In this book on diabetes mellitus both the pathogenesis and treat ment of the disease will be discussed. Pathogenetic studies have led to the distinction between type I and type II diabetes. In type I hyperglycaemia is due predominantly to insulin deficiency; in type II insulin resistance is more important. Three pathogenetic factors are thought to play a role in the etiol ogy of type I diabetes: heredity, viral infections and immunity. There may be a relationship between these three aspects since genetic pre disposition changes the susceptibility to viral infections and/or the immunological defence against these infections. Insulitis ensues. Auto immune processes initiated by this chain of events may contribute to the destruction of the B cells in the islets of Langerhans and diabetes -may eventually follow. This means that at the time of the sudden out break of the disease, the destructive process has already been active for years."

These four volumes comprlslng "GnRH Analogues in Cancer and Human Reproduction" are a distillation of the presentations of the invited speakers at a landmark International Symposium bearing the same name, organized by one of us (B. L. ) and held in Geneva, SwitLerland in February 1988. The Symposium was truly interdisciplinary spanning gonadal hormone dependent disease including various forms of cancer and ranging to control of fertility, both pro- and conception. The international flavor can be caught from the 480 participants and 259 contributors drawn from 14 countries. The Symposium, and therefore this book, would not have been possible without the backing of The International Commitlee for Research in Reproduction and the sponsorship of the International Society of Gynecologic Endocrinology, The Swiss Society of fertility and Sterility, The University of Geneva School of Medicine, The Swiss Society of Endocrinology and The US foundation for Studies in Reproduction Inc. , and help from the World Health Organization. B. H. Vickery B. Lunenfeld June 1989 xiii LIST OF CONTRIBUTORS TO THE SERIES A. Abbondante H. Bartermann First Institute of Obstetrics and Urologische Universitatsklinik Kiel Gynecology Arnold-Heller Strasse 7 University "La Sapienza" D-2300 Kiel 1, FRG Rome, Italy M. Bartholomew P. Abel Department of Medicine/Endocrinology Department of Urology Milton S. Hershey Medical Center Hammersmith Hospital Pennsylvania State University DuCaneRoad PO Box 850, Hershey, PA 17033, USA London W12 OHS, UK D. Beck H.

The conference represented by this book was made possible by support from NICHD and a planning committee headed by Dr. Richard Sherins. Two general areas of research are included: the first encompasses steroid hormone synthesis, metabolism and transport in the testis; and the second relates to hormonal regula tion of the seminiferous tubule with special emphasis on the con trol of Sertoli cell function. In addition, there are sections on the purification of unique testicular proteins and morpho logical studies with particular emphasis on the Sertoli cell. We would like to express our sincere thanks to Dr. Sherins and his staff at NICHD and to all of the people at the University of North Carolina who participated in the Conference arrangements, to Dr. Judson J. Van Wyk, Chief of the Pediatric Endocrinology Division, and Dr. H. Stanley Bennett, Director of the Laboratories for Reproductive Biology. Our very special thanks to Mrs. Carolyn Jaros for her help in handling the local arrangements. Mrs. Martha Byrd and Mrs. Linda Rollins typed the manuscripts. Miss Leslie Wells and Mr. Albert Smith kindly assisted in proof reading, and Dr. Elizabeth Wilson gave much help with the final editing process. To all of these people, we are most grateful."

CHARLES Y. c. PAK Major progress has been made in the pathophysiologic elucidation and management of nephrolithiasis during the past two decades. It is now possible to detect the cause of stone disease in more than 95% of patients, to prevent recurrent formation of stones in the majority of patients, and to remove most existing stones less invasively. The assumption of editorship of this book permits me to indulge in the discussion of this progress from my personal perspective. Three somewhat fortuitous events in my academic career dictated my directing major efforts in stone research. The first event occurred in 1963 when, after having completed medical training, I was faced with two years of military service as a participant of the Berry plan. Choices were limited and disconcerting for someone interested in a research career: a staff physician at a military installation or an indian reservation, or a member of a research team in a state penitentiary. An interesting article by Norman Gershfeld on phospholi pid monolayers prompted me to write him seeking a position in his laboratory of Health (NIH) in Bethesda, MD. Partly because of at the National Institutes my rudimentary exposure and publication in surface chemistry, I was offered a position as a staff scientist and a position in the Public Health Service which satisfied the requirements of a military service."

This book is made up of 16 papers delivered during the Paediatric Conference convened by the Royal College of Physicians of London on 20th and 21st October 1983. The main intention of the conference was to allow each contributor to deliver a personal review of his own field, indicating recent develop ments and current practice. This volume, representing the proceedings of that meeting, is not intended as a comprehensive textbook of paedi atric endocrinology but rather as a series of personal narratives. I wish to express my thanks to the Chairmen, who so ably stimulated discussion, and to Miss Gillian Andrew, Conference Secretary of the Royal College of Physicians, and her colleagues, for providing invalu able help in the organization of the conference. I am also grateful to the staff ofMTP Press Limited for their help in producing the book. A. Aynsley-Green IX LIST OF CHAIRMEN Professor R. Hoffenburg PRCP Dr D. I. Johnston MD FRCP President Queen's Medical Centre Royal College of Physicians Nottingham London Dr D. A. Price FRCP Royal Manchester Children's Professor J. W. Farquhar MD FRCP(Ed) Hospital Department of Child Life and Health Pendlebury University of Edinburgh Manchester Edinburgh Dr P. H. W. Rayner FRCP Dr C. C. Forsyth MD FRCP Institute of Child Health Department of Child Health University of Birmingham University of Dundee Birmingham Dundee x LIST OF CONTRIBUTORS Dr D. B. Grant MD FRCP Dr J."

This volume describes the proceedings of the Workshop Conference on The Human Testis which was held at Positano, Italy, April 23-25, 1970. The format of the book has been arranged according to topics discussed during the Conference. Each chapter includes individual contributions followed by discussion. Thus, this volume provides a current critical evaluation of the subjects discussed. The Editors assume responsibility for any shortcomings and wish to thank all par~ ticipants for their unprecedented cooperation in making this publi cation possible. The Editors are indebted to Miss Barbara Martin for her able secretarial and administrative assistance and to Mrs. Griff T. Ross who supervised the secretarial staff during the conference. Rec ognition is also due to Mrs. M. Flack for editorial assistance. The Workshop Conference could not have taken place but for the Serono Foundation, which supported this Meeting as well as the pub lication of the Proceedings of this Workshop. The physical as well as the technical arrangements were under the careful direction of Mr. Cesare Florimonte of the Serono Foundation. The support pro vided by the Serono Foundation is another proof of its generosity in stimulating scientific exchanges and a demonstration of its con tinuous efforts to support basic and applied studies in the field of human reproduction. We express our thanks to our Publisher, Plenum Press, for their fine cooperation and for ensuring the rapid publication of this vol ume.

The International Foundation for Biochemical Endocrinology is incorporated as a nonprofit research and educational organization. It is dedicated to the dissemination of knowledge, cooperative research programs, and cultural interaction on an international basis. The Foundation is concerned with both basic research and practical applications of biological knowledge to the betterment of humanity. Among our interests are global resource management, human reproduction, hormonal regulation of normal and cancer cells, study of aging and degenerative diseases, brain peptides, peptide neurotransmitter compounds, mechanism of action of hormones, peptide hormone synthesis, and recombinant DNA techniques. This monograph is the ninth sponsored by the Foundation in the Biochemical Endocrinology series. The previous four have been: Hormonally Active Brain Peptides: Structure and Function (1982), K. W. McKerns and V. Pantie, eds.; Reproductive Processes and Contraception (1981), K. W. McKerns, ed.; Synthesis and Release of Adenohypophyseal Hormones (1980), M. Jutisz and K. W. McKerns, eds.; and Structure and Function of the Gonadotropins (1978), K. W. McKerns, ed. These have all been published by Plenum Press.

Nineteen eighty-six is a most appropriate year in which to be writing about developments in the organ-specific, autoimmune endocrine diseases. It celebrates the publication 30 years ago in 1956 of the classic papers of Roitt and Doniach and their co-workers I , and of Rose and Witebsky2 and Adams 3 and Purves . These three sets of fundamental observations provided the initial building blocks upon which much of what has been established in the field in the last 30 years was built. No publication of this nature on endocrine autoimmune disease can cover every aspect of the subject. I have chosen to highlight the organs (thyroid and pancreeas) which have attracted the most attention, and the areas of work within these fields within which most research effort is currently focused. There are still some gaps; the insulin and TSH receptors are not considered, nor in any detail are the role of cytotoxic mechanisms in mediating gland destruction. Molecular biology will undoubtedly in the next few years clarify once and for all the controversy that surrounds the structure of the TSH receptor and T cell cloning, the role of cell-mediated cytotoxicity. The pathogenetic mechanisms underlying autoimmunity are increasingly well understood and the search for the aetiology has begun.

This 1987 ORPRC Symposium on Primate Reproductive Biology, the third in a series, marked the twenty-fifth anniversary of the Oregon Regional Primate Research Center (ORPRC). In organizing these symposia, we have emphasized the dedication of many ORPRC staff members to research with nonhuman primates as models for human reproduction. The first symposium in this series, organized by William Montagna, was held in May 1981. Appropriately for a beginning series, its topic was fetal endocrinology. The subject of this year's symposium was the primate ovary, and, as in the past, scientists from around the world, including Sweden, Scotland, England, West Germany, and India met in Beaverton, Oregon, to exchange ideas and information on this important "aspect of reproduction. The international scope of the symposium reflects our belief that both the problems and their solutions extend beyond national boundaries. Many of the nonhuman primates that we rely on as models are endangered as civilization, through population pressure, encroaches on their natural habitats. Without a deeper understanding of how primate reproduction is regulated, and without the control over human population that such an understanding can bring, the quality of life for all primate species may well become substantially diminished. Consequently, we dedicate these symposia to the thesis that a deeper understanding of primate reproductive biology will ultimately improve all primate life. Robert M. Brenner Charles H. Phoenix vii PREFACE Today there is renewed interest in the processes controlling the gametogenic and endocrine functions of the ovary.

Those who are familiar with the two volumes of The Year in Endocrinology may, at first glance, fail to recognize their relationship to the present volume, Contemporary Endocrinology. The name is different and the cover design different, but nonetheless the admonition against judging a book by its cover is very well taken in this instance. In fact, Contemporary Endocrinology is not only the direct linear descendant of The Year in Endocrinology, it is a purposeful clone thereof-the topics are unchanged, the talented group of authors is unchanged, and most importantly, both the objective of the work and the manner in which that objective is approached are unchanged. The objective is, of course, to assist the reader in maintaining currency with respect to important developments, both basic and clinical, in the major areas of endocrinology. We are all much too familiar, unfortunately, with the difficulty of maintaining currency these days. Our approach to dealing with the informational inflation that we are suffering is similar to that used by economists in dealing with monetary inflation, that is, to increase interest. This we have attempted to do by providing for the reader an easy-to-read group of essays in which advances in individual areas of endocrinology are re viewed broadly, synthesized, and placed into perspective by a group of authors who are authorities in their individual fields. They serve, not as guest artists, but as members of a stable Editorial Board that provides continuity by contributing to successive volumes."

During the last decade, circadian and episodic fluctuations of the plasma levels of pituitary hormones have been demon~ trated in man. The interest in the time dependence of the pituitary secretions partially originates from their close functional relation with the neuroendocrine mechanisms pre- sumably responsible for the control of the circadian.rhyth- micity in man. High frequency blood sampling techniques and specific radio- immunoassays have allowed to describe in detail the varia- tions over the 24-h cycle of the hormonal concentrations in healthy individuals under basal conditions as well as after manipulation of external synchronizers such as the sleep- wake cycle, the dark-light cycle and the feeding schedule. Alterations in normal hormonal var~ions have been sugges- ted to play a role in the etiopathogeny of several metabo- lic and mental diseases, such as obesity or manic-depressio~ Important clinical implications regarding treatment and pre- vention are expected to be developed in the near future. However, so far, data obtained in different groups are dif- ficult to compare because different hormones were studied using different protocols and statistical methods. As a result, unclear or controversial issues are not uncommon.

We had the pleasure and the great opportunity to organize a symposium on "Molecular Biology of Brain and Endocrine Peptidergic Systems" under the auspices of the Canadian Biochemical society and the International Foundation for Biochemical Endocrinology. We were indeed very happy to ass ble a series of first rate speakers who delivered excellent papers on a variety of subjects from the synthesis of complicated peptide analogs, to the creation of trangenic mice, site-directed mutagenesis, enzyme characterization and DNA binding sites. One hundred and seventy-five participants attended the 40 conferences while having the opportunity to look at 24 posters presented by senior scientists as well as students. We, of the organizing committee, feel extremely pleased to have received an overwhelming response from such a group of scholars. We wish to express our sincere gratitude to Mrs. Diane Marcil who arranged most aspects of the meeting with efficiency. We also thank the different organizations and companies for their generous grants which made the reunion possible. We hope that the participants have gained scientifically while having a pleasant sojourn in beautiful Montreal. The organizing committee was made up of a group of dedicated people, particularly its secretary, Dr. Philippe Crine. To all speakers and sessions chairpersons, we are indebted for the excellence of their participation.

It is unclear, and really no longer relevant, whether the information explosion that we now contend with has been fostered by the growth of specialization and subspecialization in medicine, or vice versa. What is clear is that the two are mutually supportive and constitute what would be in endocrine parlance a short-loop positive feedback system. As a result, for most areas of medicine, even the subspecialist in that area has a problem in maintaining currency, the more general specialist has substan tial difficulty in doing so, and the generalist is tempted to abandon the effort altogether. Nevertheless, for all, both the internal pressures of conscience and self-esteem and the external pressures generated by peer review, recertifi cation, and subspecialty boards create the need for continuous self-educa tion. We are, therefore, in an era in which the means of dissemination of new information deserves as much creative attention as does its acquisition.

The beautiful town of Cavtat near Dubvronic, Yugoslavia was the site of the twelfth meeting of the International Foundation for Biochemical Endocrinology. It was sponsored by the Serbian Academy for Sciences and Arts and by the Foundation. The Croatia Hotel in Cavtat was a splendid place for a meeting. The presentation of the subject matter relating to "Neuroendocrine Correlates of Stress" was interesting and informa tive. The topics included many forms of stress, their mediators and responses. They included: releasing factors; neurotransmitters in the hypothalamus; role of noradrenal ine; the reaction of the hypothalamo-pituitary-adrenocortical axis to stress; immunological stress; thermal stress; immobil ization stress; peptides in shock; stress-induced prolactin; stress and acupuncture; stress and behavior; spinal cord transection and stress; electroconvulsive stress; neuroendocrine cells and stress; protein kinase as a signal transducer; the effects of constant 1 ight and darkness on the pineal; sleep, stress and ovarian function; and finally, hormonal response to exercise. Subsequently, the papers presented were rewritten for inclusion in this monograph. The Chairmen for the sessions at Cavtat were K. McKerns and Stefan Manolov, V. Chong-Li and L. Rakic, S. Feldman and R. Mil in, M. Lee and V. Liposits. The next meeting of the Foundation will be held in Edinburgh near the end of September, 1985. The topic will be "Neuroendocrine Molecular Biology" with Professor George Fink as Honorary Chairman of the local organizing committee."

In the words of Disraeli, "To be conscious that you are ignorant of the facts is a great step to knowledge. " For most of us, the conscious awareness of relative ignorance is an uncomfortable aspect of daily life. New data appear in such inexorable profusion that the necessity for continuous retooling has joined death and taxes as an inescapable component of our destinies. Perhaps it is this "consciousness of ignorance" that accounts for the success of the preceding volumes of this new series. The Year in Metabolism and The Year in Endocrinology series were introduced with the avowed intention of "providing an efficient and enjoyable bridge between those who are creating new knowledge at the bedside and the professional consciousness of those for whom such knowledge is ultimately intended. " That objective seems particularly appropriate at a time when the award of the 1977 Nobel Prize in Medicine or Physiology to Guillemin, Schally, and Yalow has served to emphasize the epoch-making advances that have characterized the recent course of endocrinology and me bolism. For the 1977 volume of The Year in Metabolism, the previous formula has been preserved. The same internationally recognized authorities again have contributed commentaries about the progress in their areas of expertise. They have been joined by Drs. Jack W. Coburn, David L. Hartenbower, and Charles R. Kleeman, who have provided a new section on Divalent Ion Metabolism.

These Proceedinqs of the Midwest Conference on Endocrinology and Metabolism are being published by Plenum Press for the first time. Earlier Proceedings in the series Vlere published by the University of Missouri at Columbia. The shift to an internationally recognized pub lisher reflects the considerable growth in stature that the Midwest Con ferences have undergone since their inception nine years ago. Originally concerned only with the endocrinology of the thyroid, the Conferences now explore other endocrine areas. Efforts are made to assemble a panel of speakers selected from different sub-disciplines within endocrinology for the purpose of addressing a common problem. The Ninth Conference typifi es til i s approach. The format used in recent Conferences is not unique, but is unfor tunately encountered too rarely. A few prominent scholars are invited to come together to expound their findings and concepts in considerable depth, and to participate in a discussion which, together with the for mal presentation, is published in the Proceedings. The discussion, noted for its unhurried nature, permits wide participation by the audi ence. The subject of the Ninth Conference is one which is basic and im portant not only to endocrinology but also to biology in general. Many, possibly most, life processes change in a rhythmic fashion, with similar states recurring at regular time intervals. This rhythmic property of living systems expresses itself as a recognizable and definable pattern or "time-form" in a manner equivalent to the more customary spatial form."

This volume contains the edited proceedings of the Totts Gap Colloquium on Diabetes Mellitus, DILEMMAS IN DIABETES. The Collo- quium, lasting two and a half days, was organized mainly as a dia- logue among experts in the field with different disciplinary back- grounds and, to some extent, differing points of view. The effort was to synthesize existing knowledge, reconciling disparate data and interpretation, and pointing up important areas of ignorance. Thus, the book should serve not only as a summary of recent information on diabetes, but as a reliable guide to the practicing physician as he wades through often conflicting etiologic dogmas and therapeutic practices. The Colloquium was made possible through the generous support of the Geigy Pharmaceutical Company and the conscientious and expert coordination of Mr. Oscar Swarth. The participants were: Dr. George F. Cahill, Boston, Massachusetts Dr. Harvey C. Knowles, Cincinnati, Ohio Dr. Rachmiel Levine, Duarte, California Dr. Lelio Orci, Geneva, Switzerland Dr. Norton Spritz, New York, New York Dr. Roger Unger, Dallas, Texas Dr. Robert Williams, Seattle, Washington Dr. Stewart Wolf, Galveston, Texas Dr. Arnold Lazarow and Dr. I. Arthur Mirsky were to have partici- pated, but unfortunately were ill at the time of the meeting. Others in attendance included five medical students, especially selected from medical schools in the Philadelphia/New York area.

It is unclear, and really no longer relevant, whether the information explosion that we now contend with has been fostered by the growth of specialization and subspecialization in medicine, or vice versa. What is clear is that the two are mutually supportive and constitute what would be in endocrine parlance a short-loop positive feedback system. As a result, for most areas of medicine, even the subspecialist in that area has a problem in maintaining currency, the more general specialist has substan tial difficulty in doing so, and the generalist is tempted to abandon the effort altogether. Nevertheless, for all, both the internal pressures of conscience and self-esteem and the external pressures generated by peer review, recertifi cation, and subspecialty boards create the need for continuous self-educa tion. We are, therefore, in an era in which the means of dissemination of new information deserves as much creative attention as does its acquisition."

The tenth meeting of the International Foundation for Biochemical Endocrinology was held in Geilo, Norway near the end of September, 1982. The subject matter of the conference and the monograph was on "Regulation of Target Cell Respon- siveness." The local organizing committee was Asbjjllrn Aakvaag and Vidar Hansson. The scientific sessions covered a wide range of hormone action and cell response, including: peptide hormones and target cell response, regulation of insulin responsiveness, intracellular modulation of peptide hormone response, gonado- tropins and target cell responses, hypothalamic hormone- effects and regulation, steroid receptors and cellular control, hormones and growth regulation, and hormones and gene regulation. The chairpersons for the sessions were L. Birnbauer -A. Aakvaag, S. Taylor- R. S. Horn, F. Labrie- F. Rommerts, A. R. Means - K. W. McKerns, P. F. Hall - V. Hansson K. Griffiths - K. M. Gautvik, E. J. Peck, Jr. -E. Haug, F. S. French- W. T. Schrader, and E. M. Ritzen- B. Jegou. In addition to the scientific sessions in Geilo we were all delighted to sample some of the cultural and artistic attractions of Oslo, and to travel by train from Oslo via Geilo to Bergen. The scenery and hospitality were magnifi- cant.

The tenth meeting of the International Foundation for Biochemical Endocrinology was held in Geilo, Norway near the end of September, 1982. The subject matter of the conference and the monograph was on "Regulation of Target Cell Respon- siveness." The local organizing committee was Asbj rn Aakvaag and Vidar Hansson. The scientific sessions covered a wide range of hormone action and cell response, including: peptide hormones and target cell response, regulation of insulin responsiveness, intracellular modulation of peptide hormone response, gonado- tropins and target cell responses, hypothalamic hormone- effects and regulation, steroid receptors and cellular control, hormones and growth regulation, and hormones and gene regulation. The chairpersons for the sessions were L. Birnbauer - A. Aakvaag, S. Taylor - R. S. Horn, F. Labrie - F. Rommerts, A. R. Means - K. W. McKerns, P. F. Hall - V. Hansson K. Griffiths - K. M. Gautvik, E. J. Peck, Jr. - E. Haug, F. S. French - W. T. Schrader, and E. M. Ritzen - B. Jegou. In addition to the scientific sessions in Geilo we were all delighted to sample some of the cultural and artistic attractions of Oslo, and to travel by train from Oslo via Geilo to Bergen. The scenery and hospitality were magnifi- cant.

Diabetes mellitus is rapidly increasing in prevalence throughout both developed and developing countries. The social and economic burden of this disease is estimated to cost 14 billion dollars worldwide. In the USA alone, 15 million individuals are diabetic, nearly half of them unaware of their condition. Complications of diabetes mellitus are the leading causes for blindness, limb amputation and chronic renal failure and kidney transplantation in industrialized countries. Further, diabetes mellitus per se and the metabolic derangement associated with diabetes are important risk factors for cardiovascular disease. Diabetes, as defined by an elevated fasting blood glucose level is presently subdivided in etiologically distinct groups. The most prevalent being type 2 (adult onset) diabetes characterized by insulin resistance and failure of the ~-cell to supply insulin in amounts sufficient to meet the body's needs. Type 1 (juvenile) diabetes, most commonly with an onset during childhood and adolescence, is caused by an auto-immune destruction of the pancreatic ~-cells. The causations of both type 1 and type 2 diabetes involve a combination of complex genetic traits and environmental influences. A third category are the mature onset diabetes of the young (MODY). This comparatively small group of patients (-10% of diabetes) presents relative early in life "30 years of age) compared to the more common late onset type 2 diabetes.

The Fifth Annual Washington Spring Symposium on Health Sciences attracted over 400 scientists from 20 countries. It was held at the Lisner Auditorium of the George Washington University in Washington. D.C. The theme of the meeting was neural and endocrine peptides and receptors. The meeting emphasized basic and clinical research on neural and endocrine peptides and receptors. The six plenary sessions emphasized pituitary peptides, releasing factors, brain peptides, growth factors, peripheral peptides, and clinical applications. The chapters in this volume are derived from each of these six scientific sessions plus the poster and special sessions. The Abraham White Distinguished Scientist A ward was presented to Dr. Julius Axelrod for his numerous contributions to the field of neurochemistry. He presented the keynote address, which was entitled "The Regulation of the Release of ACTH." Dr. Axelrod discussed numerous factors, such as the peptides CRF, VIP, and somatostatin, that regulate hormone secretion from pituitary cells. The Distinguished Public Service Award was presented to Senator Lowell Weicker, Jr., in recognition of his leadership and outstanding achievements in the United States Senate and for his legislative support for biomedical research and education. In the symposium banquet address, Senator Weicker stressed the need for continued federal support of biomedical science research.

Macromolecular (specifically peptide-based) drugs could potentially be highly effective medicines. However they have a relatively short duration of action and variable therapeutic index. An example of such a peptide is Glucagon-like Peptide I which could potentially be used as a revolutionary drug for diabetes. This is because it stimulates insulin only when the blood glucose level is high thereby reducing the risk of hypoglycemia (a significant disadvantage of using insulin is that an insulin overdose is the single most potent cause of life-threatening hypoglycemia). However it's short duration of action (half-life of 2 minutes in plasma) precludes its therapeutic use. In this volume, the use of novel therapeutics like GLP1 as an alternative to tradition insulin-based drugs in diabetes is described. Application of Peptide-Based Prodrug Chemistry in Drug Development elucidates the traditional concept of prodrugs as "specialized non-toxic protective groups used in a transient manner to alter or to eliminate certain limiting properties in the parent small molecule" (IUPAC definition). It goes on to provide insight into how prodrugs of peptides (with GLP1 as an example) could be appropriately used to extend the biological half life, broaden the therapeutic index of macromolecules and improve the pharmacodynamics of such drugs. Author explains the logic behind designing peptide prodrugs, synthetic procedures and bioassays to examine the conversion of the prodrug to the drug under therapeutic conditions. The prodrugs described slowly convert to the parent drug at physiological conditions of 37C and pH 7.2 driven by their inherent chemical instability without the need of any enzymatic cleavage. The diketopiperazine and diketomorpholine (DKP and DMP) strategies for prodrug conversion are demonstrated in detail with special emphasis on the chemical flexibility that it offers to develop prodrugs with variable time actions. This book will be of useful to chemists, biochemists, medicinal chemists, biologists and people in the medical profession (doctors). It may be used in undergraduate classes but will certainly help post-graduate students and advanced professionals. The author is grateful to Prof. Richard DiMarchi (Standiford H. Cox Professor of Chemistry and the Linda & Jack Gill Chair in Biomolecular Sciences at Indiana University) for valuable suggestions. The foreword for the book has been written by Prof. Jean Martinez, (Legion d'Honneur awarded by the French Republic; Professor of Chemistry and Medicinal Chemistry of the University of Montpellier, France; and Chairman of European Peptide Society, 2002-2010).

The evolution ofdata about the HIV-Associated Lipodystrophy Syndrome has been rapid. The syndrome itself is complex and controversial. Although great progress has been made in understanding epidemiology and etiology of the syndrome, much about the syndrome remains mysterious. It was our intention to assist HIV providers with a framework for understanding the status and complexities ofthe field. Each author was requested to provide an evidence-based discussion of a topic for which they have expertise. While it is impossible that such a volume be completely comprehensive, we believe that the approach of this book will allow the reader to develop a relatively complete snapshot of the syndrome. We also believe that the reader of this volume will be able to confront the emerging literature on the HIV-associated lipodystrophy syndrome with a critical eye and that the volume will provide a context in which to place additional data as they are published.

Despite the advent of insulin for clinical use in 1922, our ability to control hypergly cemia and prevent the long term sequelae ofthe disease remains limited. Thus normalization of the milieu interieur with physiologic responses of insulin and metabolites remains an elusive but critically important goal. The developing endocrine pancreas provides a model system that speaks to many challenges of the transplantation biologist. Thus the attempt to of vascularization, growth and development, immunologic toler recapitulate the ontogeny ance, and glucose responsive insulin secretory capacity of fetal islet tissue provides a tantalizing possibility to replace insulin secreting tissue in persons with diabetes. Studies of this tissue are also important because of the implications such investigations have for genetic and molecular biological approaches to restoring insulin secretion as well as for providing clues to enhancing the growth and repair of islets that have been the target of autoimmune disease. Investigators in the area offetal islet transplantation comprise a small group scattered throughout the world scientific community. Therefore it seemed important to provide a forum where these scientists could gather, share ideas, and achieve consensus such that progress in this rapidly evolving area could be facilitated. The conference would have remained a dream if the support of the Okla Basil Meade, Jr. family had not made it manifest."