Inherited disorders of purine and pyrimidine metabolism in man lead to severe diseases. At the 2nd M}nchner Adventssymposium the state of the art as to the genetic basis, clinical aspects, and the biochemical basis has been given by leading experts in the fields concerning the following diseases: Hypoxanthine phosphoribosyltransferase deficiency (HGPRT-deficieny), adenine phosphoribosyltransferase deficiency (APRT-deficiency), hyperuricemia and gout, adenosine deaminase deficiency (ADA-deficiency, purine nucleoside phosphorylase deficiency (PNP-deficiency). All contributions of the symposium are published within this volume thus giving and overview of this most interesting field.

Alcohol abuse, alcohol intolerance, alcohol dependence and other alcohol-related disabilities are some of the most challenging public health problems facing our modern-day society. The purpose of this comprehensive monograph is to review the available knowledge concerning the pharmacogenetic basis of alcohol sensitivity and its physiolgical implications and to synthesize the bulk of existing knowledge regarding metabolic features and biomedical disturbances related to alcoholism. The chapters cover a broad array of disciplines including an overview of historical and epidemiological aspects, biochemistry and molecular genetics of enzymes involved in alcohol metabolism, biochemical and neuropsychopharmacological effects of alcohol. Major emphasis is placed on the role of genetic factors in alcoholism. The experimental details are summarized and a comprehensive bibliography is included.

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."

Biological membranes are often effected by diseases. Molecular events leading to or arising from pathological changes in the course of different diseases are as yet not clearly understood. This competent study by leading experts covers changes of the cellular environment, membranes and the metabolic functions during tissue growth and differentiation as well as aspects of abnormal organelle function in lysosomal storage diseases, peroxisomal and mitochondrial disorders, enzyme defects and regulatory defects of receptors due to oncogenes.

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.

Systems Metabolic Engineering is changing the way microbial cell factories are designed and optimized for industrial production.
Integrating systems biology and biotechnology with new concepts from synthetic biology enables the global analysis and engineering of microorganisms and bioprocesses at super efficiency and versatility otherwise not accessible. Without doubt, systems metabolic engineering is a major driver towards bio-based production of chemicals, materials and fuels from renewables and thus one of the core technologies of global green growth. In this book, Christoph Wittmann and Sang-Yup Lee have assembled the world leaders on systems metabolic engineering and cover the full story from genomes and networks via discovery and design to industrial implementation practises.
This book is a comprehensive resource for students and researchers from academia and industry interested in systems metabolic engineering. It provides us with the fundaments to targeted engineering of microbial cells for sustainable bio-production and stimulates those who are interested to enter this exiting research field.

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.

There has been much popular and scientific interest in the fields of nu trition and aging in recent years. As the importance of proper nutrition in children and young adults becomes more fully understood, it is natural to wonder if proper nutrition could playa similar role in later life. Recent research has indicated that nutrition can potentially intervene in the ag ing process in at least two ways. First, studies in animals and humans have shown that nutrition can be used to improve functional status, which, in turn, is related to perceived quality of life. Second, nutritional manipu lation has been used to extend maximal life span in laboratory animals. How these interesting findings apply to the human situation remains to be explored. The purpose of this book is twofold. The first is to present recent ad vances in our basic knowledge of how nutrition and aging interact with each other. The second is to discuss some applications of this knowledge to the care of the elderly patient. The interaction between aging and nutrition is complex because each may act on the other in either a synergistic or antagonistic fashion. Aging may alter the nutritional status of the elderly by affecting the way nu trients are absorbed and utilized by the body. Aging may also influence food intake and, therefore, nutritional status by decreasing the palatabil ity of food. The environment of the elderly may change so they are less likely to eat well-balanced meals."

In the years since the initial discovery that blood from diabetic patients contains increased amounts of a posttranslationally gluco sylated form of hemoglobin (hemoglobin Ale)' an impressive number of studies have clarified and expanded the use of glycohemoglobin levels to assess disease status. Many other structural proteins have been shown to undergo similar changes, including proteins from tissues most commonly affected in diabetes (e.g., lens, aorta, peripheral nerve, basement membrane). Thus, the nonenzymatic glycosylation of hemoglobin emerges as an invaluable model for the pathogenesis of certain chronic diabetes complications. In addition to reviewing a wealth of investigative possibilities in the area of these chronic complications-including eye, kidney, nerve, and vascular disease-Dr. Cohen indicates how enhanced nonenzymatic glycosylation in uncontrolled diabetes underscores the pressing need for maintenance of long-term euglycemia. Dr. Cohen is an endocrinologist and diabetes specialist whose research activities have largely focused on the chemistry and metabo lism of the basement membrane in diabetes. This superb monograph on nonenzymatic glycosylation clearly shows the major trends of her past and present research and clinical activities. This book is beautifully written and a pleasure to read. It provides great insight into the mechanisms of the pathogenesis of the oom- vii viii Foreword cations of diabetes and should be of immense value not only to basic and clinical investigators, but also to internists, diabetologists, and endocrinologists in clinical practice."

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.

As I read this unique volume on diabetes and pregnancy edited by Lois Jovanovic, I was struck by two themes that run throughout these collected chapters. First, this volume provides an excellent assessment of past problems, present management, and future challenges presented by dia betes in pregnancy. Orury's unique, longitudinal experience with diabetes iIi pregnancy provides the reader with an important overview, as does Coetzee's discussion of gestational diabetes. Current problems-deter mining the etiology and prevention of congenital malformations in infants of diabetic mothers (10M), assessment of antepartum fetal condition, management of pregnant patients with diabetic retinopathy, recognition of thyroid dysfunction in the pregnant diabetic woman, and understanding the multitude of metabolic sequelae observed in the 10M-are thoroughly reviewed. Finally, important considerations for future treatment and ther apy such as the adaptation of the fetal pancreas to the disordered intra uterine environment often seen in maternal diabetes, the use of fetal pan creatic tissue for transplantation, the application of exercise in the management of the pregnant woman with diabetes, and the long-term con sequences for the 10M provide an exciting glimpse into the future. The second important theme that emerges is the critical role the problem of diabetes in pregnancy has played in our understanding of maternal and fetal physiology. Clinical observations supported by basic research have emphasized the role of fetal fuels in teratogenesis.

The Tenth International Histocompatibility Workshop of this work, and Fran Berman for her help in preparing component concerning T-cell recognition of HLA class the report. MaryAnn Barletta, Sally Krell, and Halina II molecules drew its strength from the hard work, Korsun provided invaluable help with a multitude of diligence, and selfless spirit of the 23 participating organizational and operational issues. Bo Dupont and laboratories. The enthusiasm and camaraderie exhib- Bob Knowles provided sound advice, helpful discus- ited by the participants in Princeton during November sions, and continued support. John Hansen, Jean Marc 1987 bear testimony to the caliber of the individuals Lalouel, and the other members ofthe Organizing Com- involved. mittee made valuable contributions. Rosemarie Pliitke's Numerous individuals, both inside and outside of the enthusiasm, diligence, and statistical expertise were Organizing Committee, contributed significantly to the vital ingredients in this undertaking. John Klein was success of this component of the Workshop. We thank always ready to step in and assume whatever responsibil- David Eckels, Adrianna Zeevi, Nancy Reinsmoen, and ity was necessary to keep the work going. Above all, I Eric Mickelson for their continued advice, encourage- owe special and personal thanks to my family, whose ment, and hard work throughout this endeavor. We thank patience, support, and understanding helped to sustain Deborah Richardson for her help during the early stages me over the last 2 years.

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.

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."

It has been a challenge for us to edit this volume of Endocrinology and Metabo lism: Progress in Research and Clinical Practice. The topic of the pathogenesis of insulin-dependent, type I diabetes mellitus is particularly appropriate for this series, since advances in this area have been made, to a large extent, by applying state-of-the-art laboratory techniques to clinical samples. Over the last several years, a number of lines of evidence have been gathered, suggesting that classic type I diabetes mellitus results from the autoimmune des truction of pancreatic beta-cells in genetically susceptible individuals. This hypothesis is particularly appealing because it offers a rational approach to the prevention of diabetes by immunosuppression. We have tried to present a balanced, authoritative summary of the information currently available to support the autoimmune hypothesis for the pathogenesis of human type I diabetes, to place this information in historical perspective, to include relevant information from animal models of type I diabetes in which more invasive experimentation is ethical, and, finally, to update the reader on the current status of attempts to intervene in the progression of diabetes with immunosuppressive drugs. New York, New York Fredda Ginsberg-Fellner Robert C. McEvoy Contents Preface.. . . .. .. .. . . . . . . . . . . . . ... . . . . . . . . . . . .. . . . . . . .. . . . . v Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Xl . . . . . . . . . . . . . 1. The Autoimmune Hypothesis of Insulin-Dependent Diabetes: 1965 to the Present . . . . . . . . . . . . ..................... . . . . . .

In the middle of the 17th century, the great French philosopher Rene Descartes wrote (L'Homme, J. Le Gras, Paris, 1669) that a suitable stimulation of the brain results in two types of "movements": exterior movements, designed to seek desirable ends and to avoid undesirable or harmful ones and interior movements or "passions" which through the release of "animal spirits" regulate the heart, the liver, and other organs. When it appears appropriate to meet a threat with force, the passion of rage causes the release of strong spirits, whereas when avoidance appears to be the better choice, the passion of fear causes the brain to release weak spirits. We do not know what influence, if any, Descartes had on the thinking of Walter B. Cannon (Bodily Changes in Pain, Hunger, Fear and Rage, Appleton and Co. , New York, 1920), of Hans Selye (The Story of the Adaptation Syndrome, Acta, Inc. , Montreal, 1952), ofG. W. Harris or of R. Guillemin (Hypothalamic-Hypophysial Interrelationships. A Sym posium. c. c. Thomas, Springfield, 1956), but it is interesting to reflect upon the durable value of great ideas which constantly resurface even if modified by other ideas and by new techniques, as if propelled by a preordained intellectual imperative.

Glucagon III complements "Glucagon I" and "II" published in 1983 in this series as "Vols. 66/I" and "II." These three volumes truly represent a "glucagon encyclopedia" and as such have no competitors in the scientific literature worldwide. In this volume, the most recent data on glucagon molecular biology are reviewed together with clinically relevant information on the role of glucagon in the pathophysiology of diabetes, the place of glucagon in medical imaging or in emergency medicine. Chapters are devoted to newly identified members of the glucagon family such as glucagon-like peptide-1 (GLP-1) and oxyntomodulin. Glucagon III is a comprehensive review of all information published on this important hormone since 1983 and is "the" reference book on the subject.

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.

Current thinking holds that obesity derives primarily from overnutrition (though compelling arguments for other mechanisms, like endocrine disruption by environmental pollutants, also gain support from the literature). In animals, overnutrition is initially handled by adipose tissue expansion; however, exhaustion of this route of lipid sequestering results in oversupply of lipid to other tissues including skeletal muscle, heart, liver, and others. Failure of these tissues to clear excess lipids through either metabolism or sequestration into putatively inert triacylglycerols results in perturbation of bioactive lipid metabolism in cells. In particular, aberrant generation of bioactive sphingolipids is implicated in a multitude of pathological outcomes of metabolic disease including insulin resistance, inflammation, cardiomyopathy, and others. This volume addresses not only the fundamentals of sphingolipid metabolism and analysis, but also the roles of sphingolipids in these disease processes.

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.

Food research (and funding) is becoming more and more focused on health. While researchers and product developers have made great strides in food engineering, there needs to be increased focus on what happens when the food is actually digested. How is the food absorbed? Do the benefits remain? Digestion is a complex topic, and this will be the first book aimed at food researchers. Authored by a physiologist and a food engineer, the book willbe a welcome addition to the literature.

Insulin resistance (IR) and elevated blood pressure are two key features of the metabolic syndrome, which play an important role in the development of secondary cardiovascular complications. In this book, the effects of insulin resistance on the various vasoactive pathways are explored, which affect the equilibrium between vascular relaxation and constriction. Furthermore, the interaction between oestrogen, testosterone and insulin signalling-dependent changes in vascular reactivity and blood pressure are discussed. Also addressed in this book are the mechanisms underlying reciprocal relationships between insulin secretion, insulin resistance and inflammation in the pathological state and in its subsequent improvement. Moreover, the current concepts in understanding the underlying risk factors contributing to insulin resistance are examined, focusing on the role of magnesium deficiency that emerges as potential pathogenic key related with decreasing insulin sensitivity. In addition, it is widely accepted that metabolic syndrome is related to cardiovascular disease and that insulin resistance is one of the causes of metabolic syndrome. The authors discuss thiazolidinediones (TZDs), a class of antidiabetes agents, as a means to improve endothelial dysfunction, prevent atherosclerosis, and significantly reduce the risk of cardiovascular disease.

The literature concerning muscle Glycogenoses reflects a worldwide interest which has been greatly intensified, mainly over the last ten years. To a large extent, this renewed interest is due to recent advances in diagnosing and treating the Lysosomal disease named Glycogenosis II or Pompe disease (GSD II). The new therapeutic approaches must induce us to make a great effort in order to better diagnose, treat and follow correctly the patients with Pompe disease. This book is a comprehensive text which covers all of the aspects regarding this disease, from pathogenic to clinical and therapeutic features. (Imprint: Nova Biomedical).

This timely book provides an overview of topics related to obesity. These include associated health risks, childhood obesity, genetics, evaluation, treatment, behavioral strategies, and successes and failures in preventing obesity. The volume covers evaluation guidelines, different approaches to treatment, including diet, exercise, behavior, drugs, and surgery to deal with the current world-wide obesity epidemic.