With the invitation to edit this volume, I wanted to take the opportunity to assemble reviews on different aspects of circadian clocks and rhythms. Although most c- tributions in this volume focus on mammalian circadian clocks, the historical int- duction and comparative clocks section illustrate the importance of various other organisms in deciphering the mechanisms and principles of circadian biology. Circadian rhythms have been studied for centuries, but only recently, a mole- lar understanding of this process has emerged. This has taken research on circadian clocks from mystic phenomenology to a mechanistic level; chains of molecular events can describe phenomena with remarkable accuracy. Nevertheless, current models of the functioning of circadian clocks are still rudimentary. This is not due to the faultiness of discovered mechanisms, but due to the lack of undiscovered processes involved in contributing to circadian rhythmicity. We know for example, that the general circadian mechanism is not regulated equally in all tissues of m- mals. Hence, a lot still needs to be discovered to get a full understanding of cir- dian rhythms at the systems level. In this respect, technology has advanced at high speed in the last years and provided us with data illustrating the sheer complexity of regulation of physiological processes in organisms. To handle this information, computer aided integration of the results is of utmost importance in order to d- cover novel concepts that ultimately need to be tested experimentally.

Discovered and first isolated in 1966 in C. De Duve's laboratory, peroxisomes - organelles which are present in nearly all eukaryotic cells - are still not fully understood. More than 40 peroxisomal enzymes catalyzing a variety of reactions have been characterized. Moreover, peroxisomes can be regarded as toxicological indicators: several compounds, including hypolipemic drugs, plasticizers or pesticides trigger their proliferation. This proliferation may lead to hepatocarcinogenesis in rodents. Interest in peroxisomes stems not only fromtheir biology, but also because there is a deficiency of peroxisomal functions in several genetic diseases. Some genes involved in inborn errors of peroxisomal function have recently been identified. In this manual, based on a FEBS Advanced Course on peroxisomes, protocols on the following topics are described in detail: Isolation and characterization of peroxisomes by ultracentrifugationand immunoblotting; gene regulation studied by mRNA isolation, hybridizationand DNA cell transfection; use of cell lines as peroxisome proliferator targets; transformation with retrovirus; peroxisomes as toxicological markers; cytochrome P450 induction; drug design and computer analysis of ligand/receptor interaction involved in peroxisomal gene expression.

Diagnostic Methods in Clinical Thyroidology provides a forum for discussion of controversial issues in three major categories: diagnosis of thyroid function, non-invasive evaluation of structural abnormalities, and needle biopsy diagnosis of thyroid nodules. For each category, a free interchange of ideas based on extensive clinical experience is followed by a summary that strives to resolve these controversial issues within a framework of sound clinical practice. The volume will this serve as a ready reference for the many physicians who evaluate thyroid patients.

JIMD Reports publishes case and short research reports in the area of inherited metabolic disorders. Case reports highlight some unusual or previously unrecorded feature relevant to the disorder, or serve as an important reminder of clinical or biochemical features of a Mendelian disorder.

Traditions are dangerous; doubly so in science. Traditions are unchanging; science is about change. This was the 4th International Colloquium on Carbohydrate Metabolism in Pregnancy and the Newborn to be held in Aberdeen, and by now the form is set. How much its content has changed is a matter of nice judgement and not under the control of the organizers. It is not within their power to bring news of revolution, if there has been no revolution. Certainly many of the speakers had kent faces from previous Aberdeen meetings, but so they would be at any meeting on diabetes anywhere in the world. The written proceedings of scientific conferences have purposes other than to record changes: sometimes they need to state a consensus. The 3rd Colloquium came to an agreement about the importance of prepregnancy recognition and control of abnormalities of carbohydrate metabolism. The 4th set out to examine what results it had achieved. Much of this book is taken up with follow-up studies of the applications of similar regimes in different parts of the world. Since the first Aberdeen meeting in 1973, progress in the manage ment of diabetic pregnancy has been slow and steady, but the change in the city and the society where the meetings took place has been fast.

The breadth of research efforts represented by the many excellent papers in these proceedings is an eloquent testimonial to the idea of one man Dr. Josiah Brown-to whose memory this volume is dedicated. His tragic and unexpected loss in a swimming accident in August 1985 brought to an abrupt close a long and distinguished career as a physician and scientist. The possibility of using fetal pancreas tissue for transplantation into insulin-deficient diabetic recipients had intrigued Dr. Brown for several years prior to 1972, when he began in earnest to assemble a research team to explore this idea in detail. He felt that improvements in the formulation and administration of insulin (even the later recombinant human insulin) had taken us about as far as we could go in treating diabetes, and that methods for achieving complete cures must be explored. Numerous advantages of the fetal pancreas quickly became apparent, and were explored scientifically by Dr. Brown and his group. Transplanted pancreas tissue from a fetal donor of the appropriate developmental stage engrafts quickly, and can reverse diabetes very efficiently (1-3). By shunting the venous'drainage of the graft into the hepatic portal vein, a single pancreatic rudiment can, in time, provide enough insulin to restore normoglycemia and urine volume in a diabetic adult recipient (4). As with fetal pancreas rudiments in culture, transplanted fetal pancreas tissue loses its exocrine character, while continuing to develop and maintain endocrine function.

During the past decade many review papers and books have been devoted to descriptions and analyses of biological rhythms (chronobiology) in plants and animals. These contributed greatly to demonstrating the impor tance of bioperiodicities in living beings in general. However, the practi cal aspects of chronobiology with regard to human health and improving the treatment of disease have not yet been a major focus of publication. One of our aims is to establish the relevance of biological rhythms to the practice of medicine. Another is to organize and convey in a simple fashion information pertinent to health- and life-science professionals so that students, researchers, and practitioners can achieve a clear and pre cise understanding of chronobiology. We have limited scientific jargon to unavoidable basic and well-defined terms and we have emphasized illus trative examples of facts and concepts rather than theories or hypotheti cal mechanisms. This volume is divided into seven chapters, each of which is compre hensive in its treatment and includes an extensive bibliography. The book is organized to serve as a textbook and/or reference handbook of modem applied chronobiology. Chapter 1 describes the historical development of chronobiology and reviews why, when, and how major concepts were introduced, accepted, and transformed."

Endocrinology and Metabolism: Progress in Research and Clinical Prac tice is a new series that has been designed to present timely, critical reviews of constantly evolving fields; to provide practical and up-to-date guidance in the solution of pertinent clinical problems; to offer an alterna tive to the laborious search of the literature (and the often frustrating reading of highly technical articles); and to translate the language of the laboratory into that of the practice of medicine. We think that this volume and those to come will prove useful to physi cians (and to physicians in training), as well as to investigators in a wide variety of specialties; in short, to anyone who seeks answers to questions in endocrinology and metabolism. The first chapter of this volume could well serve as a general introduc tion to the entire series. It points out how our growing understanding of the molecular basis of biologic communication has led to the discovery of a growing number of clinical syndromes, as well as to the realization that phenotypically similar diseases may have radically different pathogenetic mechanisms and thus may require radically different therapeutic strata gems."

Thirty years have elapsed since the first description by S. A. BERSON and R. S. Y ALOW of the basic principles of radioimmunoassay (RIA). During this period of time, RIA methodology has been instrumental to the growth of many areas of biomedical research, including endocrinology, oncology, hematology, and pharmacology. It has done so by providing a relatively simple universal tool allowing, for the first time, the detection of endogenous mediators that are present 12 10 in body fluids at concentrations as low as 10- _10- M. The fundamental nature of this discovery and the wide-ranging fall-out of basic and clinical knowledge derived from its application have been acknowledged by the many honors tributed to its pioneers, including the Nobel Prize awarded to Dr. Y ALOW 10 years ago. Although several excellent books have been published during the past decades covering various aspects of RIA methodology, we felt the need, as pharmacologists, for a comprehensive discussion of the methodological and conceptual issues related to the main classes of mediators of drug action and to drugs themselves. Thus, we gladly accepted the challenge provided by the invitation to edit a volume of the Handbook of Experimental Pharmacology on Radioimmunoassay in Basic and Clinical Pharmacology. We tried to balance the emphasis placed on more general aspects of the RIA methodology and that on specific mediators.

The findings of immunogenetic linkages, autoantibodies including autoislet cell and autoinsulin antibodies-and viruses in diabetes has attracted increasing interest among immunologists, virologists, geneticists and clinicians. To gather together the recent avalanche ef new and exciting information emerging in this area, Current Topics in Microbiology and Immunology has put together two volumes on this subject. The first volume, CTMI 156, (see page VI for contents) provided data on the animal models and experimental approaches currently employed to evaluate both the autoimmune and virologic factors contributing to the causation and patho genesis of diabetes. The second is this current volume. It is edited by Drs. BAEKKESKOV and HANSEN and focuses on current knowledge in human diabetes. This volume on human diabetes contains ten chapters from leading researchers. The book is arranged in two components. The first part critically analyzes the genes in man that playa role in susceptibility to insulin dependent diabetes mellitus (IDDM). The second segment analyzes the role(s) that various environ mental factors play in IDDM and provides data on the autoantigens, aberrant immune responses, and the role of cytokines and free radicals in the pathogenesis of diabetes. La Jolla, California MICHAEL B. A. OLDSTONE, M.D. This collection of studies was conceived as part of a two-volume review of the immunology of diabetes. The contents of Volume 156, which forms part 1, are listed below."

This book is based on the Symposium "Metabolic Regulation and Functional Activity in the Central Nervous System" which was held on September 16 and 17, 1972, at Saint Vincent (Aosta)/Italy, and was sponsored by the Accademia di Medicina di Torino with the scientific cooperation of the Istituto di Farmacologia, Universita di Torino, and the Pharmakologisches Institut der Freien Universitat Berlin. Its purpose was to give a greater number of scientists from different countries an opportunity to report their latest results under a heading concerning general relationships between metabolism and function. We quite deliberately refrained from pursuing the partly heterogenous subjects into details. Thus, the organizers hoped to be able to interest a greater circle of readers for the manifold subjects from various fields dealing with the investigation of metabolic processes in the central nervous system. The discussion remarks to the lectures could not be considered for printing. The Accademia di Medicina di Torino and all others concerned do not only thank Dr. R. Di Carlo and other members of the Istituto di Farmacologia, Universita di Torino, for the excellent work they performed in preparing this Symposium, but also the Amministrazione Regionale della Valle di Aosta and SIT A V di Saint-Vincent for their generous support and their kind hospitality which made the stay at Saint-Vincent most agreeable for all participants."

Since insulin became available for the treatment of diabetes in 1922 a number of major advances have been made, which include the modification of insulin to vary its timing of action, its purification, and latterly, the production of human insulin. Human insulin in quantities sufficiently large for therapy has been made available by two techniques developed in parallel during the late 1970s. These involve either (i) formulation in E. coli bacteria suitably encoded by DNA recombinant methods of the A- and B-chains of human insulin followed by a chain combination reaction ('biosynthetic' human insulin) or (ii) enzymatic conversion (transpeptidation) of porcine insulin brought to react with a threonine ester by porcine trypsin in a mixture of water and organic solvents, yielding human insulin ('semi-synthetic' human insulin). This book includes the first clinical-pharmacological studies of each of the highly purified 'semi-synthetic' human insulin preparations: Actrapid (R) HM; Monotard (R) HM; Protaphane (R) HM; Actraphane (R) HM; and Ultratard (R) HM (Novo Industri A/S, Copenhagen). The preliminary studies established their safety and efficacy relative to their porcine and bovine counterparts emphasising the relevance of species and formulation on the pharmacokinetics and biological responses to insulin. Additional investigations with human insulin demonstrated the influence of insulin concentration, site of administration, the addition of aprotinin to insulin and the mixing of 'short-' and 'intermediate-acting' formulations on insulin 'bioavailability'. Examination of the 'within' and 'between' subject day-to-day variation in absorption and the effect of subcutaneous insulin also demonstrates the dominating influence of insulin responsiveness.

The advances in science and medicine we are now experiencing are unprec edented and exciting. Life expectancy is prolonged, and quality of life is much improved. We learn of fabulous new discoveries made at the bench or the bedside every week. Many diseases have been totally eliminated, others can be significantly improved by new therapeutic formulations. Much of the success can be attributed to a better understanding of disease processes and the specific targeting of new and more effective medications. As is the case in many areas of successful human endeavour, there can be a downside. In the case of drugs and chemicals it is their adverse effects which are of concern. Of course, every effort is made to devise medications that are safe, and the need to elucidate and understand mechanisms are crucial, yet adverse effects remain a problem. They can be unpredictable and diverse. Drugs have been shown to induce virtually the whole gamut of human liver pathology from acute fulminant hepatitis to chronic active hepatitis to cirrho sis and even malignancy. Hence the possibility of adverse drug effects must be considered in the differential diagnosis of many patients with liver disease. This is well recognized and is very important; indeed, removal of the offending agent can often lead to reversal of the adverse effect. This is an area of hepatology where we can really make a difference."

This volume provides guidance and answers to frequently asked questions in infectious diseases, thus facilitating improved patient care, prudent and cost effective management and investigation of these disorders. Other more complicated but less common conditions are also reviewed. Uniquely, this volume directly discusses several controversies regarding infectious diseases from the 21st century.

The prevalence of metabolic syndrome (MS) is rising in developing countries and developed countries at such high rates that it is now considered a worldwide public health problem of pandemic proportions. Yet its spread can usually be mitigated by diet and lifestyle behavior. Nutritional Intervention in Metabolic Syndrome brings together coverage of dietary patterns and dietary components to create a complete understanding of the mechanisms by which these diets and components may improve metabolic syndrome. It then presents information on how to treat MS through lifestyle change and nutritional intervention. Witten by experts, the book focuses on diet therapy, nutritional intervention, and oxidative stress in metabolic syndrome. It presents information on dietary patterns in metabolic syndrome, including Mediterranean style diets, DASH, and low calorie diets. The text then provides an understanding of the physiopathology mechanisms in metabolic syndrome and strategies to treat these conditions through nutritional intervention. Chapters cover prevalence of MS, pathophysiology, MS in systemic lupus erythematosus and rheumatoid arthritis, gene-nutrient interactions, MS in adolescents and children, lifestyle change and physical activity, and various effects of dietary components in MS. Research studies examining food groups are important, and there is a trend in the literature to verify the relationship between dietary patterns and cardiovascular risk factors. However, studies examining dietary components, such as olive oil, soy-based products, n-3 polyunsaturated fatty acids, berries, whole grains, nuts, dairy foods, tea, coffee, and alcoholic beverages are also important. The coverage of both in this book gives you an understanding of the pathophysiology underlying MS that you can use to develop strategies to prevent and treat these conditions through nutritional intervention.

Unique collection of case and research reports on rare metabolic disorders Contains unusual or previously unrecorded features relevant to metabolic disorders All contributions rigorously peer-reviewed JIMD Reports publishes case and short research reports in the area of inherited metabolic disorders. Case reports highlight some unusual or previously unrecorded feature relevant to the disorder, or serve as an important reminder of clinical or biochemical features of a Mendelian disorder.

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.

JIMD Reports publishes case and short research reports in the area of inherited metabolic disorders. Case reports highlight some unusual or previously unrecorded feature relevant to the disorder, or serve as an important reminder of clinical or biochemical features of a Mendelian disorder.

One person in four in the industrialized countries suffers from hyperuricemia and is therefore at risk of developing gouty arthritis, nephrolithiasis, or any of the other consequences of urate deposition. At present, far too little is known about urate deposition and the mechanisms by which it occurs, as well as about its clinical consequences, which include formation of toph; over the helix of the ear or in bones close to joints that have never exhibited an attack, development of bursitis, chronic tendovaginitis leading to carpal tunnel syndrome, and gouty paraplegia. Information on these matters is needed to estimate the risks of hyperuricemia and to determine when therapeutic intervention is indicated. The contributions and discussions in this book, resulting from an international symposium held in December 1990 in the Medizinische Poliklinik in Munich, provide an up-to-date source of current knowledge about hyperuricemia in man and its clinical consequences.

Diabetes mellitus represents one of the most frequent and serious clinical syn dromes in contemporary medicine. Since the end of the nineteenth century, the endocrine pancreas has been implicated in the pathogenesis of this disease. Several pathologists of the twentieth century detected various lesions and mor phologic alterations in the pancreatic islets of diabetic patients, but the patho physiologic basis of their findings remained long obscure. The systematic mi croscopic work of WILLY GEPTS clarified the views and related the variety in histopathology to differences in origin, duration and clinical expression of the disease. Over the past two decades, the concept of a multifactorial origin of diabetes has become widely accepted. Various agents and mechanisms have been identified which can lead to a quantitative or qualitative deficit in pancre atic B-cells. The purpose of this book is to bring an update on the many path ways which may induce an absolute or relative insufficiency in insulin release and hence a diabetic state. Rather than bringing a complete account on all re search relevant to the understanding of the pathology of the diabetic pancreas, the authors of the various chapters of this volume have focussed on selected processes which can impair B-cell function, survival or regeneration.

Atherosclerosis leading to coronary heart disease and to cerebrovascular disorders is the number one cause of death in industrialized societies. For the last two decades, great ad vances have been made in understanding the pathogenesis of those disorders. Recent studies have revealed that the earliest event in atherogenesis is the adhesion of circulating leukocytes to the vascular endothelial cells and their migration into the subendothelial space. These cells are known to playa central role in the formation of a fatty streak consist ing of lipid-laden foam cells. As pathological events continue, the lesion is converted to a more fibrous lesion associated with vascular smooth muscle cells. To solve the enigma of this complicated process, intensive studies in molecular biology have disclosed the genes involved in those events. Some of the genes have been verified by creation of novel animal models, which have led to novel therapeutic strategies for subjects with atherosclerosis. This volume contains papers presented at the International Symposium on Lipoprotein Metabolism and Atherogenesis held in Kyoto December 5-8, 1998, supported in part by the Japan Intractable Diseases Research Foundation. The following three topics were the focus of the three-day program: I) The molecular approach to studying risk factors and prevention 2) The creation of novel animal models 3) Lipoprotein disorder as a cause of activation of vascular endothelial cells Thirty distinguished researchers from the United States, the United Kingdom, Austria, Finland, Australia, and Japan were invited."

JIMD Reports publishes case and short research reports in the area of inherited metabolic disorders. Case reports highlight some unusual or previously unrecorded feature relevant to the disorder, or serve as an important reminder of clinical or biochemical features of a Mendelian disorder.

Die Beitrage dieses Buches beschaftigen sich mit Autoimmunitat, Immuntherapie des Typ-I Diabetes, Virusgenese, Insulintherapie und -allergie. Schwerpunkte liegen auf den dynamischen Aspekten der Insulinsubstitution unter Berucksichtigung einer angepassten Diat und der Therapie mit oralen Antibiotika, Insulinen und Pro-Insulinen. Gleichzeitig wird anhand der Makro-Angiopathie und der Neuropathie auf die Auswirkungen der dynamischen Insulinsubstitution bei Sekundarkomplikationen hingewiesen. Die Moglichkeit der computerunterstutzten Therapiefuhrung und glukosesensorgesteuerten Biofeedback-Kontrolle werden vorgestellt. Ein umfangreiches Kapitel vermittelt den aktuellen Stand der experimentellen Forschung und der klinischen Anwendung der Pankreas- und Inselzelltransplantation.

In the last decade, it has become increasingly evident that the clini- cal and morphologic changes underlying many of the complications of diabetes, including cataract formation, retinopathy, nephropathy, neuropathy, and macrovascular disease, are preceded by a variety of disturbances of biochemical and physiologic origin. Dr. Cohen has recently written a superb monograph, entitled Diabetes and Protein Glycosylation: Measurement and Biologic Relevance, in which she thoroughly explores how enhanced nonenzymatic glycosylation in uncontrolled diabetes underscores the pressing need for main- tenance of long-term euglycemia. In the present volume, The Polyol Paradigm and Complications of Diabetes, she reviews, in a most succinct and thorough manner, how another biochemical mechan- ism, involving the polyol pathway, is involved in the pathogenesis of such diabetes complications as retinopathy, neuropathy, nephropa- thy, and cataract formation. Dr. Cohen gives us a clearly written and comprehensive mono- graph, reviewing the chemistry of the polyol pathway and of the aldose reductase inhibitors, and the pathophysiologic significance of increased polyol pathway activity in a variety of tissues affected by Vlll Foreword diabetes mellitus. She insightfully describes the relationship of increased polyol pathway activity to altered metabolism of inositol- containing phospholipids and to changes in various tissue concentra- tions of myo-inositol. Finally, she provides us with a careful review of the existing experimental and clinical studies with a variety of different aldose reductase inhibitors that have been and are being performed in the hope of preventing or reversing long-term compli- cations of diabetes.

One of the hallmarks of aging is the decreased capacity to adapt to changes in the environment. In a constant, controlled environment, it is often difficult to distin guish the functioning of the young organism from that of the old. However, when stresses are applied-temperature stresses, dietary stresses, infection, emotional stresses-the differences are more apparent. Frequently, the response ofthe old is delayed and may never reach the same mag'nitude as the young. These responses, in most cases, are mediated by the neuroendocrine system, which communicates via hormones, neurotransmitters, and related substances. Thus, it is important to understand the age-related changes that take place in the secretion and act ion of these substances and how these changes relate to the well-being of the whole organism. Indeed, the "neuroendocrine theory of aging" proposes that almost all of the characteristics of aging can be accounted for by dysfunction of the neuroendocrine system. A book on endocrine function and aging is particularly relevant at this time. With the advent of the techniques of molecular biology, there has bee an explo sion of knowledge concerning hormone secretion and action. Hormones, pro hormones, hormone receptors, and "second messenger" mediators rapidly are being cloned and sequenced. Such knowledge gives us important insights into the molecular workings of these substances as well as into the genetic hasis of endo crine dysfunction. These new tools are now being applied to the problem of age related changes in endocrine function."