Genetics of Diabetes Mellitus is intended to be a resource for both researchers in the field as well as endocrinologists, diabetologists, and geneticists who seek to learn more about this rapidly changing and important field. The text contains chapters from experts in the area who review aspects of the genetics of both type 1 and 2 diabetes mellitus as well as various syndromic forms of diabetes. The chapters are approachable for those who are not experts in the field of genetics but also comprehensive, so as to serve as an important resource for researchers interested in the genetics of diabetes mellitus. A description of basic concepts of the genetics of complex diseases like type 1 and type 2 diabetes is provided as background. Type 1 diabetes is addressed in chapters exploring genetic determinants that affect the autoimmune process characteristic of type 1 diabetes, the role of the insulin gene in the pathogenesis of type 1 diabetes and additional genes that may impact upon the risk of type 1 diabetes. The impact of genetic determinants on the pathophysiology of type 2 diabetes is covered, as are chapters that address specific genes that are important for the development of type 2 diabetes. Finally, syndromic forms of diabetes, including Maturity Onset Diabetes of the Young and mitochondrial diabetes, and the insight that these disorders provide into more common forms of diabetes are reviewed. Thus, this comprehensive and up-to-date text will serve as an important resource for those actively engaged in research in this area and clinicians treating these patients to provide an up-to-date entree for those seeking to become more knowledgeable in the area.

The past 15 years have witnessed a marked increase in attempts to identify safe and effective treatment alternatives to prostatectomy. This book is a review of the current therapeutic efforts in the management of patients with benign prostatic hyperplasia. It is presented by a group of highly regarded basic and clinical scientists with a major interest in prostatic diseases.
The information provided in this book is aimed at a wide audience including private practice and academic urologists, research fellows and doctors in postgraduate training, and basic scientists interested in prostatic pathology.

The regulation of the organism has traditionally been ascribed to two distinct systems-the nervous and the endocrine. Though coordination between the two systems has been acknowledged, researchers and authors have tended to deal with them as comprising separate categories of cells involved in different activities. With this approach, a given regulatory mechanism would be evaluated as to whether it should be accounted for by nervous or endocrine functions. The past 15 years, however, have witnessed numerous important discoveries and conceptual developments concerning the morphological, physiological, and bio chemical relations between the nervous and endocrine systems. Advances in im munocytochemical studies have revealed that there are a wide variety of messenger substances that function in both regulatory systems. As a result, researchers have been stimulated to investigate neuronlike properties of endocrine cells and, con versely, endocrine or secretory features of neurons. It has thus become obvious that the rigidities in the classic criteria of neurotransmitters and hormones may rather impede further advances in these research fields. The activities of neurons are no longer evaluated simply in terms of EPSP, IPSP, and the release of classic trans mitters such as acetylcholine, noradrenaline, and GABA. Hormonal actions are no longer analyzed solely with regard to concentrations of classic aminic and peptidic hormones in the systemic blood circulation. The concept of the paraneuron, which we proposed in 1975, has become one of the theoretical bases for the development of this trend of study.

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."

Diabetes continues to spread across the globe at an alarming rate, with a current count of approximately 386 million worldwide. Physicians and healthcare professionals in all specialties greatly need a concise guide for managing this disease on a daily basis.

"Diabetes Mellitus A Concise Clinical Guide" covers the basics of diagnosis, complications, therapies and prevention. Major developments in understanding diabetes and in therapeutic approaches to this disease are also featured. This book is comprised of sections originally published in the comprehensive textbook, "Principles of Diabetes Mellitus, Second Edition."

Primary care physicians and endocrinologists, as well as medical students, will find this guide an invaluable and practical reference."

How to treat advanced prostatic cancer remains controversial, despite intense basic and clinical research investigating the pathogenesis and natural history of this unique cancer highly prevalent in elderly males. Nine experts were asked to meet and discuss the facts. This resulting monograph gives an overview of the available knowledge on all aspects of the subject. The objective evaluation and consensus opinion of the authors presented here set this book apart from other publications with conflicting viewpoints. For readers eager to obtain a comprehensive and balanced view of the thousands of clinical contributions and clear advice on the choices, this book is a must.

This book was written at the invitation of Dr. H. GOTZE of Springer-Verlag for the series "Monographs in Endocrinology." It is not a comprehensive account of the prostaglandins but has been writ ten with a deliberate emphasis upon those aspects of the field in which I am particularly interested and to which, in some cases, I have made a contribution. I am grateful to Miss E. PFISTERER and her colleagues of Springer Verlag for their excellent work. I should also like to thank my wife without whose patience, encouragement and help this book would never have been completed. Finally this is an appropriate time to express my sincere gratitude to those scientists who over the years have given me samples of prostaglandins-namely Professors S.BERGSTROM and B.SAMUELSSON of the Karolinska Institute, Stockholm, Professor D. A. VAN DORP of the Unilever Research Laboratories, Vlaardingen and Dr. J. E. PIlm of the Upjohn Company, Kalamazoo. Without their help work in this field would have been extremely difficult."

This study assembles current and new information on the mechanisms involved in intracellular calcium regulation and their actual or potential relationship to cellular calcium transport. Topics discussed in detail are calcium channels, cellular calcium extrusion, sodium/calcium exchange, calcium-binding proteins with special reference to the vitamin D-induced calbindin, calcium transport and disorders thereof. Each topic is introduced with an overview followed by research papers dealing with relevant topics in each category. New information deals with calcium channels which are not voltage-sensitive, the structure and function of the plasma membrane Ca ATPase, the role of the Na/Ca exchanger in intracellular Na and proton regulation, a comprehensive overview of calcium transport with quantitative analysis of the role of the intestinal and renal calcium-binding proteins, description of the structure and function of the calbindin genes, and identification of calcium transport defects in diabetes and hypertension. Readers will be brought up-to-date on current knowledge and concepts in this rapidly expanding field and be directed to the relevant primary and secondary literature.

Following 50 years of glucocorticoid use in a clinical setting, an international body of expert scientists and physicians presents the most expansive survey of glucocorticoid pharmacology to date. This work traces the history of glucocorticoid biology from the seminal description of glucocorticoid insufficiency by Thomas Addison in the mid-19th century, up to current advances in elucidating the molecular basis of glucocorticoid action. Important discoveries are presented, as well as milestones in drug development, a survey of current clinical practice, and prospects for novel glucocorticoid-based therapeutics. Scientists and clinicians will appreciate the scope of this work, which is of special interest to workers in the fields of endocrinology, inflammation and autoimmune disease.

Reproduction is the origination of new organisms from pre-existing ones. Among more than 35 separated forms of reproduction including several types of gamogony, parthenogenesis, agamogenesis, fission and division, and plas motomy, the bisexual mode of reproduction via fertilization provides genetic variability that allows species to adapt quickly to competitive and constantly changing environments. Several excellent reviews and books have been written in the past to analyse the mechanisms of fertilization in different eukaryotic species. During the last few years, however, renewed attention has been paid to examining the process of oocyte fertilization at the cellular/molecular level not only within a single species/group but also through different phylogenetic lineages. As a result of this effort, knowledge of the molecular pathways used by oocytes and spermatozoa at fertilization has increased, but still many ques tions remain to be answered. Being aware of the necessity of providing an inte grated view of the process of fertilization, this book has been entirely devoted to reviewing the process of oocyte fertilization at the cellular/molecular level in two different and separated groups of eukaryotic organisms: protozoa and metazoan animals. The book is organized into six sections dealing with oocyte fertilization in protozoa, invertebrates, teleost fishes, amphibians, birds and mammals. These sections are followed by a summary/concluding chapter that provides a com parative overview of the process of fertilization in these groups of eukaryotes."

This book originates from a symposium held at the London Hospital Medical College under the auspices of Applied Chromatography Systems Ltd. to discuss the place of HPLC in the endocrinology field. Many of the authors of the present book were speakers at this symposium. It seemed to us that many endocrinolo gists did not at that time fully appreciate the value of HPLC, and this book was designed to publicise the potential value of this technique. A survey of methods used in the steroid field Cp 185) confirmed the view that HPLC is not being used as widely, particularly in research described in clinical journals, as might be expected. We hope that this book will illustrate, albeit in a few selected areas of endocrinology, just how versatile and powerful a technique HPLC is, and en courage those who have not yet experienced it to have a go. The beginner does not need to buy expensive instrumentation - all that is required is a pump, injector, column and detector - the rest can come later! All the authors have practical experience in the use of HPLC in the particular area they discuss. All readers who discover apparent errors or who feel that the treatment of a topic of interest can be improved upon are encouraged to contact the editors. All criti cism, especially if constructive, is welcomed. We are still learning, and other peoples' experience is always valuable.

Congenital adrenal hyperplasia (CAH) consists of a group of disorders of adrenal steroidogenesis. Each disorder results from an inherited deficiency of one of the several enzymes necessary for normal steroid synthesis. The different enzyme deficiencies produce characteristic patterns of hormonal abnormalities; the clinical symptoms of the different forms of CAH depend on the particular hormones that are deficient or that are produced in excess. The earliest documented description of CAH was by DeCrecchio in 1865 (DeCrecchio 1865). This Neapolitan anatomist described a cadaver having a penis with first degree hypospadias but no externally palpable gonads. Dis- section revealed a vagina, uterus, fallopian tubes, ovaries, and markedly enlarged adrenals. It is interesting that the subject suffered a confusion of sex assignment, being declared a female at birth and a male 4 years later. He conducted himself as a male sexually and socially. Since the original descrip- tion of this case, investigators have unravelled the pathophysiology of the inborn errors of steroidogenesis. 1 Steroidogenesis and Enzymatic Conversions of Adrenal Steroid Hormones A. Steroidogenesis The adrenal synthesizes three main classes of hormones: mineralocorticoids (17-deoxy pathway), glucocorticoids (17-hydroxy pathway), and sex steroids.

This book includes the most significant contributions of the 3rd International Symposium on MULTIPLE RISK FACTORS IN CARDIOVASCULAR DISEASE held in Florence, Italy, July 6-9, 1994. The meeting focused on the risk factors for cardiovascular disease and their interactions. The need for this symposium is based on the epidemiological evidence that individuals from industrialized countries often possess two or more risk factors which synergistically increase the global risk profile. This has become more evident in recent years with the increase in life expectancy of the general population. The evidence that in high risk patients, a combination of risk factors often is detected, is highlighted in these Proceedings. Many recent epidemiological data identifYing the intrinsic and environmental factors contributing to the development of atherosclerosis are discussed. These results, in parallel with basic and clinical research, underline how atherosclerosis is a complex and multifactorial process involving the influences of lipids, including lipoprotein subfractions, blood pressure, rheologic forces, carbohydrate tolerance, and thrombogenic factors. Furthermore, the risk associated with anyone of these risk factors varies widely depending on level of the associated atherogenic risk factors.

The building of conceptual models is an inherent part of our interaction with the world, and the foundation of scientific investigation. Scientists often perform the processes of modelling subconsciously, unaware of the scope and significance of this activity, and the techniques available to assist in the description and testing of their ideas. Mathematics has three important contributions to make in biological modelling: (1) it provides unambiguous languages for expressing relationships at both qualitative and quantitative levels of observation; (2) it allows effective analysis and prediction of model behaviour, and can thereby organize experimental effort productively; (3) it offers rigorous methods of testing hypotheses by comparing models with experimental data; by providing a means of objectively excluding unsuitable concepts, the development of ideas is given a sound experimental basis. Many modern mathematical techniques can be exploited only with the aid of computers. These machines not only provide increased speed and accuracy in determining the consequences of model assumptions, but also greatly extend the range of problems which can be explored. The impact of computers in the biological sciences has been widespread and revolutionary, and will continue to be so.

1.1 Mechanism of Action of Glucocorticoid Hormones The current model of glucocorticoid hormone action is summarized in Fig. 1. After synthesis, glucocorticoids are secreted into the blood stream and trans- ported to target cells where they bind with high affinity (K-1O-9M) and d specificity to the intracellular glucocorticoid receptor (GR) protein. The sub- cellular localization of hormone-free GR is still a controversial issue. However, most data support the idea that unliganded GR is in the cytoplasmic compartment or loosely associated with the nucleus (Picard and Yamamoto 1987; Gustafsson et al. 1987 and references therein; LaFond et al. 1988; Gasc et al. 1989). Upon ligand binding, GR is activated into a form capable of interacting with DNA. The mechanism of GR activation probably involves a conformational change and dis- sociation from nonreceptor components, e.g., the 90-kDA heat shock protein (hsp90: Pratt et al. 1988; Bresnick et al. 1989; Denis and Gustafsson 1989). The subcellular location of activated GR has been firmly established to be inside the nucleus. In vivo, the hormone-receptor complex interacts with specific DNA Activation r:::.. ~ qc [!3-GC ...&.GC~ j ~ ? , BIOLOGICAL EFFECTS " t , Active Protein , , ~Vl\lent.

It is a truism that as we age there are a number of underlying physiological changes conspiring to alter our level of behavioral and cognitive function ing. Despite the inherent interrelatedness of these behavioral and cognitive changes, all too often the papers we read confine themselves to specific, isolated components of the developing process. Although exceptions nat urally exist, we believe that these exceptions should become rule. Although an integrated approach is important in all areas of adult devel opment, it is perhaps particularly germane in the study of atypical aging. Here, changes in overall functioning can occur in rapid succession, with the synchrony of decline between different subprocesses making it difficult to factor changes in one process from changes in another. For example, because changes in cognitive functioning co-occur with other dramatic changes in (motoric) response capacities, it is unclear how one can effec tively study changes in the ability to cognize independent of changes in the very mechanisms (ability to execute motor sequences) so often used to index cognitive performance."

The tridecapeptide neurotensin (NT) was first identified in bovine hypothalamic extracts and characterized by Carraway and Leeman (1973,1975,1976) and has subsequently been found in all classes of vertebrates (Carraway and Leeman 1976; Kitabgi et al. 1976; Kataoka et al. 1979; Langer et al. 1979; Reinecke et al. 1980a; Cooper et al. 1981; Grant et al. 1982; Carraway et al. 1982; Eldred and Karten 1983), many invertebrates (Reinecke et al. 1980 b; Grimmelikhuijzen et al. 1981; Price et al. 1982), and certain bacteria (Bhatnagar and Carraway 1981). It is distributed throughout the mammalian central nervous system (CNS) (Uhl and Snyder 1977 a, b), gastrointestinal tract (Sundler et al. 1977; Schultzberg et al. 1980), cerebrospinal fluid (CSF), adrenals, pancreas, and plasma (Fernstrom et al. 1980). When administered systemically, the peptide has a variety of effects such as hypotension, hyperglycemia, decreased gastric acid secretion, decreased gut motility, and altered secretion of anterior pituitary hormones (Leeman and Carraway 1982). NT apparently does not cross the blood-brain barrier in appre- ciable quantities; however, when administered directly into the CNS, it produces a number of physiological and behavioral effects. A burgeoning body of evidence supports the role of NT as a neurotransmitter or neuromodulator. Thus far, het- erogeneous CNS distribution, release of NT upon neuronal depolarization, satu- rable and specific binding of NT to receptors, and degradation by peptidases have all been demonstrated.

It is fourteen years since insulin was last reviewed in The Handbook of Ex perimental Pharmacology, in volume 32. The present endeavor is more modest in scope. Volume 32 appeared in two separate parts, each having its own subeditors, and together the two parts covered nearly all areas of insulin pharmacology. Such comprehensiveness seemed impractical in a new volume. The amount of in formation related to insulin that is now available simply would not fit in a reasonable amount of space. Furthermore, for better or worse, scientists have be come so specialized that a volume providing such broad coverage seemed likely in its totality to be of interest or value to very few individuals. We therefore decided to limit the present volume to the following areas: insulin chemistry and structure, insulin biosynthesis and secretion, insulin receptor, and insulin action at the cellular level. We felt these areas formed a coherent unit. We also felt, perhaps as much because of our own interests and perspectives as any objective reality, that these were the areas in which recent progress has been most dramatic, and yet, paradoxically and tantalizingly, these were the areas in which most has yet to be learned. Even with this limited scope, there are some major gaps in coverage. Regrettably, two important areas, the beta cell ATP-sensitive potassium channel and the glucose transporter, were among these. Nevertheless, the authors who con tributed have done an excellent job, and we would like to thank them for their diligence.

Research in diabetes has accelerated in two areas, both of which are being reviewed in CTMI. The first is the use of a variety of animal models; the second is basic research in human investigation, islet cell antigens, and mapping of genes as sociated with susceptibility to disease. Dr. Thomas Dyrberg accepted editorial responsibility for this volume, which covers the first area. A second book, to be published later in the year, is edited by Drs. Brekkeskov and Hansen (CTMI 164, see page VI for contents). Although the contributors to both volumes represent the international scientific community, the editors are from the Hagedorn Research Laboratory in Denmark. Work at this institute and the Steno Memorial Hospital has been dedicated to research in diabetes for decades, and the insti tutions were appointed WHO Collaborating Centres for Re search and Training on the Pathogenesis of Diabetes Mellitus in 1983. It is worth noting that while addressing the hypothesis of the role of class II major histocompatibility glycoproteins in autoimmune diabetes (insulin-dependent diabetes, IDDM) a number of investigators established animal models in which class II molecules were expressed under the control of the rat insulin promoter. While generating interesting information on 100M, the finding of immunologic tolerance in such transgenic mice has attracted the attention of several basic immunologic laboratories for quite different reasons. Thus, we are reminded again of the Pasteur dictum that "chance favors the prepared mind. " Michael B. A. Oldstone, M. D."

Dr. Raymond Pederson, Dr. Jill Dryburgh and I commenced work on GIP in 1968, when, with the generous help of Professor Viktor Mutt and Professor Erik Jorpes of the Karolinska Inst, itute, Stockholm, we were able to establish that there existed an inhibitory material for acid secretion in cholecystokinin-pancreozymin prepara tions. Once the physiological evidence for the inhibitor was established it seemed appropriate to seek help in its isolation. Dr. J. Dryburgh and Dr. R. Pederson were left to bioassay fractions in Vancouver whilst I enjoyed the company of Professor Mutt at the Karolinska for one year, as a Medical Research Council of Canada Visiting Scientist. Purification of the inhibitory factor proceeded rapidly due, in no small measure, to Professor Mutt's untirmg efforts on my behalf. Later that year, Dr. Dryburgh joined us in Stockholm to begin the sequence work on GIP. This was completed late in 1970 in Vancouver. In Stockholm in June 1970, I met a fellow Canadian Dr. John Dupre (McGill University) at a cocktail party who kept commenting about the possibility of GIP being an insulinotropic hormone, the "incretin" of earlier days. At that time, gastrointestinal physiologist as I was, I did not recognize the importance of his comment. This became apparent two or three years later when Dr. Dupre demonstrated that GIP was insulinotropic in man. In 1972, Maryanne Kuzio and Dr."

This monograph represents the first comprehensive review of hormones in human amniotic fluid and includes data published up to and including 1980. Recently, more extensive use of amniocentesis for prenatal diagnosis and evaluation of fetal lung maturation has shown that amniotic fluid hormone measurements can aid in the diagnosis of fetal and placental abnormalities. The material is presented in two main sections dealing with steroid and protein hormones. The methods of identification and quantitation are delineated, and the findings are discussed in relation to the clinical conditions. In addition, particular attention has been directed towards up-to-date review of the sources, metabolism and transfer of human amniotic fluid hormones. The review is intended to serve the needs of clinicians, basic scientists and students, providing detailed information on human amniotic fluid hormones in order to improve patient care and indicate possibilities for further investigations. Ttibingen, January 1982 A.E. Schindler Contents Introduction A. 1 Origin of Human Amniotic Fluid . 2 B. C. Origin and Regulation of Steroids in Human Amniotic Fluid . 5 D. Methods of Isolation and Identification of Steroids in Human Amniotic Fluid 6 I. C , C , and C Steroids . 6 30 29 28 II. C Steroids 6 27 1. Cholesterol 6 2. Cholestanol . 6 3. ,::l7 -Cholestenol and ,::l8 -Cholestenol. 6 4. 7-Dehydrocholesterol and Desmosterol . 6 ,::l5_C Steroids. III. 7 21 1. Pregnenolone 7 2. 16cx-H ydroxypregnenolone. 7 3. 17cx-Hydroxypregnenolone.

The European School of Oncology came into existence to respond to a need for information, education and training in the field of the diagnosis and treatment of cancer. There are two main reasons why such an initiative was considered necessary. Firstly, the teaching of oncology requires a rigorously multidiscipli nary approach which is difficult for the Universities to put into practice since their system is mainly disciplinary orientated. Secondly, the rate of technological development that impinges on the diagnosis and treatment of cancer has been so rapid that it is not an easy task for medical faculties to adapt their curricula flexibly. With its residential courses for organ pathologies and the seminars on new techniques (laser, monoclonal antibodies, imaging techniques etc.) or on the principal therapeutic controversies (conservative or mutilating surgery, primary or adjuvant chemotherapy, radiotherapy alone or integrated), it is the ambition of the European School of Oncology to fill a cultural and scientific gap and, thereby, create a bridge between the University and Industry and between these two and daily medical practice. One of the more recent initiatives of ESO has been the institution of permanent study groups, also called task forces, where a limited number of leading experts are invited to meet once a year with the aim of defining the state of the art and possibly reaching a consensus on future developments in specific fields of on cology."

The eleventh monograph and meeting of the Foundation on "Hormon al Control of the Hypothalamo-Pituitary-Gonadal Axis" was held in October 1983 at the Weizmann Institute of Science. This monograph honors the memory of Professor Hans R. Lindner, a productive and innovative scientist greatly respected and admired by his col leagues. When addressing the opening session I remarked that my impres sion of the Weizmann Institute was one or two large buildings hous ing the various departments. This was my first visit to Israel and I was overwhelmed by the beautiful semi-tropical gardens of the in stitute, in a setting of shrubs and trees, orange groves and flow ers. Sited among this seventy-five acres are over fifty buildings and residential areas for the staff and visiting scientists. I saw pictures of this area when Dr. Chaim Weizmann founded in 1934, the Daniel Sieff Research Institute, the forerunner of the Weizmann In stitute. The site was sand dunes without a blade of grass. That the desert shall bloom is illustrative of the progress made in Is rael. The topics of the monograph are grouped into twelve sections.

Changes in the allocation of healthcare resources have raised issues related to the efficacy and outcomes of medical therapy and how such factors may be measured. The questions associated with the quality of life and functional capability of patients with chronic health conditions have been of special interest. Endocrine disorders have the potential for disrupting the general health and well-being of affected individuals and their families; thus they warrant serious attention. This symposium was convened in November 1997 at Palm Beach Gardens, Florida, to bring together medical, behavioral, and social scientists. The meeting fostered the presentation and discussion of the most current clinical research on the effects of various therapies on a wide range of endocrine disorders from diabetes to adrenal insufficiency and growth hormone deficiency. The participants, all noted national and international experts in their fields, focused their attention on both the biomedical value and effectiveness of treatment, as well as on the impact such treatments have on psychological states such as mood and cognition. Many presentations specifically emphasized the quality of life (QOL) indicators that now regu larly appear in many research protocols and reports. The pioneering work of two clinical researchers was a major highlight of the meeting and an Award of Recognition was presented to Robert Blizzard, M. D. , and John Money, Ph. D. , for their innovative and insightful work in pediatric endocrinology and psychosexual development.

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.