003 May; 188(5): 1234-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12748489

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Intrauterine exposure to preeclampsia and adolescent blood pressure, body size, and age at menarche in female offspring. Author(s): Vatten LJ, Romundstad PR, Holmen TL, Hsieh CC, Trichopoulos D, Stuver SO. Source: Obstetrics and Gynecology. 2003 March; 101(3): 529-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12636958

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Intrauterine growth restriction, preeclampsia, and intrauterine mortality at high altitude in Bolivia. Author(s): Keyes LE, Armaza JF, Niermeyer S, Vargas E, Young DA, Moore LG. Source: Pediatric Research. 2003 July; 54(1): 20-5. Epub 2003 April 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12700368

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Is a polymorphism of the apolipoprotein E gene associated with preeclampsia? Author(s): Francoual J, Audibert F, Trioche P, Chalas J, Capel L, Lindenbaum A, Labrune P, Frydman R. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2002; 21(2): 127-33. Erratum In: Hypertens Pregnancy. 2003; 22(2): 213. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12175441

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Is mid-trimester maternal serum inhibin-A a marker of preeclampsia or intrauterine growth restriction? Author(s): D'Anna R, Baviera G, Corrado F, Leonardi I, Buemi M, Jasonni VM. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2002 June; 81(6): 540-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12047308

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Isolated microparticles, but not whole plasma, from women with preeclampsia impair endothelium-dependent relaxation in isolated myometrial arteries from healthy pregnant women. Author(s): Myers JE, Baker PN. Source: American Journal of Obstetrics and Gynecology. 2003 October; 189(4): 1209; Author Reply 1209-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14619830

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Isolated microparticles, but not whole plasma, from women with preeclampsia impair endothelium-dependent relaxation in isolated myometrial arteries from healthy pregnant women. Author(s): Vanwijk MJ, Svedas E, Boer K, Nieuwland R, Vanbavel E, Kublickiene KR. Source: American Journal of Obstetrics and Gynecology. 2002 December; 187(6): 1686-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12501084

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Lack of association of severe preeclampsia with maternal and fetal mutant alleles for tumor necrosis factor alpha and lymphotoxin alpha genes and plasma tumor necrosis factor alpha levels. Author(s): Livingston JC, Park V, Barton JR, Elfering S, Haddad B, Mabie WC, Quasney M, Sibai BM. Source: American Journal of Obstetrics and Gynecology. 2001 May; 184(6): 1273-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11349201

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L-arginine transport by the microvillous plasma membrane of the syncytiotrophoblast from human placenta in relation to nitric oxide production: effects of gestation, preeclampsia, and intrauterine growth restriction. Author(s): Ayuk PT, Theophanous D, D'Souza SW, Sibley CP, Glazier JD. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 February; 87(2): 747-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11836315

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Late onset of cortical blindness in a patient with severe preeclampsia related to retained placental fragments. Author(s): Delefosse D, Samain E, Helias A, Regimbeau JM, Deval B, Farah E, Marty J. Source: Anesthesiology. 2003 January; 98(1): 261-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12503005

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Leptin and preeclampsia. Author(s): Poston L. Source: Seminars in Reproductive Medicine. 2002 May; 20(2): 131-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12087498

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Levels of dimethylarginines and cytokines in mild and severe preeclampsia. Author(s): Ellis J, Wennerholm UB, Bengtsson A, Lilja H, Pettersson A, Sultan B, Wennergren M, Hagberg H. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2001 July; 80(7): 602-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11437716

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Levels of oxidative stress and redox-related molecules in the placenta in preeclampsia and fetal growth restriction. Author(s): Takagi Y, Nikaido T, Toki T, Kita N, Kanai M, Ashida T, Ohira S, Konishi I. Source: Virchows Archiv : an International Journal of Pathology. 2004 January; 444(1): 49-55. Epub 2003 October 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14574573

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Levels of plasminogen activators and their inhibitors in maternal and umbilical cord plasma in severe preeclampsia. Author(s): Roes EM, Sweep CG, Thomas CM, Zusterzeel PL, Geurts-Moespot A, Peters WH, Steegers EA. Source: American Journal of Obstetrics and Gynecology. 2002 October; 187(4): 1019-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12388999

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Linkage and association studies of IL1B and IL1RN gene polymorphisms in preeclampsia. Author(s): Lachmeijer AM, Nosti-Escanilla MP, Bastiaans EB, Pals G, Sandkuijl LA, Kostense PJ, Aarnoudse JG, Crusius JB, Pena AS, Dekker GA, Arngrimsson R, ten Kate LP. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2002; 21(1): 23-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044341

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Lipid and protein oxidation and antioxidant function in women with mild and severe preeclampsia. Author(s): Serdar Z, Gur E, Colakoethullary M, Develioethlu O, Sarandol E. Source: Archives of Gynecology and Obstetrics. 2003 April; 268(1): 19-25. Epub 2002 July 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12673470

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Lipid hydroperoxides and free radical scavenging enzyme activities in preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome: no evidence for circulating primary products of lipid peroxidation. Author(s): Diedrich F, Renner A, Rath W, Kuhn W, Wieland E. Source: American Journal of Obstetrics and Gynecology. 2001 July; 185(1): 166-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11483923

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Lipoprotein lipase gene mutations and the genetic susceptibility of preeclampsia. Author(s): Kim YJ, Williamson RA, Chen K, Smith JL, Murray JC, Merrill DC. Source: Hypertension. 2001 November; 38(5): 992-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11711487

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Lipoprotein(a): a longitudinal versus a cross-sectional study in normal pregnancy and its levels in preeclampsia. Author(s): Belo L, Caslake M, Santos-Silva A, Pereira-Leite L, Quintanilha A, Rebelo I. Source: Atherosclerosis. 2002 December; 165(2): 393-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12417294

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Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. Author(s): Tidwell SC, Ho HN, Chiu WH, Torry RJ, Torry DS. Source: American Journal of Obstetrics and Gynecology. 2001 May; 184(6): 1267-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11349200

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Low selenium status is associated with the occurrence of the pregnancy disease preeclampsia in women from the United Kingdom. Author(s): Rayman MP, Bode P, Redman CW. Source: American Journal of Obstetrics and Gynecology. 2003 November; 189(5): 1343-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14634566

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Low-density lipoprotein particle diameter in normal pregnancy and preeclampsia. Author(s): Ogura K, Miyatake T, Fukui O, Nakamura T, Kameda T, Yoshino G. Source: J Atheroscler Thromb. 2002; 9(1): 42-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12238637

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Lupus anticoagulant in Nigerian women with preeclampsia. Author(s): Awodu OA, Shokunbi WA, Ejele OA. Source: West Afr J Med. 2003 September; 22(3): 240-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14696949

90

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Lymphocyte subset distribution and cytokine secretion in third trimester decidua in normal pregnancy and preeclampsia. Author(s): Wilczynski JR, Tchorzewski H, Banasik M, Glowacka E, Wieczorek A, Lewkowicz P, Malinowski A, Szpakowski M, Wilczynski J. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2003 July 1; 109(1): 8-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12818436

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Magnesium sulfate for mild preeclampsia. Author(s): Scott JR. Source: Obstetrics and Gynecology. 2003 February; 101(2): 213. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12576239

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Magnesium sulfate for preeclampsia. Author(s): Greene MF. Source: The New England Journal of Medicine. 2003 January 23; 348(4): 275-6. Erratum In: N Engl J Med. 2003 Jan 23; 348(4): 1730. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12540639

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Magnesium sulfate in women with mild preeclampsia: a randomized controlled trial. Author(s): Livingston JC, Livingston LW, Ramsey R, Mabie BC, Sibai BM. Source: Obstetrics and Gynecology. 2003 February; 101(2): 217-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12576241

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Marion's message. Preeclampsia and the placenta. Author(s): McLean MT. Source: Midwifery Today Int Midwife. 2001 Summer; (58): 7, 69. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12154730

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Maternal body mass index and the risk of preeclampsia: a systematic overview. Author(s): O'Brien TE, Ray JG, Chan WS. Source: Epidemiology (Cambridge, Mass.). 2003 May; 14(3): 368-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12859040

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Maternal lymphocyte subpopulations (CD45RA+ and CD45RO+) in preeclampsia. Author(s): Chaiworapongsa T, Gervasi MT, Refuerzo J, Espinoza J, Yoshimatsu J, Berman S, Romero R. Source: American Journal of Obstetrics and Gynecology. 2002 October; 187(4): 889-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12388971

Studies

91

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Maternal periodontal disease is associated with an increased risk for preeclampsia. Author(s): Boggess KA, Lieff S, Murtha AP, Moss K, Beck J, Offenbacher S. Source: Obstetrics and Gynecology. 2003 February; 101(2): 227-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12576243

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Maternal plasma adenosine and endothelin-1 levels in twin gestation complicated by preeclampsia. Author(s): Shinagawa T, Suzuki S, Sawa R, Yoneyama Y, Asakura H, Araki T. Source: Archives of Gynecology and Obstetrics. 2002 December; 267(2): 72-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12439550

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Maternal plasma cellular fibronectin concentrations in normal and preeclamptic pregnancies: a longitudinal study for early prediction of preeclampsia. Author(s): Chavarria ME, Lara-Gonzalez L, Gonzalez-Gleason A, Sojo I, Reyes A. Source: American Journal of Obstetrics and Gynecology. 2002 September; 187(3): 595601. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12237633

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Maternal plasma cellular fibronectin for early prediction of preeclampsia. Author(s): Zhang J, Schisterman EF. Source: American Journal of Obstetrics and Gynecology. 2003 October; 189(4): 1212. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14619833

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Maternal serum activin A is not elevated before preeclampsia in women who are at high risk. Author(s): Blackburn CA, Keelan JA, Taylor RS, North RA. Source: American Journal of Obstetrics and Gynecology. 2003 March; 188(3): 807-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634661

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Maternal-fetal flow, negative events, and preeclampsia: role of ACE I/D polymorphism. Author(s): Mello G, Parretti E, Gensini F, Sticchi E, Mecacci F, Scarselli G, Genuardi M, Abbate R, Fatini C. Source: Hypertension. 2003 April; 41(4): 932-7. Epub 2003 March 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12654717

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Matrix metalloproteinase-2 is elevated in the plasma of women with preeclampsia. Author(s): Narumiya H, Zhang Y, Fernandez-Patron C, Guilbert LJ, Davidge ST. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2001; 20(2): 185-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044329

92

Preeclampsia

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Mechanism of increased maternal serum total activin a and inhibin a in preeclampsia. Author(s): Silver HM, Lambert-Messerlian GM, Reis FM, Diblasio AM, Petraglia F, Canick JA. Source: Journal of the Society for Gynecologic Investigation. 2002 September-October; 9(5): 308-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12383916

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Microparticle subpopulations are increased in preeclampsia: possible involvement in vascular dysfunction? Author(s): VanWijk MJ, Nieuwland R, Boer K, van der Post JA, VanBavel E, Sturk A. Source: American Journal of Obstetrics and Gynecology. 2002 August; 187(2): 450-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12193942

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Microsatellite marker association at chromosome region 2p13 in Finnish patients with preeclampsia and obstetric cholestasis suggests a common risk locus. Author(s): Laasanen J, Hiltunen M, Romppanen EL, Punnonen K, Mannermaa A, Heinonen S. Source: European Journal of Human Genetics : Ejhg. 2003 March; 11(3): 232-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12673277

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Midtrimester triple test levels in women with severe preeclampsia and HELLP syndrome. Author(s): Shenhav S, Gemer O, Volodarsky M, Zohav E, Segal S. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 October; 82(10): 912-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12956840

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Mishandling of copper by albumin: role in redox-cycling and oxidative stress in preeclampsia plasma. Author(s): Kagan VE, Tyurin VA, Borisenko GG, Fabisiak JP, Hubel CA, Ness RB, Gandley R, McLaughlin MK, Roberts JM. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2001; 20(3): 221-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044332

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Mitochondrial tRNA(leu)(UUR) gene mutation and the decreased activity of cytochrome c oxidase in preeclampsia. Author(s): Wang Z, Zhang G, Lin M. Source: J Tongji Med Univ. 1999; 19(3): 209-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12840896

Studies

93

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Molecular epidemiology of preeclampsia. Author(s): Wilson ML, Goodwin TM, Pan VL, Ingles SA. Source: Obstetrical & Gynecological Survey. 2003 January; 58(1): 39-66. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12544785

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NADPH oxidase activity in preeclampsia with immortalized lymphoblasts used as models. Author(s): Lee VM, Quinn PA, Jennings SC, Ng LL. Source: Hypertension. 2003 April; 41(4): 925-31. Epub 2003 March 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12629036

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Neurodevelopmental and cognitive assessment of children born growth restricted to mothers with and without preeclampsia. Author(s): Many A, Fattal A, Leitner Y, Kupferminc MJ, Harel S, Jaffa A. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2003; 22(1): 25-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12648440

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Neutrophil activation and C-reactive protein concentration in preeclampsia. Author(s): Belo L, Santos-Silva A, Caslake M, Cooney J, Pereira-Leite L, Quintanilha A, Rebelo I. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2003; 22(2): 129-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12908997

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Neutrophils are stimulated by syncytiotrophoblast microvillous membranes to generate superoxide radicals in women with preeclampsia. Author(s): Aly AS, Khandelwal M, Zhao J, Mehmet AH, Sammel MD, Parry S. Source: American Journal of Obstetrics and Gynecology. 2004 January; 190(1): 252-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14749668

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Newborn birth weight correlates with placental zinc, umbilical insulin-like growth factor I, and leptin levels in preeclampsia. Author(s): Diaz E, Halhali A, Luna C, Diaz L, Avila E, Larrea F. Source: Archives of Medical Research. 2002 January-February; 33(1): 40-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11825630

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Nifedipine or hydralazine as a first-line agent to control hypertension in severe preeclampsia. Author(s): Aali BS, Nejad SS. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2002 January; 81(1): 25-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11942883

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Nitric oxide production by decidual endothelial cells is not reduced in preeclampsia. Author(s): Rowe J, Campbell S, Gallery ED. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2003; 22(1): 63-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12648444

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Nitric oxide production increases during normal pregnancy and decreases in preeclampsia. Author(s): Choi JW, Im MW, Pai SH. Source: Ann Clin Lab Sci. 2002 Summer; 32(3): 257-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12175088

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Nitric oxide/endothelin-1 in preeclampsia. Author(s): Vural P. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2002 March; 317(1-2): 65-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11814459

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No difference in structure between omental small arteries isolated from women with preeclampsia, intrauterine growth restriction, and normal pregnancies. Author(s): Ong SS, Baker PN, Mayhew TM, Dunn WR. Source: American Journal of Obstetrics and Gynecology. 2002 September; 187(3): 606-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12237635

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No evidence for lipid peroxidation in severe preeclampsia. Author(s): Poston L, Mallet A. Source: American Journal of Obstetrics and Gynecology. 2002 October; 187(4): 1118; Author Reply 1119-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12389014

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No evidence for lipid peroxidation in severe preeclampsia. Author(s): Regan CL, Levine RJ, Baird DD, Ewell MG, Martz KL, Sibai BM, Rokach J, Lawson JA, Fitzgerald GA. Source: American Journal of Obstetrics and Gynecology. 2001 September; 185(3): 572-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11568780

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Normalization of vasoactive changes in preeclampsia precedes clinical recovery. Author(s): Makkonen N, Heinonen S, Hongisto T, Penttila I, Kirkinen P. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2002; 21(1): 51-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044343

Studies

95

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Novel chemiluminescence assay for serum periostin levels in women with preeclampsia and in normotensive pregnant women. Author(s): Sasaki H, Roberts J, Lykins D, Fujii Y, Auclair D, Chen LB. Source: American Journal of Obstetrics and Gynecology. 2002 January; 186(1): 103-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11810094

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Nutrient involvement in preeclampsia. Author(s): Roberts JM, Balk JL, Bodnar LM, Belizan JM, Bergel E, Martinez A. Source: The Journal of Nutrition. 2003 May; 133(5 Suppl 2): 1684S-1692S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12730485

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Obesity and preeclampsia: the potential role of inflammation. Author(s): Wolf M, Kettyle E, Sandler L, Ecker JL, Roberts J, Thadhani R. Source: Obstetrics and Gynecology. 2001 November; 98(5 Pt 1): 757-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11704165

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On the prevention of preeclampsia: nutritional factors back in the spotlight? Author(s): Alexander S. Source: Epidemiology (Cambridge, Mass.). 2002 July; 13(4): 382-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12094091

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Ophthalmic artery color Doppler ultrasonography in mild-to-moderate preeclampsia. Author(s): Ayaz T, Akansel G, Hayirlioglu A, Arslan A, Suer N, Kuru I. Source: European Journal of Radiology. 2003 June; 46(3): 244-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12758119

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Oxidative stress reproduces placental abnormalities of preeclampsia. Author(s): Vaughan JE, Walsh SW. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2002; 21(3): 205-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12517328

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Pancreatic necrosis associated with preeclampsia-eclampsia. Author(s): Parmar MS. Source: Jop [electronic Resource] : Journal of the Pancreas. 2004 March; 5(2): 101-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15007192

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Paradoxical elevation in adiponectin concentrations in women with preeclampsia. Author(s): Ramsay JE, Jamieson N, Greer IA, Sattar N. Source: Hypertension. 2003 November; 42(5): 891-4. Epub 2003 September 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14517227

96

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Pathophysiology of preeclampsia: linking placental ischemia/hypoxia with microvascular dysfunction. Author(s): Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA. Source: Microcirculation (New York, N.Y. : 1994). 2002 July; 9(3): 147-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12080413

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Patients with severe preeclampsia experience less hypotension during spinal anesthesia for elective cesarean delivery than healthy parturients: a prospective cohort comparison. Author(s): Aya AG, Mangin R, Vialles N, Ferrer JM, Robert C, Ripart J, de La Coussaye JE. Source: Anesthesia and Analgesia. 2003 September; 97(3): 867-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12933418

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Pharmacokinetics of ionized versus total magnesium in subjects with preterm labor and preeclampsia. Author(s): Taber EB, Tan L, Chao CR, Beall MH, Ross MG. Source: American Journal of Obstetrics and Gynecology. 2002 May; 186(5): 1017-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12015530

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Plasma homocysteine in early and late pregnancies complicated with preeclampsia and isolated intrauterine growth restriction. Author(s): D'Anna R, Baviera G, Corrado F, Ientile R, Granese D, Stella NC. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2004 February; 83(2): 155-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14756732

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Polymorphism in the tumor necrosis factor-alpha gene in women with preeclampsia. Author(s): Heiskanen J, Romppanen EL, Hiltunen M, Iivonen S, Mannermaa A, Punnonen K, Heinonen S. Source: Journal of Assisted Reproduction and Genetics. 2002 May; 19(5): 220-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12099552

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Predicting the risk of preeclampsia and small for gestational age infants by uterine artery Doppler in low-risk women. Author(s): Phupong V, Dejthevaporn T, Tanawattanacharoen S, Manotaya S, Tannirandorn Y, Charoenvidhya D. Source: Archives of Gynecology and Obstetrics. 2003 August; 268(3): 158-61. Epub 2002 September 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12942242

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Preeclampsia -- searching for the cause. Author(s): Solomon CG, Seely EW. Source: The New England Journal of Medicine. 2004 February 12; 350(7): 641-2. Epub 2004 Feb 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14764924

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Preeclampsia and calcium-ATPase activity of plasma membranes from human myometrium and placental trophoblast. Author(s): Carrera F, Casart YC, Proverbio T, Proverbio F, Marin R. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2003; 22(3): 295-304. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14572366

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Preeclampsia and calcium-ATPase activity of red cell ghosts from neonatal and maternal blood. Author(s): Carreiras MM, Proverbio T, Proverbio F, Marin R. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2002; 21(2): 97-107. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12175437

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Preeclampsia and cerebral palsy in low-birth-weight and preterm infants: implications for the current “ischemic model” of preeclampsia. Author(s): Xiong X, Saunders LD, Wang FL, Davidge ST, Buekens P. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2001; 20(1): 1-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044309

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Preeclampsia and eclampsia revisited. Author(s): Longo SA, Dola CP, Pridjian G. Source: Southern Medical Journal. 2003 September; 96(9): 891-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14513987

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Preeclampsia is associated with increased susceptibility of serum lipids to copperinduced peroxidation in vitro. Author(s): Fainaru O, Lichtenberg D, Pinchuk I, Almog B, Gamzu R, Kupferminc M. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 August; 82(8): 711-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12848641

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Preeclampsia, an implantation disorder. Author(s): Waite LL, Atwood AK, Taylor RN. Source: Reviews in Endocrine & Metabolic Disorders. 2002 May; 3(2): 151-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12007292

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Preeclampsia: theories and speculations. Author(s): Livingston JC, Maxwell BD. Source: Wiener Klinische Wochenschrift. 2003 March 31; 115(5-6): 145-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12741070

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Preeclampsia-related chorioretinopathy with Purtscher's-like findings and macular ischemia. Author(s): Shaikh S, Ruby AJ, Piotrowski M. Source: Retina (Philadelphia, Pa.). 2003 April; 23(2): 247-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12707610

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Prenatal screening, epidemiology, diagnosis, and management of preeclampsia. Author(s): Lyell DJ, Lambert-Messerlian GM, Giudice LC. Source: Clin Lab Med. 2003 June; 23(2): 413-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12848452

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Prostacyclin/thromboxane early changes in pregnancies that are complicated by preeclampsia. Author(s): Chavarria ME, Lara-Gonzalez L, Gonzalez-Gleason A, Garcia-Paleta Y, VitalReyes VS, Reyes A. Source: American Journal of Obstetrics and Gynecology. 2003 April; 188(4): 986-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12712098

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Prothrombin 20210 G: a mutation and Factor V Leiden mutation in women with a history of severe preeclampsia and (H)ELLP syndrome. Author(s): van Pampus MG, Wolf H, Koopman MM, van den Ende A, Buller HR, Reitsma PH. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2001; 20(3): 291-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044337

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Quantitative analysis of trophoblast invasion in preeclampsia. Author(s): Naicker T, Khedun SM, Moodley J, Pijnenborg R. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 August; 82(8): 722-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12848643

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Re: “Abortion,changed paternity, and risk of preeclampsia in nulliparous women”. Author(s): Basso O. Source: American Journal of Epidemiology. 2003 October 15; 158(8): 825. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14561674

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Receptor double-trouble in preeclampsia. Author(s): Lodwick D. Source: Nature Medicine. 2001 September; 7(9): 999-1000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11533700

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Recreational physical activity during pregnancy and risk of preeclampsia. Author(s): Sorensen TK, Williams MA, Lee IM, Dashow EE, Thompson ML, Luthy DA. Source: Hypertension. 2003 June; 41(6): 1273-80. Epub 2003 April 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12719446

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Recurrence risk of preterm birth due to preeclampsia. Author(s): Koike T, Minakami H, Izumi A, Watanabe T, Matsubara S, Sato I. Source: Gynecologic and Obstetric Investigation. 2002; 53(1): 22-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11803224

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Reduced amount of cytochrome c oxidase subunit I messenger RNA in placentas from pregnancies complicated by preeclampsia. Author(s): He L, Wang Z, Sun Y. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2004 February; 83(2): 144-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14756730

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Reduced red blood cell deformability, an indicator for high fetal or maternal risk, is found in preeclampsia and IUGR. Author(s): Schauf B, Lang U, Stute P, Schneider S, Dietz K, Aydeniz B, Wallwiener D. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2002; 21(2): 147-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12175443

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Relation between adenosine and T-helper 1/T-helper 2 imbalance in women with preeclampsia. Author(s): Yoneyama Y, Suzuki S, Sawa R, Yoneyama K, Power GG, Araki T. Source: Obstetrics and Gynecology. 2002 April; 99(4): 641-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12039127

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Relation between adenosine deaminase activities and cytokine-producing T cells in women with preeclampsia. Author(s): Yoneyama Y, Sawa R, Suzuki S, Miura A, Kobayashi H, Doi D, Yoneyama K, Araki T. Source: Clinical Biochemistry. 2002 June; 35(4): 303-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12135693

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Relation between plasma endothelin 1 levels and T helper 1: T helper 2 cell immunity in women with preeclampsia. Author(s): Kuwajima T, Suzuki S, Yoneyama Y, Sawa R, Asakura H, Araki T. Source: Gynecologic and Obstetric Investigation. 2001; 52(4): 260-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11729341

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Relationship between plasma malondialdehyde levels and adenosine deaminase activities in preeclampsia. Author(s): Yoneyama Y, Sawa R, Suzuki S, Doi D, Yoneyama K, Otsubo Y, Araki T. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2002 August; 322(1-2): 169-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12104097

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Relationship of insulin-like growth factor-I and insulin-like growth factor binding proteins in umbilical cord plasma to preeclampsia and infant birth weight. Author(s): Vatten LJ, Odegard RA, Nilsen ST, Salvesen KA, Austgulen R. Source: Obstetrics and Gynecology. 2002 January; 99(1): 85-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11777516

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Relationship of twin zygosity and risk of preeclampsia. Author(s): Maxwell CV, Lieberman E, Norton M, Cohen A, Seely EW, Lee-Parritz A. Source: American Journal of Obstetrics and Gynecology. 2001 October; 185(4): 819-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11641658

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Renal handling of homocysteine during normal pregnancy and preeclampsia. Author(s): Powers RW, Majors AK, Kerchner LJ, Conrad KP. Source: Journal of the Society for Gynecologic Investigation. 2004 January; 11(1): 45-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14706683

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Resistance artery smooth muscle function in pregnancy and preeclampsia. Author(s): VanWijk MJ, Boer K, van der Meulen ET, Bleker OP, Spaan JA, VanBavel E. Source: American Journal of Obstetrics and Gynecology. 2002 January; 186(1): 148-54. Erratum In: Am J Obstet Gynecol 2002 April; 186(4): 722. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11810101

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Retinal detachment in preeclampsia. Author(s): Prado RS, Figueiredo EL, Magalhaes TV. Source: Arquivos Brasileiros De Cardiologia. 2002 August; 79(2): 183-6. English, Portuguese. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12219193

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Retinal disorders in preeclampsia studied with optical coherence tomography. Author(s): Theodossiadis PG, Kollia AK, Gogas P, Panagiotidis D, Moschos M, Theodossiadis GP. Source: American Journal of Ophthalmology. 2002 May; 133(5): 707-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11992874

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Reversible cortical blindness in preeclampsia. Author(s): Do DV, Rismondo V, Nguyen QD. Source: American Journal of Ophthalmology. 2002 December; 134(6): 916-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12470768

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Role of placenta in preeclampsia. Author(s): Myatt L. Source: Endocrine. 2002 October; 19(1): 103-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12583607

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Second- and third-trimester serum levels of placental proteins in preeclampsia and small-for-gestational age pregnancies. Author(s): Bersinger NA, Odegard RA. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2004 January; 83(1): 37-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678084

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Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia. Author(s): Polliotti BM, Fry AG, Saller DN, Mooney RA, Cox C, Miller RK. Source: Obstetrics and Gynecology. 2003 June; 101(6): 1266-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798535

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Seroprevalence of antibodies to chlamydia pneumoniae in women with preeclampsia. Author(s): Teran E, Escudero C, Calle A. Source: Obstetrics and Gynecology. 2003 July; 102(1): 198-9; Author Reply 199. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12850633

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Seroprevalence of antibodies to Chlamydia pneumoniae in women with preeclampsia. Author(s): Heine RP, Ness RB, Roberts JM. Source: Obstetrics and Gynecology. 2003 February; 101(2): 221-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12576242

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Serum androgen markers in preeclampsia. Author(s): Miller NR, Garry D, Cohen HW, Figueroa R. Source: J Reprod Med. 2003 April; 48(4): 225-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12746983

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Serum antibodies to oxidized low-density lipoprotein in pregnant women with preeclampsia and chronic hypertension: lack of correlation with lipid peroxides. Author(s): Gratacos E, Casals E, Deulofeu R, Gomez O, Cararach V, Alonso PL, Fortuny A. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2001; 20(2): 177-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044328

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Serum IGF-I and IGFBP-3 in healthy pregnancies and patients with preeclampsia. Author(s): Altinkaynak K, Aksoy H H, Bakan E, Kumtepe Y. Source: Clinical Biochemistry. 2003 May; 36(3): 221-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12726932

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Serum insulin-like growth factors in normal pregnancy and in pregnancies complicated by preeclampsia. Author(s): Hubinette A, Lichtenstein P, Brismar K, Vatten L, Jacobsen G, Ekbom A, Cnattingius S. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 November; 82(11): 1004-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14616273

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Serum levels of heat shock protein 70 in patients with preeclampsia: a pilot-study. Author(s): Jirecek S, Hohlagschwandtner M, Tempfer C, Knofler M, Husslein P, Zeisler H. Source: Wiener Klinische Wochenschrift. 2002 August 30; 114(15-16): 730-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12602119

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Severe preeclampsia and delivery outcomes: is immediate cesarean delivery beneficial? Author(s): Coppage KH, Polzin WJ. Source: American Journal of Obstetrics and Gynecology. 2002 May; 186(5): 921-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12015514

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Severe preeclampsia at T polymorphism and preeclampsia in two populations. Author(s): Prasmusinto D, Skrablin S, Hofstaetter C, Fimmers R, van der Ven K. Source: Obstetrics and Gynecology. 2002 June; 99(6): 1085-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12052604

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The partner's role in the etiology of preeclampsia. Author(s): Dekker G. Source: Journal of Reproductive Immunology. 2002 October-November; 57(1-2): 203-15. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12385843

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The possible role of prolactin in preeclampsia: 2001, a hypothesis revisited a quarter of century later. Author(s): Parra A, Ramirez-Peredo J. Source: Medical Hypotheses. 2002 October; 59(4): 378-84. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12208175

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The receptor for advanced glycation end products (RAGE) is elevated in women with preeclampsia. Author(s): Cooke CL, Brockelsby JC, Baker PN, Davidge ST. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2003; 22(2): 173-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12909002

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Thrombophilia, preeclampsia, and fetal demise: a case report. Author(s): Vallejo MC, Abdullah RS, Kaul B, Ramanathan S. Source: Journal of Clinical Anesthesia. 2002 September; 14(6): 449-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12393115

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Transcranial doppler measurement of cerebral velocity indices as a predictor of preeclampsia. Author(s): Riskin-Mashiah S, Belfort MA, Saade GR, Herd JA. Source: American Journal of Obstetrics and Gynecology. 2002 December; 187(6): 1667-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12501081

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Transferrin microheterogeneity in pregnancies with preeclampsia. Author(s): Wu Y, Sakamoto H, Kanenishi K, Li J, Khatun R, Hata T. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2003 June; 332(1-2): 103-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12763287

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Triglyceride-rich lipoproteins are associated with hypertension in preeclampsia. Author(s): Winkler K, Wetzka B, Hoffmann MM, Friedrich I, Kinner M, Baumstark MW, Zahradnik HP, Wieland H, Marz W. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 March; 88(3): 11626. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12629100

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Trophoblastic injury: new etiological and pathological concept of preeclampsia. Author(s): Kanayama N. Source: Croatian Medical Journal. 2003 April; 44(2): 148-56. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12698504

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Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are jointly associated with preeclampsia. Author(s): Laasanen J, Romppanen EL, Hiltunen M, Helisalmi S, Mannermaa A, Punnonen K, Heinonen S. Source: European Journal of Human Genetics : Ejhg. 2002 September; 10(9): 569-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12173035

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Ultrastructural changes in omental resistance artery in women with preeclampsia. Author(s): Suzuki Y, Yamamoto T, Mabuchi Y, Tada T, Suzumori K, Soji T, Herbert DC, Itoh T. Source: American Journal of Obstetrics and Gynecology. 2003 July; 189(1): 216-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12861165

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Umbilical cord plasma interleukin-6 and fetal growth restriction in preeclampsia: a prospective study in Norway. Author(s): Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Vefring H, Austgulen R. Source: Obstetrics and Gynecology. 2001 August; 98(2): 289-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11506847

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Umbilical cord plasma leptin is increased in preeclampsia. Author(s): Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R. Source: American Journal of Obstetrics and Gynecology. 2002 March; 186(3): 427-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11904602

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Validation of the DCA 2000 microalbumin:creatinine ratio urinanalyzer for its use in pregnancy and preeclampsia. Author(s): Waugh J, Kilby M, Lambert P, Bell SC, Blackwell CN, Shennan A, Halligan A. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2003; 22(1): 77-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12648445

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Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Author(s): Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, Alitalo K, Damsky C, Fisher SJ. Source: American Journal of Pathology. 2002 April; 160(4): 1405-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11943725

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Vasospasms are characteristic in cases with eclampsia/preeclampsia and HELLP syndrome: proposal of an angiospastic syndrome of pregnancy. Author(s): Kobayashi T, Tokunaga N, Isoda H, Kanayama N, Terao T. Source: Seminars in Thrombosis and Hemostasis. 2001; 27(2): 131-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11372766

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Vitamin C and E supplementation in women at risk of preeclampsia is associated with changes in indices of oxidative stress and placental function. Author(s): Chappell LC, Seed PT, Kelly FJ, Briley A, Hunt BJ, Charnock-Jones DS, Mallet A, Poston L. Source: American Journal of Obstetrics and Gynecology. 2002 September; 187(3): 777-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12237663

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Vitamin C and the risk of preeclampsia--results from dietary questionnaire and plasma assay. Author(s): Zhang C, Williams MA, King IB, Dashow EE, Sorensen TK, Frederick IO, Thompson ML, Luthy DA. Source: Epidemiology (Cambridge, Mass.). 2002 July; 13(4): 409-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12094095

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Weight at birth and subsequent risk of preeclampsia as an adult. Author(s): Dempsey JC, Williams MA, Luthy DA, Emanuel I, Shy K. Source: American Journal of Obstetrics and Gynecology. 2003 August; 189(2): 494-500. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14520224

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What we have learned about preeclampsia. Author(s): Sibai BM, Caritis S, Hauth J; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Source: Semin Perinatol. 2003 June; 27(3): 239-46. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12889591

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

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

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

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

Activation of endothelial cells by plasma from women with preeclampsia: differential effects on four endothelial cell types. Author(s): Department of Obstetrics and Gynaecology, Nottingham City Hospital, UK. Source: Wellings, R P Brockelsby, J C Baker, P N J-Soc-Gynecol-Investig. 1998 JanFebruary; 5(1): 31-7 1071-5576

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An imbalance between prostacyclin and thromboxane in relation to cerebral blood flow in neonates with maternal preeclampsia. Author(s): Department of Pediatrics, Yokohama City University School of Medicine, Kanagawa, Japan. [email protected] Source: Nishimaki, S Seki, K Prostaglandins-Other-Lipid-Mediat. 1999 August; 58(1): 439 1098-8823

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Antihypertensive treatment decreased serum leptin levels in severe preeclampsia during pregnancy. Author(s): Instituto de Inmunologia, Facultad de Medicina, Universidad Central de Venezuela, Caracas 1050-A, Venezuela. Source: Anato, V Garmendia, J V Bianco, N E De Sanctis, J B Ann-Nutr-Metab. 2001; 45(5): 190-2 0250-6807

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Calcium, nitric oxide, and preeclampsia. Author(s): Instituto Colombiano de Investigaciones Biomedicas, Bucaramanga, Colombia. [email protected] Source: Lopez Jaramillo, P Semin-Perinatol. 2000 February; 24(1): 33-6 0146-0005

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Circulating factors as markers and mediators of endothelial cell dysfunction in preeclampsia. Author(s): Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco 94143, USA. Source: Taylor, R N de Groot, C J Cho, Y K Lim, K H Semin-Reprod-Endocrinol. 1998; 16(1): 17-31 0734-8630

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Correlation between oral sex and a low incidence of preeclampsia: a role for soluble HLA in seminal fluid? Author(s): Department of Immunohematology and Blood Bank, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands. Source: Koelman, C A Coumans, A B Nijman, H W Doxiadis, I I Dekker, G A Claas, F H J-Reprod-Immunol. 2000 March; 46(2): 155-66 0165-0378

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Counseling for women with preeclampsia or eclampsia. Author(s): Department of Obstetrics and Gynecology, the University of Texas Medical Branch, Galveston, USA. Source: Witlin, A G Semin-Perinatol. 1999 February; 23(1): 91-8 0146-0005

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Deficient detoxifying capacity in the pathophysiology of preeclampsia. Author(s): Department of Obstetrics and Gynaecology, University Hospital, Nijmegen, The Netherlands. Source: Roes, E M Raijmakers, M T Zusterzeel, P L Knapen, M C Peters, W H Steegers, E A Med-Hypotheses. 2000 November; 55(5): 415-8 0306-9877

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Effect of calcium supplementation on pregnancy-induced hypertension and preeclampsia. Source: Bucher, H.C. Guyatt, G.H. Cook, R.J. Hatala, R. Cook, D.J. Lang, J.D. Hunt, D. JAMA-j-Am-Med-Assoc. Chicago, Ill : American Medical Association. April 10, 1996. volume 275 (14) page 1113-1117. 0098-7484

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Effects of calcium antagonists on contractions of chorionic arteries in normal and preeclampsia placenta. Author(s): Department of Pharmacology, Chonnam University Medical School, Kwangju, Korea. Source: Kook, H Yoon, Y D Baik, Y H J-Korean-Med-Sci. 1996 June; 11(3): 250-7 10118934

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Erythrocyte deformability and erythrocyte aggregation in preeclampsia. Author(s): Department of Basic Medical Sciences, University of the West Indies, Kingston, Jamaica. [email protected] Source: Pepple, D J Hardeman, M R Mullings, A M Reid, H L Clin-HemorheolMicrocirc. 2001; 24(1): 43-8 1386-0291

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Hypertension in pregnancy: current concepts of preeclampsia. Author(s): Department of Obstetrics and Gynecology, University of Tennessee, Memphis 38103, USA. Source: Witlin, A G Sibai, B M Annu-Rev-Med. 1997; 48115-27 0066-4219

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Hypothesis to explain the association between hypocalciuria and low circulating 1,25dihydroxyvitamin D levels in preeclampsia. Author(s): Instituto Nacional de la Nutricion Salvador Zubiran, Mexico DF, Mexico. Source: Bourges, H Halhali, A Med-Hypotheses. 1993 September; 41(3): 239-43 0306-9877

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Lower circulating insulin-like growth factor I and 1,25-dihydroxyvitamin D levels in preeclampsia. Author(s): Depto. de Fisiologia de la Nutricion, Instituto Nacional de la Nutricion, Mexico, D.F. Source: Halhali, A Bourges, H Carrillo, A Garabedian, M Rev-Invest-Clin. 1995 JulAugust; 47(4): 259-66 0034-8376

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Magnesium for preeclampsia and eclampsia. Source: Roberts, J.M. N-Engl-j-med. Boston : Massachusetts Medical Society,. July 27, 1995. volume 333 (4) page 250-251. 0028-4793

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Magnesium sulfate loading: preeclampsia vs preterm labor (a clinical pearl). Source: Wright, J.W. Seelig, C.B. Ridgway, L.E. J-Am-Coll-Nutr. New York, NY : American College of Nutrition. October 1994. volume 13 (5) page 499-501. 0731-5724

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Mechanisms of endothelium-dependent relaxation in myometrial resistance vessels and their alteration in preeclampsia. Author(s): Department of Obstetrics and Gynaecology, City Hospital, Nottingham, United Kingdom. Source: Ashworth, J R Baker, P N Warren, A Y Johnson, I R Hypertens-Pregnancy. 1999; 18(1): 57-71 1064-1955

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Methylenetetrahydrofolate reductase 677 C --> T polymorphism, plasma folate, vitamin B(12) concentrations, and risk of preeclampsia among black African women from Zimbabwe. Author(s): Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030, USA. [email protected]

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Source: Rajkovic, A Mahomed, K Rozen, R Malinow, M R King, I B Williams, M A MolGenet-Metab. 2000 January; 69(1): 33-9 1096-7192 •

Nitric oxide dysfunction in the pathophysiology of preeclampsia. Author(s): 375th Medical Group, Scott Air Force Base, Illinois 62225, USA. [email protected] Source: Lowe, D T Nitric-Oxide. 2000 August; 4(4): 441-58 1089-8603

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Omega-3 fatty acids in maternal erythrocytes and risk of preeclampsia. Author(s): Center for Perinatal Studies, Swedish Medical Center/Seattle, WA 981140999, USA. Source: Williams, M A Zingheim, R W King, I B Zebelman, A M Epidemiology. 1995 May; 6(3): 232-7 1044-3983

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Physiology of low-dose aspirin therapy for the prevention of preeclampsia. Author(s): Department of Obstetrics, Gynecology, University of Texas Medical School, Houston. Source: Walsh, S W Semin-Perinatol. 1990 April; 14(2): 152-70 0146-0005

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Placental and serum levels of carotenoids in preeclampsia. Author(s): Department of Obstetrics and Gynecology, Bronx-Lebanon Hospital Center, Bronx, New York 10457, USA. [email protected] Source: Palan, P R Mikhail, M S Romney, S L Obstet-Gynecol. 2001 September; 98(3): 459-62 0029-7844

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Plasma levels of vitamin E in pregnant women prior to the development of preeclampsia and other hypertensive complications. Author(s): Perinatal Division, Department of Obstetrics and Gynecology, Rabin Medical Center, Beilinson Campus, Petah Tiqva, Israel. Source: Ben Haroush, A Harell, D Hod, M Bardin, R Kaplan, B Orvieto, R Bar, J GynecolObstet-Invest. 2002; 54(1): 26-30 0378-7346

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Plasma nitric oxide levels and the expression of P-selectin on platelets in preeclampsia. Author(s): Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan. [email protected] Source: Yoneyama, Y Suzuki, S Sawa, R Miura, A Doi, D Otsubo, Y Araki, T Am-JObstet-Gynecol. 2002 September; 187(3): 676-80 0002-9378

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Population pharmacokinetics of magnesium in preeclampsia. Author(s): School of Pharmacy, The University of Queensland, Brisbane, Australia. Source: Chuan, F S Charles, B G Boyle, R K Rasiah, R L Am-J-Obstet-Gynecol. 2001 September; 185(3): 593-9 0002-9378

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Possible beneficial effect of exercise, by reducing oxidative stress, on the incidence of preeclampsia. Author(s): The University of Michigan, School of Nursing Division of Health Promotion and Risk Reduction, Ann Arbor, Michigan, USA. Source: Yeo, S Davidge, S T J-Womens-Health-Gend-Based-Med. 2001 December; 10(10): 983-9 1524-6094

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Preeclampsia in multiple gestation: the role of assisted reproductive technologies. Author(s): Department of Research and Development, Kaiser Permanente, Denver, Colorado 80205, USA. [email protected] Source: Lynch, Anne McDuffie, Robert Jr Murphy, James Faber, Kenneth Orleans, Miriam Obstet-Gynecol. 2002 March; 99(3): 445-51 0029-7844

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Preeclampsia. Author(s): Department of Family Practice, University of Michigan School of Medicine, Ann Arbor. Source: Smith, M A Prim-Care. 1993 September; 20(3): 655-64 0095-4543

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Prevention of preeclampsia. Author(s): Johns Hopkins University School of Medicine, Baltimore, Maryland. Source: Repke, J T Clin-Perinatol. 1991 December; 18(4): 779-92 0095-5108

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Reduced excretion of vasodilator prostaglandins in preeclampsia. Author(s): Clinica Medica dell'Universita, Policlinico di Borgo Roma, Verona, Italy. Source: Minuz, P Covi, G Corsato, M Probitzer, P Spiazzi, L Paluani, F Degan, M Lechi, C Lechi, A Agents-Actions-Suppl. 1987; 22175-81 0379-0363

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Relationship of serum selenium and lipid peroxidation in preeclampsia. Source: Kauppila, A. Makila, U.M. Korpela, H. Viinikka, L. Yrjanheikki, E. Selenium in biology and medicine : proceedings of the Third International Symposium on Selenium in Biology and Medicine, held May 27-June 1, 1984, Xiangshan (Fragrance Hills) Hotel Beijing, People's Republic of China. New York : Van Nostrand Reinhold, c1987. page 996-1001. ISBN: 0442221088

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Risk of pregnancy-related hypertension and preeclampsia in relation to folic acid supplementation. Author(s): (Slone Epidemiology Unit, Boston University School of Medicine, Brookline, MA, USA). Source: Hernandez Diaz, S Werler, M Louik, C Mitchell, A Paediatr-Perinat-Epidemiol. 2001 October; 15(4): A15 0269-5022

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Serum and placental lipid peroxides in chronic hypertension during pregnancy with and without superimposed preeclampsia. Author(s): Department d'Obstetricia i Ginecologia, Hospital Clinic de Barcelona, Universitat de Barcelona, Catalonia, Spain. [email protected] Source: Gratacos, E Casals, E Deulofeu, R Gomez, O Cararach, V Alonso, P L Fortuny, A Hypertens-Pregnancy. 1999; 18(2): 139-46 1064-1955

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Stimulation of glycosaminoglycan biosynthesis by umbilical cord serum of newborns delivered by mothers with EPH gestosis (preeclampsia). Author(s): Department of Biochemistry, Medical Academy of Bialystok, ul. Mickiewicza 2, PL-15- 230 Bialystok-8, Poland. Source: Romanowicz, L Bankowski, E Jaworski, S Pathobiology. 2000; 68(6): 264-9 10152008

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Study of plasma factors associated with neutrophil activation and lipid peroxidation in preeclampsia. Author(s): University Department of Medicine, University of Western Australia. [email protected] Source: Barden, A Ritchie, J Walters, B Michael, C Rivera, J Mori, T Croft, K Beilin, L Hypertension. 2001 October; 38(4): 803-8 1524-4563

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The effect of acute volume expansion and vasodilatation with verapamil on uterine and umbilical artery Doppler indices in severe preeclampsia. Author(s): Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas. Source: Belfort, M Akovic, K Anthony, J Saade, G Kirshon, B Moise, K J-ClinUltrasound. 1994 June; 22(5): 317-25 0091-2751

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The effect of garlic tablet on plasma lipids and platelet aggregation in nulliparous pregnants at high risk of preeclampsia. Author(s): Department of Obstetrics and Gynecology, Faculty of Medical Science, Tarbiat Modarres University, P.O. Box 1415-111, Tehran, Iran. [email protected] Source: Ziaei, S Hantoshzadeh, S Rezasoltani, P Lamyian, M Eur-J-Obstet-GynecolReprod-Biol. 2001 December 1; 99(2): 201-6 0301-2115

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The relation of calcium nutrition and metabolism to preeclampsia and premature labor. Source: Myatt, L. Carnat-Nutr-Educ-Ser. New York : Raven Press. 1992. volume 3 page 129-141. 1049-4901

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The renin-angiotensin-aldosterone system in preeclampsia. A review. Author(s): Department of Obstetrics and Gynecology, Free University Hospital, Amsterdam, The Netherlands. Source: de Jong, C L Dekker, G A Sibai, B M Clin-Perinatol. 1991 December; 18(4): 683711 0095-5108

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The role of fatty acid peroxidation and antioxidant status in normal pregnancy and in pregnancy complicated by preeclampsia. Source: Walsh, S.W. World-rev-nutr-diet. Basel; New York : S. Karger, 1959-. 1994. volume 76 page 114-118. 0084-2230

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Treatment of severe preeclampsia remote from term: a clinical dilemma. Author(s): Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv, Israel. [email protected] Source: Many, A Kuperminc, M J Pausner, D Lessing, J B Obstet-Gynecol-Survolume 1999 November; 54(11): 723-7 0029-7828

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The following is a specific Web list relating to preeclampsia; 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 Vitamin B12 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B2 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B6 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin C Source: Healthnotes, Inc.; www.healthnotes.com Vitamin C Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin E Source: Healthnotes, Inc.; www.healthnotes.com Vitamin E Source: Prima Communications, Inc.www.personalhealthzone.com

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Minerals Calcium Source: Healthnotes, Inc.; www.healthnotes.com Calcium Source: Integrative Medicine Communications; www.drkoop.com Calcium Source: Prima Communications, Inc.www.personalhealthzone.com Magnesium Source: Healthnotes, Inc.; www.healthnotes.com Magnesium Source: Integrative Medicine Communications; www.drkoop.com Magnesium Source: Prima Communications, Inc.www.personalhealthzone.com Zinc Source: Healthnotes, Inc.; www.healthnotes.com

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Food and Diet Low-Salt Diet Source: Healthnotes, Inc.; www.healthnotes.com Trans-Fats Source: Healthnotes, Inc.; www.healthnotes.com Water Source: Healthnotes, Inc.; www.healthnotes.com Weight Loss and Obesity Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. DISSERTATIONS ON PREECLAMPSIA Overview In this chapter, we will give you a bibliography on recent dissertations relating to preeclampsia. 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 “preeclampsia” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on preeclampsia, we have not necessarily excluded nonmedical dissertations in this bibliography.

Dissertations on Preeclampsia 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 preeclampsia. 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: •

Detection of Activated Platelets in Normal Pregnancy and Preeclampsia by Herbolsheimer, Judy Ellen; MPAS from Grand Valley State University, 2003, 69 pages http://wwwlib.umi.com/dissertations/fullcit/1413059

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The Role of AT-1 Receptor Autoantibodies in the Pathophysiology of Preeclampsia by Bobst, Sol Mio; PhD from The Univ. of Texas H.S.C. at Houston Grad. Sch. of Biomed. Sci., 2003, 148 pages http://wwwlib.umi.com/dissertations/fullcit/3106857

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Vascular Cell Dysfunction and Transendothelial Migration of Neutrophils in Preeclampsia by Leik, Courtney Elizabeth; PhD from Virginia Commonwealth University, 2003, 176 pages http://wwwlib.umi.com/dissertations/fullcit/3101580

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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 4. CLINICAL TRIALS AND PREECLAMPSIA Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning preeclampsia.

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

Randomized Study of Nimodipine versus Magnesium Sulfate in the Prevention of Eclamptic Seizures in Patients with Severe Preeclampsia Condition(s): Pre-Eclampsia Study Status: This study is completed. Sponsor(s): FDA Office of Orphan Products Development; University of Utah Purpose - Excerpt: Objectives: I. Determine the effectiveness of nimodipine versus magnesium sulfate in the prevention of eclamptic seizures in patients with severe preeclampsia. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004399

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Regulation of Placental Vascular Reactivity in Pregnancy-induced Hypertension Condition(s): Cardiovascular Diseases; Heart Diseases; Hypertension; Pregnancy Toxemias Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI)

8

These are listed at www.ClinicalTrials.gov.

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Purpose - Excerpt: To elucidate the role of an imbalance in vasodilator prostacyclin (PGI2) and vasoconstrictor thromboxane (TxA2) in pregnancy-induced hypertension Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005208

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “preeclampsia” (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 5. PATENTS ON PREECLAMPSIA 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 “preeclampsia” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on preeclampsia, we have not necessarily excluded nonmedical patents in this bibliography.

Patents on Preeclampsia By performing a patent search focusing on preeclampsia, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 9Adapted

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

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

Antisense oligonucleotides to suppress eicosanoid formation Inventor(s): Kniss; Douglas A. (Hilliard, OH) Assignee(s): The Ohio State University (columbus, Oh) Patent Number: 5,859,229 Date filed: April 3, 1996 Abstract: The present invention provides a new antisense oligonucleotides for the treatment of premature labor, premature rupture of the fetal membranes, premature cervical dilation and effacement, preeclampsia, endometriosis, rheumatoid arthritis, ARDs, and glomerulitis. The drugs are antisense oligonucleotides which attenuate the expression of either the mRNA encoding the cyclooxygenase protein or the mRNA encoding the thromboxane A.sub.2 synthase protein. Once the mRNA encoding for cyclooxygenase is inhibited, the production of cyclooxygenase is inhibited thereby inhibiting the production of the cyclooxygenase products such as prostaglandins and thromboxane. Thus, the antisense oligonucleotides provide novel therapy for the treatment of diseases involving cyclooxygenase products, prostaglandins and thromboxane metabolism. Such diseases include immunological, reproductive, cardiovascular, dermatologic, central nervous system disorders in which the release of cyclooxygenase products effects the genesis and progression of the disease. A second object of the invention is to provide new reagents for the research and study of the diseases involving cyclooxygenase products. Excerpt(s): Prostaglandins are synthesized in mammals, including humans and are involved in inflammatory disease. Prostaglandins induce/contribute to a myriad of conditions, including the changes in vascular permeability leading to tissue edema and swelling, biochemical changes in the production of extracellular matrix degrading enzymes, such as fibroblast collagenase and elastase, fever and pain. Prostaglandins alter the contractile properties of vascular and non-vascular smooth muscle, leading to vasodilatation, vasoconstriction, uterine contractions, and bronchospasm. The release of arachidonic acid from cellular membrane phospholipids and the subsequent production of eicosanoids such as cyclooxygenase products and lipoxygenase products is a hallmark feature of nearly all inflammatory diseases. Free arachidonic acid is the obligate precursor of cyclooxygenase, and its products. Under unstimulated cellular conditions, nearly all arachidonic acid is esterified in membrane phospholipids and is unavailable for eicosanoid biosynthesis. However, when a cell encounters certain extracellular stimuli, phospholipase A.sub.2 cleaves arachidonic acid from the phospholipid, thereby permitting the arachidonic acid to be converted into prostaglandins by cyclooxygenase. The levels of PGE.sub.2 and PGF.sub.2.alpha. and their metabolites are also increased in the amniotic fluid of women in preterm labor with clinical signs of infection and are believed to be a causative factor of pre-term labor, Romero, R., Avila, C., and Sepulveda, W. "The Role of Systemic and Intrauterine Infection in Preterm Labor In: Preterm Birth: Causes, Prevention, and Management," 2d. ed., Fuchs, A. -R., Fuchs, F., and Stubblefield, P. G., eds., MacGraw-Hill, Inc., New York, 97-136. Preterm labor occurs in approximately 8-9% of all pregnancies, but accounts for 80% of perinatal morbidity and mortality in the United States. The cost of caring for premature infants who require long-term hospitalization can be as much as $500,000 per

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infant. Moreover, many of these babies suffer long-range medical problems as a result of their prematurity. Web site: http://www.delphion.com/details?pn=US05859229__ •

Butenolide endothelin antagonists Inventor(s): Patt; William C. (Chelsea, MI), Reisdorph; Bill R. (Ann Arbor, MI), Repine; Joseph T. (Ann Arbor, MI) Assignee(s): Warner-lambert Company (morris Plains, Nj) Patent Number: 6,017,951 Date filed: February 10, 1999 Abstract: Novel nonpeptides characterized as having a carbamic group which are antagonists of endothelin I are described, as well as methods for their preparation and pharmaceutical compositions containing the same. The compounds are useful in treating elevated levels of endothelin and are therefore useful in the treatment of hypertension, myocardial infarction, diabetes, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythminas, asthma, chronic and acute renal failure, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, stroke, head injury, and ischemic bowel syndrome. Excerpt(s): The present invention relates to novel antagonists of endothelin useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction and myocardial ischemia, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, and diabetes. Also, the compounds will be useful in cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, head injury, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma. Endothelin is involved in many human disease states. Web site: http://www.delphion.com/details?pn=US06017951__

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COMBINATION OF PROSTACYCLIN WITH AN ESTROGEN OR PROGESTIN FOR THE PREVENTION AND TREATMENT OF ATHEROSCLEROTIC VASCULAR DISEASE INCLUDING PREECLAMPSIA AND FOR THE TREATMENT OF HYPERTENSION, AND FOR HORMONE REPLACEMENT THERAPY Inventor(s): Chwalisz; Kristof (Berlin, DE), Garfield; Robert E. (Friendswood, TX) Assignee(s): Board of Regents, the University of Texas System (austin, Tx) Patent Number: 6,613,757 Date filed: September 22, 1994 Abstract: Cardiovascular disease, including preeclampsia in pregnant women and hypertension in both women and men, are prevented or treated by administering thereto prostacyclin or a prostacyclin analog in combination with one or both of an estrogen and a progestin, which combination is also useful for HRT in peri- and postmenopausal women. Excerpt(s): This invention relates to a method for the prevention and treatment of atherosclerotic vascular disease (cardiovascular disease); for the prevention and treatment preeclampsia in pregnant women and for hormone replacement therapy in peri- and post-menopausal women, and for the treatment of hypertension in women and men. Epidemiological data indicate that approximately one half of the deaths in economically developed countries are attributable to a single major cause, viz., cardiovascular disease, including coronary heart disease, stroke and other forms of vascular disease (Green, A., Bain, C., 1993). The commonest and most lethal form of cardiovascular disease is coronary heart disease. In men, there is a continuous increase in the prevalence of cardiovascular disease after the age of 30-40 years. On the other hand, the rate of cardiovascular disease, especially coronary heart disease, is relatively low among premenopausal women but rises sharply with increasing age, suggesting that sex steroids (estrogens and progesterone) have a protective effect in women. The increased risk of coronary heart disease among women with bilateral oophorectomy further supports the view that steroid hormones may play a protective role with regard to cardiovascular disease. Cardiovascular disease can be prevented in postmenopausal women by hormone replacement therapy (HRT) with estrogens. The recently performed meta-analysis of 29 studies has demonstrated a reduced cardiovascular disease risk among estrogen users in 23 of these studies (Stampfer et al., 1991). There is also experimental evidence from studies in monkeys that the development of coronary atherosclerosis induced by oophorectomy and diet may be reversed by estrogen supplementation (Adams et al., 1992). On the other hand, there are no effective methods for the prevention of cardiovascular disease in man, since estrogen cannot be used because of side-effects. Web site: http://www.delphion.com/details?pn=US06613757__

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•

Determining existence of preeclampsia in pregnancies by measuring levels of glycerophosphatidyl compounds, glycerophosphatidycholine, lysophospholipids and lysophosphatidylcholine Inventor(s): Parrott; Jeff A. (Irvine, CA) Assignee(s): Atairgin Technologies, Inc. (irvine, Ca) Patent Number: 6,461,830 Date filed: June 1, 2000 Abstract: The present invention relates generally to methods for detecting preeclampsia in pregnancies. The present invention comprises the steps of obtaining a sample specimen from a patient, assaying the specimen to determine the level of glycerophosphatidyl compounds, glycerophosphatidylcholine, lysophospholipids and/or lysophosphatidylcholine in the sample, comparing levels in the sample to levels in normal samples, and correlating significant decreases as compared to normal samples as a positive indicator of preeclampsia. Excerpt(s): The present invention relates to methods for the early detection of complications in pregnancy based on the detection of bioactive lipids. Specifically, the present invention relates to methods for early detection of preeclampsia and related disorders by detecting levels of glycerophosphatidyl compounds and lysophospholipids in a sample specimen obtained from a pregnant woman. Preeclampsia is a condition responsible for up to 50-70% of hypertensive. complications in pregnancies. Although a leading cause of morbidity and mortality in pregnancies, its etiology and causes remain largely unknown. In severe cases, preeclampsia may develop into eclampsia, which often leads to death. Despite the dangers associated with preeclampsia, no cure exists for preeclampsia, although early detection and diagnosis enables therapy and treatment protocols that offer the best chance to save the lives of the baby and the mother. Preeclampsia generally occurs after the 20.sup.th week of pregnancy and appears without much warning. The most common symptoms are high blood pressure, swelling or edema of hands and feet, and increased protein in the urine. In the United States, preeclampsia is responsible for up to 10% of pregnancy-related mortality and morbidity each year. Preeclampsia is more prevalent in women under 20 or over 40 years of age. Those with pre-existing existing conditions of diabetes mellitus, renal diseases, high blood pressure, family history of preeclampsia, or previous complications with preeclampsia, are often at increased risk. Web site: http://www.delphion.com/details?pn=US06461830__

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Diagnosis of preeclampsia in mammals Inventor(s): Olson; Camilla M. (805 Melville Ave., Palo Alto, CA 94301), Peterson; Charles (2219 Bath St., Santa Barbara, CA 93105) Assignee(s): None Reported Patent Number: 5,849,474 Date filed: December 6, 1995 Abstract: An improved method of diagnosing preeclampsia comprising the steps ofa. collecting blood from a pregnant female mammal; andb. detecting in said blood significantly elevated levels of at least one substance selected from the group consisting of:(1) a hemoglobin variant or hemoglobin variant precursor and(2) a red blood cell

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Preeclampsia

glycolytic enzyme or a red blood cell glycolytic enzyme precursor.By detecting the presence of an appropriate "marker" in the blood, preeclampsia can be diagnosed at an earlier stage, thus making possible timely therapeutic intervention. An assay kit for detecting the markers is also provided. Excerpt(s): The present invention relates to the early detection of a marker for preeclampsia during pregnancy. In particular, the invention relates to testing the blood of a pregnant female mammal to detect significantly elevated levels of particular substances, thus enabling early diagnosis and clinical intervention when a preeclamptic condition is found. (1) Pregnancy-induced-hypertension: Hypertension alone. (2) Preeclampsia: Diagnosed by development of hypertension plus proteinuria or edema that is generalized and overt, or both. Web site: http://www.delphion.com/details?pn=US05849474__ •

Diagnostic assay for the detection of preeclampsia Inventor(s): Roberts; James M. (Mill Valley, CA), Taylor; Robert N. (San Francisco, CA) Assignee(s): The Regents of the University of California (oakland, Ca) Patent Number: 5,238,819 Date filed: June 10, 1991 Abstract: This invention relates to the diagnosis of preeclampsia using an assay to measure a mitogenic factor in blood. Preeclampsia is a serious problem in pregnant women. It is an idiopathic life threatening hypertensive condition. The condition of preeclamptic women can often deteriorate to a point where serious injury will occur to either the mother, child or both. Preeclampsia is a leading cause of death both maternal and infant. Excerpt(s): Preeclampsia occurs in 7-10% of pregnancies and is responsible for significant maternal and fetal morbidity (Roberts, J. M., Pregnancy-related hypertension. In: Creasy, R. K.; Resnick R., eds., Maternal-Fetal Medicine-Principles and Practice, Philadelphia: W. B. Saunders, 1984, 703-752). Despite decades of interest and research, the pathogenesis of this disease is still poorly understood. Recent evidence, however, suggests that endothelial cell injury may play an important role in the preeclamptic syndrome. The histopathological findings of endothelial lesions in renal and umbilical vessels obtained from preeclamptic patients have been recognized (Spargo, B. H.; McCartney, C. P.; Winemiller, R., Glomerular capillary endotheliosis in toxemia of pregnancy. AMA Arch. Pathol., 1959, 68:593-497; Dadak C., Ulrich W., Sinzinger H. Morphological changes in the umbilical arteries of babies born to preeclamptic mothers: an ultrastructural study. Placenta 1984, 5:419-426). Lately, several reports have documented biochemical abnormalities in serum from preeclamptic patients which support the concept that endothelial cell perturbation and sublethal injury of these cells may contribute to the pathogenesis of preeclampsia. Most of these studies have been indirect, showing elevated levels of endothelial cell products in serum (e.g., fibronectin (Stubbs, T. M.; Lazarchick, J.; Horger, E. O., III, Plasma fibronectin levels in preeclampsia: a possible biochemical marker for vascular endothelial damage. Am. J. Obstet. Gynecol, 1984, 150:885-887), factor VIII antigen (Redman, C. W. G.; Beilin, L. J.; Stirrat, G. M., et al., Factor VIII consumption in preeclampisa. Lancet 1977, II:1249-1252), or platelet and coagulation abnormalities (Roberts, J.M., Pregnancy-related hypertension, In: Creasy, R. K.; Resnick, R., eds., Maternal-Fetal Medicine-Principles and Practice. Philadelphia: W. B. Saunders, 1984, 703-752). We have recently demonstrated

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directly that serum from preeclamptic women injures endothelial cells in vitro (Rodgers, G. M.; Taylor, R. N.; Roberts, J. M., Preeclampsia is associated with a serum factor cytotoxic to human endothelial cells, Am. J. Obstet. Gynecol, 159:908-914, 1988). Mitogenic dose-response of cultured fibroblasts exposed to serum from normal and preeclamptic patients. Quiescent fibroblasts were incubated with paired pre- and postpartum sera from normal and preeclamptic patients as described in Materials and Methods. Incorporation of.sup.3 H-thymidine into fibroblast DNA increased in a dosedependent, logarithmic fashion. Shown are mitogenic activities of prepartum (open box) and postpartum (closed box) sera from normal (A) and preeclamptic (B) patients. There was a significant left-shift of the curve for prepartum as compared to postpartum preeclamptic serum but not in paired sera from normal pregnancy (P