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 ...

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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.

3

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

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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

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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

•

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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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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Preeclampsia

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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Preeclampsia

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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99

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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

100

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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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101

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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

102

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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 <25 weeks of gestation: maternal and neonatal outcomes. Author(s): Jenkins SM, Head BB, Hauth JC. Source: American Journal of Obstetrics and Gynecology. 2002 April; 186(4): 790-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11967509

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Severe preeclampsia is associated with high inhibin A levels and normal leptin levels at 7 to 13 weeks into pregnancy. Author(s): Salomon LJ, Benattar C, Audibert F, Fernandez H, Duyme M, Taieb J, Frydman R. Source: American Journal of Obstetrics and Gynecology. 2003 December; 189(6): 1517-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14710054

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Smoking before pregnancy and risk of gestational hypertension and preeclampsia. Author(s): England LJ, Levine RJ, Qian C, Morris CD, Sibai BM, Catalano PM, Curet LB, Klebanoff MA. Source: American Journal of Obstetrics and Gynecology. 2002 May; 186(5): 1035-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12015533

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Soluble tumor necrosis factor receptor II and soluble cell adhesion molecule 1 as markers of tumor necrosis factor-alpha release in preeclampsia. Author(s): Visser W, Beckmann I, Knook MA, Wallenburg HC. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2002 August; 81(8): 713-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12174154

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Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered? Author(s): Luttun A, Carmeliet P. Source: The Journal of Clinical Investigation. 2003 March; 111(5): 600-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12618513

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Sperm exposure and development of preeclampsia. Author(s): Einarsson JI, Sangi-Haghpeykar H, Gardner MO. Source: American Journal of Obstetrics and Gynecology. 2003 May; 188(5): 1241-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12748491

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Spinal anesthesia in the parturient with severe preeclampsia: time for reconsideration. Author(s): Santos AC, Birnbach DJ. Source: Anesthesia and Analgesia. 2003 September; 97(3): 621-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12933372

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Stress-related preeclampsia: an evolutionary maladaptation in exaggerated stress during pregnancy? Author(s): Takiuti NH, Kahhale S, Zugaib M. Source: Medical Hypotheses. 2003 March; 60(3): 328-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12581605

104

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Study of serum levels of superoxide dismutase in preeclampsia and eclampsia: role of the test as a predictive tool. Author(s): Mahadik KV, Sina SA. Source: The Journal of Obstetrics and Gynaecology Research. 2003 August; 29(4): 262-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12959150

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Subclassification of preeclampsia. Author(s): von Dadelszen P, Magee LA, Roberts JM. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2003; 22(2): 143-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12908998

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Tertiary care improves the chance for vaginal delivery in women with preeclampsia. Author(s): Mostello D, Droll DA, Bierig SM, Cruz-Flores S, Leet T. Source: American Journal of Obstetrics and Gynecology. 2003 September; 189(3): 824-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14526323

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The changes of trace elements, malondialdehyde levels and superoxide dismutase activities in pregnancy with or without preeclampsia. Author(s): Ilhan N, Ilhan N, Simsek M. Source: Clinical Biochemistry. 2002 July; 35(5): 393-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12270770

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The concentration of circulating corticotropin-releasing hormone mRNA in maternal plasma is increased in preeclampsia. Author(s): Ng EK, Leung TN, Tsui NB, Lau TK, Panesar NS, Chiu RW, Lo YM. Source: Clinical Chemistry. 2003 May; 49(5): 727-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12709362

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The diversity of diagnoses of preeclampsia. Author(s): Harlow FH, Brown MA. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2001; 20(1): 57-67. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044314

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The effect of isosorbide dinitrate, a donor of nitric oxide, on maternal cerebral blood flow in gestational hypertension and preeclampsia. Author(s): Nevo O, Thaler I, Shik V, Vortman T, Soustiel JF. Source: American Journal of Obstetrics and Gynecology. 2003 May; 188(5): 1360-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12748512

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The effect of treatment on endothelin-1 concentration and mean arterial pressure in preeclampsia and eclampsia. Author(s): Sagsoz N, Kucukozkan T. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2003; 22(2): 185-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12909003

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The frequency and severity of placental findings in women with preeclampsia are gestational age dependent. Author(s): Moldenhauer JS, Stanek J, Warshak C, Khoury J, Sibai B. Source: American Journal of Obstetrics and Gynecology. 2003 October; 189(4): 1173-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14586374

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The interval between pregnancies and preeclampsia. Author(s): Saftlas AF, Levine RJ. Source: The New England Journal of Medicine. 2002 June 6; 346(23): 1831-2; Author Reply 1831-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12050350

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The levels of circulatory cell free fetal DNA in maternal plasma are elevated prior to the onset of preeclampsia. Author(s): Zhong XY, Holzgreve W, Hahn S. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2002; 21(1): 77-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044339

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The magnitude of sympathetic hyperactivity in pregnancy-induced hypertension and preeclampsia. Author(s): Greenwood JP, Scott EM, Walker JJ, Stoker JB, Mary DA. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2003 March; 16(3): 194-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12620697

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The methylenetetrahydrofolate reductase 677 C-->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.

7

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

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The following 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

•

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/

•

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

•

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

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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

•

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

•

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

•

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

•

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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Preeclampsia

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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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<0.01). Web site: http://www.delphion.com/details?pn=US05238819__ •

Diagnostic assay for the prediction of preeclampsia Inventor(s): Leavitt; John (Palo Alto, CA), Shorter; Simon (Los Gatos, CA), Taylor; Robert N. (San Francisco, CA), Varma; Madhu (Mountain View, CA) Assignee(s): Regents of the University of California (oakland, Ca) Patent Number: 5,712,103 Date filed: February 13, 1995 Abstract: The present invention provides methods and diagnostic kits for the detection or prediction of preeclampsia. More particularly, the present invention provides for the diagnosis of preeclampsia before the third trimester of pregnancy by detecting reduced levels of Insulin-like Growth Factor Binding Protein 1 (IGFBP-1) in maternal blood. Excerpt(s): This invention relates to an assay to detect or predict the onset of preeclampsia in pregnant women. More specifically, this invention provides for an assay that identifies pregnant women at high risk for preeclampsia by measuring the levels of Insulin-like Growth Factor Binding Protein-1 (IGFBP-1) in biological samples obtained during the first or second trimester of pregnancy. Preeclampsia is an idiopathic, life-threatening disease of late pregnancy in which hypertension is associated with hepatic, neurologic, hematologic, or renal involvement. Rapid development of edema, particularly of the ankles, face and hands, along with a rise in blood pressure, usually signals the onset of this condition. Jaundice and abnormal liver function may be present. When preeclampsia occurs in a hypertensive patient, a rapid acceleration of the blood pressure elevation is accompanied by an increase in proteinuria, oliguria, edema, and coagulopathy. This is a life threatening syndrome and tends to recur with future pregnancies. In the postpartum period, proteinuric patients are particularly susceptible to the development of postpartum renal failure. Preeclampsia is often characterized by hyperreflexia, visual disturbances and headache indicating neurologic involvement which may ultimately progress to eclampsia characterized by convulsions. Preeclampsia occurs in 7-10% of pregnancies and is responsible for significant maternal and fetal morbidity (Roberts, Pregnancy-related hypertension., pages 703-752 In Maternal-Fetal Medicine-Principles and Practice, Creasy & Resnick, eds., W. B. Saunders, Philadelphia (1984). Web site: http://www.delphion.com/details?pn=US05712103__

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Emulsions of perfluoro compounds as solvents for nitric oxide (NO) Inventor(s): Balaban; A. T. (Bucharest, RO), Garfield; R. E. (Friendswood, TX), Seitz; W. A. (Dickinson, TX) Assignee(s): Board of Regents, the University of Texas System (austin, Tx), The Texas A&m University System (college Station, Tx) Patent Number: 5,869,539 Date filed: April 17, 1996 Abstract: The present invention involves perfluoro compound emulsions including nitric oxide, their preparation and their use. These emulsions provide a new source of nitric oxide. Such nitric oxide-containing emulsions may be used for the administration of nitric oxide to individuals in need thereof. Individuals in need of nitric oxide administration can include those suffering from hypertension, preeclampsia and a number of other situations where an increased blood flow, for example, is desirable. In addition, given the long use of perfluoro compound emulsions as blood substitutes, the present invention provides a relatively safe mode for administering and distributing nitric oxide-without potential negative side effects such as toxicities due to drug metabolites. Excerpt(s): The present invention relates to nitric oxide sources and their uses. Perfluorocarbon emulsions comprising nitric oxide and preferred nitric oxide sources. Furchgott and Zawadski first showed in 1980 that the endothelium must be intact for acetylcholine to produce vascular relaxation. Subsequently, numerous studies have shown that neurohumoral or pharmacological agents mediate vasodilation via the endothelium. It is now recognized that the endothelium releases a potent, labile, nonprostanoid vasodilating agent in response to various stimuli that either cause vasodilation or modulates vasoconstruction. This factor, originally termed endotheliumderived relaxing factor (EDRF), has been shown to be nitric oxide (NO) or a compound with a nitric oxide moiety. Nitric oxide synthases (NOs) are enzymes that synthesize NO from arginine. These enzymes have been cloned and characterized since they were first described in 1989. Three distinct isoforms have been purified, cloned and expressed, and there is evidence for the presence of NOS in almost every tissue of the mammalian body, albeit at widely different levels. The isoforms include bNOS (brain NOS), eNOS (epithelial NOS), and mNOS (macrophage NOS ir iNOS--inducible NOS). The bNOS and eNOS isoforms are constitutive and stimulated by calcium. The iNOS form is expressed in response to a variety of cytokines. Their roles are briefly outlined below. Web site: http://www.delphion.com/details?pn=US05869539__

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Endothelin antagonist and/or endothelin synthase inhibitor in combination with a progestin, an estrogen, a cyclooxygenase inhibitor, or a nitric acid donor or substrate Inventor(s): Chwalisz; Kristof (Berlin, DE), Garfield; Robert E. (Friendswood, TX) Assignee(s): Board of Regents the University of Texas System (austin, Tx), Schering Aktiengesellschaft (berlin, De) Patent Number: 5,811,416 Date filed: May 8, 1995 Abstract: A pharmaceutical composition for and methods of treatment of menstrual disorders, e.g., dysmenorrhea, in a non-pregnant female, preterm labor, preeclampsia

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and/or fetal growth retardation in a pregnant female mammal, treatment of atherosclerotic vascular disease and hypertension in males as well as females, and for hormone replacement therapy in peri- and post-menopausal females, comprising administering effective amounts of an endothelin antagonist and/or an endothelin synthase inhibitor or both, in combination witha progestin, and/or an estrogen, and/ora cyclooxygenase inhibitor, and/ora nitric oxide donor and/or nitric oxide substrate,to prevent and/or ameliorate said conditions, are disclosed. In the method aspects, the endothelin antagonist and/or endothelin synthase inhibitor can be administered alone for treatment of menstrual disorders, e.g., dysmenorrhea, in a non-pregnant female, preterm labor, preeclampsia and/or fetal growth retardation in a pregnant female mammal. Further, methods for screening compounds for such treatments are disclosed. Excerpt(s): This invention relates to a method for the treatment of uterine contractility disorders, such as preterm labor, abortion, dysmenorrhea and menstrual disorders and to the treatment of preeclampsia with an endothelin antagonist, an endothelin synthase inhibitor, or both, alone or further in combination with a progesterone or a cyclooxygenase inhibitor. In addition, the invention relates to the treatment of atherosclerotic vascular disease and hypertension in males as well as females with an endothelin antagonist and/or an endothelin synthase inhibitor in combination with estrogens and/or progestins, and as a component of hormone replacement therapy in peri- and post-menopausal females. Preterm labor, and subsequent preterm birth is a major problem of perinatology in general. By definition, a term gestation in human is one that is completed between 38 and 42 weeks. However, in approximately 5 to 15% of women, birth occurs prematurely, i.e., before 37 completed weeks. In humans, premature birth is responsible for 75% of infant mortality and 50% of long-term neurological handicaps (Creasy, 1989). To date, there are no effective methods of treatment and prevention for either preterm labor or preterm birth. The current use of.beta.-mimetics in the treatment of preterm labor is only of limited value. The metaanalyses of the results of controlled trials show little or no effect of.beta.-mimetics on the frequency of the respiratory distress syndrome or on perinatal mortality (King et al., 1988). There is growing evidence that preterm labor is syndrome which can be induced by a variety of factors. Moreover, preterm labor has to be considered a chronic pathological condition of the uterus in response to a variety of etiological factors. In some clinical situations, decrease in progesterone levels or in progesterone action at the receptor level may result in preterm labor. In many species, preterm labor can be induced with progesterone antagonists (e.g., RU 486, onapristone) or progesterone synthase inhibitors (epostane, trilostane). There is growing evidence, however, that intrauterine or systemic infections play a key role in the etiology and pathogenesis of preterm labor in humans (for review see Romero et al.). In 20-40% of pre-term labor, there is clinical and/or biochemical evidence of the intrauterine infection such as hyperthermia, positive bacterial cultures, increase in cytokines such as IL-1b, TNF.alpha., IL-8 in the amniotic fluid (Romero et al., 1991, 1992). It is well established that the cytokines are released from uterine macrophages, activated lymphocytes and other white blood cells in response to a lipopolysaccharide (LPS) which is a major constituent of outer bacterial membrane. The cytokines stimulate in turn the release of prostaglandins from the decidual and amnion cells which directly induce uterine contractions leading to preterm labor and subsequently to preterm birth. Web site: http://www.delphion.com/details?pn=US05811416__

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Endothelin antagonists with ether-linked groups Inventor(s): Cheng; Xue-Min (Ann Arbor, MI), Doherty; Annette Marian (Ann Arbor, MI), Patt; William Chester (Chelsea, MI), Repine; Joseph Thomas (Ann Arbor, MI) Assignee(s): Warner-lambert Company (morris Plains, Nj) Patent Number: 6,133,263 Date filed: August 3, 1998 Abstract: Novel nonpeptide endothelin antagonists with ether-linked groups are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating atherosclerosis, restenosis, Raynaud's phenomenon, mild or severe congestive heart failure, cerebral ischemia, cerebral infarction, embolic stroke, cerebral vasospasm, subarachnoid hemorrhage, hemorrhagic stroke, diabetes, gastric ulceration and mucosal damage, ischemnic bowel disease, Chrohn's disease, essential or malignant hypertension, pulmonary hypertension, pulmonary hypertension after bypass, acute respiratory distress syndrome, chronic obstructive pulmonary diseases, male penile erectile dysfunction, cancer, especially malignant hemangicendothelioma or prostate cancer, myocardial infarction or ischemia, acute or chronic renal failure, renal ischemia, radiocontrast-induced nepbrotoxicity, endotoxic, septic, hemorrhagic shock, angina, preeclampsia, asthma, arhythmias, benign prostatic hyperplasia, and elevated levels of endothelin. 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, angina, arrhythmias, asthma, atherosclerosis, benign prostatic hyperplasia, Buerger's Disease, cardiac arrest, cardiogenic shock, cerebral trauma, Chrohn's Disease, congenital heart disease, congestive heart failure (CHF) (mild), congestive heart failure (CHF) (severe), cerebral ischemia, cerebral infarction, cerebral vasospasm, cirrhosis, diabetes, dilated cardiomyopathy, drowning (anoxia), endotoxic shock, gastric mucosal damage, glaucoma, head injury, hemodialysis, hemorrhagic shock, hypertension (essential), hypertension (malignant), hypertension (pulmonary), hypertension (pulmonary, after bypass), hypoglycemia, inflammatory arthritides, ischemic bowel disease, ischemic disease, male penile erectile dysfunction, malignant hemangioendothelioma, myocardial infarction, myocardial ischemia, prenatal asphyxia, postoperative cardiac surgery, prostate cancer, preeclampsia, Raynaud's Phenomenon, renal failure (acute), renal failure (chronic), renal ischemia, restenosis, sepsis syndrome, subarachnoid hemorrhage (acute), surgical operations, status epilepticus, stroke (thromboembolic), stroke (hemorrhagic), Takayasu's arteritis, ulcerative colitis, uremia after hemodialysis, and uremia before hemodialysis. Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1, is one of a family of structurally similar bicyclic peptides which include: ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTXs). The distribution of the two cloned receptor subtypes, termed ET.sub.A and ET.sub.B, have been studied extensively (Arai H., et al., Nature, 1990;348:730, Sakurai T., et al., Nature, 1990;348:732). The ET.sub.A, or vascular smooth muscle receptor, is widely distributed in cardiovascular tissues and in certain regions of the brain (Lin H. Y., et al., Proc. Natl. Acad. Sci., 1991;88:3185). The ET.sub.B receptor, originally cloned from rat lung, has been found in rat cerebellum and in endothelial cells. The human ET receptor subtypes have been cloned and expressed (Sakamoto A., et al., Biochem. Biphys. Res. Chem.,

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1991;178:656, Hosoda K., et al., FEBS Lett., 1991;287:23). The ET.sub.A receptor clearly mediates vasoconstriction and there have been a few reports implicating the ET.sub.B receptor in the initial vasodilatory response to ET (Takayanagi R., et al., FEBS Lett., 1991;282:103). However, recent data has shown that the ET.sub.B receptor can also mediate vasoconstriction in some tissue beds (Panek R. L., et al., Biochem. Biophys. Res. Commun., 1992;183(2):566). Web site: http://www.delphion.com/details?pn=US06133263__ •

Hydroxamate inhibitors of endothelin converting enzyme Inventor(s): Doherty; Annette Marian (Ann Arbor, MI), Kornberg; Brian Edward (Ann Arbor, MI), Nikam; Sham (Ann Arbor, MI) Assignee(s): Warner-lambert Company (morris Plains, Nj) Patent Number: 5,663,296 Date filed: January 17, 1995 Abstract: Hydroxamate compounds of the following formula are disclosed:R--AA.sup.3 --AA.sup.4 --AA.sup.5 --AA.sup.6 --NH--OR.sup.2wherein AA.sup.3 --AA.sup.6 represent amino acid residues. The disclosed compounds are inhibitors of endothelin converting enzyme, and as such are useful for the treatment of disorders resulting from overproduction of endothelin, i.e., acute and chronic renal failure, cyclosporin-A induced nephrotoxicity, hypertension, myocardial infarction, metabolic, endocrinological, neurological disorders, congestire heart failure, endotoxic shock and hemorrhagic shock, septic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease, cerebral vasospasm, restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, ischemic bowel disease, and diabetes. Excerpt(s): The present invention relates to novel hydroxamate inhibitors of endothelin converting enzyme 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 novel compounds of the present invention are inhibitors of endothelin converting enzyme useful in treating elevated levels of endothelin and in controlling hypertension, myocardial infarction, metabolic, endocrinological, and neurological disorders, congestire heart failure, endotoxic and hemorrhagic shock, septic shock, subarachnoid hemorrhage, arrhythmias, asthma, acute and chronic renal failure, cyclosporin-A induced nephrotoxicity, restenosis, angina, ischemic disease, gastric mucosal damage, ischemic bowel disease, cancer, pulmonary hypertension, preeclampsia, atherosclerotic disorders including Raynaud's disease, cerebral vasospasm, and diabetes. Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1, is one of a family of structurally similar bicyclic peptides which include; ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTXs). The unique bicyclic structure and corresponding arrangement of the disulfide bridges of ET-1, which are the same for the endothelins, VIC, and the sarafotoxins, has led to significant speculation as to the importance of the resulting induced secondary structure to receptor binding and functional activity. ET-1 analogs with incorrect disulfide pairings exhibit at least 100fold less vasoconstrictor activity. Endothelin-1 is generated from a 203 amino acid peptide known as preproendothelin by an unknown dibasic endopeptidase. This enzyme cleaves the prepropeptide to a 38 (human) or 39 (porcine) amino acid peptide

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known as big endothelin or proendothelin. Big ET is then cleaved by an enzyme, known as endothelin converting enzyme or ECE, to afford the biologically active molecule ET-1. Big ET is only 1% as potent as ET-1 in inducing contractile activity in vascular strips but it is equally potent in vivo at raising blood pressure, presumably by rapid conversion to ET-1 (Kimura S, Kasuya Y, Sawamura T, et al, "Conversion of big endothelin-1 to 21residue endothelin-1 is essential for expression of full vasoconstrictor activity: Structureactivity relationship of big endothelin-1," J. Cardiovasc Pharmacol 1989;13:S5). There have been numerous reports describing possible proteases in both the cytoplasm and membrane bound cellular fractions of endothelial cells (Ikegawa R, Matsumura Y, Takaoka M, et al, "Evidence for pepstatin-sensitive conversion of porcine big endothelin1 to endothelin-1 by the endothelial cell extract," Biochem Biophys Res Commun 1990;167:860; Sawamura T, Kimura S, Shinmi O, et al, "Characterization of endothelin converting enzyme activities in soluble fraction of bovine cultured endothelial cells," Biochem Biophys Res Commun 1990;169:1138; Sawamura T, Shinmi O, Kishi N, et al, "Analysis of big endothelin-1 digestion by cathepsin D." Biochem Biophys Res Commun 1990;172:883; Shields P P, Gonzales T A, Charles D, et al, "Accumulation of pepstatin in cultured endothelial cells and its effect on endothelin processing," Biochem Biophys Res Commun 1991;177:1006; Matsumura Y, Ikegawa R, Tsukahara Y, et al, "Conversion of big endothelin-1 to endothelin-1 by two types of metalloproteinases derived from porcine aortic endothelial cells," FEBS Lett, 1990;272:166; Sawamura T, Kasuya Y, Matsushita S N, et al, "Phosphoramidon inhibits the intracellular conversion of big endothelin-1 to endothelin-1 in cultured endothelial cells," Biochem Biophys Res Commun 1991;174:779; Takada J, Okada K, Ikenaga T, et al, "Phosphoramidon-sensitive endothelin-converting enzyme in the cytosol of cultured bovine endothelial cells," Biochem Biophys Res Commun 1991;176:860; Ahn K, Beningo K, Olds G, Hupe D, "Endothelin-converting enzyme from bovine and human endothelial cells," J Vasc Res 1991;29:76, 2nd International symposium on endothelium-derived vasoactive factors). Many groups have chosen to isolate ECE from endothelial cells of various species, since endothelin is known to be synthesized and secreted by this cell type. It was initially reported that two types of protease activity were present in porcine or bovine endothelial cells that could cause conversion of big ET to ET in vitro (Ikegawa R, supra; Sawamura T, supra; Matsumura Y, supra; Takada J, supra; Ahn K, supra). However, it was subsequently found that the aspartic protease activity from porcine endothelial cells, thought to be predominantly cathepsin D, also caused further degradation of ET-1 and was therefore unlikely to be the true ECE (Sawamura T, supra). Moreover, human cathepsin D also causes rapid degradation of ET-1. In addition, there has been one study showing that the intracellular accumulation of pepstatin, an aspartic protease inhibitor, did not inhibit ET-1 production in cultured bovine aortic endothelial cells (Shields P P, supra). Stronger evidence that ECE is in fact a neutral metalloprotease has appeared (Matsumura Y, supra; Sawarnura T, supra; Takada J, supra; Ahn K, supra), although to date there have been no known specific metalloprotease ECE inhibitors to confirm these findings in vivo. However, the nonspecific metalloproteinase inhibitor, phosphoramidon, has been shown to inhibit the intracellular conversion of big ET-1 to ET-1 in cultured vascular endothelial cells and smooth muscle cells (Sawamura T, supra). Web site: http://www.delphion.com/details?pn=US05663296__

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Linear and monocyclic endothelin antagonists Inventor(s): Cody; Wayne L. (Saline, MI), Doherty; Annette M. (Ann Arbor, MI), He; John X. (Ann Arbor, MI) Assignee(s): Warner-lambert Company (morris Plains, Nj) Patent Number: 5,260,276 Date filed: June 14, 1991 Abstract: Novel linear and monocyclic antagonists of endothelin are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in controlling hypertension, myocardial infarction, metabolic, endocrinological, and neurological disorders, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, acute renal failure, preeclampsia, and diabetes. Excerpt(s): The present invention relates to novel linear and monocyclic 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 novel compounds of the present invention are antagonists of endothelin useful in controlling hypertension, myocardial infarction, metabolic, endocrinological, and neurological disorders, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, acute renal failure, preeclampsia, and diabetes. Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1, is one of a family of structurally similar bicyclic peptides which include; ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTXs). The unique bicyclic structure and corresponding arrangement of the disulfide bridges of ET-1, which are the same for the endothelins, VIC, and the sarafotoxins, has led to significant speculation as to the importance of the resulting induced secondary structure to receptor binding and functional activity. ET-1 analogues with incorrect disulfide pairings exhibit at least 100fold less vasoconstrictor activity. The flexible C-terminal hexapeptide of ET-1 has been shown to be important for binding to the ET receptor and functional activity in selected tissues. Additionally, the C-terminal amino acid (Trp-21) has a critical role in binding and vasoconstrictor activity, since ET[1-20] exhibits approximately 1000-fold less functional activity. Cody, W. L., et al, Abstract, Second International Conference on Endothelin, Tsukuba, Japan, Dec. 9, 1990, and Johansen, N. L., et al, Peptides 1990, Proceedings of the Twenty First European Peptide Symposium, edited by Giralt, E. and Andreu, D., pages 680-681, Escom Science Publishers B.V. (1990) disclosed various monocyclic analogs of ET-1, none of which exhibited any functional vasoconstricting activity. Web site: http://www.delphion.com/details?pn=US05260276__

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Method for screening for reproductive tract inflammation and preeclampsia using neutrophil defensins Inventor(s): Heine; Robert Phillips (Wexford, PA) Assignee(s): University of Pittsburgh (pittsburgh, Pa) Patent Number: 5,972,594 Date filed: February 5, 1997

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Abstract: A method and apparatus for screening for reproductive tract inflammation and preeclampsia which utilizes the increase in neutrophil defensins to indicate that a patient is at risk of having reproductive tract inflammation or preeclampsia. The apparatus consists either an ELISA based measurement of defensins levels or a dipstick test that can be administered by the provider or self-administered by the patient. Excerpt(s): The present invention relates to a method and an apparatus for screening for reproductive tract inflammation and preeclampsia. More particularly, this invention concerns the method and apparatus for screening for reproductive tract inflammation and preeclampsia which utilize the presence of neutrophil defensins found in bodily fluids and tissues of a patient to indicate that the patient is at risk of having reproductive tract inflammation or preeclampsia. Detection of reproductive tract inflammation and preeclampsia may be divided into two categories: diagnosis and screening. Diagnosis is a method of establishing the presence of a particular disease in a patient. Limitations of the current diagnostic methods include the high cost of a medical professional performing an invasive examination to take samples, run tests and analyze results as well as the inefficient utilization of the sensitive, yet expensive, diagnostic tests. For example, when polymerase chain reaction testing and ligase chain reaction testing, two standard diagnostic tests for sexually transmitted diseases, are performed, the medical professional must administer the test which results in an average of ten patients testing negative for every one patient that tests positive. Optimally, a diagnostic test is employed only after a screening test indicates that the patient is at risk of having a disease in order to eliminate the unnecessary cost of expensive diagnostic tests. Screening is a method of establishing the absence of a particular disease or class of diseases in a patient. When a screening test indicates that a patient does not have a disease, in many cases the need for further diagnostic testing is eliminated. Such screening saves money for patients, health insurance companies and government health programs. In addition, screening provides a way for patients to avoid the discomfort associated with more invasive diagnostic procedures. The following are some of the conventional screening and diagnostic methods used to detect female reproductive tract inflammation and preeclampsia wherein the female reproductive tract inflammation include, but are not limited to, intraamniotic infection, pelvic inflammatory diseases and sexually transmitted diseases such as gonorrhea, chlamydia and trichomoniasis. Web site: http://www.delphion.com/details?pn=US05972594__ •

Method for the detection of pregnancy disorders Inventor(s): Silberman; Michael (P.O. Box 9697, Haifa 31096, IL) Assignee(s): Silberman; Michael (haifa, Il), Technion Research & Development Foundation Ltd. (haifa, Il) Patent Number: 5,198,366 Date filed: August 16, 1991 Abstract: The present invention relates to a method for an early stage detection of three specific pregnancy-related disorders: preeclampsia, intrauterine growth retardation and preterm delivery. According to the method, an antigen consisting of a specific humanderived placental soluble protein, known as PP-13, is determined by radioimmunoassay or ELISA. In the radioimmunoassay method, the PP-13 is labelled by a radioactive iodine and the bounded iodine is counted and correlated with standard curves. The best results are obtained when the protein to be labelled by radioactive iodine is present at a concentration of above 0.71 mg/ml. In case of the ELISA method, the quantitative

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determination of PP-13 is carried out with an alkaline phosphatase substrate and measured at an optical density of 405 nm. Excerpt(s): The present invention relates to a new method for the detection of pregnancy-related disorders. More particularly, the invention relates to a new method for the detection of three specific pregnancy-associated disorders: severe preeclampsia, Intra-Uterine Growth Retardation (IUGR) and preterm delivery, at a relatively early stage of pregnancy. As known, high risk pregnancies constitute about 10 to 25% of pregnancies. Among the high risk pregnancy disorders the following can be mentioned: diabetes, kidney diseases (such as chronic pyelonephritis, chronic pyelonephritis and renal insufficiency), heart diseases (such as primary pulmonary and hypertension).The known methods for controlling the progress of pregnancy, have the disadvantage of detecting the status of pregnancy disorders at a relatively late stage, when the clinical signs and symptoms are already apparent. There are several hormone assays suggested to give an indication whether placental function is normal or to predict impending fetal death. The tests most widely used are: urine estriol, urine total estrogens, serum unconjugated estriol and serum placental lactogen. As known, estriol is an estrogenic compound produced by the placental from precursors derived from fetal adrenal cortex and fetal liver. The conjugated form of estriol is excreted into the maternal urine. Serum estriol can be measured either as total estriol or as unconjugated estriol. It usually is measured as unconjugated estriol in order to exclude maternal contribution to the conjugated fraction. Urine estriol can be measured as total estriol or as total estrogens, since estriol normally constitutes about 90% of urine total estrogens. Web site: http://www.delphion.com/details?pn=US05198366__ •

Method for the prediction of preeclampsia and other diseases Inventor(s): Arbogast; Bradley W. (Johnson City, TN) Assignee(s): Arbogast Pharmaceuticals, Inc. (johnson City, Tn) Patent Number: 6,642,055 Date filed: March 31, 2000 Abstract: The invention disclosed is a process for determining the cytoprotective activity of plasma that prevents the destruction of endothelial cells and forestalls the development of a number of diseases such as atherosclerosis, preeclampsia, edema, nephrotic syndrome, and stroke. The present invention includes a method of diagnosing a patient's proclivity to develop a disease having a correlation to a reduction in the concentration of pI 5.6 albumin in the plasma by determining a value indicative of the concentration of the pI 5.6 albumin that is not bound to VLDL ("free pI 5.6 albumin") in the patient's blood serum. The preferred embodiment of the process utilizes in vitro methods to obtain an indicator of the free pI 5.6 albumin instead of directly measuring the concentration of the free pI 5.6 albumin. The preferred method comprises the steps of:(a) providing a plasma sample containing free albumin, triglycerides, very low density lipoproteins, low density lipoproteins, and non-esterified fatty acids bound to the free albumin;(b) determining the concentration of the free albumin;(c) determining the concentration of the non-esterified fatty acids bound to the free albumin; and(d) calculating a value indicative of the toxicity preventing ability of the plasma by comparing the concentration of the free albumin to the concentration of the nonesterified fatty acids bound to the free albumin. The present process does not provide direct measurement of the cytoprotective activity of plasma, but rather, an empirical

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value which has clinical relevance in identifying patients with a high chance of developing diseases inhibited by pI 5.6 albumin. Excerpt(s): The present invention relates to methods for predicting and following illnesses. More particularly, the present invention relates to the diagnosis of preeclampsia and other diseases. Vascular disease is often related to the composition of blood flowing therethrough. In particular, high concentrations of very low density lipoproteins (VLDL) in blood have a deleterious effect on vascular integrity. Very low density lipoproteins in blood tend to break down the inner vascular walls causing vascular diseases including preeclampsia, atherosclerosis, stroke, peripheral vascular disease, diabetic vascular disease, and such. Methods providing earlier detection of vascular diseases, and methods for diagnosing a patient's proclivity toward developing a vascular disease at a later point in his life are desirable so that such disease may be better controlled, or even avoided. The early detection of preeclampsia is particularly important. Web site: http://www.delphion.com/details?pn=US06642055__ •

Method for using breath carbon monoxide concentration measurements to detect pregnant women at risk for or experiencing various pathological conditions relating to pregnancy Inventor(s): Seidman; Daniel (Tel-Hashomer, IL) Assignee(s): Natus Medical, Inc. (san Carlos, Ca) Patent Number: 6,416,479 Date filed: July 14, 2000 Abstract: A non-invasive method for the early detection and assessment of the severity of various pathological conditions in pregnancy including pregnancy-induced hypertension, preeclampsia, premature uterine contractions and intrauterine growth retardation. The carbon monoxide or end-tidal carbon monoxide concentration is measured in a pregnant woman's breath and compared to thresholds for determining the likelihood of onset or actual onset of these pathological conditions. The measurements can be made in a clinic, hospital, physician's office, or any other location easily accessible to pregnant women using any of a number of devices for measuring breath carbon monoxide. One solution is to measure end-tidal breath carbon monoxide using the Natus.RTM. CO-Stat.RTM. End Tidal Breath Analyzer, manufactured and sold by Natus Medical Inc. of San Carlos, Calif. This particular device allows an operator to perform non-invasive, simple and rapid, automatic sampling and analysis of end-tidal carbon monoxide in expiratory air without the requirement for laboratory analysis or highly trained personnel. Thus, the method can be employed using a device that does not required laboratory analysis or highly trained personnel, and results in an on-thespot, immediate determination which is vital for rapid treatment of these serious conditions of pregnancy. Excerpt(s): The present invention relates generally to methods for using breath carbon monoxide ("CO"), more particularly end-tidal carbon monoxide ("ETCOc") concentration measurements, to predict the occurrence of various pathological conditions during pregnancy as well as methods for using such measurements to determine the actual onset of such conditions. Pregnancy-induced hypertension ("PIH") is a common medical complication of pregnancy which encompasses a group of disorders including preeclampsia ("PET"). PET is primarily a disease of the last

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trimester of pregnancy and is the most common medical complication of pregnancy. It has a reported incidence ranging between 5% and 10% depending on the population demographics.sup.1 As the pathogenesis of these disorders is unclear, prediction and prevention remain an elusive goal. End-organ damage, especially to the kidneys and liver, may result if the condition is not recognized early enough, and the condition can be life-threatening. Consequences for the late-term fetus include diminished placental blood flow, and subsequent wasting and asymmetrical growth of the fetus. At present, the best cure for the disease is delivery of the preterm baby followed by intensive neonatal care for the baby and intensive surgical care for the mother. Web site: http://www.delphion.com/details?pn=US06416479__ •

Method of treating preeclampsia Inventor(s): Killian; Anthony (Libertyville, IL) Assignee(s): Tap Pharmaceuticals, Inc. (deerfield, Il) Patent Number: 5,534,548 Date filed: May 3, 1994 Abstract: Straight-chain alkanoic acids, substituted at the.OMEGA.-carbon atom by a substituted phenyl, naphthyl, furyl, or thienyl group and by a substituted 1,4benzoquinon-2-yl group are effective in the therapy or prophylaxis of conditions associated with lipid peroxide injury to vascular endothelium particularly preeclampsia and eclampsia in pregnant females. Excerpt(s): The present invention relates to medical methods of treatment. More particularly, the present invention concerns the use of a class of substituted.OMEGA.(1,4-benzoquinon-2-yl)alkanoic acids for the therapy or prophylaxis of conditions associated with excess production of lipid peroxides which may lead to vascular endothelial injury, particularly the conditions of preeclampsia and eclampsia. Preeclampsia is the development of hypertension with proteinuria or edema in pregnant women between the twentieth week of pregnancy and the end of the first week following delivery without apparent cause. Preeclampsia develops in roughly 5% of pregnant women, typically in women with a prior history of hypertension or vascular disease. If left untreated, preeclampsia can often rapidly progress to eclampsia which is fatal if untreated and which occurs in about 1 out of every 200 women who develop preeclampsia. Mild preeclampsia is typically treated with bed rest. If the condition persists or develops into eclampsia, the usual treatment is the immediate induction of labor and delivery of the fetus. Web site: http://www.delphion.com/details?pn=US05534548__

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Method of using IL-11 for treating spondyloarthropies Inventor(s): Keith; James (28 Vine St., Andover, MA 01810), Schendel; Paul (39 Jeffrey Rd., Wayland, MA 01778) Assignee(s): None Reported Patent Number: 5,679,339 Date filed: June 27, 1995

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Abstract: Provided by the present invention are methods of treating a variety of disorders including AIDS, arthritis (rheumatoid arthritis, osteoarthritis, spondyloarthropathies), antibiotic induced diarrheal diseases (Clostridium difficile), multiple sclerosis, osteoporosis, gingivitis, peptic ulcer disease, esophagitis, diabetes, retinitis, uveitis, reperfusion injury after myocardial infarction (MI) or cerebral vascular accident (CVA), aphthous ulcers (oral), atherosclerosis (plaque rupture), prevention of minor metastases, asthma, preeclampsia, and allergic disorders such as rhinitis, conjunctivitis, and urticaria. Excerpt(s): The present invention relates generally to methods of treating disorders such as AIDS, arthritis (rheumatoid arthritis, osteoarthritis, spondyloarthropathies), antibiotic induced diarrheal diseases (Clostridium difficile), multiple sclerosis, osteoporosis, gingivitis, peptic ulcer disease, esophagitis, diabetes, retinitis, uveitis, reperfusion injury after myocardial infarction (MI), cerebral vascular accident (CVA), aphthous ulcers (oral), atherosclerosis (plaque rapture), prevention of minor metastases, asthma, preeclampsia, and allergic disorders such as rhinitis, conjunctivitis, and urticaria. Inflammatory responses include a broad range of host reaction to a variety of insults, such as injury, infection, or rejection. It is the over production of mediators that is believed to be associated with a broad range of disorders, including AIDS, arthritis (rheumatoid arthritis, osteoarthritis, spondyloarthropathies), antibiotic induced diarrheal diseases (Clostridium difficile), multiple sclerosis, osteoporosis, gingivitis, peptic ulcer disease, esophagitis, diabetes, retinitis, uveitis, reperfusion injury after myocardial infarction (MI), cerebral vascular accident (CVA), aphthous ulcers (oral), atherosclerosis (plaque rupture), tumor metastases, asthma, preeclampsia, and allergic disorders such as rhinitis, conjunctivitis, and urticaria. These disorders and their symptoms are briefly summarized below. According to the methods of the present invention, IL-11 is administered to modulate the hosts' over reaction to insult thereby treating the following disorders. Web site: http://www.delphion.com/details?pn=US05679339__ •

Methods of diagnosing and treating preeclampsia Inventor(s): Keith; James C. (Andover, MA) Assignee(s): Genetics Institute, Inc. (cambridge, Ma), Virginia Polytechnic Institute and State Univ. (blacksburg, Va) Patent Number: 5,543,138 Date filed: March 10, 1994 Abstract: Methods are provided for the diagnosis and treatment of patients with increased risk of gestational hypertension or preeclampsia. The methods involve measuring serum M-CSF levels, and administration of M-CSF. Excerpt(s): This invention relates to the use of cytokines, particulary M-CSF, for the diagnosis and treatment of preeclampsia. Preeclampsia is a major cause of maternal and fetal mortality and morbidity, and is a disuse unique to human beings during pregnancy. Recent evidence has indicated that preeclampsia is characterized by placental maladaptation and body-wide endothelial cell injury. Failure of trophoblastic invasion into myometrial segments of maternal spiral arteries and the production of cytotoxic mediators which cause systemic endothelial damage also seem to be implicate. Trophoblasts are a unique cell type in that they share characteristics of both normal and neoplastic tissue. During normal development, like neoplastic cells, human trophoblasts

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invade through the extracellular matrix into the myometrial portion of spiral arteries. However, unlike neoplastic cells which endlessly invade and finally spread to other organs, the invasive properties of the trophoblasts are eventually brought under control, further cell differentiation proems and cell senescence occurs. In normal gestation, trophoblasts convert spiral arteries into uteroplacental arteries by the above process. Pijnenborg et al., in Trophoblast Research (Denker and Aplin, eds.) Plenum Press, New York, p. 33 (1990). Uteroplacental arteries then dilate approximately 30-fold as large as the spiral arteries. Resulting hemodynamic changes enable the placental bed to satisfy the increased demand for oxygen from the fetus during the latter stages of gestation. In preeclamptic women, however, spiral arteries are not properly converted into uteroplacental arteries due to the failure of the second wave of trophoblastic migration into the myometrium at the beginning of the second trimester. Khong et al., Br. J. Obstet. Gynecol., 93:1049-1059 (1986). As a result, preeclamptic women typically demonstrate a high-resistance, high-pressure, and low-flow state with intact, non-dilated spiral arteries, Robertson et al., Am. J. Obstet. Gynecol., 155:401-412 (1986), and demonstrate a wide variety of clinical syndromes. Therefore, abnormal behavior of the fetus-derived trophoblast appears to be a central asset of the disease. Web site: http://www.delphion.com/details?pn=US05543138__ •

Nonpeptide endothelin antagonists I Inventor(s): Berryman; Kent Alan (Ann Arbor, MI), Doherty; Annette Marian (Ann Arbor, MI), Edmunds; Jeremy John (Ypsilanti, MI), Patt; William Chester (Chelsea, MI), Plummer; Mark Stephen (Dexter, MI), Repine; Joseph Thomas (Ann Arbor, MI) Assignee(s): Warner-lambert Company (morris Plains, Nj) Patent Number: 5,691,373 Date filed: February 6, 1995 Abstract: Novel nonpeptide antagonists of endothelin I are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction, myocardial ischemia, cerebral vasospasm, cerebral ischemia, cerebral infarction, 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, stroke, benign prosthatic hyperplasia (BPH), and diabetes. 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,

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status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma. Several studies have been reported with both peptide and non-peptide ET antagonists showing efficacy in various models of subarachnoid hemorrhage (SAH). For example, BQ-123-prevents early cerebral vasospasm following SAH in various rat (Clozel M., et al., Life Sci, 1993;52:825) and rabbit (Lee K. S., et al., Cerebral Vasospasm 1993:217; and Neurosurgery 1994; 34:108) models. FR 139317 significantly inhibited the vascoconstriction of the basilar artery after 7 days in a canine two-hemorrhage model of SAH (Nirei H., et al., Life Sci. 1993;52:1869). BQ-485 also significantly inhibited the vascoconstriction of the basilar artery after 7 days in a canine two-hemorrhage model of SAH (Yano, et al., Biochem Biophys. Res Commun. 1993; 195:969). Ro 46-2005 (Clozel M., et al., Nature 1993;365:759) has been shown to prevent early cerebral vasospasm following SAH in the rat with no significant effect on systemic arterial blood pressure. Treatment with Ro 47-0203=Bosentan (Clozel et al., Circulation 1993;88(4) part 2:0907) to rabbits with SAH had a 36.+-.7% reduction of basilar artery cross-sectional area compared to sham rabbits. All of these studies show in vivo efficacy of endothelin antagonists in cerebral vasospasm resulting from SAH. Web site: http://www.delphion.com/details?pn=US05691373__ •

Phosphocholinate cardenolides Inventor(s): Chasalow; Fred I. (San Carlos, CA) Assignee(s): Kerix, L.l.c. (san Carlos, Ca) Patent Number: 6,130,211 Date filed: January 21, 1999 Abstract: Disclosed herein are cardenolides and related compounds covalently linked to phosphocholine moieties and pharmaceutical formulations comprising such compounds. Also disclosed herein are methods for treating hypertension, premenstrual syndrome (PMS), preeclampsia and polycystic kidney disease using the compounds. Excerpt(s): This invention is related to cardenolides and related compounds covalently linked to phosphocholine moieties, pharmaceutical formulations comprising such compounds and their therapeutic and diagnostic use. Digoxin, digitalis and related cardiotonic agents act on the heart in a variety of ways resulting in an increase in the force of contraction (a positive inotropic effect), a slowing in the rate of atrioventricular conduction thereby leading to improved hemodynamics and renal function. Such agents are useful in treating congestive heart disease and atrial fibrillation. Congestive heart disease is characterized by an incomplete emptying of blood from the heart during ventricular contraction, which leads to an enlargement of the heart. When congestive heart disease is treated with cardiac glycosides there is a reduction of heart rate, a more complete filling of the ventricules, and the size of the heart decreases and begins to return to normal. Atrial fibrillation is a condition in which the atria contract much more often then the ventricules, causing the lower heart chambers to be bombarded by impulses. The ventricules respond by weakly and inefficiently contracting. When used to treat atrial fibrillation, cardiac glycosides depress the conduction rate, slowing the rate of ventricular contraction and reestablishing a synchronous and effective heart beat. Web site: http://www.delphion.com/details?pn=US06130211__

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Treatment of fatigue syndrome Inventor(s): Snorrason; Ernir (Stigahlid 80, 105 Reykjavik, IS) Assignee(s): None Reported Patent Number: 5,312,817 Date filed: May 14, 1992 Abstract: The use of a pharmaceutically acceptable cholinesterase inhibitor or a prodrug therefor for the treatment of fatigue syndromes, including chronic fatigue syndrome, post-infectious fatigue syndromes, fatigue syndromes associated with human immunodeficiency virus (HIV) infection or with preeclampsia. The acetyl cholinesterase is preferably one that acts substantially selectively at nicotinic receptor sites, and which has selectivity for acetyl cholinesterase as opposed to butyryl cholinesterase. Compounds of the invention include galanthamine and galanthamine derivatives. Excerpt(s): The present invention relates to the use of pharmaceutically acceptable acetylcholinesterase inhibitors for the preparation of a pharmaceutical composition for treatment of fatigue syndromes, particularly a fatigue syndrome, such as Chronic Fatigue Syndrome (CFS), Post-infectious Fatigue Syndrome, fatigue associated with human immunodeficiency virus infection and related syndromes such as fatigue associated with pre-eclampsia. Preferably, the cholinesterase inhibitors are selected from a group of nicotinic acetylcholinesterase inhibitors such as galanthamine-hydrobromide, which are able to cross the blood brain barrier in humans. Fatigue syndrome designates a condition where fatigue (or synonyme thereof including tiredness and weariness) is considered to be the principal symptom of uncertain cause, i.e. that no recognized underlying disease causes the fatigue. Fatigue is commonly reported as having two aspects, namely mental fatigue and physical fatigue, where mental fatigue is a subjective sensation characterized by lack of motivation and of alertness and physical fatigue is the feeling as lack of energy of strength and is often felt in the muscles. To be regarded as a symptom, fatigue must be complained of, and should affect the person's functioning and be disproportionate to exertion. Furthermore, it should represent a clear change from a previous state and be persistent, or, if intermittent, should be present more than 50% of the time. Web site: http://www.delphion.com/details?pn=US05312817__

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Treatment of preeclampsia and preterm labor with combination of progestational agent and a nitric oxide synthase substrate and/or donor Inventor(s): Bukowski; Radoslaw (Berlin, DE), Chwalisz; Krzysztof (Berlin, DE), Garfield; Robert E. (Friendswood, TX), Yallampal Li; Chandra (Houston, TX) Assignee(s): Schering Aktiengesellschaft (de), The University of Texas (austin, Tx) Patent Number: 5,895,783 Date filed: July 16, 1993 Abstract: Preeclampsia and preterm labor in a pregnant female mammal are treated by administering thereto a combination of a progestin and a nitric oxide synthase substrate, a nitric oxide donor or both, optionally in further combination with one or more of a cyclooxygenase inhibitor, a PGI.sub.2 -mimetic, a thromboxane (TXA.sub.2) inhibitor, a compound possessing TXA.sub.2 -agonistic and TXA.sub.2 -inhibiting properties, a

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compound possessing TXA.sub.2 -antagonistic and PGI.sub.2 -memetic activities, and a TXA.sub.2 antagonist. Excerpt(s): This invention relates to a method for the treatment of preeclampsia and of preterm labor with the combination of a progestational agent and a nitric oxide synthase substrate, a nitric oxide donor or both, alone or in further combination with one or more of a cyclooxygenase inhibitor, a PGI.sub.2 -mimetic, a thromboxane (TXA.sub.2) inhibitor, A compound possessing TXA.sub.2 -agonistic and TXA.sub.2 -inhibiting properties, a compound possessing TXA.sub.2 antagonistic and PGI.sub.2 -memetic activities, and a TXA.sub.2 antagonist, and to pharmaceutical compositions comprising such a combination. Preeclampsia, toxemia or eclampsia of pregnancy can be a significant health problem during pregnancy and they are the leading causes of fetal growth retardation, fetal mortality and morbidity, premature birth and maternal mortality. The etiology of the disease is largely unknown and effective therapy is not available. Preeclampsia of pregnancy is characterized by a triad of hypertension, pathological edema and proteinuria. This disease affects 6 to 10% of all pregnancies. Recently, nitric oxide has been shown to be endothelium derived relaxing factor (EDRF) from the endothelium of blood vessels. Nitric oxide is considered to be a major mediator in the control of vascular reactivity. Nitric oxide is synthesized from L-arginine by nitric oxide synthase located in endothelial cells. Nitric Oxide can also be generated by application of various nitric oxide donors such as sodium nitroprusside, nitroglycerin, glyceryl trinitrite, SIN-1, isosorbid mononitrite, isosorbid dinitrite, etc. Web site: http://www.delphion.com/details?pn=US05895783__ •

Treatment or prevention of preeclampsia, eclampsia with calcitonin gene related peptide, CGRP analog, progestational agent, nitric oxide source, and cyclooxygenase inhibitor Inventor(s): Wimalawansa; Sunil J. (Friendswood, TX), Yallampalli; Chandrasekhar (Houston, TX) Assignee(s): Board of Regents, the University of Texas System (austin, Tx) Patent Number: 5,910,482 Date filed: March 19, 1996 Abstract: The present invention provides a method for counteracting preeclampsia, eclampsia of pregnancy and preterm labor in a pregnant female mammal treated by administering thereto calcitonin gene-related peptide (CGRP) or its analogues including CGRP/adrenomedullin or their peptide or receptor-based analogues, or in combination with a progestin, and with or without a nitric oxide substrate, or a nitric oxide donor or both, optionally in further combination with one or more of a cyclooxygenase inhibitor, a PGI.sub.2 -mimetic, a thromboxane (TXA.sub.2) inhibitor, a compound possessing TXA.sub.2 -agonistic, and TXA.sub.2 -inhibiting properties, a compound possessing TXA.sub.2 -antagonistic and PGI.sub.2 -mimetic activities, and a TXA.sub.2 antagonist. CGRP, progesterone and some of the nitric oxide substrate and donor compounds are naturally occurring compounds. As such these agents do not have the same toxicity and allergy problems as the foreign substances that are currently used for similar purposes. During pregnancy uterine blood vessels and the uterine muscles are particularly sensitive to CGRP as well as nitric oxide. Therefore, one could administer a very small quantities of these drugs (i.e., intravenously, subcutaneous, or Implants), the effects are then seen mainly in the uterine muscle and blood vessels, namely increase the blood supply to the uteroplacental unit (hence nutrients and oxygen supply to the fetus

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through the improved placental circulation), and uterine muscular relaxation thereby ameliorate the signs and symptoms of preeclampsia, and eclampsia, and prevent preterm labor. At these dosages, virtually no systemic effects are induced, making CGRP (which is an endogenous natural product present in human body) extremely safe and effective. Excerpt(s): This invention relates to a method for the treatment of preeclampsia and of preterm labor with calcitonin gene-related peptide (CGRP) or CGRP/CGRP receptorbased analogue and combinations with a progestational agent (with or without a nitric oxide synthase substrate such as L-arginine, a nitric oxide donor or both), alone or in further combination with one or more of a cyclooxygenase inhibitor, a PGI.sub.2 mimetic, a thromboxane (TXA.sub.2) inhibitor, A compound possessing TXA.sub.2 agonistic and TXA.sub.2 -inhibiting properties, a compound possessing TXA.sub.2 antagonistic and PGI.sub.2 -mimetic activities, and a TXA.sub.2 antagonist, and to pharmaceutical compositions comprising such a combination. Preeclampsia, toxemia, or eclampsia of pregnancy can be significant health problems during pregnancy and are the leading causes of fetal growth retardation, fetal mortality, premature birth, and maternal mortality. The etiology of this pathology is largely unknown and effective therapy is not available. Preeclampsia of pregnancy is characterized by a triad of hypertension, pathological edema and proteinuria. This disease affects 6 to 10% of all pregnancies. Nitric oxide (NO) has been shown to be the endothelium derived relaxing factor (EDRF) generated from the endothelium of blood vessels. Nitric oxide is a major mediator in the control of vascular relaxation. Nitric oxide is synthesized from Larginine by nitric oxide synthase located in endothelial and other cells. Nitric oxide can also be generated by application of various nitric oxide donors such as sodium nitroprusside, nitroglycerin, SIN-1, isosorbid mononitrate, isosorbid dinitrate, and the like. Web site: http://www.delphion.com/details?pn=US05910482__ •

Use of fibronectin having a variable included type III repeat sequence as a marker for toxemia in pregnancy Inventor(s): Lockwood; Charles J. (210 Hobart, Hingham, MA 02043), Peters; John H. (3290-58 Via Marin, La Jolla, CA 92037) Assignee(s): None Reported Patent Number: 5,108,898 Date filed: January 18, 1989 Abstract: The elevation of human cellular fibronectin monomers having a variably included Type III repeat in a pregnant woman, as early as the first trimester, has been found to precede the onset of the clinical manifestations of toxemia and correlate with the severity of the disease state. The present invention provides a means of detection for and the monitoring of the toxemias of pregnancy, particularly preeclampsia and eclampsia, by the use a marker, human fibronectin having a variably included Type III repeat sequence, ED1 or ED2. Excerpt(s): The present invention relates to a method for the detection and monitoring of toxemia, particularly preeclampsia, in a pregnant woman by use of a marker, human fibronectin having a variably included Type III repeat (ED1+Fn or ED2+Fn). More specifically, it relates to a method for the determination of the concentration of the fibronectin in a body sample from a pregnant woman, which concentration has been

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found to correlate with the disease state. Preeclampsia and eclampsia are toxemias associated with pregnancy. Preeclampsia is classically defined as the triad of hypertension, proteinuria, and edema associated with pregnancy. Other manifestations of preeclampsia are vascular prostenoid and platelet derangements, vasospasm, uteroplacental vascular lesions, and in severe cases, convulsions and coma (eclampsia). Walsh et al., Am. J. Obstet. Gynecol., 151:100-15 (1985); Goodman et al., Am. J. Obstet. Gynecol., 142:817-22 (1982); Kitzmiller et al., Am. J. Obstet. Gynecol., 118:362-8 (1974); Giles et al., Br. J. Obstet. Gynecol., 88:1115-19(1981); and Gant et al., J. Clin Invest., 52:2682-89 (1973). Toxemia occurs more often in women pregnant for the first time and in those over the age of thirty-five. Toxemia is especially frequent in patients with prior renal and vascular disease. A significant percentage of pregnant women with preexisting hypertension are also likely to have a toxemic episode. Web site: http://www.delphion.com/details?pn=US05108898__ •

Use of L-arginine in the treatment of hypertension and other vascular disorders Inventor(s): Abraham; Nader G. (143 Charter Cir., Ossining, NY 10562), Levere; Richard D. (5 Seymour Pl. W., Armonk, NY 10504), Martasek; Pavel (60 Hillcrest Rd., Hartsdale, NY 10530), Schwartzman; Michel L. (415 Old Country Rd., Elmsford, NY 10523) Assignee(s): None Reported Patent Number: 5,217,997 Date filed: April 24, 1992 Abstract: A method for treating a high vascular resistance disorder in a mammal by administering to a mammalian organism in need of such treatment a sufficient amount of L-arginine or pharmaceutically acceptable salt thereof to treat a high vascular resistance disorder. The L-arginine is typically administered in the range of about 1 mg to 1500 mg per day. High vascular resistance disorders include hypertension, primary or secondary vasospasm, angina pectoris, cerebral ischemia and preeclampsia. Also disclosed is a method for preventing or treating bronchial asthma in a mammal by administering to a mammalian organism in need of such prevention or treatment a sufficient amount of L-arginine to prevent or treat bronchial asthma. Excerpt(s): The present invention relates to a method of using L-arginine or pharmaceutically acceptable salts thereof in the treatment of hypertension and other high vascular resistance disorders. High vascular resistance disorders include primary or secondary vasospasm, angina pectoris, cerebral ischemia and preeclampsia of pregnancy. The present invention is also concerned with a method of preventing or treating bronchial asthma using L-arginine or a pharmaceutically acceptable salt thereof. The disposition of hypertensive patients to develop vascular disease which leads to increased mortality from stroke and myocardial infarction is a major problem in the western world. The development of hypertension can relate to abnormalities in the production or activities of vasoactive substances. Alteration in the responsiveness to both vasoconstrictors and vasodilators has been well documented in spontaneous hypertensive rats, the most frequently used animal model for the study of human essential hypertension. Thus, an increase in the contractile response of vascular smooth muscle of spontaneous hypertensive rats to vasoconstrictors such as norepinephrine as noted by Lais et al, "Mechanism of Vascular Hyperresponsiveness in the Spontaneously Hypertensive Rat", Cir. Res., 36/37: Suppl. 1, I-216 to I-222 (1975), and a decrease in the relaxant response to vasodilators such as acetylcholine, nitrovasodilators, prostaglandin and other arachidonic acid metabolites as noted by Pinto et al, "Arachidonic Acid-

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Induced Endothelial-Dependent Relaxations of Canine Coronary Arteries: Contribution of a Cytochrome P-450-Dependent Pathway", J Pharmacol. Exp. Therap., 240, 856-863 (1987) and Luscher et al, "Endothelium-Dependent Responses in Carotid and Renal Arteries of Normotensive and Hypertensive Rats", Hypertension, 11, 573-578 (1988), may contribute overall to the development of high blood pressure. It has also been demonstrated that cytochrome P-450-arachidonate metabolism is increased in the kidney of young spontaneous hypertensive rats and a selective reduction in the formation of these metabolites via induction of heme degradation with SnCl.sub.2 caused a marked decrease in blood pressure as noted by Sacerdoti et al, "Treatment with Tin Prevents the Development of Hypertension in Spontaneously Hypertensive Rats", Science, 243, 388-390 (1989). Martasek et al, "Heme Arginate Lowers Blood Pressure in Spontaneous Hypertensive Rats", Clin. Res., 37, 553A (1989) also noted that other heme oxygenase inducers such as heme arginate have been demonstrated to be an inducer of heme oxygenase causing reduction of renal P-450 and a decrease in blood pressure in young spontaneous hypertensive rats. The blood pressure lowering effect of heme arginate could be attributed to the heme component. The heme effect may be due to an induction of heme oxygenase, since it is blocked by an inhibitor of heme oxygenase. Web site: http://www.delphion.com/details?pn=US05217997__

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

Method for controlling preeclampsia and eclampsia Inventor(s): Adair, Charles David; (Signal Mountain, TN) Correspondence: Husch & Eppenberger, Llc; 190 Carondelet Plaza; Suite 600; ST. Louis; MO; 63105-3441; US Patent Application Number: 20040018201 Date filed: July 25, 2002 Abstract: A method of controlling preeclampsia includes the steps of providing a supply of digoxin immune Fab (ovine), calculating an appropriate dosage of the digoxin immune Fab (ovine) based on a patient's weight and using an assumed endogenous digitalis-like factor level, administering the appropriate dosage as an intravenous bolus, and repeating the administration of the appropriate dosage on a fixed schedule. Excerpt(s): The present invention relates generally to the field of medicine and, more particularly, to a method of controlling preeclampsia and eclampsia. Preeclampsia is a rapidly progressive condition occurring during pregnancy characterized by high blood pressure, swelling and protein in the urine. It is specifically defined as the presence of hypertension or pregnancy-induced hypertension ("PIH") accompanied by proteinuria, edema, or both after 20 weeks gestation. Preeclampsia occurs in 5 to 10 percent of all pregnancies and is most common in first-time pregnancies or in first pregnancies with a new partner or husband. Typically, preeclampsia occurs in the late second or third

10

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

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trimesters of pregnancy. Complications of preeclampsia include eclamptic seizures, hemolysis, elevated liver function tests, low platelet count (HELLP) syndrome, hepatic rupture, DIC pulmonary edema, acute renal failure, placental abruption, intrauterine fetal demise (IUFD), cerebral hemorrhage, cortical blindness, and retinal detachment. Preeclampsia causes vasospasm, which constricts and damages the smooth lining of the blood vessels. This leads to the accumulation of platelets in the damaged blood vessels, which form small clots along the blood vessel wall and further narrow the blood vessel. This damage to blood vessels can also lead to edema, including cerebral edema. Vasospasm can occur throughout the body, damaging the heart, kidneys and liver. Vasospasm can also develop in the placenta, decreasing the blood supply to the fetus. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

METHOD OF TREATMENT AND PREVENTION OF NITRIC OXIDE DEFICIENCYRELATED DISORDERS WITH CITRULLINE AND CITRULLINE DERIVATIVES Inventor(s): CHWALISZ, KRISTOF; (BERLIN, DE), GARFIELD, ROBERT E.; (FRIENDSWOOD, TX), SHI, SHAO-QUING; (GALVESTON, TX) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20010056068 Date filed: March 4, 1998 Abstract: The invention provides methods for control, management, treatment and prevention of conditions related to nitric oxide deficiency such as hypertension, cardiovascular disease, osteoporosis, diabetes mellitus, preeclampsia HELLP, syndrome and fetal growth retardation; uterine contractility disorders such as preterm labor and dysmenorrhea, cervical dystocia, infertility and early pregnancy loss; male impotence; urinary incontinence; intestinal tract disorders (e.g. altered motility and pyloric stenosis), respiratory system diseases (e.g. asthma, neonatal respiratory distress syndrome, pulmonary hypertension, and adult respiratory distress syndrome); inflammatory diseases (e.g. acute inflammation, resistance to infection, SLE-lupus, anaphylactic reaction, allograft rejection); Alzheimer's disease, stroke, growth hormone disorders, and behavior changes; dermatological conditions such as atopic eczema, topical hair loss, and burn injury; by administering citrulline or a citrulline analogue, optionally in combination with other enhancing or modulating agents, e.g., an estrogenic, partial estrogenic, progestagenic, or androgenic agent, and pharmaceutical preparations for such uses. Excerpt(s): This invention concerns a method and agents for control, management, treatment and prevention of disorders and diseases related to nitric oxide deficiency or those disorders or diseases which can be improved by enhancing endogenous nitric oxide synthesis by providing to a mammal citrulline or a citrulline analogue alone or in combination with other enhancing or modulating agent. This invention relates to nitric oxide dependent disorders and diseases including, hypertension, cardiovascular disease, atherosclerosis, myocardial ischemia, preeclampsia, HELLP (severe preeclampsia (Hemolysis+Elevated Liver enzymes+Low Platelets) syndrome), and fetal growth retardation, osteoporosis, uterine contractility disorders, such as preterm labor and dysmenorrhea, cervical dystocia, male impotence, urinary incontinence, renal arterial stenosis. In addition, this invention relates to a method and agents for treatment of infertility by improving implantation rates or controlling ovulation. Furthermore, this invention relates to a method and agents for hormone replacement therapy (HRT) alone

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or in combination with steroid hormones or other enhancing or modulating agents in females during the menopause to prevent climacteric disorders such as hot flushes, abnormal clotting patterns, urogenital discomfort, increased incidence of cardiovascular diseases, etc., associated with the reduction in ovarian function in middle-aged women. This invention also concerns a method and agents for HRT alone or in combination with steroid hormones or other enhancing or modulating agents in males to prevent cardiovascular disease, osteoporosis and impotence. There are also other potential uses of citrulline or citrulline analogues in those clinical situations in which nitric oxide plays a modulatory role. For example (1) regarding the cardiovascular system: regulation of vascular conductance, regulation of blood flow, regulation of blood pressure, (2) regarding the gastrointestinal tract and pancreas pathology: altered motility, pyloric stenosis, diabetes mellitus, (3) regarding respiratory system: asthma, treatment of premature babies to increase lung function (neonatal respiratory distress syndrome), pulmonary hypertension, adult respiratory distress syndrome, (4) in inflammation: autoimmune and immune diseases, acute inflammation, resistance to infection, SLElupus, anaphylactic reaction, allograft rejection, within the central nervous system: Alzheimer's disease, stroke, growth hormone disorders, behavior changes, (5) in dermatological conditions: atopic eczema, topical hair loss, and burn injury. One of the most exciting recent advances in biology and medicine is the discovery that the diffusible molecule nitric oxide is produced by endothelial cells and that it is involved in the regulation of vascular tone, plate-let aggregation, peripheral nitrergic transmission at smooth muscle, intra-cellular communication in the CNS, and macrophage defense mechanisms following exposure to bacterial products (Furchgott R F, Zawadzki J V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetycholine. Nature 1980; 288:373-376.; Moncada S and Higgs E A. The L-arginine-nitric oxide pathway. New Engl J Med 1993; 329:2002-2012). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods to diagnose a required regulation of trophoblast invasion Inventor(s): Caniggia, Isabella; (Toronto, CA), Lye, Stephen; (Toronto, CA), Post, Martin; (Toronto, CA) Correspondence: Merchant & Gould PC; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20020110833 Date filed: December 20, 2001 Abstract: Methods are provided for the diagnosis and treatment of patients with increased risk of preeclampsia. The methods involve measuring levels of TGF.beta.sub.3, receptors of cytokines of the TG.beta. family, or HIF-1.alpha. Excerpt(s): The invention relates to methods and compositions for diagnosing and treating conditions requiring regulation of trophoblast invasion. During placental development the establishment of fetal-maternal interactions is critical for a successful human pregnancy (1). Abnormalities of placenta formation due to shallow trophoblast invasion have been linked to preeclampsia and fetal growth restriction (2). In contrast, uncontrolled trophoblast invasion and abnormal trophoblast growth are associated with hydatiform mole and choriocarcinoma In the course of placenta formation, chorionic villous cytotrophoblasts undergo two morphologically distinct pathways of differentiation. The vast majority of cytotrophoblasts in both floating and anchoring villi fuse to form the syncyuotrophoblast layer, which permits gas and nutrient exchange for

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the developing embryo. A small percentage of cytotrophoblasts in anchoring villi break through the syncytium, at selected sites, and generate columns of non-polarized cells which migrate into the endometrium. These extravillous trophoblasts (EVT) invade deeply into the uterus reaching the first third of the myometrium at which point they invade the spiral arteries, replacing their endothelium and vascular wall. Invasion peaks at 12 weeks of gestation and rapidly declines thereafter, indicating that, unlike tumour invasion, it is spatially and temporally regulated (3). Trophoblast invasion in the decidua is accompanied by a complex modulation of the synthesis and degradation of extracellular matrix (ECM) proteins and in the expression of adhesion molecules (4-6). Along the invasive pathway, ECM proteins undergo changes in their spatial distribution with loss of laminin and appearance of fibronectin (3, 4). EVT loose the expression of Ecadherins. responsible for cell-cell adhesion between polarized stem cytotrophoblasts, down-regulate.alpha.sub.6.beta.sub.4 integrin, a laminin receptor, and acquire.alpha.sub.5.beta.sub.1 integrin, a fibronectin receptor (7). Once the EVT invade the endometrium they express the.alpha.sub.1.beta.sub.1 integrin, a collagen/laminin receptor. Thus, specific changes in ECM proteins and their receptors are associated with the acquisition of an invasive phenotype by the extravillous trophoblasts (4). Preeclampsia occurs in 5-10% of pregnancies and is the leading cause of death and illness in women during pregnancy. Preeclampsia is also associated with considerable fetal/neonatal complications because of adverse intrauterine conditions and preterm delivery. There is currently no effective pharmacologic treatment for preeclampsia and the only remedy is to remove the placenta (and hence deliver the fetus preterm). Current protocols, including bedrest and antihypertensive drugs, seek to stabilize maternal/fetal condition until delivery is necessitated. It is estimated that around 200,000 children are born preterm in North America due to preeclampsia. Many of these babies will require costly intensive care at birth and if they survive may face a lifetime of chronic illness (e.g. lung disease) or disability (e.g. cerebral palsy, mental handicaps, blindness). These conditions represent a significant impact on subsequent requirements for community health care resources. Therefore, reducing the incidence of preeclampsia and pretern birth would have a tremendous positive impact on health care delivery. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Non-invasive measurement of suprasystolic signals Inventor(s): Sharrock, Nigel E.; (New York, NY) Correspondence: William H Dippert; Reed Smith; 29th Floor; 599 Lexington Avenue; New York; NY; 10022; US Patent Application Number: 20030040675 Date filed: September 13, 2002 Abstract: An apparatus for assessing cardiovascular status of a mammal comprises a system for locally applying a pressure to an artery capable of restricting blood flow through said artery, a wideband external pulse transducer having an output and situated to measure suprasystolic signals proximate to said artery, and a computing device receiving said output for calculating vascular compliance values. The method described is particularly useful for determining cardiac output, assessing whether a pregnant female has preeclampsia or a patient has cardiac insufficiency, or assessing cardiac arrhythmias. Excerpt(s): This invention relates to non-invasive cardiovascular assessment. More particularly, the invention relates to non-invasive assessment of aortic compliance and

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other cardiovascular parameters by analyzing signals recorded with a sensor having a transducer. When the heart pumps, a pressure gradient is generated within the cardiovascular system. This results in pulse pressure waves traveling peripherally from the heart through the arteries. Like any wave, they reflect back off a surface or other change in impedance. Arterial pulse waves reflect back from both the peripheral circulation and from the distal aorta when it becomes less compliant (Murgo, Westerhof et al. 1980; Latham, Westerhof et al. 1985). These reflection waves are identifiable in arterial pressure tracings, but the exact timing and magnitude of the waves are difficult to discern. Nevertheless, they have been the basis of several commercial systems to assess reflectance waves. These systems measure arterial contours using applanation tonometry from the radial artery. The second suprasystolic wave is, in fact, a reflectance wave from the distal abdominal aorta--most likely originating from the bifurcation of the aorta and not from the peripheral circulation as proposed by Blank. This has been verified in human experiments (Murgo, Westerhof et al. 1980; Latham, Westerhof et al. 1985) and in our studies using pulse wave velocity (PWV) measurements. The relative amplitude of the first reflectance wave is therefore a measure of the stiffness, compliance, or elasticity of the abdominal aorta rather than peripheral resistance. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Thromboxane inhibitors, compositions and methods of use Inventor(s): Tejada, Inigo Saenz de; (Madrid, ES) Correspondence: Edward D Grieff; Hale & Dorr Llp; 1455 Pennsylvania Ave, NW; Washington; DC; 20004; US Patent Application Number: 20030050305 Date filed: November 1, 2002 Abstract: The present invention describes methods for treating or preventing sexual dysfunctions in males and females, and for enhancing sexual responses in males and females by administering a therapeutically effective amount of at least one thromboxane inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and/or at least one vasoactive agent. The male or female may preferably be diabetic. The present invention also provides novel compositions comprising at least one thromboxane inhibitor, and, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and, optionally, at least one therapeutic agent, such as, vasoactive agents, nonsteroidal antiinflanmmatory compounds (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, anticoagulants, angiotensin converting enzymes (ACE) inhibitors, angiotensin II receptor antagonists, renin inhibitors, and mixtures thereof. The present invention also provides methods for treating or preventing ischemic heart disorders, myocardial infarction, angina pectoris, stroke, migraine, cerebral hemorrhage, cardiac fatalities, transient ischaemic attacks, complications following organ transplants, coronary artery bypasses, angioplasty, endarterectomy, atherosclerosis, pulmonary embolism, bronchial asthma, bronchitis, pneumonia, circulatory shock of various organs, nephritis, graft rejection, cancerous metastases, pregnancy-induced hypertension, preeclampsia, eclampsia, thrombotic and thromboembolic disorders, intrauterine growth, gastrointestinal disorders, renal diseases and disorders, disorders

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resulting from elevated uric acid levels and dysmenorrhea, and for inhibiting platelet aggregation or platelet adhesion or relaxing smooth muscles. Excerpt(s): This application is a continuation of PCT/US01/16318 filed May 22, 2001, which claims priority to U.S. Provisional Application No. 60/205,536 filed May 22, 2000. The present invention describes methods for treating or preventing sexual dysfunctions in males and females, and for enhancing sexual responses in males and females by administering a therapeutically effective amount of at least one thromboxaiie inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and/or at least one vasoactive agent. The male or female may preferably be diabetic. The present invention also provides novel compositions comprising at least one thromboxane inhibitor, and, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and, optionally, at least one therapeutic agent, such as, vasoactive agents, nonsteroidal antiinflammatory compounds (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, anticoagulaits, angiotensin converting enzymes (ACE) inhibitors, angiotensin II receptor antagonists, renin inhibitors, and mixtures thereof. The present invention also provides methods for treating or preventing ischemic heart disorders, myocardial infarction, angina pectoris, stroke, migraine, cerebral hemorrhage, cardiac fatalities, transient ischaemic attacks, complications following organ transplants, coronary artery bypasses, angioplasty, endarterectomy, atherosclerosis, pulmonary embolism, bronchial asthma, bronchitis, pneumonia, circulatory shock of various organs, nephritis, graft rejection, cancerous metastases, pregnancy-induced hypertension, preeclampsia, eclampsia, thrombotic and thromboembolic disorders, intrauterine growth, gastrointestinal disorders, renal diseases and disorders, disorders resulting from elevated uric acid levels and dysmenorrhea, and for inhibiting platelet aggregation or platelet adhesion or relaxing smooth muscles. Adequate sexual function is a complex interaction of hormonal events and psychosocial relationships. There are four stages to sexual response as described in the International Journal of Gynecology & Obstetrics, 51(3):265277 (1995). The first stage of sexual response is desire. The second stage of sexual response is arousal. Both physical and emotional stimulation may lead to breast and genital vasodilation and clitoral engorgement (vasocongestion). In the female, dilation and engorgement of the blood vessels in the labia and tissue surrounding the vagina produce the "orgasmic platform," an area at the distal third of the vagina where blood becomes sequestered. Localized perivaginal swelling and vaginal lubrication make up the changes in this stage of sexual response. Subsequently, ballooning of the proximal portion of the vagina and elevation of the uterus occurs. In the male, vasodilation of the cavernosal arteries and closure of the venous channels that drain the penis produce an erection. The third stage of sexual response is orgasm, while the fourth stage is resolution. Interruption or absence of any of the stages of the sexual response cycle can result in sexual dysfunction. One study found that 35% of males and 42% of females reported some form of sexual dysfunction. Read et al, J. Public Health Med., 19(4):387391 (1997). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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•

Treatment of eclampsia and preeclampsia Inventor(s): Johnson, Richard J.; (Seattle, WA), Schreiner, George F.; (Los Altos Hills, CA) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20030220262 Date filed: April 16, 2003 Abstract: The invention concerns the prevention and treatment of endothelial injury and the injury of tissues containing injured blood vessels by administration of angiogenic factors, such as vascular endothelial cell growth factor (VEGF). Excerpt(s): This application is a continuation of co-pending U.S. patent application Ser. No. 09/392,931, filed Sep. 9, 1999, which is a non-provisional application of provisional application Serial No. 60/099,694 filed on Sep. 9, 1998, of provisional application Seral No. 60/126,406 filed Mar. 26, 1999 and of provisional application Serial No. 60/126,615 filed Mar. 27, 1999, the disclosures of which are hereby incorporated by reference and to which application priority is claimed under 35 USC 119. The present invention concerns the treatment of endothelial cell injury. More particularly, the invention concerns the treatment of the endothelium of blood vessels and tissues containing injured blood vessels. The invention specifically concerns the prevention or repair of injury to blood vessels, and, in particular, the treatment of disorders cbaracterized by microvascular angiopathies, such as thrombotic microangiopathies (TMA). The invention also relates to the treatment of kidney diseases associated with injury to, or atrophy of, the vasculature of the glomerulus and interstitium, and the treatment of hypoxia or hypercapnia or fibrosis arising from injury to the endothelium of the lungs. Acute injuries to smaller blood vessels and subsequent dysfunction of the tissue in which the injured blood vessels are located (microvascular angiopathies) are a common feature of the pathology of a variety of diseases of various organs, such as kidney, heart, and lungs. The injury is often associated with endothelial cell injury or death and the presence of products of coagulation or thrombosis. The agent of injury may, for example, be a toxin, an immune factor, an infectious agent, a metabolic or physiological stress, or a component of the humoral or cellular immune system, or may be as of yet unidentified. A subgroup of such diseases is unified by the presence of thrombotic microangiopathies (TMA), and is characterized clinically by non-immune hemolytic anemia, thrombocytopenia, and/or renal failure. The most common cause of TMA is the hemolytic uremic syndrome (HUS), a disease that more frequently occurs in childhood, where it is the most common cause of acute renal failure, but also affects adults where more severe clinical course is often observed. Although the pathogenesis of HUS has not been fully elucidated, it is widely accepted that the majority of these cases are associated with enteric infection with the verotoxin producing strain, E. coli O157. Verotoxins produced by E. coli induce glomerular endothelial cell (GEN) injury and generate renal thrombotic microangiopathy in most cases of epidemic HUS (Boyce et al., N. Engl. J. Med. 333:364-368 (1995)). Some patients, especially adults, may have a relative lack of renal involvement and are sometimes classified as having thrombotic thrombocytopenic purpura (TTP). However, thrombotic microangiopathies may also occur as a complication of pregnancy (eclampsia), with malignant hypertension following radiation to the kidney, after transplantation (often secondary to cyclosporine or FK506 treatment), with cancer chemotherapies (especially mitomycin C), with certain infections (e.g., Shigella or HIV), in association with systemic lupus or the antiphospholipid syndrome, or may be idiopathic or familial. Experimental data suggest that endothelial

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cell injury is a common feature in the pathogenesis of HUS/TTP. See, e.g. Kaplan et al., Pediatr. Nephrol. 4:276 (1990). Endothelial cell injury triggers a cascade of subsequent events, including local intravascular coagulation, fibrin deposition, and platelet activation and aggregation. The mechanisms that mediate these events are not well understood. In the case of verotoxin-mediated HUS, injury to the endothelium leads to detachment and death, with local platelet activation and consumption, fibrin deposition and microangiopathic hemolysis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Vascular reinforcement device and method Inventor(s): Adams, John M.; (Sammamish, WA), Fitzsimmons, William James; (Bellevue, WA), Reuter, David G.; (Bothell, WA) Correspondence: Graybeal, Jackson, Haley Llp; 155 - 108th Avenue NE; Suite 350; Bellevue; WA; 98004-5901; US Patent Application Number: 20030055486 Date filed: September 19, 2001 Abstract: A vascular reinforcement device and method reduces increased vascular pressure of a vein in the presence of forces applied externally to the vein. The device is arranged to continuously overlie of a vein and has a longitudinal dimension and a crosssectional dimension. The longitudinal dimension is greater than the cross-sectional dimension and is flexible while the cross-sectional dimension of the device is resistant to change. The device is deployed so as to overlie a wall of the vein. The device and method find particular advantageous application for treating preeclampsia or hypertension associated with obesity. Excerpt(s): The present invention generally relates to a device and method for reinforcing a vein when exposed to external forces. The present invention more particularly relates to a device and method for reinforcing a renal vein for treating hypertension associated with, for example, obesity or treating preeclampsia. Preeclampsia is defined as pregnancy induced hypertension associated with either proteinuria (an excess of serum proteins in the urine) and/or edema. It occurs in five to ten percent of pregnancies, typically after the twentieth week of gestation. Risk factors include multiple gestation pregnancies and first time pregnancies. Preeclampsia can progress to eclampsia, with cerebral symptoms leading to convulsions. The condition is associated with systemic vasospasm wherein arteries throughout the body narrow. This can lead to multi-organ system dysfunction wherein many organs of the body, including the kidneys, brain, eyes, liver, etc., are unable to function normally because of altered blood flow and increased blood pressure. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with preeclampsia, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps:

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Under “Issued Patents,” click “Quick Search.” Then, type “preeclampsia” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on preeclampsia. You can also use this procedure to view pending patent applications concerning preeclampsia. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 6. BOOKS ON PREECLAMPSIA Overview This chapter provides bibliographic book references relating to preeclampsia. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on preeclampsia include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

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

Molecular Mechanisms of Preeclampsia (Medical Intelligence Unit Series) by Bradley W. Arbogast, Robert N. Taylor; ISBN: 0412114712; http://www.amazon.com/exec/obidos/ASIN/0412114712/icongroupinterna

Chapters on Preeclampsia In order to find chapters that specifically relate to preeclampsia, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and preeclampsia using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “preeclampsia” (or

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synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on preeclampsia: •

Preeclampsia in Pregnant Women with Chronic Hypertension and Renal Disease Source: Belfort, M.A.; Thornton, S.; Saade, G.R., eds. Hypertension in Pregnancy. Monticello, NY: Marcel Dekker, Inc. 2003. p.117-139. Contact: Available from Marcel Dekker, Inc. P.O. Box 5005, Monticello, NY 12701-5185. (800) 228-1160 or (212) 696-9000. Fax (845) 796-1772. E-mail: [email protected]. Website: www.dekker.com. ISBN: 082470827X. PRICE: $000.00 plus shipping and handling. Summary: Preeclampsia (acute hypertension, proteinuria, and edema) is an important cause of maternal and fetal morbidity (complications) and mortality (death), complicating 5 to 10 percent of all pregnancies. This chapter on preeclampsia in pregnant women with chronic hypertension and renal (kidney) disease is from a textbook on hypertension (high blood pressure) in pregnancy. The authors note that there are major diagnostic difficulties in distinguishing preeclampsia, chronic hypertension, renal disease, and combinations of these separate entities. The chapter focuses on defining hypertension in pregnancy in relation to preexisting pathology, identifying the pitfalls in the detection and diagnosis of preeclampsia in women with chronic hypertension or renal disease (or both), and highlighting the controversies surrounding the prenatal care and obstetric problems in these women. 1 figure. 7 tables. 104 references.

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CHAPTER 7. PERIODICALS AND NEWS ON PREECLAMPSIA Overview In this chapter, we suggest a number of news sources and present various periodicals that cover preeclampsia.

News Services and Press Releases One of the simplest ways of tracking press releases on preeclampsia is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “preeclampsia” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to preeclampsia. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “preeclampsia” (or synonyms). The following was recently listed in this archive for preeclampsia: •

Upper airway narrowing seen in women with preeclampsia Source: Reuters Medical News Date: January 27, 2003

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Activated protein C proposed as treatment for severe preeclampsia Source: Reuters Medical News Date: October 03, 2002

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Ambulatory blood pressure monitoring can identify preeclampsia risk Source: Reuters Medical News Date: September 26, 2002

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Iron supplements deemed unwise in women at risk for preeclampsia Source: Reuters Medical News Date: September 04, 2002

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Lean umbilical cord by ultrasound may predict early-onset preeclampsia Source: Reuters Medical News Date: August 15, 2002

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Possible biomarkers for risk of preeclampsia identified Source: Reuters Medical News Date: July 25, 2002

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Vitamin C deficiency may contribute to preeclampsia Source: Reuters Medical News Date: June 11, 2002

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Condom use linked to risk of preeclampsia Source: Reuters Medical News Date: May 09, 2002

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Working moms-to-be at higher risk of preeclampsia Source: Reuters Health eLine Date: April 18, 2002

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Increased risk for preeclampsia tied to working during pregnancy Source: Reuters Medical News Date: April 17, 2002

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Insulin resistance in early pregnancy predicts preeclampsia Source: Reuters Medical News Date: April 04, 2002

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Dysregulation of placental syncytin may contribute to preeclampsia Source: Reuters Medical News Date: March 11, 2002

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Assisted reproduction linked to increased preeclampsia risk Source: Reuters Medical News Date: March 05, 2002

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Increased periostin levels associated with preeclampsia Source: Reuters Medical News Date: February 14, 2002

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Exercise may lower preeclampsia risk Source: Reuters Medical News Date: January 21, 2002

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Previous pregnancy's protective effect against preeclampsia wanes over time Source: Reuters Medical News Date: January 02, 2002

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Preeclampsia augments obstructive sleep apnea Source: Reuters Medical News Date: December 17, 2001

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Aspirin can prevent preeclampsia in women with abnormal uterine artery Doppler Source: Reuters Medical News Date: November 13, 2001

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Risk of preeclampsia lowest in August Source: Reuters Medical News Date: November 12, 2001

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High intakes of energy, sucrose, fatty acids increase preeclampsia risk Source: Reuters Medical News Date: September 07, 2001

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Study sheds light on preeclampsia etiology Source: Reuters Medical News Date: June 08, 2001

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Study sheds light on mystery behind preeclampsia Source: Reuters Health eLine Date: June 07, 2001

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Insulin-like growth factor, binding protein may be markers of preeclampsia Source: Reuters Medical News Date: April 12, 2001

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Elevated pulse pressure in early pregnancy linked to preeclampsia Source: Reuters Medical News Date: April 12, 2001

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Polymorphism of epoxide hydrolase linked to preeclampsia Source: Reuters Medical News Date: April 03, 2001

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Gene variant linked to preeclampsia risk Source: Reuters Health eLine Date: April 03, 2001

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Black women at greater risk from preeclampsia Source: Reuters Health eLine Date: April 02, 2001

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Blood vessel defect found in preeclampsia Source: Reuters Health eLine Date: March 27, 2001

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Fathers contribute to risk of preeclampsia Source: Reuters Medical News Date: March 21, 2001

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Aspirin may prevent preeclampsia in pregnancy Source: Reuters Health eLine Date: February 09, 2001

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Platelet alteration may point to preeclampsia severity Source: Reuters Medical News Date: February 05, 2001

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Early severe preeclampsia and proteinuria predict renal disease Source: Reuters Medical News Date: December 26, 2000

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Low birthweight predicts risk of preeclampsia in future pregnancies Source: Reuters Medical News Date: November 01, 2000

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Preeclampsia linked to low birth weight babies Source: Reuters Health eLine Date: October 31, 2000

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Abnormal angiotensin-(1-7) levels implicated in preeclampsia Source: Reuters Industry Breifing Date: October 26, 2000

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Circadian BP predicts gestational hypertension, preeclampsia Source: Reuters Medical News Date: August 23, 2000

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Preeclampsia, gestational hypertension linked to large-for-gestational-age babies Source: Reuters Medical News Date: August 21, 2000

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Vitamin B2 deficiency may be linked to preeclampsia Source: Reuters Health eLine Date: July 28, 2000

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Riboflavin deficiency a possible risk factor for preeclampsia Source: Reuters Medical News Date: July 21, 2000

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Depression raises risk of preeclampsia Source: Reuters Health eLine Date: March 31, 2000

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Changing paternity alters preeclampsia risk Source: Reuters Medical News Date: January 04, 2000

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Pregnancy-induced hypertension in nulliparas increases morbidity but not mortality Source: Reuters Medical News Date: January 03, 2000

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Preeclampsia linked with increased cancer risk Source: Reuters Health eLine Date: March 05, 2004

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Low selenium levels linked to preeclampsia Source: Reuters Medical News Date: December 16, 2003

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ICAM-1 levels may explain heart disease risk in women with prior preeclampsia Source: Reuters Medical News Date: July 17, 2003

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Exercise prior to, during early pregnancy reduces risk of preeclampsia Source: Reuters Medical News Date: June 10, 2003

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Low-dose aspirin may prevent preeclampsia in high-risk women Source: Reuters Industry Breifing Date: June 03, 2003

Periodicals and News

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ACE DD genotype may increase the risk of recurrent preeclampsia Source: Reuters Medical News Date: April 14, 2003

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Parental history of hypertension, diabetes tied to preeclampsia risk Source: Reuters Medical News Date: March 14, 2003

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Potential targets for preeclampsia therapy revealed Source: Reuters Medical News Date: March 04, 2003

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The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “preeclampsia” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “preeclampsia” (or synonyms). If you know the name of a company that is relevant to preeclampsia, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/.

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

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

Systemic Lupus Erythematosus: Women's Health Issues Source: Bulletin on the Rheumatic Diseases. 49(8): 1-3. 2001. Contact: Available from Arthritis Foundation. 1330 West Peachtree Street, Atlanta, GA 30309. (404) 872-7100. Fax (404) 872-9559. Summary: This newsletter article provides health professionals with information on systemic lupus erythematosus (SLE) in relation to issues specific to women's health, including pregnancy, contraception, fertility, sexuality, management of menopause, osteoporosis, coronary artery disease, and chronic fatigue. Pregnancy is high risk for both the woman with SLE and her fetus. Pregnant women with SLE are at higher risk for both preeclampsia and premature membrane rupture. Fetal problems associated with SLE include preterm birth, intrauterine growth retardation, placental insufficiency, pregnancy loss, and congenital heart block. Although barrier contraception is the safest method in SLE, other options include oral contraceptives, the intrauterine device, and tubal ligation. Fertility is usually not a problem in women with SLE, but some SLE treatment regimens, such as monthly pulse intravenous cyclophosphamide, put fertility at risk. Women with SLE may face sexuality issues because their body image is affected both by the disease and by its treatment. More women with SLE are reaching menopause, and studies have suggested that estrogen replacement therapy does not increase SLE flares. Both premenopausal and postmenopausal women with SLE are at risk for osteoporosis because of the use of prednisone. The major cause of death in women with SLE is cardiovascular disease, so they should be considered as candidates for screening for early atherosclerosis. Chronic fatigue is a major complaint of women with SLE. 4 tables and 18 references.

•

Lupus and Pregnancy: Can They Go Together? Source: Lupus News. 20(5): 8-11. Winter 2000. Contact: Available from Lupus Foundation of America. 1300 Piccard Drive, Suite 200, Rockville, MD 20850-4303. (800) 558-0121 or (301) 670-9292. Fax (301) 670-9486. Website: www.lupus.org/lupus.

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Summary: This newsletter article uses a question and answer format to provide women who have lupus with information on managing a pregnancy. Lupus is more common among women than men, and it is often diagnosed during the childbearing years. Therefore, women with lupus are faced with the difficult decision of whether or not to become pregnant. Most women who have lupus can have successful pregnancies. One of the most common questions women who have lupus ask is how pregnancy will affect their lupus. Although recent studies show that lupus flares are common in pregnancy, most are mild or moderate and are manageable. Women who have lupus nephritis appear to be at more risk during pregnancy than women without kidney disease, and recent studies support this observation. However, most women with lupus nephritis, particularly women with well controlled lupus nephritis, have a satisfactory pregnancy outcome. Another issue of concern to women with lupus is how it will affect them and their baby during pregnancy. Pregnancy loss is one complication. Women who have antiphospholipid syndrome are at particular risk for pregnancy loss. Preeclampsia is a common complication in all pregnancies, but some patients with lupus are at greater risk for this complication than others, including women using steroids, women with kidney damage, and women with lupus nephritis. Other complications that women or their baby may experience include preterm birth, fetal growth impairment, and neonatal lupus erythematosus. Women with lupus may also be concerned about the effect of the drugs used to treat lupus on their pregnancy. Drugs that may safely be used to treat lupus during pregnancy are glucocorticoids. A final issue of concern to women with lupus is prenatal care. The article offers guidelines for prepregnancy, prenatal, and postnatal care and care during labor and delivery.

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

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CHAPTER 8. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

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

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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to preeclampsia: Headache Medicines, Ergot Derivative-Containing •

Systemic - U.S. Brands: Cafergot; Cafertine; Cafetrate; D.H.E. 45; Ercaf; ErgoCaff; Ergomar; Ergostat; Gotamine; Migergot; Wigraine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202216.html

Oxytocin •

Systemic - U.S. Brands: Pitocin; Syntocinon http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202434.html

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

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

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APPENDICES

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

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute11: •

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

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

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

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

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

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

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

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

11

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:13 •

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

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

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

•

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

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

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

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

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

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

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

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

12

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 13 See http://www.nlm.nih.gov/databases/databases.html.

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

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

The NLM Gateway14 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “preeclampsia” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 10089 109 69 10 39 10316

HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.18 Simply search by “preeclampsia” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

14

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

15

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18

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

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

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Coffee Break: Tutorials for Biologists19 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

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

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

•

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

The Genome Project and Preeclampsia In the following section, we will discuss databases and references which relate to the Genome Project and preeclampsia. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).22 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 19 Adapted 20

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

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 21 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 22 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “preeclampsia” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for preeclampsia: •

Preeclampsia/eclampsia 1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=189800 Genes and Disease (NCBI - Map)

The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •

Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html

•

Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

•

Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

•

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

•

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

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•

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

•

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

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

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

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Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

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Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

•

NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

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Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

•

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

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PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

•

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

•

PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

•

Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then

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select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “preeclampsia” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database23 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database24 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “preeclampsia” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

23

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

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on preeclampsia can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to preeclampsia. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to preeclampsia. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “preeclampsia”:

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Guides on preeclampsia Preeclampsia http://www.nlm.nih.gov/medlineplus/preeclampsia.html

•

Other guides Diabetes and Pregnancy http://www.nlm.nih.gov/medlineplus/diabetesandpregnancy.html High Risk Pregnancy http://www.nlm.nih.gov/medlineplus/highriskpregnancy.html Pregnancy Loss http://www.nlm.nih.gov/medlineplus/pregnancyloss.html Prenatal Care http://www.nlm.nih.gov/medlineplus/prenatalcare.html Twins, Triplets, Multiple Births http://www.nlm.nih.gov/medlineplus/twinstripletsmultiplebirths.html

Within the health topic page dedicated to preeclampsia, the following was listed: •

General/Overviews Hypertension and Pregnancy: Careful Monitoring Is Crucial Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=PR00052 Preeclampsia Source: American Academy of Family Physicians http://familydoctor.org/064.xml Preeclampsia (High Blood Pressure) Source: March of Dimes Birth Defects Foundation http://www.marchofdimes.com/pnhec/188_1054.asp

•

Diagnosis/Symptoms Urinalysis Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/urinalysis/test.html

•

Treatment Low-dose Aspirin Lowers Incidence of Hypertension in Pregnancy Source: American College of Obstetricians and Gynecologists http://www.medem.com/MedLB/article_detaillb.cfm?article_ID=ZZZ8JM1SETC& sub_cat=2005

Patient Resources

•

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Coping Surviving Bed Rest Source: Nemours Foundation http://kidshealth.org/parent/pregnancy_newborn/pregnancy/bed_rest.html

•

Specific Conditions/Aspects Is Preeclampsia Influenced by Fetal Sex? Source: American College of Obstetricians and Gynecologists http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZ4G38II5D&s ub_cat=2009

•

Children Infants of Mothers with Hypertension or Pre-eclampsia Source: University of Wisconsin http://www.pediatrics.wisc.edu/childrenshosp/parents_of_preemies/IHM.html

•

From the National Institutes of Health Disorders of Pregnancy: Gestational Diabetes Mellitus (GDM) & Preeclampsia and Eclampsia Source: National Institute of Child Health and Human Development http://www.nichd.nih.gov/about/womenhealth/disorders_of_pregnancy.cfm Your Guide to Lowering High Blood Pressure: Preeclampsia in Pregnancy Source: National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/hbp/issues/preg/preg.htm

•

Latest News Preeclampsia Linked with Increased Cancer Risk Source: 03/05/2004, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_16430 .html Substances Found in Blood May Predict Development of Preeclampsia Source: 02/05/2004, National Institute of Child Health and Human Development http://www.nih.gov/news/pr/feb2004/nichd-05.htm

•

Organizations American College of Obstetricians and Gynecologists http://www.acog.org/ National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/

•

Research Periodontal Disease Increases Risk of Preeclampsia Source: American College of Obstetricians and Gynecologists http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZCKHVGSBD

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&sub_cat=2 Researchers Discover How Embryo Attaches to the Uterus Source: National Institute of Child Health and Human Development http://www.nih.gov/news/pr/jan2003/nichd-16.htm Substances Found in Blood May Predict Development of Preeclampsia Source: National Institute of Child Health and Human Development http://www.nih.gov/news/pr/feb2004/nichd-05.htm •

Statistics Pregnancy-Related Mortality from Preeclampsia and Eclampsia Source: American College of Obstetricians and Gynecologists http://www.medem.com/search/article_display.cfm?path=n:&mstr=/ZZZND7UI YKC.html&soc=ACOG&srch_typ=NAV_SERCH

You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on preeclampsia. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

Giving Calcium Its Due Source: San Diego, CA: American Council on Exercise, 1997. Contact: American Council on Exercise, 5820 Oberlin Dr., Suite 102, San Diego, CA 92121. (800) 529-8227. Summary: This brief article discusses the value of calcium in the diet. The authors say that most women do not get enough calcium, which is used by the body to strengthen bones and teeth, aid in muscle contraction, coagulate the blood and possibly lower the blood pressure. In addition, calcium may play a role in preventing preeclampsia, a blood pressure- related condition of pregnancy. The authors list several foods rich in calcium such as fish with bones, green leafy vegetables, dairy products, and legumes.

•

Diabetes and Pregnancy Source: Washington, DC: American College of Obstetricians and Gynecologists. 1995. 4 p.

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Contact: Available from American College of Obstetricians and Gynecologists. 409 12th Street, SW, Washington, DC 20024-2188. (800) 762-2264, ext. 197. PRICE: $15.00 for 50 copies. Summary: This brochure provides information about both gestational diabetes and pregnancy for women who have pre-existing diabetes. The brochure notes that good control of glucose levels before and during pregnancy can lower the risk of complications. Topics include the causes of diabetes, the effects of diabetes during pregnancy, preparing for pregnancy, diabetes control, prenatal care, delivery, and postpartum care. Complications that may arise include birth defects, macrosomia, preeclampsia, hydramnios, urinary tract infections, and respiratory distress syndrome (RDS). Blood glucose can be controlled with diet and exercise and, in some cases, by taking insulin. While insulin shots can be safely used during pregnancy to control diabetes, diabetes pills are not recommended. The brochure includes three illustrations. A glossary concludes the brochure. (AA-M). Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

Preeclampsia Frequently Asked Questions Summary: This document provides answers to questions about the causes of and treatment for preeclampsia. Source: Preeclampsia Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7750 The NIH Search Utility

The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to preeclampsia. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

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

•

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

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•

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

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

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

•

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

•

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

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to preeclampsia. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with preeclampsia. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about preeclampsia. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “preeclampsia” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “preeclampsia”. Type the following hyperlink into your

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Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “preeclampsia” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “preeclampsia” (or a synonym) into the search box, and click “Submit Query.”

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

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.25

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

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

25

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

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)26: •

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

•

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

•

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

•

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

•

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

•

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

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

26

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

Finding Medical Libraries 189

•

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

•

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

•

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

•

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

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

•

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

•

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

•

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

•

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

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

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

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

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

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

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

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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

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MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

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Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

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On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

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Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on preeclampsia: •

Basic Guidelines for Preeclampsia Preeclampsia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000898.htm

•

Signs & Symptoms for Preeclampsia Abdominal pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003120.htm Agitation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003212.htm Amnesia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003257.htm Blood pressure, high Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003082.htm

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Edema Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm Facial swelling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003105.htm Generalized swelling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm Headache Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003024.htm Headaches Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003024.htm High blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003082.htm Nausea and vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Nausea and vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Oliguria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003147.htm Rales Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003323.htm Seizures Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003200.htm Swelling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm Swelling of the feet Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003104.htm Tachycardia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003077.htm Urine output, Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003147.htm Vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Weight gain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003084.htm

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•

Diagnostics and Tests for Preeclampsia Aldosterone Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003704.htm ALT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003473.htm Amylase, urine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003607.htm Blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003398.htm BUN Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003474.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm Complement Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003456.htm Contraction Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003405.htm Creatinine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003475.htm Creatinine clearance Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003611.htm CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Diastolic blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003398.htm Differential Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003657.htm Fibrin degradation products Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003655.htm Fibrinogen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003650.htm HCT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003646.htm Immunoelectrophoresis - serum Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003541.htm

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LDH Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003471.htm Liver function tests Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003436.htm Peripheral smear Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003665.htm Platelet count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003647.htm Pregnanediol Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003914.htm Protein in the urine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003580.htm Proteinuria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003580.htm PT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003652.htm PTT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003653.htm Quantitative immunoglobulins (nephelometry) Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003545.htm Serum creatinine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003475.htm Serum magnesium - test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003487.htm Serum progesterone Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003714.htm Sodium, urine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003599.htm Sonogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003336.htm T4 Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003517.htm Ultrasound Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003336.htm

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Uric acid Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003476.htm Urine specific gravity Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003587.htm •

Nutrition for Preeclampsia Protein Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm

•

Surgery and Procedures for Preeclampsia Cesarean section Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002911.htm C-section Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002911.htm

•

Background Topics for Preeclampsia Acute Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002215.htm Auscultation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002226.htm Cardiovascular Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002310.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Hepatic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002378.htm Kidney disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000457.htm Peripheral Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002273.htm

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

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

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•

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

•

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

•

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

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PREECLAMPSIA DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Abortion: 1. The premature expulsion from the uterus of the products of conception - of the embryo, or of a nonviable fetus. The four classic symptoms, usually present in each type of abortion, are uterine contractions, uterine haemorrhage, softening and dilatation of the cervix, and presentation or expulsion of all or part of the products of conception. 2. Premature stoppage of a natural or a pathological process. [EU] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcholinesterase: An enzyme that catalyzes the hydrolysis of acetylcholine to choline and acetate. In the CNS, this enzyme plays a role in the function of peripheral neuromuscular junctions. EC 3.1.1.7. [NIH] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Actin: Essential component of the cell skeleton. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine

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derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Deaminase: An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Since there are wide tissue and species variations in the enzyme, it has been used as a tool in the study of human and animal genetics and in medical diagnosis. EC 3.5.4.4. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU]

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Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Albuminuria: More than normal amounts of a protein called albumin in the urine. Albuminuria may be a sign of kidney disease. [NIH] Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alkaline: Having the reactions of an alkali. [EU] Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1. [NIH] Allantois: An embryonic diverticulum of the hindgut of reptiles, birds, and mammals; in man its blood vessels give rise to those of the umbilical cord. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-Defensins: Defensins found in azurophilic granules of neutrophils and in the secretory granules of intestinal paneth cells. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alveolar Process: The thickest and spongiest part of the maxilla and mandible hollowed out into deep cavities for the teeth. [NIH] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH)

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group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]

Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]

Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgenic: Producing masculine characteristics. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Androstenedione: A steroid with androgenic properties that is produced in the testis, ovary, and adrenal cortex. It is a precursor to testosterone and other androgenic hormones. [NIH]

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Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anionic: Pertaining to or containing an anion. [EU] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anomalies: Birth defects; abnormalities. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anoxia: Clinical manifestation of respiratory distress consisting of a relatively complete absence of oxygen. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antecedent: Existing or occurring before in time or order often with consequential effects. [EU]

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Anterior Cerebral Artery: Artery formed by the bifurcation of the internal carotid artery. Branches of the anterior cerebral artery supply the caudate nucleus, internal capsule, putamen, septal nuclei, gyrus cinguli, and surfaces of the frontal lobe and parietal lobe. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibodies, Anticardiolipin: Antiphospholipid antibodies found in association with systemic lupus erythematosus (lupus erythematosus, systemic), antiphospholipid syndrome, and in a variety of other diseases as well as in healthy individuals. The antibodies are detected by solid-phase immunoassay employing the purified phospholipid antigen cardiolipin. [NIH] Antibodies, Antiphospholipid: Autoantibodies directed against phospholipids. These antibodies are characteristically found in patients with systemic lupus erythematosus, antiphospholipid syndrome, related autoimmune diseases, some non-autoimmune diseases, and also in healthy individuals. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antidiuretic: Suppressing the rate of urine formation. [EU] Antifibrinolytic: Inhibiting fibrinolysis. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the

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maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiphospholipid Syndrome: The presence of antibodies directed against phospholipids (antibodies, antiphospholipid). The condition is associated with a variety of diseases, notably systemic lupus erythematosus and other connective tissue diseases, thrombopenia, and arterial or venous thromboses. In pregnancy it can cause abortion. Of the phospholipids, the cardiolipins show markedly elevated levels of anticardiolipin antibodies (antibodies, anticardiolipin). Present also are high levels of lupus anticoagulant (lupus coagulation inhibitor). [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Aphakia: Absence of crystalline lens totally or partially from field of vision, from any cause except after cataract extraction. Aphakia is mainly congenital or as result of lens dislocation and subluxation. [NIH] Apnea: A transient absence of spontaneous respiration. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aqueous: Having to do with water. [NIH] Arachidonate 15-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 15-hydroperoxyarachidonate (15-HPETE) which is rapidly converted to 15-hydroxy5,8,11,13-eicosatetraenoate (15-HETE). The 15-hydroperoxides are preferentially formed in neutrophils and lymphocytes. EC 1.13.11.33. [NIH] Arachidonate Lipoxygenases: Enzymes catalyzing the oxidation of arachidonic acid to hydroperoxyarachidonates (HPETES). These products are then rapidly converted by a peroxidase to hydroxyeicosatetraenoic acids (HETES). The positional specificity of the enzyme reaction varies from tissue to tissue. The final lipoxygenase pathway leads to the leukotrienes. EC 1.13.11.- . [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU]

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Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Arteritis: Inflammation of an artery. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articular: Of or pertaining to a joint. [EU] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Asphyxia: A pathological condition caused by lack of oxygen, manifested in impending or actual cessation of life. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atherectomy: Endovascular procedure in which atheromatous plaque is excised by a cutting or rotating catheter. It differs from balloon and laser angioplasty procedures which enlarge vessels by dilation but frequently do not remove much plaque. If the plaque is removed by surgical excision under general anesthesia rather than by an endovascular procedure through a catheter, it is called endarterectomy. [NIH] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] Atopic Eczema: Generic term for acute or chronic inflammatory conditions of the skin, typically erythematous, edematous, papular, vesicular, and crusting; often accompanied by sensations of itching and burning. [NIH] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU]

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Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autopsy: Postmortem examination of the body. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]

Axillary Artery: The continuation of the subclavian artery; it distributes over the upper limb, axilla, chest and shoulder. [NIH] Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Bacteriuria: The presence of bacteria in the urine with or without consequent urinary tract infection. Since bacteriuria is a clinical entity, the term does not preclude the use of urine/microbiology for technical discussions on the isolation and segregation of bacteria in the urine. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance

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whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basilar Artery: The artery formed by the union of the right and left vertebral arteries; it runs from the lower to the upper border of the pons, where it bifurcates into the two posterior cerebral arteries. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Bed Rest: Confinement of an individual to bed for therapeutic or experimental reasons. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benign prostatic hyperplasia: A benign (noncancerous) condition in which an overgrowth of prostate tissue pushes against the urethra and the bladder, blocking the flow of urine. Also called benign prostatic hypertrophy or BPH. [NIH] Beta-Defensins: Defensins found mainly in epithelial cells. [NIH] Beta-Thromboglobulin: A platelet-specific protein which is released when platelets aggregate. Elevated plasma levels have been reported after deep venous thrombosis, preeclampsia, myocardial infarction with mural thrombosis, and myeloproliferative disorders. Measurement of beta-thromboglobulin in biological fluids by radioimmunoassay is used for the diagnosis and assessment of progress of thromboembolic disorders. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological Markers: Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental

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exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Coagulation Factors: Endogenous substances, usually proteins, that are involved in the blood coagulation process. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood Substitutes: Substances that can carry oxygen to and carbon dioxide away from the tissues when introduced into the blood stream. They are used to replace hemoglobin in severe hemorrhage and also to perfuse isolated organs. The best known are perfluorocarbon emulsions and various hemoglobin solutions. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH]

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Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Fluids: Liquid components of living organisms. [NIH] Body Image: Individuals' personal concept of their bodies as objects in and bound by space, independently and apart from all other objects. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Artery: The continuation of the axillary artery; it branches into the radial and ulnar arteries. [NIH] Bradycardia: Excessive slowness in the action of the heart, usually with a heart rate below 60 beats per minute. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchospasm: Spasmodic contraction of the smooth muscle of the bronchi, as occurs in asthma. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH]

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Cadherins: A group of functionally related glycoproteins responsible for the calciumdependent cell-to-cell adhesion mechanism. They are divided into subclasses E-, P-, and Ncadherins, which are distinct in immunological specificity and tissue distribution. They promote cell adhesion via a homophilic mechanism. These compounds play a role in the construction of tissues and of the whole animal body. [NIH] Calcitonin: A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. [NIH] Calcitonin Gene-Related Peptide: Calcitonin gene-related peptide. A 37-amino acid peptide derived from the calcitonin gene. It occurs as a result of alternative processing of mRNA from the calcitonin gene. The neuropeptide is widely distributed in neural tissue of the brain, gut, perivascular nerves, and other tissue. The peptide produces multiple biological effects and has both circulatory and neurotransmitter modes of action. In particular, it is a potent endogenous vasodilator. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium channel blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardenolides: C(23)-steroids with methyl groups at C-10 and C-13 and a five-membered lactone at C-17. They are aglycone constituents of cardiac glycosides and must have at least one double bond in the molecule. the class includes cardadienolides and cardatrienolides. Members include digitoxin and digoxin and their derivatives and the strophanthins. [NIH] Cardiac: Having to do with the heart. [NIH]

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Cardiac arrest: A sudden stop of heart function. [NIH] Cardiac Glycosides: Substances obtained from species of Digitalis, Strophanthus, and other plants that contain specific steroid glycosides or their semisynthetic derivatives and used in congestive heart failure. They increase the force of cardiac contraction without significantly affecting other parameters, but are very toxic at larger doses. Their mechanism of action usually involves inhibition of the Na(+)-K(+)-exchanging ATPase and they are often used in cell biological studies for that purpose. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiogenic: Originating in the heart; caused by abnormal function of the heart. [EU] Cardiolipins: Acidic phospholipids composed of two molecules of phosphatidic acid covalently linked to a molecule of glycerol. They occur primarily in mitochondrial inner membranes and in bacterial plasma membranes. They are the main antigenic components of the Wassermann-type antigen that is used in nontreponemal syphilis serodiagnosis. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiotonic: 1. Having a tonic effect on the heart. 2. An agent that has a tonic effect on the heart. [EU] Cardiotonic Agents: Agents that have a tonic effect on the heart or increase cardiac output. They may be glycosidic steroids related to Digitalis products, sympathomimetics, or other drugs and are used after myocardial infarcts, cardiac surgery, in shock, or in congestive heart failure. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carotenoids: Substance found in yellow and orange fruits and vegetables and in dark green, leafy vegetables. May reduce the risk of developing cancer. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all

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cellular proteins. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caveolae: Endocytic/exocytic cell membrane structures rich in glycosphingolipids, cholesterol, and lipid-anchored membrane proteins that function in endocytosis (potocytosis), transcytosis, and signal transduction. Caveolae assume various shapes from open pits to closed vesicles. Caveolar coats are composed of caveolins. [NIH] Caveolins: The main structural proteins of caveolae. Several distinct genes for caveolins have been identified. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell Lineage: The developmental history of cells as traced from the first division of the original cell or cells in the embryo. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Membrane Structures: Structures which are part of the cell membrane or have cell membrane as a major part of their structure. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH]

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Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Arteries: The arteries supplying the cerebral cortex. [NIH] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral Hemorrhage: Bleeding into a cerebral hemisphere of the brain, including lobar, subcortical white matter, and basal ganglia hemorrhages. Commonly associated conditions include hypertension; intracranial arteriosclerosis; intracranial aneurysm; craniocerebral trauma; intracranial arteriovenous malformations; cerebral amyloid angiopathy; and cerebral infarction. [NIH] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Cesarean Section: Extraction of the fetus by means of abdominal hysterotomy. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH]

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Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [NIH]

Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Cholinesterase Inhibitors: Drugs that inhibit cholinesterases. The neurotransmitter acetylcholine is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system. [NIH] Chorioamnionitis: An inflammatory process involving the chorion, its fetal blood vessels, the umbilical cord, and the amnion by extension of the inflammation, as the amnion itself has no blood supply. This inflammatory process is potentially fatal to mother and fetus. [NIH]

Choriocarcinoma: A malignant tumor of trophoblastic epithelium characterized by secretion of large amounts of chorionic gonadotropin. It usually originates from chorionic products of conception (i.e., hydatidiform mole, normal pregnancy, or following abortion), but can originate in a teratoma of the testis, mediastinum, or pineal gland. [NIH] Chorion: The outermost extraembryonic membrane. [NIH] Chorioretinitis: Inflammation of the choroid in which the sensory retina becomes edematous and opaque. The inflammatory cells and exudate may burst through the sensory retina to cloud the vitreous body. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic Fatigue Syndrome: Fatigue caused by the combined effects of different types of prolonged fatigue. [NIH]

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Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Climacteric: Physiologic period, characterized by endocrine, somatic, and psychic changes with the termination of ovarian function in the female. It may also accompany the normal diminution of sexual activity in the male. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clitoral: Pertaining to the clitoris. [EU] Clonal Deletion: Removal, via cell death, of immature lymphocytes that interact with antigens during maturation. For T-lymphocytes this occurs in the thymus and ensures that mature T-lymphocytes are self tolerant. B-lymphocytes may also undergo clonal deletion. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cochlea: The part of the internal ear that is concerned with hearing. It forms the anterior part of the labyrinth, is conical, and is placed almost horizontally anterior to the vestibule. [NIH]

Cochlear: Of or pertaining to the cochlea. [EU] Cochlear Implants: Electronic devices implanted beneath the skin with electrodes to the cochlear nerve to create sound sensation in persons with sensorineural deafness. [NIH] Cochlear Nerve: The cochlear part of the 8th cranial nerve (vestibulocochlear nerve). The cochlear nerve fibers originate from neurons of the spiral ganglion and project peripherally to cochlear hair cells and centrally to the cochlear nuclei (cochlear nucleus) of the brain stem. They mediate the sense of hearing. [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the

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action of another entity such as a disease-causing agent. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complement Activation: The sequential activation of serum components C1 through C9, initiated by an erythrocyte-antibody complex or by microbial polysaccharides and properdin, and producing an inflammatory response. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or

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bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Compress: A plug used to occludate an orifice in the control of bleeding, or to mop up secretions; an absorbent pad. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Diseases: A heterogeneous group of disorders, some hereditary, others acquired, characterized by abnormal structure or function of one or more of the elements of connective tissue, i.e., collagen, elastin, or the mucopolysaccharides. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contraception: Use of agents, devices, methods, or procedures which diminish the likelihood of or prevent conception. [NIH] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being

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studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary Circulation: The circulation of blood through the coronary vessels of the heart. [NIH]

Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Cortical Blindness: The inability to understand or interpret what is seen due to a

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disturbance in the cerebral associational areas, the retina, the sensory pathways, and the striate area being intact. [NIH] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Corticotropin-Releasing Hormone: A neuropeptide released by the hypothalamus that stimulates the release of corticotropin by the anterior pituitary gland. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cystathionine beta-Synthase: A multifunctional pyridoxal phosphate enzyme. In the second stage of cysteine biosynthesis it catalyzes the reaction of homocysteine with serine to form cystathionine with the elimination of water. Deficiency of this enzyme leads to hyperhomocysteinemia and homocystinuria. EC 4.2.1.22. [NIH]

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Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytochrome b: Cytochromes (electron-transporting proteins) with protoheme or a related heme as the prosthetic group. The prosthetic group is not covalently bound to the protein moiety. [NIH] Cytochrome b5: A cytochrome occurring in the endoplasmic reticulum that acts as an intermediate electron carrier in some reactions catalyzed by mixed function oxidases, e.g., fatty acid desaturation. It further activates molecular oxygen for an attack on the substrate. MW 16kDa. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytotoxic: Cell-killing. [NIH] Dairy Products: Raw and processed or manufactured milk and milk-derived products. These are usually from cows (bovine) but are also from goats, sheep, reindeer, and water buffalo. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Defensins: Family of antimicrobial peptides that have been identified in humans, animals, and plants. They are thought to play a role in host defenses against infections, inflammation, wound repair, and acquired immunity. Based on the disulfide pairing of their characteristic six cysteine residues, they are divided into alpha-defensins and beta-defensins. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU]

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Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]

Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Dietary Fats: Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados.

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[NIH]

Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Digitalis: A genus of toxic herbaceous Eurasian plants of the Scrophulaceae which yield cardiotonic glycosides. The most useful are Digitalis lanata and D. purpurea. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilate: Relax; expand. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilator: A device used to stretch or enlarge an opening. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disposition: A tendency either physical or mental toward certain diseases. [EU] Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH]

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Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dyslipidemia: Disorders in the lipoprotein metabolism; classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high-density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol predispose to premature atherosclerosis. [NIH] Dysmenorrhea: Painful menstruation. [NIH] Dyspareunia: Painful sexual intercourse. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystocia: Difficult childbirth or labor. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]

Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH]

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Eicosanoids: A class of oxygenated, endogenous, unsaturated fatty acids derived from arachidonic acid. They include prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acid compounds (HETE). They are hormone-like substances that act near the site of synthesis without altering functions throughout the body. [NIH] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryo Transfer: Removal of a mammalian embryo from one environment and replacement in the same or a new environment. The embryo is usually in the pre-nidation phase, i.e., a blastocyst. The process includes embryo or blastocyst transplantation or transfer after in vitro fertilization and transfer of the inner cell mass of the blastocyst. It is not used for transfer of differentiated embryonic tissue, e.g., germ layer cells. [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Emulsions: Colloids of two immiscible liquids where either phase may be either fatty or aqueous; lipid-in-water emulsions are usually liquid, like milk or lotion and water-in-lipid emulsions tend to be creams. [NIH] Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endoderm: The inner of the three germ layers of the embryo. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]

Endometriosis: A condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelins: 21-Amino-acid peptides produced by vascular endothelial cells and

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functioning as potent vasoconstrictors. The endothelin family consists of three members, endothelin-1, endothelin-2, and endothelin-3. All three peptides contain 21 amino acids, but vary in amino acid composition. The three peptides produce vasoconstrictor and pressor responses in various parts of the body. However, the quantitative profiles of the pharmacological activities are considerably different among the three isopeptides. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Enzyme-Linked Immunosorbent Assay: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are

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uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiologic Factors: Events, characteristics, or other definable entities that have the potential to bring about a change in a health condition or other defined outcome. [NIH] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythrocyte Aggregation: Aggregation of erythrocytes probably resulting from changes in the negative surface charge (zeta potential) of the cells caused by the dielectric effect of proteins in the surrounding plasma, especially asymmetric macromolecules like fibrinogen and gamma-globulin. [NIH] Erythrocyte Volume: Volume of circulating erythrocytes. It is usually measured by radioisotope dilution technique. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the

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liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Esophagitis: Inflammation, acute or chronic, of the esophagus caused by bacteria, chemicals, or trauma. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estriol: (16 alpha,17 beta)-Estra-1,3,5(10)-triene-3,16,17-triol. A metabolite of estradiol and usually the predominant estrogenic metabolite in urine. During pregnancy, large amounts of estriol are produced by the placenta. It has also been obtained from plant sources. The 16 beta-isomer has also been isolated from the urine of pregnant women. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Estrogen Replacement Therapy: The use of hormonal agents with estrogen-like activity in postmenopausal or other estrogen-deficient women to alleviate effects of hormone deficiency, such as vasomotor symptoms, dyspareunia, and progressive development of osteoporosis. This may also include the use of progestational agents in combination therapy. [NIH]

Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Expiratory: The volume of air which leaves the breathing organs in each expiration. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation,

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visual impairment, or blindness. [NIH] Fallopian tube: The oviduct, a muscular tube about 10 cm long, lying in the upper border of the broad ligament. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fertilization in Vitro: Fertilization of an egg outside the body when the egg is normally fertilized in the body. [NIH] Fertilizers: Substances or mixtures that are added to the soil to supply nutrients or to make available nutrients already present in the soil, in order to increase plant growth and productivity. [NIH] Fetal Blood: Blood of the fetus. Exchange of nutrients and waste between the fetal and maternal blood occurs via the placenta. The cord blood is blood contained in the umbilical vessels at the time of delivery. [NIH] Fetal Death: Death of the young developing in utero. [NIH] Fetal Distress: Adverse or threatening condition of the fetus identified by fetal bradycardia or tachycardia and passage of meconium in vertex presentation. [NIH] Fetal Growth Retardation: The failure of a fetus to attain its expected growth potential at any gestational stage. [NIH] Fetal Membranes: Thin layers of tissue which surround the embryo or fetus and provide for its nutrition, respiration, excretion and protection; they are the yolk sac, allantois, amnion, and chorion. [NIH] Fetal Movement: Motion of the fetus perceived by the mother and felt by palpation of the abdomen. [NIH] Fetal Viability: The potential of the fetus-in-utero to survive after birth. [NIH] Fetal Weight: The weight of the fetus in utero, which is usually estimated by various formulas based on measurements made during prenatal ultrasonography. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrillation: A small, local, involuntary contraction of muscle, invisible under the skin, resulting from spontaneous activation of single muscle cells or muscle fibres. [EU] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by

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enzymatic action [EU] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Follicles: Shafts through which hair grows. [NIH] Follicular Phase: The period of the menstrual cycle that begins with menstruation and ends with ovulation. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Fungemia: The presence of fungi circulating in the blood. Opportunistic fungal sepsis is seen most often in immunosuppressed patients with severe neutropenia or in postoperative patients with intravenous catheters and usually follows prolonged antibiotic therapy. [NIH] Furosemide: A sulfamyl saluretic and diuretic. It has a fast onset and short duration of

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action and is used in edema and chronic renal insufficiency. [NIH] Galanthamine: A cholinesterase inhibitor. It has been used to reverse the muscular effects of gallamine and tubocurarine and has been studied as a treatment for Alzheimer's disease and other central nervous system disorders. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Juices: Liquids produced in the stomach to help break down food and kill bacteria. [NIH]

Gastric Mucosa: Surface epithelium in the stomach that invaginates into the lamina propria, forming gastric pits. Tubular glands, characteristic of each region of the stomach (cardiac, gastric, and pyloric), empty into the gastric pits. The gastric mucosa is made up of several different kinds of cells. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH]

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Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gestational Age: Age of the conceptus. In humans, this may be assessed by medical history, physical examination, early immunologic pregnancy tests, radiography, ultrasonography, and amniotic fluid analysis. [NIH] Gingivitis: Inflammation of the gingivae. Gingivitis associated with bony changes is referred to as periodontitis. Called also oulitis and ulitis. [EU] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] Glomeruli: Plural of glomerulus. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

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

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

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[NIH]

Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycan: A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [NIH] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Goats: Any of numerous agile, hollow-horned ruminants of the genus Capra, closely related to the sheep. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Gonorrhea: Acute infectious disease characterized by primary invasion of the urogenital tract. The etiologic agent, Neisseria gonorrhoeae, was isolated by Neisser in 1879. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-Negative Bacteria: Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. [NIH] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Granulosa Cells: Cells of the membrana granulosa lining the vesicular ovarian follicle which become luteal cells after ovulation. [NIH]

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Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Gravidity: Pregnancy; the condition of being pregnant, without regard to the outcome. [EU] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Haemorrhage: The escape of blood from the vessels; bleeding. Small haemorrhages are classified according to size as petechiae (very small), purpura (up to 1 cm), and ecchymoses (larger). The massive accumulation of blood within a tissue is called a haematoma. [EU] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Behavior: Behaviors expressed by individuals to protect, maintain or promote their health status. For example, proper diet, and appropriate exercise are activities perceived to influence health status. Life style is closely associated with health behavior and factors influencing life style are socioeconomic, educational, and cultural. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Hematoma: An extravasation of blood localized in an organ, space, or tissue. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematuria: Presence of blood in the urine. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemodynamics: The movements of the blood and the forces involved in systemic or

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regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhagic stroke: A disorder involving bleeding within ischemic brain tissue. Hemorrhagic stroke occurs when blood vessels that are damaged or dead from lack of blood supply (infarcted), located within an area of infarcted brain tissue, rupture and transform an "ischemic" stroke into a hemorrhagic stroke. Ischemia is inadequate tissue oxygenation caused by reduced blood flow; infarction is tissue death resulting from ischemia. Bleeding irritates the brain tissues, causing swelling (cerebral edema). Blood collects into a mass (hematoma). Both swelling and hematoma will compress and displace brain tissue. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocyte: A liver cell. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterodimer: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH]

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Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydatidiform Mole: A trophoblastic disease characterized by hydrops of the mesenchymal portion of the villus. Its karyotype is paternal and usually homozygotic. The tumor is indistinguishable from chorioadenoma destruens or invasive mole ( = hydatidiform mole, invasive) except by karyotype. There is no apparent relation by karyotype to choriocarcinoma. Hydatidiform refers to the presence of the hydropic state of some or all of the villi (Greek hydatis, a drop of water). [NIH] Hydralazine: A direct-acting vasodilator that is used as an antihypertensive agent. [NIH] Hydration: Combining with water. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH]

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Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercapnia: A clinical manifestation of abnormal increase in the amount of carbon dioxide in arterial blood. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperhomocysteinemia: An inborn error of methionone metabolism which produces an excess of homocysteine in the blood. It is often caused by a deficiency of cystathionine betasynthase and is a risk factor for coronary vascular disease. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hyperreflexia: Exaggeration of reflexes. [EU] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertension, Pulmonary: Increased pressure within the pulmonary circulation, usually secondary to cardiac or pulmonary disease. [NIH] Hypertension, Renal: Hypertension due to renal diseases, especially chronic parenchymal disease. Hypertension as a result of compression or obstruction of the renal artery or its branches is hypertension, renovascular. [NIH] Hypertension, Renovascular: Hypertension due to compression or obstruction of the renal artery or its branches. [NIH] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypoglycemia: Abnormally low blood sugar [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamic: Of or involving the hypothalamus. [EU]

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Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Hypoxemia: Deficient oxygenation of the blood; hypoxia. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Hysterotomy: An incision in the uterus, performed through either the abdomen or the vagina. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Iliac Artery: Either of two large arteries originating from the abdominal aorta; they supply blood to the pelvis, abdominal wall and legs. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immune Tolerance: The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulins: Glycoproteins present in the blood (antibodies) and in other tissue. They are classified by structure and activity into five classes (IgA, IgD, IgE, IgG, IgM). [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH]

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Immunology: The study of the body's immune system. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant Mortality: Perinatal, neonatal, and infant deaths in a given population. [NIH] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical

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signs of pain, heat, redness, swelling, and loss of function. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhibin: Glyceroprotein hormone produced in the seminiferous tubules by the Sertoli cells in the male and by the granulosa cells in the female follicles. The hormone inhibits FSH and LH synthesis and secretion by the pituitary cells thereby affecting sexual maturation and fertility. [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]

Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Interleukin-8: A cytokine that activates neutrophils and attracts neutrophils and Tlymphocytes. It is released by several cell types including monocytes, macrophages, Tlymphocytes, fibroblasts, endothelial cells, and keratinocytes by an inflammatory stimulus. IL-8 is a member of the beta-thromboglobulin superfamily and structurally related to platelet factor 4. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU]

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Intracellular: Inside a cell. [NIH] Intracranial Aneurysm: A saclike dilatation of the walls of a blood vessel, usually an artery. [NIH]

Intraocular: Within the eye. [EU] Intraocular pressure: Pressure of the fluid inside the eye; normal IOP varies among individuals. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoelectric: Separation of amphoteric substances, dissolved in water, based on their isoelectric behavior. The amphoteric substances are a mixture of proteins to be separated and of auxiliary "carrier ampholytes". [NIH] Isoelectric Focusing: Electrophoresis in which a pH gradient is established in a gel medium and proteins migrate until they reach the site (or focus) at which the pH is equal to their isoelectric point. [NIH] Isoelectric Point: The pH in solutions of proteins and related compounds at which the dipolar ions are at a maximum. [NIH] Isosorbide: 1,4:3,6-Dianhydro D-glucitol. Chemically inert osmotic diuretic used mainly to

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treat hydrocephalus; also used in glaucoma. [NIH] Isosorbide Dinitrate: A vasodilator used in the treatment of angina. Its actions are similar to nitroglycerin but with a slower onset of action. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Ketoacidosis: Acidosis accompanied by the accumulation of ketone bodies (ketosis) in the body tissues and fluids, as in diabetic acidosis. [EU] Ketone Bodies: Chemicals that the body makes when there is not enough insulin in the blood and it must break down fat for its energy. Ketone bodies can poison and even kill body cells. When the body does not have the help of insulin, the ketones build up in the blood and then "spill" over into the urine so that the body can get rid of them. The body can also rid itself of one type of ketone, called acetone, through the lungs. This gives the breath a fruity odor. Ketones that build up in the body for a long time lead to serious illness and coma. [NIH] Ketosis: A condition of having ketone bodies build up in body tissues and fluids. The signs of ketosis are nausea, vomiting, and stomach pain. Ketosis can lead to ketoacidosis. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney stone: A stone that develops from crystals that form in urine and build up on the inner surfaces of the kidney, in the renal pelvis, or in the ureters. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lactation: The period of the secretion of milk. [EU] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Least-Squares Analysis: A principle of estimation in which the estimates of a set of

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parameters in a statistical model are those quantities minimizing the sum of squared differences between the observed values of a dependent variable and the values predicted by the model. [NIH] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligase: An enzyme that repairs single stranded discontinuities in double-stranded DNA molecules in the cell. Purified DNA ligase is used in gene cloning to join DNA molecules together. [NIH] Ligase Chain Reaction: A DNA amplification technique based upon the ligation of oligonucleotide probes. The probes are designed to exactly match two adjacent sequences of a specific target DNA. The chain reaction is repeated in three steps in the presence of excess probe: (1) heat denaturation of double-stranded DNA, (2) annealing of probes to target DNA, and (3) joining of the probes by thermostable DNA ligase. After the reaction is repeated for 20-30 cycles the production of ligated probe is measured. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Likelihood Functions: Functions constructed from a statistical model and a set of observed data which give the probability of that data for various values of the unknown model parameters. Those parameter values that maximize the probability are the maximum likelihood estimates of the parameters. [NIH] Linear Models: Statistical models in which the value of a parameter for a given value of a factor is assumed to be equal to a + bx, where a and b are constants. The models predict a linear regression. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of

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independent assortment. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipid Peroxides: Peroxides produced in the presence of a free radical by the oxidation of unsaturated fatty acids in the cell in the presence of molecular oxygen. The formation of lipid peroxides results in the destruction of the original lipid leading to the loss of integrity of the membranes. They therefore cause a variety of toxic effects in vivo and their formation is considered a pathological process in biological systems. Their formation can be inhibited by antioxidants, such as vitamin E, structural separation or low oxygen tension. [NIH] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Lipoprotein(a): A family of lipoprotein particles varying in density and size depending on the protein-lipid ratio and the protein composition. These particles consist of apolipoprotein B-100 covalently linked to apolipoprotein-a by one or two disulfide bonds. There is a correlation between high plasma levels of this lipoprotein and increased risk for atherosclerotic cardiovascular disease. [NIH] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Logistic Models: Statistical models which describe the relationship between a qualitative dependent variable (that is, one which can take only certain discrete values, such as the presence or absence of a disease) and an independent variable. A common application is in epidemiology for estimating an individual's risk (probability of a disease) as a function of a given risk factor. [NIH] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH]

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Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lubricants: Oily or slippery substances. [NIH] Lubrication: The application of a substance to diminish friction between two surfaces. It may refer to oils, greases, and similar substances for the lubrication of medical equipment but it can be used for the application of substances to tissue to reduce friction, such as lotions for skin and vaginal lubricants. [NIH] Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view and on which the outline of the object may be traced. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lupus Nephritis: Glomerulonephritis associated with systemic lupus erythematosus. It is classified into four histologic types: mesangial, focal, diffuse, and membranous. [NIH] Luteal Phase: The period of the menstrual cycle that begins with ovulation and ends with menstruation. [NIH] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH]

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Lymphotoxin: Soluble substance released by lymphocytes activated by antigens or T-cell mitogens, that is cytotoxic to other cells. It is involved in allergies and chronic inflammatory diseases. Lymphotoxin is antigenically distinct from tumor necrosis factor-alpha (tumor necrosis factor), though they both share a common receptor, biological activities, and significant amino acid sequences. [NIH] Lysophospholipids: Derivatives of phosphatidic acids that lack one of its fatty acyl chains due to its hydrolytic removal. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macrophage Colony-Stimulating Factor: A mononuclear phagocyte colony-stimulating factor synthesized by mesenchymal cells. The compound stimulates the survival, proliferation, and differentiation of hematopoietic cells of the monocyte-macrophage series. M-CSF is a disulfide-bonded glycoprotein dimer with a MW of 70 kDa. It binds to a specific high affinity receptor (receptor, macrophage colony-stimulating factor). [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Malondialdehyde: The dialdehyde of malonic acid. [NIH] Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [NIH] Maternal Mortality: Maternal deaths resulting from complications of pregnancy and childbirth in a given population. [NIH] Meconium: The thick green-to-black mucilaginous material found in the intestines of a fullterm fetus. It consists of secretions of the intestinal glands, bile pigments, fatty acids, amniotic fluid, and intrauterine debris. It constitutes the first stools passed by a newborn. [NIH]

Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH]

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Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Lipids: Lipids, predominantly phospholipids, cholesterol and small amounts of glycolipids found in membranes including cellular and intracellular membranes. These lipids may be arranged in bilayers in the membranes with integral proteins between the layers and peripheral proteins attached to the outside. Membrane lipids are required for active transport, several enzymatic activities and membrane formation. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Menarche: The establishment or beginning of the menstrual function. [EU] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Fatigue: Fatigue arising in consequence of mental effort. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH]

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Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesenteric Arteries: Arteries which arise from the abdominal aorta and distribute to most of the intestines. [NIH] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microsomal: Of or pertaining to microsomes : vesicular fragments of endoplasmic reticulum formed after disruption and centrifugation of cells. [EU] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the second trimester. [NIH] Mitomycin: An antineoplastic antibiotic produced by Streptomyces caespitosus. It acts as a bi- or trifunctional alkylating agent causing cross-linking of DNA and inhibition of DNA

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synthesis. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mixed Function Oxidases: Catalyse the insertion of one oxygen atom of molecular oxygen into the organ substrate. Require a second substrate to donate electrons for the reduction of the second atom in the oxygen molecule to water. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monocyte: A type of white blood cell. [NIH] Monocyte Chemoattractant Protein-1: A chemokine that is a chemoattractant for human monocytes and may also cause cellular activation of specific functions related to host defense. It is produced by leukocytes of both monocyte and lymphocyte lineage and by fibroblasts during tissue injury. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]

Morphological: Relating to the configuration or the structure of live organs. [NIH] Morula: The early embryo at the developmental stage in which the blastomeres, resulting from repeated mitotic divisions of the fertilized ovum, form a compact mass. [NIH] Motility: The ability to move spontaneously. [EU] Motor Activity: The physical activity of an organism as a behavioral phenomenon. [NIH] Motor Cortex: Area of the frontal lobe concerned with primary motor control. It lies anterior to the central sulcus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multicenter Studies: Controlled studies which are planned and carried out by several cooperating institutions to assess certain variables and outcomes in specific patient populations, for example, a multicenter study of congenital anomalies in children. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution.

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[NIH]

Multiparous: 1. Having had two or more pregnancies which resulted in viable fetuses. 2. Producing several ova or offspring at one time. [EU] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH]

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Myometrium: The smooth muscle coat of the uterus, which forms the main mass of the organ. [NIH] Myopia: That error of refraction in which rays of light entering the eye parallel to the optic axis are brought to a focus in front of the retina, as a result of the eyeball being too long from front to back (axial m.) or of an increased strength in refractive power of the media of the eye (index m.). Called also nearsightedness, because the near point is less distant than it is in emmetropia with an equal amplitude of accommodation. [EU] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Nadir: The lowest point; point of greatest adversity or despair. [EU] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatology: A subspecialty of pediatrics concerned with the newborn infant. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephrology: A subspecialty of internal medicine concerned with the anatomy, physiology, and pathology of the kidney. [NIH] Nephron: A tiny part of the kidneys. Each kidney is made up of about 1 million nephrons, which are the working units of the kidneys, removing wastes and extra fluids from the blood. [NIH] Nephropathy: Disease of the kidneys. [EU] Nephrosis: Descriptive histopathologic term for renal disease without an inflammatory component. [NIH] Nephrotic: Pertaining to, resembling, or caused by nephrosis. [EU] Nephrotic Syndrome: Clinical association of heavy proteinuria, hypoalbuminemia, and generalized edema. [NIH] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and

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ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Neutrophil Activation: The process in which the neutrophil is stimulated by diverse substances, resulting in degranulation and/or generation of reactive oxygen products, and culminating in the destruction of invading pathogens. The stimulatory substances, including opsonized particles, immune complexes, and chemotactic factors, bind to specific cellsurface receptors on the neutrophil. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nimodipine: A calcium channel blockader with preferential cerebrovascular activity. It has marked cerebrovascular dilating effects and lowers blood pressure. [NIH] Nitric acid: A toxic, corrosive, colorless liquid used to make fertilizers, dyes, explosives, and other chemicals. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase.

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Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nitroglycerin: A highly volatile organic nitrate that acts as a dilator of arterial and venous smooth muscle and is used in the treatment of angina. It provides relief through improvement of the balance between myocardial oxygen supply and demand. Although total coronary blood flow is not increased, there is redistribution of blood flow in the heart when partial occlusion of coronary circulation is effected. [NIH] Nitroprusside: (OC-6-22)-Pentakis(cyano-C)nitrosoferrate(2-). A powerful vasodilator used in emergencies to lower blood pressure or to improve cardiac function. It is also an indicator for free sulfhydryl groups in proteins. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Normotensive: 1. Characterized by normal tone, tension, or pressure, as by normal blood pressure. 2. A person with normal blood pressure. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nulliparous: Having never given birth to a viable infant. [EU] Nurseries: Facilities which provide care for infants. [NIH] Obstetrics: A medical-surgical specialty concerned with management and care of women during pregnancy, parturition, and the puerperium. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The

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prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] Oedema: The presence of abnormally large amounts of fluid in the intercellular tissue spaces of the body; usually applied to demonstrable accumulation of excessive fluid in the subcutaneous tissues. Edema may be localized, due to venous or lymphatic obstruction or to increased vascular permeability, or it may be systemic due to heart failure or renal disease. Collections of edema fluid are designated according to the site, e.g. ascites (peritoneal cavity), hydrothorax (pleural cavity), and hydropericardium (pericardial sac). Massive generalized edema is called anasarca. [EU] Oligohydramnios: Presence of less than 300 ml of amniotic fluid at term. Principal causes include malformations of fetal urinary tracts, intra-uterine growth retardation, high maternal blood pressure, nicotine poisoning, and prolonged pregnancy. [NIH] Oligonucleotide Probes: Synthetic or natural oligonucleotides used in hybridization studies in order to identify and study specific nucleic acid fragments, e.g., DNA segments near or within a specific gene locus or gene. The probe hybridizes with a specific mRNA, if present. Conventional techniques used for testing for the hybridization product include dot blot assays, Southern blot assays, and DNA:RNA hybrid-specific antibody tests. Conventional labels for the probe include the radioisotope labels 32P and 125I and the chemical label biotin. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oophorectomy: Surgery to remove one or both ovaries. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [NIH]

Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Orgasm: The crisis of sexual excitement in either humans or animals. [NIH] Osmolality: The concentration of osmotically active particles in solution expressed in terms of osmoles of solute per kilogram of solvent. The osmolality is directly proportional to the colligative properties of solutions; osmotic pressure, boiling point elevation, freezing point depression, and vapour pressure lowering. [EU]

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Osmoles: The standard unit of osmotic pressure. [NIH] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Ovum Implantation: Endometrial implantation of the blastocyst. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress,

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1991, pxv-xvi). [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Palpation: Application of fingers with light pressure to the surface of the body to determine consistence of parts beneath in physical diagnosis; includes palpation for determining the outlines of organs. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parity: The number of offspring a female has borne. It is contrasted with gravidity, which refers to the number of pregnancies, regardless of outcome. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Parturition: The act or process of given birth to a child. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Paternity: Establishing the father relationship of a man and a child. [NIH] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvic inflammatory disease: A bacteriological disease sometimes associated with intrauterine device (IUD) usage. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH]

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Penicillin: An antibiotic drug used to treat infection. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: An ulceration of the mucous membrane of the esophagus, stomach or duodenum, caused by the action of the acid gastric juice. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [NIH]

Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [NIH] Perivascular: Situated around a vessel. [EU] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH]

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Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phosphatidic Acids: Fatty acid derivatives of glycerophosphates. They are composed of glycerol bound in ester linkage with 1 mole of phosphoric acid at the terminal 3-hydroxyl group and with 2 moles of fatty acids at the other two hydroxyl groups. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Phosphotyrosine: An amino acid that occurs in endogenous proteins. Tyrosine phosphorylation and dephosphorylation plays a role in cellular signal transduction and possibly in cell growth control and carcinogenesis. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]

Pineal gland: A tiny organ located in the cerebrum that produces melatonin. Also called pineal body or pineal organ. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth

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day of gestation when the blastocyst adheres to the decidua. [NIH] Placental Circulation: The circulation of blood, of both the mother and the fetus, through the placenta. [NIH] Placental Insufficiency: Failure of the placenta to deliver an adequate supply of nutrients and oxygen to the fetus. [NIH] Placental tissue: The tissue intervening between fetal blood and maternal blood in the placenta; it acts as a selective membrane regulating the passage of substances from the maternal to the fetal blood. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activator Inhibitor 1: A member of the serpin family of proteins. It inhibits both the tissue-type and urokinase-type plasminogen activators. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelet Count: A count of the number of platelets per unit volume in a sample of venous blood. [NIH]

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Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postnatal Care: The care provided a woman following the birth of a child. [NIH] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government

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agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Preeclampsia: A toxaemia of late pregnancy characterized by hypertension, edema, and proteinuria, when convulsions and coma are associated, it is called eclampsia. [EU] Pre-Eclampsia: Development of hypertension with proteinuria, edema, or both, due to pregnancy or the influence of a recent pregnancy. It occurs after the 20th week of gestation, but it may develop before this time in the presence of trophoblastic disease. [NIH] Pre-eclamptic: A syndrome characterized by hypertension, albuminuria, and generalized oedema, occurring only in pregnancy. [NIH] Pregnancy Complications: The co-occurrence of pregnancy and a disease. The disease may precede or follow conception and it may or may not have a deleterious effect on the pregnant woman or fetus. [NIH] Pregnancy Outcome: Results of conception and ensuing pregnancy, including live birth, stillbirth, spontaneous abortion, induced abortion. The outcome may follow natural or artificial insemination or any of the various reproduction techniques, such as embryo transfer or fertilization in vitro. [NIH] Pregnancy Tests: Tests to determine whether or not an individual is pregnant. [NIH] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH] Premenstrual: Occurring before menstruation. [EU] Premenstrual Syndrome: A syndrome occurring most often during the last week of the menstrual cycle and ending soon after the onset of menses. Some of the symptoms are emotional instability, insomnia, headache, nausea, vomiting, abdominal distension, and painful breasts. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prenatal Care: Care provided the pregnant woman in order to prevent complications, and decrease the incidence of maternal and prenatal mortality. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare

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the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring

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secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostaglandins B: Physiologically active prostaglandins found in many tissues and organs. They are potent pressor substances and have many other physiological activities. [NIH] Prostaglandins D: Physiologically active prostaglandins found in many tissues and organs. They show pressor activity, are mediators of inflammation, and have potential antithrombotic effects. [NIH] Prostaglandins F: (9 alpha,11 alpha,13E,15S)-9,11,15-Trihydroxyprost-13-en-1-oic acid (PGF(1 alpha)); (5Z,9 alpha,11,alpha,13E,15S)-9,11,15-trihydroxyprosta-5,13-dien-1-oic acid (PGF(2 alpha)); (5Z,9 alpha,11 alpha,13E,15S,17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1oic acid (PGF(3 alpha)). A family of prostaglandins that includes three of the six naturally occurring prostaglandins. All naturally occurring PGF have an alpha configuration at the 9carbon position. They stimulate uterine and bronchial smooth muscle and are often used as oxytocics. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prostatic Hyperplasia: Enlargement or overgrowth of the prostate gland as a result of an increase in the number of its constituent cells. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]

Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU]

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Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Puerperium: Period from delivery of the placenta until return of the reproductive organs to their normal nonpregnant morphologic state. In humans, the puerperium generally lasts for six to eight weeks. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Circulation: The circulation of blood through the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulmonary Ventilation: The total volume of gas per minute inspired or expired measured in liters per minute. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Pupil: The aperture in the iris through which light passes. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Pyelonephritis: Inflammation of the kidney and its pelvis, beginning in the interstitium and rapidly extending to involve the tubules, glomeruli, and blood vessels; due to bacterial infection. [EU] Pyloric Stenosis: Obstruction of the pyloric canal. [NIH] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Pyridoxal Phosphate: 3-Hydroxy-2-methyl-5-((phosphonooxy)methyl)-4pyridinecarboxaldehyde. An enzyme co-factor vitamin. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radial Artery: The direct continuation of the brachial trunk, originating at the bifurcation of the brachial artery opposite the neck of the radius. Its branches may be divided into three groups corresponding to the three regions in which the vessel is situated, the forearm, wrist, and hand. [NIH]

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Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radioactive: Giving off radiation. [NIH] Radioactive iodine: A radioactive form of the chemical element iodine, often used for imaging tests or as a treatment for cancer. [NIH] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radioimmunoassay: Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Nonimmunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. [NIH] Radius: The lateral bone of the forearm. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH]

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Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regression Analysis: Procedures for finding the mathematical function which best describes the relationship between a dependent variable and one or more independent variables. In linear regression (see linear models) the relationship is constrained to be a straight line and least-squares analysis is used to determine the best fit. In logistic regression (see logistic models) the dependent variable is qualitative rather than continuously variable and likelihood functions are used to find the best relationship. In multiple regression the dependent variable is considered to depend on more than a single independent variable. [NIH]

Relaxant: 1. Lessening or reducing tension. 2. An agent that lessens tension. [EU] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal Artery: A branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Reproduction Techniques: Methods pertaining to the generation of new individuals. [NIH] Reproductive History: An important aggregate factor in epidemiological studies of women's health. The concept usually includes the number and timing of pregnancies and their outcomes, the incidence of breast feeding, and may include age of menarche and menopause, regularity of menstruation, fertility, gynecological or obstetric problems, or contraceptive usage. [NIH] Research Design: A plan for collecting and utilizing data so that desired information can be obtained with sufficient precision or so that an hypothesis can be tested properly. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into

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the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Detachment: Separation of the inner layers of the retina (neural retina) from the pigment epithelium. Retinal detachment occurs more commonly in men than in women, in eyes with degenerative myopia, in aging and in aphakia. It may occur after an uncomplicated cataract extraction, but it is seen more often if vitreous humor has been lost during surgery. (Dorland, 27th ed; Newell, Ophthalmology: Principles and Concepts, 7th ed, p310-12). [NIH] Retinitis: Inflammation of the retina. It is rarely limited to the retina, but is commonly associated with diseases of the choroid (chorioretinitis) and of the optic nerve (neuroretinitis). The disease may be confined to one eye, but since it is generally dependent on a constitutional factor, it is almost always bilateral. It may be acute in course, but as a rule it lasts many weeks or even several months. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the

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binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rosiglitazone: A drug taken to help reduce the amount of sugar in the blood. Rosiglitazone helps make insulin more effective and improves regulation of blood sugar. It belongs to the family of drugs called thiazolidinediones. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedentary: 1. Sitting habitually; of inactive habits. 2. Pertaining to a sitting posture. [EU] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH]

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Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Seminal fluid: Fluid from the prostate and other sex glands that helps transport sperm out of the man's body during orgasm. Seminal fluid contains sugar as an energy source for sperm. [NIH] Seminiferous tubule: Tube used to transport sperm made in the testes. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH]

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Sexually Transmitted Diseases: Diseases due to or propagated by sexual contact. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Shock, Septic: Shock due to circulatory insufficiency caused most commonly by gramnegative bacteremia. It is less often the result of the persistent presence of other microorganisms in the blood (fungemia, viremia); in rare instances, it is caused by gram-positive organisms, but with different symptomatology. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH]

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Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Somite: One of the paired blocks of mesoderm present in each segment of the early embryo. [NIH]

Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Soybean Oil: Oil from soybean or soybean plant. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spermatocytes: Male germ cells derived from spermatogonia and developing into spermatids. [NIH] Spermatogonia: The spermatocytes. [NIH]

primitive

differentiated

male

gametes

which

give

rise

to

Sphincter: A ringlike band of muscle fibres that constricts a passage or closes a natural orifice; called also musculus sphincter. [EU] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Status Epilepticus: Repeated and prolonged epileptic seizures without recovery of consciousness between attacks. [NIH] Steady state: Dynamic equilibrium. [EU]

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Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Striate: Recurrent branch of the anterior cerebral artery which supplies the anterior limb of the internal capsule. [NIH] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Strophanthins: A number of different cardioactive glycosides obtained from Strophanthus species. ouabain is from S. gratus and cymarine from S. kombe. They are used like the digitalis glycosides. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH]

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Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic discussion of symptoms. 2. The combined symptoms of a disease. [EU] Synapses: Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate through direct electrical connections which are sometimes called electrical synapses; these are not included here but rather in gap junctions. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Syncytium: A living nucleated tissue without apparent cellular structure; a tissue composed of a mass of nucleated protoplasm without cell boundaries. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Systolic blood pressure: The maximum pressure in the artery produced as the heart contracts and blood begins to flow. [NIH]

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Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Teratoma: A type of germ cell tumor that may contain several different types of tissue, such as hair, muscle, and bone. Teratomas occur most often in the ovaries in women, the testicles in men, and the tailbone in children. Not all teratomas are malignant. [NIH] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombopenia: Reduction in the number of platelets in the blood. [NIH] Thrombophilia: A disorder of hemostasis in which there is a tendency for the occurrence of thrombosis. [NIH] Thromboses: The formation or presence of a blood clot within a blood vessel during life. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation,

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contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Tonicity: The normal state of muscular tension. [NIH] Tonometry: The standard to determine the fluid pressure inside the eye (intraocular pressure). [NIH] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxaemia: 1. The condition resulting from the spread of bacterial products (toxins) by the bloodstream. 2. A condition resulting from metabolic disturbances, e.g. toxaemia of pregnancy. [EU] Toxemia: A generalized intoxication produced by toxins and other substances elaborated by

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an infectious agent. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [NIH] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Triad: Trivalent. [NIH] Trichomoniasis: An infection with the protozoan parasite Trichomonas vaginalis. [NIH] Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent

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or not functional. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]

Trophoblast: The outer layer of cells of the blastocyst which works its way into the endometrium during ovum implantation and grows rapidly, later combining with mesoderm. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tubal ligation: An operation to tie the fallopian tubes closed. This procedure prevents pregnancy by blocking the passage of eggs from the ovaries to the uterus. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tubocurarine: A neuromuscular blocker and active ingredient in curare; plant based alkaloid of Menispermaceae. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]

Tunica Intima: The innermost coat of blood vessels, consisting of a thin lining of endothelial cells longitudinally oriented and continuous with the endothelium of capillaries on the one hand and the endocardium of the heart on the other. [NIH] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This

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condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10 megahertz. [NIH] Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein, which connects the embryo or fetus to the placenta. [NIH] Umbilical cord blood: Blood from the placenta (afterbirth) that contains high concentrations of stem cells needed to produce new blood cells. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinalysis: Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]

Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH] Urticaria: A vascular reaction of the skin characterized by erythema and wheal formation due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress. [NIH] Uterine Contraction: Contraction of the uterine muscle. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH]

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Uvea: The middle coat of the eyeball, consisting of the choroid in the back of the eye and the ciliary body and iris in the front of the eye. [NIH] Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilatation: A state of increased calibre of the blood vessels. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Verapamil: A calcium channel blocker that is a class IV anti-arrhythmia agent. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villi: The tiny, fingerlike projections on the surface of the small intestine. Villi help absorb

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nutrients. [NIH] Villous: Of a surface, covered with villi. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viremia: The presence of viruses in the blood. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Vitelline Membrane: The plasma membrane of the egg. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [NIH] Vitreous Humor: The transparent, colorless mass of gel that lies behind the lens and in front of the retina and fills the center of the eyeball. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xanthine: An urinary calculus. [NIH] Xanthine Oxidase: An iron-molybdenum flavoprotein containing FAD that oxidizes hypoxanthine, some other purines and pterins, and aldehydes. Deficiency of the enzyme, an autosomal recessive trait, causes xanthinuria. EC 1.1.3.22. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Yolk Sac: An embryonic membrane formed from endoderm and mesoderm. In reptiles and birds it incorporates the yolk into the digestive tract for nourishing the embryo. In placental mammals its nutritional function is vestigial; however, it is the source of most of the intestinal mucosa and the site of formation of the germ cells. It is sometimes called the vitelline sac, which should not be confused with the vitelline membrane of the egg. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

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283

INDEX A Abdomen, 199, 210, 227, 229, 238, 240, 244, 256, 271, 272 Abdominal, 64, 151, 193, 199, 200, 214, 238, 248, 256, 261, 266, 278 Abdominal Pain, 199, 278 Aberrant, 40, 51, 199 Abortion, 65, 82, 98, 131, 199, 205, 215, 261 Acceptor, 199, 244, 255 Acetylcholine, 130, 146, 199, 215, 252, 253 Acetylcholinesterase, 143, 199 Acidosis, 199, 242 Actin, 199, 250, 251 Acute renal, 65, 125, 135, 148, 153, 199, 235 Acyl, 199, 246 Adaptability, 199, 213 Adaptation, 6, 28, 38, 50, 60, 199 Adenine, 199, 264 Adenosine, 85, 91, 99, 100, 199, 200, 238, 258 Adenosine Deaminase, 99, 100, 200 Adenovirus, 61, 200 Adipocytes, 200, 243 Adjustment, 199, 200 Adolescence, 45, 200, 256 Adrenal Cortex, 137, 200, 201, 202, 220, 228, 261 Adrenal Medulla, 200, 213, 227, 253 Adrenergic, 200, 223, 227, 273 Adverse Effect, 52, 200, 270 Afferent, 13, 200, 243 Affinity, 59, 200, 246, 270 Agar, 200, 259 Age of Onset, 200, 277 Agonist, 34, 55, 200, 223, 252 Airway, 159, 201, 270 Albumin, 17, 24, 92, 137, 201, 255, 259 Albuminuria, 201, 261 Aldehydes, 201, 280 Aldosterone, 10, 54, 114, 195, 201 Alertness, 143, 201 Algorithms, 201, 209 Alkaline, 137, 199, 201, 202, 211 Alkaline Phosphatase, 137, 201 Allantois, 201, 229 Alleles, 11, 40, 87, 201 Allergen, 201, 269 Allogeneic, 30, 37, 201, 233

Allograft, 35, 148, 149, 201 Alopecia, 201, 220 Alpha Particles, 201, 265 Alpha-Defensins, 201, 221 Alternative medicine, 163, 201 Alveolar Process, 201, 266 Amino Acid Sequence, 202, 204, 228, 246 Ammonia, 200, 202, 278 Amnion, 131, 202, 215, 229 Amniotic Fluid, 84, 124, 131, 202, 232, 246, 254 Amplification, 202, 243 Ampulla, 202, 215 Amyloid, 202, 214 Anaesthesia, 202, 239 Anal, 202, 227, 230, 245 Analog, 126, 144, 202 Analogous, 202, 276 Analytes, 180, 202 Anaphylatoxins, 202, 217 Anatomical, 202, 207, 215, 218, 223, 239, 268 Androgenic, 148, 202 Androgens, 7, 200, 202, 220 Androstenedione, 12, 202 Anemia, 153, 177, 203, 230 Anesthesia, 66, 68, 71, 96, 103, 106, 201, 203, 206, 225 Aneuploidy, 48, 203 Aneurysm, 203, 279 Angina, 125, 132, 133, 141, 146, 151, 152, 203, 242, 253 Angina Pectoris, 146, 151, 152, 203 Angiogenesis, 7, 8, 9, 39, 55, 60, 203 Angioplasty, 151, 152, 203, 206, 250 Angiotensinogen, 11, 50, 54, 203, 266 Animal model, 29, 31, 33, 146, 203 Anionic, 59, 203 Anions, 201, 203, 241, 269, 273 Annealing, 203, 243, 260 Anomalies, 48, 203, 249 Anorexia, 25, 203 Anoxia, 125, 132, 142, 203 Antagonism, 31, 203 Antecedent, 89, 203 Anterior Cerebral Artery, 204, 214, 272 Antibacterial, 204, 271 Antibiotic, 140, 203, 204, 230, 248, 257, 271

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Preeclampsia

Antibodies, 12, 30, 49, 59, 61, 67, 101, 102, 204, 205, 207, 234, 235, 236, 238, 245, 259 Antibodies, Anticardiolipin, 204, 205 Antibodies, Antiphospholipid, 204, 205 Antibody, 44, 59, 69, 200, 204, 217, 226, 234, 236, 238, 239, 246, 254, 265, 269, 271 Anticoagulant, 89, 204, 205, 263 Antidiuretic, 34, 204 Antifibrinolytic, 48, 204 Antigen, 37, 128, 136, 200, 204, 212, 217, 222, 226, 236, 237, 238, 239, 246, 265, 269 Antigen-Antibody Complex, 204, 217 Antigen-presenting cell, 204, 222 Antihypertensive, 110, 150, 204, 236 Anti-infective, 204, 236, 241 Anti-inflammatory, 204, 206, 220, 232, 261 Anti-Inflammatory Agents, 204, 206, 220 Antimicrobial, 42, 204, 221 Antineoplastic, 204, 220, 248 Antioxidant, 22, 26, 52, 57, 67, 88, 114, 205, 255 Antiphospholipid Syndrome, 59, 153, 165, 204, 205 Antiviral, 205, 257 Anus, 202, 205, 210, 217 Aorta, 151, 205, 219, 238, 248, 266, 279 Aphakia, 205, 267 Apnea, 205 Apolipoproteins, 71, 205, 244 Apoptosis, 29, 40, 48, 62, 205, 212 Aqueous, 205, 207, 221, 225, 236 Arachidonate 15-Lipoxygenase, 205, 244 Arachidonate Lipoxygenases, 205, 244 Arachidonic Acid, 44, 63, 124, 146, 205, 225, 243, 262 Arginine, 33, 34, 87, 130, 144, 145, 146, 149, 202, 205, 252 Arrhythmia, 205, 279 Arterial, 5, 36, 49, 50, 51, 59, 61, 105, 142, 148, 151, 205, 206, 214, 215, 219, 237, 253, 263, 273 Arterioles, 4, 54, 206, 209, 211, 248, 250, 279 Arteriosclerosis, 206, 214, 237 Arteriovenous, 206, 214, 248 Arteritis, 132, 206 Articular, 206, 255 Aspartic, 134, 206 Aspartic Acid, 206 Asphyxia, 125, 132, 142, 206 Aspirin, 11, 42, 52, 67, 112, 161, 162, 180, 206

Assay, 44, 62, 95, 108, 128, 129, 206, 238, 265 Asymptomatic, 14, 206 Ataxia, 176, 177, 206, 274 Atherectomy, 206, 225 Atopic, 148, 149, 206 Atopic Eczema, 148, 149, 206 Atrial, 14, 142, 206, 219, 276 Atrial Fibrillation, 142, 206 Atrioventricular, 142, 206, 219 Atrium, 206, 207, 219, 276, 279 Atrophy, 153, 176, 207 Attenuation, 37, 207 Autoantibodies, 66, 117, 204, 207 Autoantigens, 207 Autoimmune disease, 30, 204, 207, 250 Autonomic, 13, 199, 207, 253 Autopsy, 53, 207 Axillary, 207, 210 Axillary Artery, 207, 210 B Bacteremia, 207, 270 Bacterial Physiology, 199, 207 Bacteriophage, 207, 259, 276 Bacterium, 207, 235 Bacteriuria, 207, 278 Basal Ganglia, 206, 207, 214 Basal Ganglia Diseases, 206, 207 Base, 14, 21, 35, 42, 81, 112, 199, 207, 222, 242, 274 Basement Membrane, 208, 228, 242 Basilar Artery, 142, 208 Basophils, 208, 233, 243 Bed Rest, 139, 181, 208 Benign, 132, 141, 208, 234, 251 Benign prostatic hyperplasia, 132, 208 Beta-Defensins, 208, 221 Beta-Thromboglobulin, 208, 240 Bilateral, 68, 126, 208, 267 Bile, 208, 231, 236, 242, 244, 246, 272 Bile Pigments, 208, 242, 246 Biliary, 208, 215 Bilirubin, 201, 208, 237 Bioassay, 24, 38, 208 Bioavailability, 38, 39, 208 Bioavailable, 22, 39, 208 Biochemical, 19, 23, 64, 70, 124, 128, 131, 201, 208, 255, 269 Biological Markers, 52, 57, 208 Biological therapy, 209, 234 Biomarkers, 21, 47, 160, 209

Index 285

Biotechnology, 63, 163, 173, 175, 176, 177, 209 Biotransformation, 209 Bladder, 208, 209, 215, 218, 239, 250, 263, 278 Blastocyst, 18, 40, 45, 209, 218, 225, 255, 259, 277 Blood Coagulation, 59, 209, 211, 274 Blood Coagulation Factors, 209 Blood Glucose, 209, 235, 240 Blood Platelets, 209, 269, 274 Blood Substitutes, 130, 209 Blood transfusion, 25, 209 Blood Volume, 11, 13, 209 Blot, 8, 39, 44, 210, 254 Body Fluids, 209, 210, 224, 270, 277 Body Image, 164, 210 Body Mass Index, 21, 74, 90, 210 Bolus, 147, 210 Bolus infusion, 210 Bone Marrow, 210, 220, 228, 231, 238, 245, 270, 272 Bowel, 125, 132, 133, 141, 202, 210, 223, 240, 272, 278 Bowel Movement, 210, 223, 272 Brachial, 15, 210, 264 Brachial Artery, 15, 210, 264 Bradycardia, 210, 229 Bradykinin, 210, 253, 259 Brain Stem, 210, 214, 216 Branch, 67, 110, 191, 210, 256, 266, 271, 272, 273, 274 Breakdown, 30, 210, 223, 231, 254 Bronchi, 210, 227, 276 Bronchial, 146, 151, 152, 210, 263 Bronchitis, 151, 152, 210, 216 Bronchospasm, 124, 210 Buccal, 36, 210, 245 Bypass, 132, 210, 250 C Cadherins, 150, 211 Calcitonin, 28, 144, 145, 211 Calcitonin Gene-Related Peptide, 144, 145, 211 Calcium channel blocker, 211, 279 Capillary, 7, 9, 128, 210, 211, 232, 279 Capsules, 211, 232 Carbohydrate, 16, 211, 220, 232, 260 Carbon Dioxide, 209, 211, 230, 231, 237, 258, 267, 279 Carcinogenesis, 45, 211, 258 Carcinogenic, 45, 211, 240, 262, 272

Carcinogens, 211, 254, 255 Carcinoma, 211 Cardenolides, 142, 211 Cardiac arrest, 125, 132, 141, 212 Cardiac Glycosides, 142, 211, 212 Cardiac Output, 10, 38, 51, 150, 212 Cardiogenic, 132, 212 Cardiolipins, 205, 212 Cardiomyopathy, 212 Cardiotonic, 142, 212, 223 Cardiotonic Agents, 142, 212 Cardiovascular disease, 6, 14, 23, 32, 60, 126, 148, 164, 212, 244 Cardiovascular System, 6, 58, 149, 151, 212 Carotene, 212, 267 Carotenoids, 112, 212 Carrier Proteins, 212, 259, 265 Case report, 35, 106, 212 Case-Control Studies, 25, 61, 212, 227 Caspase, 62, 212 Catabolism, 73, 213 Cataract, 205, 213, 267 Catecholamine, 213, 223 Catheter, 206, 213, 225 Catheterization, 203, 213, 250 Causal, 12, 38, 213, 227, 235 Cause of Death, 26, 128, 150, 164, 213 Caveolae, 6, 213 Caveolins, 213 Cell Adhesion, 103, 150, 211, 213 Cell Death, 29, 205, 213, 216 Cell Differentiation, 141, 213, 270 Cell Division, 176, 207, 213, 234, 247, 249, 259 Cell Lineage, 24, 213 Cell membrane, 212, 213, 222, 241, 258, 260 Cell Membrane Structures, 213 Cell proliferation, 206, 213, 270 Cell Survival, 213, 234 Central Nervous System, 124, 149, 199, 214, 215, 231, 232, 234, 243, 250, 254, 260, 269 Central Nervous System Infections, 214, 234 Centrifugation, 214, 248 Cerebellar, 206, 214, 265 Cerebellum, 62, 132, 214, 260, 265 Cerebral, 69, 97, 104, 106, 110, 125, 132, 133, 140, 141, 146, 148, 150, 151, 152,

286

Preeclampsia

154, 204, 206, 207, 208, 210, 214, 219, 220, 227, 230, 235 Cerebral Arteries, 208, 214 Cerebral Cortex, 206, 214 Cerebral Hemorrhage, 148, 151, 152, 214 Cerebral Infarction, 125, 132, 141, 214 Cerebral Palsy, 97, 150, 214 Cerebrovascular, 69, 207, 212, 214, 252, 274 Cerebrum, 214, 258, 277 Cervical, 124, 148, 214 Cervix, 199, 214 Cesarean Section, 52, 70, 71, 214 Character, 46, 203, 214, 221 Chemotactic Factors, 214, 217, 252 Chemotherapeutic agent, 30, 214 Chin, 215, 247 Cholestasis, 92, 215 Cholesterol, 32, 208, 213, 215, 216, 219, 224, 237, 244, 245, 247, 272 Cholesterol Esters, 215, 244 Choline, 199, 215 Cholinergic, 215, 252 Cholinesterase Inhibitors, 143, 215 Chorioamnionitis, 47, 215 Choriocarcinoma, 19, 149, 215, 236 Chorion, 215, 229 Chorioretinitis, 215, 267 Choroid, 215, 267, 279 Chromatin, 205, 215, 226 Chromosomal, 40, 202, 203, 215 Chromosome, 40, 92, 203, 215, 243, 249, 277 Chronic Disease, 20, 46, 215 Chronic Fatigue Syndrome, 143, 215 Chronic Obstructive Pulmonary Disease, 132, 216 Chronic renal, 125, 132, 133, 141, 216, 231, 260 Chylomicrons, 216, 244 Cirrhosis, 125, 132, 141, 216 CIS, 15, 216, 267 Climacteric, 149, 216 Clinical Medicine, 216, 261 Clinical Protocols, 16, 216 Clinical trial, 4, 42, 119, 120, 173, 216, 218, 220, 224, 249, 263, 265 Clitoral, 152, 216 Clonal Deletion, 29, 216 Cloning, 209, 216, 243 Coagulation, 59, 71, 77, 128, 153, 205, 209, 216, 235, 259, 275

Cochlea, 216 Cochlear, 25, 216 Cochlear Implants, 25, 216 Cochlear Nerve, 216 Cofactor, 216, 263, 274 Cohort Studies, 217, 227 Colitis, 217 Collagen, 150, 202, 208, 217, 218, 230, 259, 262 Collapse, 210, 217, 270 Colloidal, 201, 217, 269 Colon, 176, 217, 242, 277 Combination Therapy, 217, 228 Complement, 21, 195, 202, 217, 259, 269 Complement Activation, 21, 202, 217 Compliance, 49, 51, 150, 217 Compress, 218, 235 Computational Biology, 173, 175, 218 Conception, 35, 51, 199, 215, 218, 229, 261, 272 Conduction, 142, 218 Cones, 218, 267 Confounding, 12, 20, 52, 57, 218 Congestive heart failure, 125, 132, 135, 141, 212, 218 Conjugated, 137, 218, 221 Conjunctiva, 218 Conjunctivitis, 140, 218 Connective Tissue, 205, 210, 217, 218, 222, 230, 231, 245, 248, 267, 272, 273 Connective Tissue Diseases, 205, 218 Consciousness, 218, 223, 271 Constitutional, 32, 218, 267 Constriction, 50, 218, 241, 279 Constriction, Pathologic, 218, 279 Consultation, 18, 218 Consumption, 128, 154, 218, 222, 267 Contraception, 35, 164, 218 Contractility, 28, 36, 51, 131, 148, 218 Contraindications, ii, 218 Control group, 23, 25, 52, 57, 218 Convulsions, 129, 146, 154, 219, 224, 261 Coordination, 35, 43, 56, 214, 219, 250 Cor, 104, 219, 220 Cornea, 219, 233, 268, 279 Coronary, 18, 27, 126, 147, 151, 152, 164, 203, 212, 219, 237, 248, 250, 253 Coronary Arteriosclerosis, 219, 250 Coronary Artery Bypass, 151, 152, 219 Coronary Circulation, 203, 219, 253 Coronary heart disease, 126, 212, 219 Coronary Thrombosis, 219, 248, 250

Index 287

Corpus, 219, 245, 257, 261, 280 Corpus Luteum, 219, 245, 261 Cortex, 219, 226 Cortical, 74, 87, 101, 148, 219, 268, 274 Cortical Blindness, 74, 87, 101, 148, 219 Corticosteroid, 42, 220, 261 Corticotropin-Releasing Hormone, 104, 220 Cortisol, 201, 220 Cortisone, 220, 261 Cranial, 214, 216, 220, 234, 254 Craniocerebral Trauma, 207, 214, 220, 234, 274 Creatinine, 64, 72, 107, 195, 196, 220 Cross-Sectional Studies, 220, 227 Curative, 220, 252, 274 Cutaneous, 220, 245 Cyclic, 220, 234, 253, 262 Cyclophosphamide, 164, 220 Cyclosporine, 153, 220 Cystathionine beta-Synthase, 81, 220, 237 Cytochrome, 5, 44, 62, 92, 99, 147, 221 Cytochrome b, 44, 221 Cytochrome b5, 44, 221 Cytokine, 18, 30, 44, 73, 90, 99, 221, 240 Cytomegalovirus, 61, 221 Cytoplasm, 134, 205, 208, 213, 221, 226, 268 Cytotoxic, 29, 43, 129, 140, 221, 246, 270 D Dairy Products, 182, 221 Data Collection, 18, 221 De novo, 9, 13, 47, 221 Decidua, 90, 150, 221, 259 Defense Mechanisms, 149, 221 Defensins, 135, 136, 201, 208, 221 Degenerative, 221, 235, 255, 267 Deletion, 29, 40, 205, 216, 222 Denaturation, 222, 243, 260 Dendrites, 222, 252 Dendritic, 37, 222, 247 Dendritic cell, 37, 222 Density, 7, 12, 32, 52, 60, 137, 138, 210, 214, 222, 224, 244, 254, 271 Dentate Gyrus, 222, 235 Deoxyribonucleic, 222, 268 Deoxyribonucleic acid, 222, 268 Depolarization, 222, 270 Dermis, 222, 276 Developed Countries, 26, 30, 126, 222 Developing Countries, 26, 222

Diabetes Mellitus, 25, 127, 148, 149, 181, 222, 232, 235 Diabetic Retinopathy, 58, 222, 258 Diagnostic procedure, 123, 136, 163, 222 Dialyzer, 222, 234 Diastolic, 195, 222, 237 Dietary Fats, 222, 244 Digestion, 134, 208, 210, 223, 240, 244, 257, 272 Digestive system, 121, 223, 249 Digestive tract, 223, 270, 280 Digitalis, 142, 147, 212, 223, 272 Dihydrotestosterone, 223, 265 Dilatation, 199, 203, 223, 241, 261, 279 Dilatation, Pathologic, 223, 279 Dilate, 141, 223 Dilated cardiomyopathy, 132, 223 Dilation, 11, 124, 152, 206, 210, 223, 279 Dilator, 223, 253 Diploid, 203, 223, 249, 259, 277 Direct, iii, 6, 26, 34, 36, 43, 137, 167, 216, 223, 236, 245, 264, 265, 273 Disposition, 60, 146, 223 Dissection, 71, 223 Dissociation, 5, 200, 223 Dissociative Disorders, 223 Distal, 151, 152, 219, 223, 264 Dopamine, 71, 223, 252, 258 Dorsal, 28, 224, 260 Dose-dependent, 28, 129, 224 Double-blind, 26, 38, 224 Double-blinded, 26, 224 Drive, ii, vi, 20, 45, 109, 164, 224, 241, 243 Drug Interactions, 168, 224 Drug Tolerance, 224, 275 Duct, 202, 213, 224, 228, 268, 272 Duodenum, 208, 224, 257, 272 Dyes, 202, 208, 224, 252 Dyslipidemia, 32, 51, 224 Dysmenorrhea, 130, 131, 148, 152, 224 Dyspareunia, 224, 228 Dysplasia, 177, 224 Dystocia, 148, 224 Dystrophy, 176, 224 E Eclampsia, 8, 25, 26, 38, 39, 40, 45, 50, 65, 68, 71, 74, 76, 95, 97, 104, 105, 108, 110, 111, 127, 129, 139, 144, 145, 146, 147, 151, 152, 153, 154, 176, 181, 182, 224, 261 Effector, 37, 199, 217, 224 Efficacy, 23, 26, 31, 34, 71, 142, 224 Eicosanoids, 124, 225

288

Preeclampsia

Elasticity, 151, 206, 219, 225 Elastin, 217, 218, 225 Elective, 70, 96, 225 Electrocoagulation, 216, 225 Electrolyte, 5, 201, 220, 225, 248, 260, 270 Embolus, 225, 239 Embryo, 21, 40, 56, 150, 182, 199, 202, 209, 213, 225, 229, 239, 248, 249, 261, 271, 278, 280 Embryo Transfer, 225, 261 Emphysema, 216, 225 Empirical, 137, 225 Emulsions, 130, 200, 209, 225 Endarterectomy, 151, 152, 203, 206, 225 Endocytosis, 213, 225 Endoderm, 225, 280 Endogenous, 28, 31, 41, 63, 145, 147, 148, 151, 152, 207, 209, 211, 223, 225, 255, 258, 276 Endometrial, 19, 225, 255 Endometriosis, 124, 225 Endometrium, 150, 221, 225, 247, 277 Endothelins, 133, 135, 225 Endothelium, Lymphatic, 226 Endothelium, Vascular, 226 Endothelium-derived, 36, 130, 134, 151, 152, 226, 253 Endotoxic, 125, 132, 133, 135, 141, 226, 244 Endotoxin, 226, 277 End-stage renal, 216, 226, 260 Energy balance, 226, 243 Entorhinal Cortex, 226, 235 Environmental Exposure, 209, 226, 254 Environmental Health, 172, 174, 226 Enzymatic, 32, 57, 62, 202, 211, 212, 217, 226, 229, 230, 247, 260, 267 Enzyme Inhibitors, 226, 259 Enzyme-Linked Immunosorbent Assay, 8, 226 Eosinophils, 226, 233, 243 Epidemic, 153, 227, 271 Epidemiologic Factors, 35, 227 Epidemiologic Studies, 19, 209, 227 Epidemiological, 35, 62, 126, 227, 266 Epidermal, 66, 227, 242, 247 Epidermal Growth Factor, 66, 227 Epidermis, 222, 227, 242, 264 Epigastric, 227, 256 Epinephrine, 200, 223, 227, 252, 253, 277 Epithelial, 130, 208, 221, 227, 242 Epithelial Cells, 208, 227, 242

Epithelium, 208, 215, 226, 227, 231, 256, 267 Erectile, 132, 227, 257 Erection, 152, 227 Erythema, 227, 278 Erythrocyte Aggregation, 111, 227 Erythrocyte Volume, 209, 227 Erythrocytes, 112, 203, 210, 227, 235, 265, 269 Erythropoietin, 25, 227 Esophagitis, 140, 228 Esophagus, 223, 228, 257, 272 Essential Tremor, 176, 228 Estradiol, 228 Estriol, 137, 228 Estrogen, 5, 12, 36, 81, 126, 130, 131, 164, 228, 262 Estrogen receptor, 5, 81, 228 Estrogen Replacement Therapy, 164, 228 Ether, 132, 228 Eukaryotic Cells, 228, 239, 254, 277 Exhaustion, 203, 228 Exocrine, 228, 256 Exogenous, 14, 38, 43, 209, 225, 228, 277 Exon, 15, 228 Expiration, 228, 267 Expiratory, 138, 228 Extracellular, 6, 55, 59, 124, 141, 150, 202, 218, 225, 228, 230, 270 Extracellular Matrix, 124, 141, 150, 218, 228, 230 Extracellular Space, 228 Extraction, 205, 214, 228, 267 Extrapyramidal, 223, 228 Eye Infections, 200, 228 F Fallopian tube, 229, 277 Family Planning, 173, 229 Fat, 44, 200, 205, 210, 212, 219, 220, 225, 229, 242, 243, 244, 250, 260, 267, 277 Fathers, 13, 161, 229 Fatigue, 143, 164, 215, 229, 234, 247 Fatty acids, 17, 24, 32, 44, 49, 112, 137, 161, 201, 225, 229, 233, 244, 246, 258, 262 Fertilization in Vitro, 229, 261 Fertilizers, 229, 252 Fetal Blood, 215, 229, 259 Fetal Death, 19, 137, 229 Fetal Distress, 59, 229 Fetal Growth Retardation, 44, 46, 58, 74, 131, 144, 145, 148, 229 Fetal Membranes, 34, 48, 124, 229

Index 289

Fetal Movement, 34, 229 Fetal Viability, 30, 59, 229 Fetal Weight, 60, 229 Fibrillation, 142, 229 Fibrin, 154, 195, 209, 229, 259, 274, 275 Fibrinogen, 79, 195, 227, 229, 259, 274 Fibrinolysis, 74, 204, 229 Fibrinolytic, 48, 229 Fibroblasts, 129, 230, 240, 249 Fibrosis, 25, 153, 177, 230, 268 Fixation, 230, 269 Flatus, 230, 231 Folate, 111, 230 Fold, 20, 21, 26, 27, 32, 36, 53, 133, 135, 141, 230, 248 Folic Acid, 67, 113, 115, 230 Follicles, 222, 230, 240 Follicular Phase, 56, 230 Forearm, 51, 209, 230, 264, 265 Fossa, 214, 230 Free Radicals, 205, 223, 230, 250 Friction, 230, 245 Frontal Lobe, 204, 214, 230, 249 Fungemia, 230, 270 Furosemide, 71, 230 G Galanthamine, 143, 231 Gallbladder, 199, 208, 223, 231 Ganglia, 28, 199, 207, 231, 252 Gas, 149, 202, 211, 230, 231, 236, 252, 253, 264, 267, 279 Gas exchange, 231, 267, 279 Gastric, 125, 132, 133, 141, 227, 231, 257 Gastric Juices, 231, 257 Gastric Mucosa, 125, 132, 133, 141, 231 Gastrin, 231, 236 Gastrointestinal, 149, 151, 152, 210, 215, 227, 231, 243, 269, 273, 277 Gastrointestinal tract, 149, 215, 231, 243, 269, 277 Gene Expression, 8, 11, 15, 19, 24, 45, 47, 48, 177, 231 Gene Therapy, 200, 231 Genetic testing, 231, 260 Genetics, 5, 11, 25, 39, 55, 81, 92, 96, 107, 111, 140, 200, 231 Genital, 152, 231, 278 Genitourinary, 231, 278 Genotype, 32, 48, 50, 163, 231, 258 Germ Cells, 231, 247, 255, 271, 274, 280 Gestational Age, 20, 21, 26, 48, 68, 84, 96, 101, 105, 232

Gingivitis, 140, 232 Gland, 200, 220, 232, 245, 256, 258, 263, 268, 272, 275 Glomerular, 5, 10, 12, 33, 128, 153, 232, 241, 266 Glomerular Filtration Rate, 5, 10, 232 Glomeruli, 232, 264 Glomerulus, 153, 232, 251 Glucocorticoid, 48, 232, 261 Glucose, 15, 25, 60, 176, 183, 209, 222, 232, 233, 235, 240, 268 Glucose Intolerance, 222, 232 Glucose tolerance, 15, 25, 232 Glucose Tolerance Test, 15, 25, 232 Glutamic Acid, 230, 232, 252, 262 Glutathione Peroxidase, 232, 268 Glycerol, 212, 232, 233, 258 Glycerophospholipids, 233, 258 Glycine, 202, 233, 252, 269 Glycogen, 24, 233 Glycoprotein, 18, 67, 227, 229, 233, 242, 246, 274, 277 Glycosaminoglycan, 113, 233 Glycosidic, 212, 233 Goats, 221, 233 Gonadal, 233, 272 Gonadotropin, 18, 215, 233 Gonorrhea, 136, 233 Governing Board, 233, 261 Gp120, 233, 257 Graft, 151, 152, 233, 236, 250 Graft Rejection, 151, 152, 233 Grafting, 219, 233, 239 Gram-negative, 226, 233, 270 Gram-Negative Bacteria, 226, 233 Gram-positive, 233, 270 Granulocyte, 86, 233 Granulosa Cells, 233, 240, 245 Grasses, 230, 234 Gravidity, 234, 256 Growth factors, 7, 8, 9, 55, 102, 234 Guanylate Cyclase, 33, 234, 253 H Habitual, 214, 234 Haemorrhage, 199, 234 Haptens, 200, 234, 265 Headache, 129, 168, 194, 234, 261 Headache Disorders, 234 Health Behavior, 23, 234 Health Status, 234 Heart attack, 212, 234 Heart failure, 132, 133, 234, 254

290

Preeclampsia

Hematoma, 234, 235 Hematopoiesis, 58, 234 Hematuria, 85, 234 Heme, 81, 147, 208, 221, 234, 256 Hemodialysis, 132, 222, 234 Hemodynamics, 38, 142, 234 Hemoglobin, 39, 127, 203, 209, 227, 234, 235, 243 Hemoglobinuria, 176, 235 Hemolysis, 82, 89, 107, 148, 154, 235 Hemolytic, 153, 235 Hemorrhage, 125, 132, 133, 135, 141, 209, 220, 225, 234, 235, 250, 264, 272, 280 Hemorrhagic stroke, 125, 132, 141, 235 Hemostasis, 66, 71, 108, 235, 269, 274 Hepatic, 129, 148, 197, 201, 232, 235 Hepatitis, 68, 235 Hepatocyte, 215, 235 Hereditary, 218, 235, 267 Heredity, 231, 235 Heterodimer, 58, 235 Heterogeneity, 200, 235 Hippocampus, 62, 222, 235, 272 Histocompatibility, 35, 235 Histology, 11, 45, 236 Homeostasis, 59, 236 Homologous, 201, 231, 236, 269, 273 Hormonal, 24, 37, 152, 207, 220, 228, 236 Hormone Replacement Therapy, 126, 131, 148, 236 Horseradish Peroxidase, 226, 236 Host, 140, 207, 221, 236, 238, 243, 249, 280 Humoral, 153, 233, 236 Humour, 236 Hybrid, 236, 254 Hybridization, 48, 236, 254 Hybridomas, 236, 240 Hydatidiform Mole, 215, 236 Hydralazine, 93, 236 Hydration, 34, 236 Hydrogen, 199, 208, 211, 222, 232, 236, 244, 249, 252, 253, 255, 263, 273 Hydrogen Peroxide, 232, 236, 244, 273 Hydrolysis, 199, 200, 206, 209, 237, 241, 258, 263 Hydrophobic, 233, 237, 244 Hydroxylysine, 217, 237 Hydroxyproline, 202, 217, 237 Hyperbilirubinemia, 25, 237, 242 Hypercapnia, 153, 237 Hypercholesterolemia, 224, 237 Hyperglycemia, 26, 237

Hyperhomocysteinemia, 27, 83, 220, 237 Hyperlipidemia, 224, 237 Hyperplasia, 141, 237 Hyperreflexia, 129, 237 Hypersensitivity, 201, 237, 243, 267, 269 Hypertension, Pulmonary, 132, 237 Hypertension, Renal, 158, 237 Hypertension, Renovascular, 237 Hyperthermia, 131, 237 Hypertriglyceridemia, 32, 224, 237 Hypertrophy, 25, 208, 219, 237, 276 Hypoglycemia, 25, 125, 132, 141, 237 Hypotension, 96, 219, 237 Hypothalamic, 34, 237 Hypothalamus, 220, 237, 238, 258 Hypoxanthine, 238, 280 Hypoxemia, 19, 62, 238 Hypoxia, 6, 15, 19, 28, 31, 39, 48, 49, 53, 58, 60, 62, 84, 96, 153, 238, 274 Hypoxic, 39, 47, 58, 62, 238 Hysterotomy, 214, 238 I Id, 115, 176, 180, 183, 190, 192, 238 Idiopathic, 85, 128, 129, 153, 238 Iliac Artery, 238, 278 Immune function, 48, 238 Immune response, 29, 37, 204, 207, 220, 233, 234, 238, 269, 273, 280 Immune system, 19, 23, 29, 30, 37, 153, 204, 209, 238, 239, 243, 245, 246, 250, 257, 279, 280 Immune Tolerance, 21, 35, 238 Immunity, 100, 221, 238 Immunization, 238, 269 Immunoassay, 39, 204, 226, 238 Immunodeficiency, 143, 176, 238 Immunogenic, 238, 244, 265 Immunoglobulins, 196, 238, 259 Immunohistochemistry, 44, 56, 238 Immunologic, 25, 214, 232, 238 Immunology, 11, 37, 40, 73, 78, 85, 106, 200, 236, 239 Immunosuppressive, 220, 232, 239 Impairment, 52, 59, 74, 165, 206, 215, 229, 239, 247 Implantation, 11, 18, 21, 29, 30, 35, 49, 56, 97, 148, 218, 239, 255 Impotence, 148, 227, 239 In situ, 34, 48, 239 In Situ Hybridization, 34, 48, 239

Index 291

In vitro, 6, 12, 18, 19, 24, 29, 37, 47, 53, 56, 57, 59, 60, 61, 97, 129, 134, 137, 225, 231, 239, 260 In vivo, 6, 7, 24, 29, 33, 47, 48, 53, 56, 59, 134, 142, 231, 239, 244, 255, 274 Incision, 52, 238, 239, 241 Incontinence, 148, 239 Incubated, 129, 239 Indicative, 35, 137, 157, 239, 256, 279 Induction, 16, 19, 37, 56, 86, 139, 147, 202, 239, 262 Infancy, 49, 239 Infant Mortality, 131, 239 Infarction, 140, 214, 235, 239, 266 Infertility, 30, 148, 239 Infiltration, 30, 44, 239 Infusion, 54, 59, 71, 240, 250, 276 Ingestion, 232, 240, 260 Inhibin, 80, 86, 87, 92, 103, 240 Initiation, 18, 60, 240, 276 Inotropic, 142, 223, 240 Insight, 3, 12, 15, 30, 240 Insomnia, 240, 261 Insulator, 240, 250 Insulin, 7, 14, 24, 27, 38, 68, 80, 93, 100, 102, 111, 129, 160, 161, 183, 232, 240, 242, 268, 277 Insulin-dependent diabetes mellitus, 240 Insulin-like, 24, 93, 100, 102, 111, 129, 161, 240 Intensive Care, 65, 150, 240 Interleukin-6, 85, 107, 240 Interleukin-8, 44, 84, 240 Intermittent, 143, 240 Internal Medicine, 14, 67, 240, 251 Interstitial, 48, 228, 240, 251, 266 Intestinal, 132, 133, 135, 148, 201, 212, 232, 240, 246, 280 Intestinal Mucosa, 240, 280 Intestine, 210, 240, 242 Intoxication, 240, 275 Intracellular, 36, 134, 239, 241, 247, 253, 260, 262, 268, 270 Intracranial Aneurysm, 214, 241 Intraocular, 241, 275 Intraocular pressure, 241, 275 Intravascular, 4, 50, 154, 241 Intravenous, 15, 147, 164, 230, 240, 241 Intrinsic, 4, 200, 208, 241 Inulin, 232, 241 Invasive, 51, 52, 61, 76, 136, 138, 141, 150, 236, 238, 241, 246

Involuntary, 207, 228, 229, 241, 250, 266 Iodine, 136, 241, 265 Ion Channels, 36, 241 Ion Transport, 5, 241, 248 Ions, 207, 223, 225, 236, 241, 260, 263 Ischemia, 3, 58, 61, 62, 96, 98, 125, 132, 141, 146, 207, 235, 241, 250, 266 Isoelectric, 24, 241 Isoelectric Focusing, 24, 241 Isoelectric Point, 241 Isosorbide, 104, 241, 242 Isosorbide Dinitrate, 104, 242 J Jaundice, 45, 129, 237, 242 Joint, 206, 242, 255, 273 K Kb, 172, 242 Keratinocytes, 240, 242 Ketoacidosis, 60, 242 Ketone Bodies, 242 Ketosis, 242 Kidney Disease, 70, 121, 137, 142, 153, 165, 172, 177, 201, 242 Kidney stone, 242, 278 Kinetic, 242 L Labile, 130, 217, 242 Lactation, 242, 262 Laminin, 150, 208, 242 Large Intestine, 223, 240, 242, 265, 270 Larynx, 13, 242, 276 Least-Squares Analysis, 242, 266 Leptin, 31, 49, 66, 73, 88, 93, 103, 107, 110, 243 Lethal, 40, 126, 243 Leucine, 75, 243 Leucocyte, 243, 245 Leukemia, 13, 18, 176, 231, 243 Leukocytes, 208, 210, 214, 226, 243, 249, 277 Leukotrienes, 205, 225, 243 Libido, 202, 243 Library Services, 190, 243 Ligament, 229, 243, 263 Ligands, 30, 107, 243 Ligase, 136, 243 Ligase Chain Reaction, 136, 243 Ligation, 243 Likelihood Functions, 243, 266 Linear Models, 243, 266 Linkage, 11, 45, 49, 88, 243, 258 Lipase, 32, 89, 244

292

Preeclampsia

Lipid A, 32, 244 Lipid Peroxidation, 32, 67, 89, 94, 113, 244, 255 Lipid Peroxides, 22, 44, 102, 113, 139, 244 Lipopolysaccharide, 131, 233, 244 Lipoprotein, 32, 52, 72, 89, 224, 233, 244, 245 Lipoprotein(a), 72, 89, 244 Lipoxygenase, 124, 205, 243, 244 Lobe, 204, 214, 244 Localization, 43, 238, 244 Localized, 36, 61, 152, 230, 234, 239, 242, 244, 254, 259, 277, 278 Logistic Models, 244, 266 Longitudinal Studies, 17, 220, 244 Longitudinal study, 50, 51, 64, 91, 245 Low-density lipoprotein, 89, 102, 224, 244, 245 Lubricants, 245 Lubrication, 152, 245 Lucida, 242, 245 Luciferase, 44, 245 Lupus, 89, 148, 149, 153, 164, 165, 204, 205, 245, 273 Lupus Nephritis, 165, 245 Luteal Phase, 56, 245 Lutein Cells, 245, 262 Lymph, 207, 214, 225, 226, 236, 245, 272 Lymph node, 207, 214, 245 Lymphatic, 226, 239, 245, 248, 254, 270, 271, 275 Lymphoblasts, 93, 245 Lymphocyte, 30, 37, 90, 204, 245, 246, 249 Lymphoid, 204, 243, 245 Lymphoma, 176, 245 Lymphotoxin, 87, 246 Lysophospholipids, 127, 246 Lytic, 246, 269 M Macrophage, 70, 76, 85, 130, 149, 246 Macrophage Colony-Stimulating Factor, 70, 76, 85, 246 Magnetic Resonance Imaging, 74, 246 Malabsorption, 176, 246 Malignancy, 246, 256 Malignant, 132, 153, 176, 205, 215, 246, 251, 274 Malignant tumor, 215, 246 Malnutrition, 201, 207, 246, 250 Malondialdehyde, 52, 100, 104, 246 Mammary, 15, 219, 246 Mammogram, 12, 246

Mandible, 201, 215, 246, 266 Maternal Mortality, 26, 27, 33, 144, 145, 246 Meconium, 229, 246 Mediate, 14, 15, 19, 33, 56, 130, 133, 154, 216, 223, 246 Mediator, 58, 144, 145, 246, 269 Medical Records, 26, 246 Medical Staff, 224, 247 MEDLINE, 173, 175, 177, 247 Medullary, 5, 247 Megaloblastic, 230, 247 Meiosis, 13, 247, 273 Melanin, 247, 258, 277 Melanocytes, 247 Melanoma, 25, 176, 247 Membrane Glycoproteins, 247 Membrane Lipids, 247, 258 Membrane Proteins, 213, 247 Memory, 203, 247 Menarche, 45, 86, 247, 266 Meninges, 214, 220, 247 Menopause, 149, 164, 247, 260, 261, 266 Menstrual Cycle, 18, 230, 245, 247, 261, 262 Menstruation, 221, 224, 230, 245, 247, 261, 266 Mental, iv, 4, 51, 121, 143, 150, 172, 174, 178, 214, 215, 223, 229, 247, 264, 269, 278 Mental Disorders, 121, 247 Mental Fatigue, 143, 247 Mental Processes, 223, 247, 264 Mentors, 11, 248 Mesenchymal, 48, 227, 236, 246, 248 Mesenteric, 17, 38, 54, 248 Mesenteric Arteries, 17, 38, 248 Mesentery, 248 Mesoderm, 40, 248, 271, 277, 280 Meta-Analysis, 126, 248 Metabolite, 33, 209, 228, 248, 261 MI, 61, 68, 125, 132, 133, 135, 140, 141, 198, 248 Microbe, 248, 276 Microbiology, 199, 207, 248 Microcirculation, 96, 248, 259 Microorganism, 216, 248, 280 Micro-organism, 248, 258, 270 Microscopy, 75, 208, 236, 248 Microsomal, 107, 248 Migration, 44, 53, 117, 141, 248 Mineralocorticoids, 200, 220, 248 Miscarriage, 20, 61, 248

Index 293

Mitomycin, 153, 248 Mitosis, 205, 249 Mixed Function Oxidases, 221, 249 Modification, 17, 202, 249 Modulator, 8, 37, 249 Molecular, 5, 11, 15, 17, 19, 23, 29, 30, 31, 34, 36, 39, 40, 45, 46, 48, 49, 58, 60, 93, 111, 157, 173, 175, 209, 218, 221, 222, 229, 244, 249, 259, 262, 273, 276, 277 Monitor, 54, 57, 220, 249, 253 Monocyte, 10, 84, 246, 249 Monocyte Chemoattractant Protein-1, 84, 249 Mononuclear, 76, 246, 249, 277 Monosomy, 203, 249 Morphogenesis, 53, 249 Morphological, 128, 225, 247, 249 Morula, 209, 249 Motility, 53, 148, 149, 249, 269 Motor Activity, 219, 249 Motor Cortex, 62, 249, 265 Mucosa, 231, 245, 249, 262, 272 Mucositis, 249, 275 Mucus, 249, 278 Multicenter Studies, 16, 43, 249 Multicenter study, 249 Multiparous, 21, 23, 250 Multiple sclerosis, 140, 250 Muscle Contraction, 182, 202, 250 Muscle Fibers, 250, 251 Muscular Atrophy, 176, 250 Muscular Dystrophies, 224, 250 Mydriatic, 223, 250 Myelin, 250 Myocardial infarction, 125, 132, 133, 135, 140, 141, 146, 151, 152, 208, 219, 248, 250 Myocardial Ischemia, 125, 132, 141, 148, 203, 250 Myocardial Reperfusion, 250, 266 Myocardial Reperfusion Injury, 250, 266 Myocardium, 203, 248, 250 Myometrium, 97, 141, 150, 251 Myopia, 251, 266, 267 Myosin, 250, 251 Myotonic Dystrophy, 176, 251 N Nadir, 10, 251 Nausea, 194, 242, 251, 261, 278 NCI, 1, 120, 171, 216, 251 Need, 3, 130, 136, 146, 157, 164, 184, 216, 233, 251, 275 Neonatology, 17, 35, 53, 251

Neoplasia, 176, 251 Neoplasm, 251, 277 Neoplastic, 140, 236, 245, 251 Nephritis, 151, 152, 165, 251 Nephrology, 14, 78, 85, 251 Nephron, 232, 251 Nephropathy, 242, 251 Nephrosis, 251 Nephrotic, 137, 251 Nephrotic Syndrome, 137, 251 Nerve, 200, 203, 206, 215, 216, 222, 246, 250, 251, 252, 254, 260, 268, 272, 276 Nervous System, 176, 200, 214, 246, 251, 252, 273 Networks, 16, 34, 252 Neural, 13, 40, 42, 62, 200, 202, 211, 236, 252, 267 Neurologic, 129, 252 Neuromuscular, 199, 252, 277 Neuromuscular Junction, 199, 252 Neuronal, 62, 252 Neurons, 62, 216, 222, 231, 252, 273 Neuropeptide, 211, 220, 252 Neuroretinitis, 252, 267 Neurotransmitter, 199, 200, 202, 206, 210, 211, 215, 223, 232, 233, 241, 252, 253, 270, 273 Neutrons, 201, 252, 265 Neutrophil, 44, 46, 93, 113, 135, 136, 252 Neutrophil Activation, 46, 113, 252 Niacin, 252, 277 Nicotine, 252, 254 Nimodipine, 119, 252 Nitric acid, 130, 252 Nitrogen, 202, 220, 230, 253, 277 Nitroglycerin, 144, 145, 242, 253 Nitroprusside, 144, 145, 253 Norepinephrine, 146, 200, 223, 252, 253 Normotensive, 14, 18, 21, 35, 70, 73, 95, 147, 253 Nuclear, 44, 207, 228, 253 Nuclei, 201, 204, 216, 231, 246, 249, 252, 253, 254, 263 Nucleic acid, 236, 238, 239, 253, 254, 264, 268 Nucleic Acid Hybridization, 236, 253 Nucleus, 6, 204, 205, 207, 208, 215, 216, 220, 221, 226, 228, 247, 249, 252, 253, 263, 272, 274 Nulliparous, 18, 21, 35, 57, 65, 85, 98, 114, 253 Nurseries, 42, 253

294

Preeclampsia

O Ocular, 25, 253 Odds Ratio, 26, 253 Oedema, 254, 261 Oligohydramnios, 34, 254 Oligonucleotide Probes, 243, 254 Oliguria, 71, 129, 194, 254 Oncogene, 176, 254 Oophorectomy, 126, 254 Opacity, 213, 222, 254 Opsin, 254, 267, 268 Optic Disk, 222, 254 Optic Nerve, 252, 254, 267, 268 Organ Transplantation, 37, 254 Organelles, 214, 221, 247, 254 Orgasm, 152, 254, 269 Osmolality, 34, 254 Osmoles, 254, 255 Osmosis, 255 Osmotic, 34, 201, 241, 254, 255, 269 Osteoarthritis, 140, 255 Osteoclasts, 211, 255 Osteoporosis, 140, 148, 164, 228, 255 Ovalbumin, 37, 255 Ovaries, 254, 255, 269, 274, 277 Ovary, 13, 15, 202, 219, 228, 255, 272 Ovulation, 148, 230, 233, 245, 255 Ovum, 219, 221, 232, 249, 255, 262, 277, 280 Ovum Implantation, 255, 277 Oxidants, 38, 255 Oxidation, 17, 27, 88, 199, 205, 209, 221, 232, 244, 255 Oxidation-Reduction, 209, 255 Oxidative Stress, 17, 32, 44, 46, 49, 51, 52, 60, 84, 88, 92, 108, 112, 255 Oxygenase, 81, 147, 256 Oxygenation, 235, 238, 256 P Palliative, 256, 274 Palpation, 229, 256 Pancreas, 95, 149, 199, 209, 223, 240, 244, 256, 277 Pancreatic, 95, 176, 256 Pancreatic cancer, 176, 256 Papillomavirus, 61, 256 Parasite, 256, 276 Parity, 21, 256 Paroxysmal, 176, 203, 234, 256 Parturition, 253, 256, 262 Patch, 256, 276 Paternity, 65, 98, 162, 256

Pathogenesis, 12, 25, 32, 39, 40, 46, 47, 51, 54, 62, 72, 128, 131, 139, 153, 256 Pathologic, 9, 14, 29, 43, 44, 52, 61, 199, 205, 219, 237, 256, 266 Pathologic Processes, 205, 256 Pathologies, 6, 30, 47, 256 Pathophysiology, 10, 16, 18, 23, 27, 28, 29, 31, 38, 51, 60, 96, 110, 112, 117, 256 Patient Education, 182, 188, 190, 198, 256 Pediatrics, 24, 42, 43, 110, 181, 251, 256 Pelvic, 136, 225, 256, 263 Pelvic inflammatory disease, 136, 256 Pelvis, 199, 238, 242, 255, 256, 264, 278 Penicillin, 203, 257 Penis, 152, 257 Pepsin, 257 Peptic, 140, 257 Peptic Ulcer, 140, 257 Peptide, 28, 45, 132, 133, 135, 142, 144, 202, 211, 243, 257, 263 Peptide T, 132, 133, 135, 257 Perfusion, 9, 30, 49, 54, 60, 61, 69, 238, 257, 275 Pericardium, 257, 273 Periodontal disease, 20, 91, 257 Periodontitis, 232, 257 Peripheral blood, 73, 76, 79, 257 Peripheral Vascular Disease, 27, 138, 257 Perivascular, 211, 257 Peroxide, 139, 257 Phagocyte, 246, 255, 257 Pharmaceutical Preparations, 148, 257 Pharmacokinetic, 258 Pharmacologic, 150, 203, 258, 275, 276 Phenotype, 48, 50, 150, 208, 258 Phenyl, 139, 258 Phenylalanine, 258, 277 Phorbol, 55, 258 Phosphatidic Acids, 246, 258 Phospholipases, 24, 258, 270 Phospholipids, 124, 204, 205, 212, 229, 244, 247, 258 Phosphorus, 211, 258 Phosphorylation, 5, 55, 258 Phosphotyrosine, 55, 258 Photocoagulation, 216, 258 Physical Examination, 232, 258 Physiologic, 4, 11, 14, 32, 34, 50, 200, 216, 241, 247, 258, 262, 265, 266 Physiology, 4, 18, 30, 33, 66, 112, 208, 251, 258 Pigments, 208, 212, 258, 267

Index 295

Pineal gland, 215, 258 Pituitary Gland, 220, 258 Placental Circulation, 43, 145, 259 Placental Insufficiency, 62, 164, 259 Placental tissue, 30, 37, 44, 61, 259 Plants, 206, 211, 212, 215, 221, 223, 232, 241, 253, 258, 259, 260, 268, 276 Plaque, 140, 203, 206, 259 Plasma cells, 204, 259 Plasma protein, 75, 201, 226, 259, 263, 269 Plasmin, 259 Plasminogen, 48, 67, 88, 259 Plasminogen Activator Inhibitor 1, 67, 259 Plasminogen Activators, 88, 259 Platelet Activation, 50, 154, 259, 270 Platelet Aggregation, 114, 152, 202, 253, 259, 274 Platelet Count, 82, 89, 148, 259 Platelets, 107, 112, 117, 148, 208, 253, 259, 260, 274, 275 Pneumonia, 151, 152, 218, 260 Poisoning, 240, 251, 254, 260 Polycystic, 142, 177, 260 Polymerase, 136, 260 Polymerase Chain Reaction, 136, 260 Polymorphism, 50, 66, 77, 86, 91, 96, 105, 111, 161, 260 Polysaccharide, 204, 233, 260 Polyunsaturated fat, 82, 260, 275 Pons, 208, 210, 260 Posterior, 202, 206, 208, 214, 215, 224, 256, 260, 268 Postmenopausal, 126, 164, 228, 255, 260 Postnatal, 12, 20, 59, 165, 260, 272 Postnatal Care, 165, 260 Postoperative, 132, 230, 260 Postsynaptic, 260, 270, 273 Potassium, 5, 36, 201, 248, 260 Potassium Channels, 36, 260 Potentiation, 215, 260, 270 Practice Guidelines, 174, 260 Precursor, 124, 127, 202, 203, 205, 215, 220, 223, 224, 226, 253, 258, 259, 261, 263, 277 Prednisolone, 261 Prednisone, 164, 261 Pre-Eclampsia, 8, 38, 39, 45, 49, 50, 56, 119, 143, 208, 261 Pre-eclamptic, 39, 224, 261 Pregnancy Complications, 11, 47, 261 Pregnancy Outcome, 20, 23, 49, 52, 58, 165, 261 Pregnancy Tests, 232, 261

Premenopausal, 126, 164, 261 Premenstrual, 142, 261 Premenstrual Syndrome, 142, 261 Prenatal, 7, 16, 19, 49, 67, 98, 132, 158, 165, 180, 183, 225, 229, 261 Prenatal Care, 7, 158, 165, 180, 183, 261 Prevalence, 32, 38, 39, 126, 254, 261 Probe, 34, 243, 254, 261 Prodrug, 143, 261 Progesterone, 42, 126, 131, 144, 196, 261, 262, 272 Progression, 53, 55, 124, 203, 262 Progressive, 147, 213, 216, 224, 228, 234, 250, 251, 255, 259, 262, 266, 277 Projection, 23, 221, 253, 254, 262, 265 Prolactin, 106, 262 Proline, 217, 237, 262 Promoter, 15, 32, 79, 262 Prone, 62, 262 Prophylaxis, 24, 139, 262 Proportional, 226, 254, 262 Prospective Studies, 7, 262 Prospective study, 57, 80, 107, 245, 262 Prostaglandin, 24, 146, 262, 274 Prostaglandins A, 124, 262 Prostaglandins B, 124, 263 Prostaglandins D, 263 Prostaglandins F, 131, 263 Prostate, 25, 132, 176, 208, 209, 263, 269, 277 Prostatic Hyperplasia, 263 Protease, 134, 217, 263 Protein C, 93, 201, 202, 205, 207, 244, 263, 278 Protein S, 177, 209, 263, 268 Proteolytic, 217, 229, 259, 263 Prothrombin, 80, 98, 263, 274 Protocol, 42, 263 Protons, 201, 236, 263, 265 Protozoan, 214, 263, 276 Proximal, 152, 223, 264 Psychiatric, 208, 247, 264 Psychic, 216, 243, 247, 264, 268 Psychology, 223, 264 Public Policy, 26, 173, 264 Puerperium, 253, 264 Pulmonary Artery, 209, 264, 279 Pulmonary Circulation, 237, 264 Pulmonary Edema, 8, 148, 264 Pulmonary Embolism, 151, 152, 264 Pulmonary hypertension, 125, 132, 133, 141, 148, 149, 219, 264

296

Preeclampsia

Pulmonary Ventilation, 264, 267 Pulse, 51, 150, 151, 161, 164, 249, 264 Pupil, 219, 223, 250, 264 Purines, 264, 269, 280 Purpura, 153, 234, 264 Pyelonephritis, 60, 137, 264 Pyloric Stenosis, 148, 149, 264 Pyridoxal, 220, 264 Pyridoxal Phosphate, 220, 264 R Race, 248, 264 Radial Artery, 151, 264 Radiation, 153, 203, 226, 230, 237, 238, 265, 280 Radioactive, 136, 236, 239, 253, 265 Radioactive iodine, 136, 265 Radiography, 232, 265 Radioimmunoassay, 136, 208, 265 Radius, 264, 265 Randomized, 16, 23, 26, 35, 38, 52, 64, 90, 119, 224, 265 Randomized clinical trial, 16, 23, 35, 52, 265 Reactive Oxygen Species, 17, 37, 265 Reagent, 37, 245, 265 Recombinant, 86, 265, 279 Rectum, 205, 210, 217, 223, 230, 231, 239, 242, 263, 265 Recur, 129, 265 Recurrence, 23, 99, 265 Red blood cells, 227, 235, 256, 265, 268 Red Nucleus, 206, 265 Reductase, 80, 81, 105, 111, 265 Refer, 1, 210, 217, 230, 244, 245, 252, 265, 276 Reflex, 13, 266 Refraction, 251, 266, 271 Refractory, 55, 225, 266 Regimen, 52, 216, 224, 266 Regression Analysis, 52, 266 Relaxant, 28, 146, 266 Remission, 265, 266 Renal Artery, 237, 266 Renal failure, 3, 129, 132, 153, 266 Renin, 10, 11, 46, 54, 114, 151, 152, 203, 266 Reperfusion, 140, 250, 266 Reperfusion Injury, 140, 266 Reproduction Techniques, 261, 266 Reproductive History, 50, 266 Research Design, 53, 266 Resorption, 34, 255, 266 Respiration, 205, 211, 229, 249, 266

Respiratory distress syndrome, 25, 131, 132, 148, 149, 183, 267 Respiratory System, 148, 149, 267 Retina, 98, 215, 218, 220, 222, 251, 252, 254, 267, 279, 280 Retinal, 68, 100, 101, 148, 222, 254, 267 Retinal Detachment, 148, 222, 267 Retinitis, 140, 267 Retinoblastoma, 176, 267 Retinol, 267, 268 Retrospective, 45, 86, 267 Rheumatism, 267 Rheumatoid, 124, 140, 255, 267 Rheumatoid arthritis, 124, 140, 267 Rhinitis, 140, 267 Rhodopsin, 254, 267 Ribonucleic acid, 39, 268 Ribose, 199, 268 Ribosome, 268, 276 Risk factor, 12, 13, 15, 20, 21, 23, 27, 45, 49, 67, 71, 75, 76, 154, 162, 227, 237, 244, 262, 268 Rosiglitazone, 39, 268 S Salivary, 221, 223, 256, 268, 272 Salivary glands, 221, 223, 268 Saphenous, 219, 268 Saphenous Vein, 219, 268 Saponins, 268, 272 Sclera, 215, 218, 268, 279 Sclerosis, 140, 176, 206, 250, 268 Screening, 25, 77, 98, 131, 135, 136, 164, 216, 268, 278 Secretion, 18, 34, 56, 90, 215, 220, 227, 236, 240, 242, 248, 249, 268, 269 Secretory, 19, 201, 268, 273 Sedentary, 23, 268 Sediment, 268, 278 Seizures, 12, 33, 119, 148, 194, 256, 268, 271 Selenium, 58, 89, 113, 162, 268 Semen, 263, 269 Seminal fluid, 110, 269 Seminiferous tubule, 240, 269 Semisynthetic, 212, 269 Senescence, 141, 269 Senile, 255, 269 Sensitization, 36, 269 Sensor, 151, 269 Sepsis, 86, 132, 230, 269 Septic, 125, 132, 141, 269 Sequence Homology, 257, 269 Sequencing, 260, 269

Index 297

Serine, 220, 269 Serologic, 20, 238, 269 Serotonin, 252, 269, 277 Serous, 226, 269 Serum Albumin, 17, 265, 269 Sex Characteristics, 200, 202, 269, 274 Sex Determination, 177, 269 Sexually Transmitted Diseases, 136, 270 Shock, 5, 81, 102, 125, 132, 133, 135, 141, 151, 152, 212, 270, 276 Shock, Septic, 133, 270 Side effect, 130, 167, 200, 209, 220, 270, 276 Signal Transduction, 19, 41, 43, 56, 213, 258, 270 Signs and Symptoms, 137, 145, 266, 270 Skeletal, 202, 215, 250, 270 Skeleton, 199, 242, 262, 270 Skull, 220, 270, 274 Sleep apnea, 160, 270 Small intestine, 216, 224, 236, 240, 270, 279 Sodium, 5, 144, 145, 196, 201, 248, 270 Solid tumor, 203, 270 Solvent, 232, 254, 255, 271 Soma, 271 Somatic, 45, 200, 216, 236, 247, 249, 271 Somatic cells, 247, 249, 271 Somite, 40, 271 Sound wave, 218, 271 Soybean Oil, 260, 271 Specialist, 184, 223, 271 Specificity, 200, 205, 211, 271, 275 Spectrum, 51, 61, 271 Sperm, 103, 202, 215, 269, 271 Spermatocytes, 271 Spermatogonia, 13, 271 Sphincter, 242, 271 Spinal cord, 210, 214, 215, 247, 251, 266, 271 Spleen, 221, 245, 271 Spontaneous Abortion, 37, 56, 261, 271 Sporadic, 267, 271 Status Epilepticus, 125, 132, 142, 271 Steady state, 36, 271 Stem Cells, 37, 228, 272, 278 Stenosis, 148, 272 Sterility, 220, 239, 272 Steroid, 28, 126, 149, 202, 212, 220, 268, 272 Stillbirth, 19, 54, 75, 261, 272 Stimulus, 218, 224, 240, 241, 266, 272, 274 Stomach, 13, 199, 223, 228, 231, 232, 236, 242, 251, 257, 270, 271, 272 Stool, 217, 239, 242, 272

Strand, 260, 272 Stress, 9, 17, 34, 44, 48, 49, 51, 52, 60, 95, 103, 153, 213, 220, 251, 255, 267, 272, 278 Striate, 220, 272 Striatum, 62, 272 Stricture, 272 Stroke, 4, 121, 125, 126, 132, 137, 138, 141, 146, 148, 149, 151, 152, 172, 212, 235, 272 Stromal, 19, 225, 272 Stromal Cells, 19, 272 Strophanthins, 211, 272 Subacute, 239, 272 Subarachnoid, 125, 132, 133, 135, 141, 234, 272 Subclinical, 60, 239, 268, 272 Subcutaneous, 37, 52, 144, 200, 224, 254, 272 Subiculum, 235, 272 Submaxillary, 227, 272 Subspecies, 271, 273 Substance P, 248, 268, 273 Substrate, 4, 24, 43, 130, 131, 137, 143, 144, 145, 151, 152, 221, 226, 249, 273 Superoxide, 37, 43, 44, 52, 53, 93, 104, 273 Superoxide Dismutase, 43, 52, 53, 104, 273 Supplementation, 51, 108, 111, 113, 126, 273 Suppression, 35, 220, 273 Sympathomimetic, 223, 227, 253, 273 Symphysis, 215, 263, 273 Symptomatology, 270, 273 Synapses, 215, 273 Synaptic, 252, 270, 273 Syncytium, 150, 273 Synergistic, 9, 19, 262, 273 Systemic lupus erythematosus, 69, 164, 204, 205, 245, 273 Systolic, 5, 237, 273 Systolic blood pressure, 5, 273 T Tachycardia, 194, 207, 229, 274 Telangiectasia, 177, 274 Temporal, 41, 234, 235, 274 Teratoma, 215, 274 Testis, 15, 29, 202, 215, 228, 274 Testosterone, 7, 12, 202, 265, 274 Thalamic, 206, 274 Thalamic Diseases, 206, 274 Therapeutics, 168, 274 Thermal, 223, 252, 260, 274 Threonine, 257, 269, 274 Threshold, 237, 274

298

Preeclampsia

Thrombin, 19, 74, 229, 259, 263, 274 Thrombocytes, 260, 274 Thrombocytopenia, 59, 70, 153, 274 Thrombolytic, 259, 274 Thrombomodulin, 263, 274 Thrombopenia, 205, 274 Thrombophilia, 19, 106, 274 Thromboses, 205, 274 Thrombosis, 19, 59, 66, 71, 74, 77, 108, 153, 208, 263, 272, 274 Thromboxanes, 205, 225, 274 Thrombus, 219, 239, 250, 259, 274, 275 Thymidine, 129, 275 Thymus, 216, 238, 245, 275 Thyroid, 211, 241, 275, 277 Thyroxine, 201, 258, 275 Tissue Distribution, 211, 275 Tolerance, 21, 29, 30, 37, 199, 232, 275 Tomography, 101, 275 Tone, 4, 5, 28, 31, 50, 149, 253, 275 Tonic, 212, 275 Tonicity, 34, 235, 275 Tonometry, 151, 275 Tonus, 275 Tooth Preparation, 199, 275 Topical, 148, 149, 236, 275 Torsion, 239, 275 Toxaemia, 261, 275 Toxemia, 128, 144, 145, 275 Toxic, iv, 44, 212, 223, 226, 234, 238, 244, 252, 268, 276 Toxicity, 137, 144, 224, 276 Toxicokinetics, 276 Toxicology, 174, 276 Toxin, 153, 226, 275, 276 Trace element, 104, 276 Trachea, 210, 242, 275, 276 Transcription Factors, 6, 15, 28, 49, 276 Transdermal, 64, 276 Transduction, 56, 270, 276 Transfection, 44, 53, 209, 231, 276 Transfusion, 276 Translation, 34, 202, 276 Translocation, 21, 62, 276 Transmitter, 199, 223, 241, 246, 253, 273, 276 Transplantation, 153, 216, 225, 238, 276 Trauma, 125, 132, 142, 228, 276 Triad, 32, 144, 145, 146, 276 Trichomoniasis, 136, 276 Tricuspid Atresia, 219, 276 Triglyceride, 32, 106, 237, 277

Trisomy, 203, 277 Tryptophan, 73, 217, 269, 277 Tubal ligation, 164, 277 Tuberous Sclerosis, 177, 277 Tubocurarine, 231, 277 Tumor marker, 209, 277 Tumor Necrosis Factor, 19, 57, 87, 96, 103, 246, 277 Tumor suppressor gene, 52, 277 Tumour, 150, 277 Tunica, 225, 249, 277 Tunica Intima, 225, 277 Type 2 diabetes, 78, 277 Tyrosine, 43, 47, 63, 77, 80, 223, 258, 277 U Ubiquitin, 28, 277 Ulcer, 140, 277 Ulceration, 132, 257, 277 Ulcerative colitis, 132, 277 Ultrasonography, 95, 229, 232, 278 Umbilical Arteries, 128, 278 Umbilical Cord, 66, 75, 79, 88, 100, 113, 160, 201, 215, 278 Umbilical cord blood, 79, 278 Unconscious, 221, 238, 278 Urea, 278 Uremia, 132, 266, 278 Ureters, 242, 266, 278 Urethra, 208, 257, 263, 278 Uric, 152, 197, 264, 278 Urinalysis, 180, 278 Urinary, 5, 10, 33, 54, 70, 72, 148, 183, 207, 215, 231, 239, 254, 278, 280 Urinary tract, 183, 207, 254, 278 Urinary tract infection, 183, 207, 278 Urogenital, 149, 231, 233, 278 Urokinase, 259, 278 Urticaria, 140, 278 Uterine Contraction, 124, 131, 138, 199, 278 Uvea, 279 Uveitis, 140, 279 V Vaccine, 263, 279 Vagina, 152, 214, 238, 247, 279 Vaginal, 104, 152, 245, 279 Vascular endothelial growth factor, 8, 19, 39, 47, 76, 101, 107, 279 Vascular Resistance, 11, 27, 33, 43, 51, 55, 61, 146, 279 Vasoactive, 10, 94, 132, 133, 135, 146, 151, 152, 279

Index 299

Vasoconstriction, 7, 61, 124, 133, 227, 279 Vasodilatation, 9, 113, 124, 279 Vasodilation, 33, 36, 130, 152, 279 Vasodilator, 10, 28, 33, 43, 45, 54, 113, 120, 210, 211, 223, 236, 242, 250, 253, 279 Vasomotor, 228, 279 Vector, 44, 276, 279 Vein, 24, 77, 154, 203, 206, 241, 253, 268, 278, 279 Venous, 39, 59, 152, 205, 206, 208, 214, 253, 254, 259, 263, 276, 279 Venous blood, 39, 214, 259, 279 Ventricle, 206, 219, 235, 238, 264, 273, 276, 279 Ventricular, 51, 142, 219, 250, 276, 279 Venules, 209, 211, 226, 248, 279 Verapamil, 113, 279 Vertebral, 208, 279 Vesicular, 206, 233, 248, 279 Veterinary Medicine, 173, 279 Villi, 28, 149, 236, 279, 280 Villous, 28, 43, 59, 60, 62, 149, 280 Viral, 61, 276, 280 Viremia, 270, 280 Virulence, 276, 280

Virus, 61, 143, 207, 214, 233, 259, 276, 280 Vitelline Membrane, 280 Vitreous, 215, 222, 267, 280 Vitreous Hemorrhage, 222, 280 Vitreous Humor, 267, 280 Vitro, 62, 280 Vivo, 6, 14, 33, 56, 59, 134, 280 W Weight Gain, 12, 280 White blood cell, 131, 204, 233, 239, 243, 245, 246, 249, 252, 259, 280 Womb, 278, 280 Wound Healing, 58, 280 X Xanthine, 43, 280 Xanthine Oxidase, 43, 280 Xenograft, 203, 280 X-ray, 246, 253, 280 Y Yeasts, 258, 280 Yolk Sac, 58, 229, 280 Z Zygote, 218, 280 Zymogen, 263, 280

300

Preeclampsia

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