The TGF-13 superfamily is a large and expanding multigene family which in verte- brates includes the TGF-13 proteins themselves, the bone morphogenetic proteins (BMPs), the growth and differentiation factors (GDF), the activins/inhibins (INH), Mullerian inhibitory substance (MIS), glial derived neurotropic factor (GDNF) and more recently macrophage inhibitory cytokine 1 (MIC-1). They are characterised by conserved structural elements and a broad commonality of function. Major structural elements All members of the TGF-13 superfamily contain as their major structural hallmark a conserved spacing and distribution of seven cysteine residues. This structure is known as the cysteine knot and tethers together regions of the peptide as well as binding the two chains of the dimer to each other. High resolution structures are now available on proteins from three families within this group including glial derived neurotropic factor (GDNF), BMP-7 and several of the TGF-13s. Despite low similarity between some of these proteins (eg, TGF-13s and GDNF are only 13% identical) they share a strikingly similar three dimensional conformation (Fig. 1). These structural elements imbue the protein with some of its familial characteristics. These include its physico-chemical stability due to tight tethering of portions of the peptide chain via criss-crossing disulphide bonds. Much of its surfaces are coated with hydrophobic patches leading to a propensity to bind non-specifically to other proteins as well as to its self. This also causes a marked propensity for aggregation when the recombinant protein is present at high concentration.

course, also aware that many who use this volume One in every three slides examined by a general diagnostic pathologist in the United Kingdom, and will be well familiar with the classical, or 'textbook', in most other countries, comes from a gynaecological appearances of most of the more common conditions patient. Few pathologists can hope, therefore, to and have therefore often chosen an example which, escape a constant exposure to gynaecological path whilst being typical, is not necessarily classical. ology, and it is the aim of this atlas to lessen the We have deliberately chosen not to include any difficulties of this diagnostic burden by acting as an illustrations of gross specimens. This is partly because illustrated guide to the histological diagnosis of of ou r view that such illustrations are of I ittle real value female genital tract abnormalities. to any but the least experienced of pathologists, and Gynaecological pathology does, however, pose a partly because their inclusion would have narrowed number of specific problems: the range and scope of still further our selection of histological figures.

This book is designed primarily for anatomic pathologists to facilitate their task of accurately diagnosing embryos and fetuses. A detailed examination of the products of spontaneous and induced abortions is necessary for accurate genetic counseling and for establishing the risk for specific abnormalities or another spontaneous pregnancy loss in the future. The growing interest in the defects of early development reflects the profound change in general life-style. In the past, spontaneous abortions were considered a common, usually sporadic event in a patient's reproductive history. Only reassurance and encour agement were given to the patient and scant attention was paid to the detailed pathology of the abortus. Nowadays, however, as a result of reliable methods of contraception and of the availability of reliable prenatal diagnosis for chromosome abnormalities more frequent in advanced maternal age, significant numbers of parents plan to have pregnan cies later in their reproductive life. Consequently, in a case of spontaneous abortion, the question of "cause" and of "future risk" of recurrence of abortion or an abnormal infant is particularly important. In the era of more elaborate and accurate prenatal diagnostic tests, the pathologist examining products of conception has a primary responsibility to detect, in both spontaneous and induced abortions, any developmental abnormality that would indicate an increased risk of multifactorial, chromosomal, and single gene disorders in a subsequent child.

There is a large and rapidly growing body of literature on the importance of mag nesium in biochemical and physiological processes. There is also much evidence that magnesium deficiency, alone and in combination with agents that interfere with its utilization, is associated with functional and structural abnormalities of mem branes, cells, organs, and systems. The manifestations of the changes caused by magnesium deficiency depend upon its extent and duration and on variable factors. Among the conditions that increase the risk of magnesium deficiency are (1) meta bolic factors that affect the absorption, distribution, and excretion of this mineral; (2) disease and therapy; (3) physiologic states that increase requirements for nutrients; and (4) nutritional imbalances. Excesses of nutrients that interfere with the absorption or increase the excretion of magnesium-such as fat, phosphate, sugar, and vitamin D-can contribute to long-lasting relative magnesium deficiency. All have been implicated in several of the diseases considered in this book. Whether their influence on the need for magnesium is a common denominator remains to be investigated further."

The present volume contains the scientific contributions to the Fifth International Symposium on "Current Trends in Sphingo lipidoses and Allied Disorders" under the auspices of the Isaac Albert Research Institute of the Kingsbrook Jewish Medical Center, the Department of Pathology, Downstate Medical Center, State Uni versity of New York, Brooklyn, New York, and the National Tay-Sachs and Allied Diseases Association, Inc., New York. A review of the four previous Symposia shows the increase in scope of the scientific exploration in this rapidly expanding field. The first meeting, held in 1958, was devoted to the discussion al most entirely of Tay-Sachs disease. The majority of the work emanated from local laboratories. The participants at the present Symposium came from many other domestic and foreign research in stitutions. The scope of the papers presented at these meetings and the interest shown in the Symposium demonstrates the signifi cance attached by the scientific community to the problems of these hereditary diseases. The reasons for this are apparent, when one considers the contributions during recent years to our basic know ledge by lipid and enzyme chemistry, genetics, and neuropathology. Partly because of the hereditary nature of these diseases any new discovery in this field has general meaning and permits cautious generalization well beyond its clinical significance."

The seventh annual multidisciplinary symposium on clinical oncology organised by the Royal College of Radiologists discussed the subject of malignant brain tumours. It was held in London in February 1985 and this volume collects together the edited texts of the papers which were presented at the meeting. Primary tumours of the central nervous system account for about 9070 of all malignant diseases but as much as 20% of all paediatric neoplasms. The prognosis ranges from excellent for some of the less aggressive tumours, through good for children's tumours such as medulloblastoma, to appalling for the high-grade adult astrocytomas. Improvements in pathological diagnosis and surgical and radiothera peutic techniques have led to considerable sequential improvements in outcome over those obtained in the past. In contrast the response to chemotherapy over the whole range of tumours remains disappoint ing, and clearly awaits new drugs and methods of delivery. The relative rarity of individual types of tumours, apart from the commoner high-grade adult astrocytomas, has made progress in terms of clinical trials difficult to organise. In spite of this much investigative work is in progress. The symposium, and the present volume, were designed to provide a comprehensive overview of the subject by experts, with an emphasis on the possible routes to future progress. The topics included aspects of pathology, imaging, diagno sis and treatment of both the common and uncommon primary tumours. It is hoped the papers will stimulate further interest and activity in this difficult area of clinical therapy and investigation."

Melanocytic neoplasms are of capital importance for all surgical pathologists and dermatopathologists. These tumors span a huge range of morphologic expression and biologic behavior, are potentially of the highest medical significance and are often fraught with diagnostic pitfalls and high litigation risk.

"Pathology of Challenging Melanocytic Neoplasms "offers a dynamic text where readers will encounter a broad spectrum of challenging melanocytic lesions, both benign and malignant and will thereby acquire a solid, working knowledge that they can immediately apply to daily diagnosis. The authors aim to clarify this often thorny field, keeping a steady focus on patient-related issues. The volume emphasizes the practical application of basic morphologic principles, immunohistochemistry and molecular methods in order to secure a confident diagnosis. Abundant illustrations display the characteristic features of the most important disease entities.

Rather than being yet another encyclopedic work of reference, this volume takes a fresh approach as it resembles a series of stimulating seminars employing exemplary case material to highlight, illustrate, and succinctly discuss the key points. To this end, the reader will be guided through a series of paired cases that pose a significant diagnostic challenge. By comprehensively comparing and contrasting two related entities, each such chapter will illuminate an intellectual pathway through which an important diagnostic puzzle can be solved. To broaden the differential diagnosis even further, additional illustrative cases are added to each discussion. Algorithms and tables summarize key points. Clinically relevant, up-to-date references will be provided to guide further study. Written by experts in the field, this novel text will be of great value to surgical pathologists in practice and dermatologists as well as residents and fellows training in these specialties.

Experts from Europe, Japan and the United States have contributed to this in-depth volume on digestive disease pathology. Each chapter contains numerous electron micrographs, often supplemented byline drawings, and extensive references to the literature.The clear illustrations and text are an excellent aid for the diagnosis of pathological entities in the gastrointestinal tract.

Needle biopsy of the liver is now an accepted procedure in most large hospitals, and surgeons and laparoscopists are more likely to biopsy the liver under direct vision than in the past. Consequently, increasing demands are being made on pathologists for rapid diagnosis. This full colour atlas provides a practical guide to the histopathological diagnosis of liver disorders, with particular emphasis on clinicopathological correlation and the need for the pathologist to be in full possession of all the available clinical information. Although containing over 350 colour illustrations, the book is more than just an atlas and each section includes a brief description of the main clinical and pathological features of the subject under discussion. For this second edition, many chapters have been rewritten - e.g. on viral hepatitis - and many new illustrations added. The book is intended for the practising and trainee pathologist and the clinician who performs liver biopsies, but will also be of value to postgraduates, residents and students in other branches of medicine.

Biotargets of Cancer in Current Clinical Practice presents an updated and reasoned review of the current status of knowledge concerning the major cancer types with a special focus on the current biomarkers, genes involved and the potential future targets of innovative therapies. The volume includes for each major cancer type, a comprehensive although concise discussion of epidemiology, affirmed and innovative biomarkers for diagnosis, and descriptions of the relevant genes for prognosis and (individualized) therapy through biotarget-specific new molecular treatments, with the latest information on the validation status of each novel biomarker. Individual chapters are dedicated to the major cancer types, plus a special chapter on metastasis. The present debate on patentability of genetic information applied to diagnostics and therapeutics of cancer is also discussed.

Autoimmune myasthenia gravis (MG) is a classical autoimmune disease, for which the target antigen, nicotinic acetylcholine receptor, has been cloned, sequenced and biochemically characterized. Antibodies to acetylcholine receptors destroy acetylcholine receptor at the neuromuscular junction, thus leading to defective neuromuscular transmission, muscle fatigue, and weakness. In the last few years, rapid advances have been made in unraveling the cellular and molecular mechanisms involved in the pathogenesis of MG, both in the animal model, experimental autoimmune MG (EAMG), and in human MG. Significant advances are being made in characterizing the cells and molecules involved in the autoimmune response to the acetylcholine receptor (AChR). These advances are leading to the development of specific methods of immunointervention in EAMG. Further understanding of the intricate involvement of the major histocompatibility complex (MHC) and non-MHC genes, T cell receptors (TCR), costimulator molecules, and specific cytokines in the afferent and efferent autoimmune response of AChR should pave the way to future antigen/clone-specific therapy of MG. This book is the outcome of the MG workshop proceedings in Mysore, India, 1998. The majority of the chapters in this book are contributed by world-renowned authors and their students. The book not only contains a timely review of specific topics, but also up-to-date findings. Immunologists and neurologists will find, in this volume, the latest in MG/EAMG cutting-edge research. Clinicians will be interested in the applications of the various immunointervention strategies into clinical trials in MG patients. Finally, students will not only be interested in reading the latest in EAMG/MG research, but will also find information to help them develop a future strategy to unravel the precise mechanism of disease. To summarize, in this book, the readers should find up-to-date information related to immunological mechanisms involved in MG pathogenesis and various modalities for possible approaches to immunointervention to treat MG.

This volume contains selected works from the 25th Anniversary of the International Conference on Intracranial Pressure (ICP) held in Williamsburg, Virginia. The theme of the meeting was Intracranial Pressure and Neuromonitoring and focused on all the current state of the art brain monitoring methodologies and their application to brain injury. The brain monitoring techniques covered a wide spectrum from neurochemical monitoring of the injured brain to specialized techniques for assessing shunt function in normal pressure hydrocephalus. It also includes the most recent advances in monitoring of the brain oxygen levels using electrodes or the less invasive Near Infrared Sprectroscopy devices. Controversial issues regarding the management of ICP and CPP or both are also addressed and there are several works dealing with this topic. Of particular interest is the group of papers describing diagnosis and outcome in normal pressure hydrocephalus. It is the first compilation of papers which covers all the latest brain monitoring studies in both ischemia, trauma and hydrocephalus. The manuscripts in this volume have been selected from over 300 abstracts submitted to this international symposium. The abstracts are also published in order to provide the most comprehensive view of the progress made in brain injury research.

Toxicological and pharmacological effects arise when chemicals interact with biophysiological functions in discrete cell types. There is a continuing need to screen novel compounds for their potential therapeutic effects, and once these have been "discovered" to understand their molecular actions, as the basis of using such compounds safely and for rational drug design. Pharmacology now uses all of the sophisticated molecular research techniques that are available for the development of safer and more efficacious drugs. Histochemistry has been usefully applied to developing new drugs (and assessing chemical safley) and is potentially cost effective. The need to test novel substances for their potential adverse effects has raised many questions. Toxicological pathology has moved away from the cataloging of lesions towards understanding the basis of the events that underly cell injury, especially for those secondary consequences of chemical injury that lead to malignancy and chronic disease. The focal nature of toxicologic lesions de mands the use of microtechniques to provide data to help understand these questions. Histochemistry is under-utilized, but offers one of the key ap proaches necessary to address the problem of understanding interactions between a cell population and a chemical, the modulation of cellular biochem istryor the presence of a lesion in a test animal can be rationalised in terms of species differences that have no relevance to man as opposed to those that are of clinical significance or represent a warning of dire consequences to man.

The vasculature of the central nervous system (eNS) is characterized by the existence of the blood-brain barrier (BBB), which can be regarded as both an anatomical and physiological phenomenon. The BBB is formed by a complex cellular system of endothelial cells, astroglia, pericytes, perivascular macrophages and a basal membrane, although the anatomic substrate of the BBB is the interendothelial tight junctions that form a continuous sealing. The BBB serves as an exquisitely controlled, functional gate to the eNS. It not only protects the brain from agents in the blood that could impair neurological function, but also controls the influx and efflux of numerous substances to maintain proper homeostasis and provide the brain with necessary nutrients. The structural and functional integrity of the BBB was shown to be dramatically altered during various diseases of the eNS, including neoplasia, ischemia, trauma, hypertension, inflammation and epilepsy. Recent years research has partially elucidated the mechanisms underlying the development of some of these brain disorders as well as the pathways used by different pathogens, like bacteria and viruses, to initiate eNS infections. The development of in vitro models of the BBB had instrumental role in the understanding of the involvement of the BBB in the pathogenesis of several eNS diseases. The intimate, functional association between the function of the brain and the activity of the BBB makes the later a target for pharmacological modulation that will expand the therapeutic possibilities for a range of neurological diseases.

Like all specialized areas of medicine, that of joint disease informative. The techniques, practical and interpretive, has become surrounded by a practical mystique and are highly reproducible and simple, allowing them to be applied in any laboratory. jargon specific to itself. The number of clinicians working Although we see this volume as being of value to all in the field is large but the number of pathologists small. interested in joint disease it is specifically aimed at It follows that the majority of pathologists are at somewhat laboratory staff wishing to offer a synovial fluid analytical of an immediate disadvantage when discussing and ana service. Like most cytology we believe much of the cell lysing articular problems with their rheumatological and and non-cell identification and quantitation can, and orthopaedic colleagues. should, be undertaken by trained technical staff. The book In the specific area of synovial fluid examination the is therefore aimed primarily at two groups: pathologists difficulties for the pathologist are compounded because who do not specialize in joint disease and technical staff to date there have been no basic texts that detail the who will be generating the data on which interpretation methods, findings and interpretation of the macroscopic will be based. It is therefore both a text book and a bench and microscopic characteristics of the fluid in the common reference manual. arthropathies. In this book we hope to go some way We do not believe our data or methodology represent towards rectifying this omission."

This atlas is a practical approach to problems commonly encountered in paediatric tumour diagnosis. It comprehensively covers a wide range of common and unusual entities. Over 300 full-colour illustrations are complemented by a text which is pragmatic and succinct. References have been carefully selected to reflect current thought and well-written reviews. New treatment strategies have led to considerable improvement in the salvage rate and prognosis in childhood neoplasia. Histological diagnosis in this area is fraught with problems and the demand invariably has been for a prompt and accurate histological reporting. The problems although wide-ranging, are particularly manifest in the area of the small round-cell tumours which constitute an important proportion of paediatric cancers. This atlas will be invaluable as a bench manual for the practising pathologist and as a study aid for the trainee. It will also be of interest to all oncologists and paediatricians.

The 1997 European Conference on Spectroscopy of Biological Molecules (ECSBM) is the seventh in a biennial series of conferences devoted to the applications of molecular spectroscopy to biological molecules and related systems. The interest of these conferences rests mainly on the relationship between the structure and physiological activity of biological molecules and related systems of which these molecular species form part. This volume ofECSBM contains articles prepared by the invited lecturers and those making poster presentations at the seventh ECSBM. The reader will find mainly applications of vibrational spectroscopy to protein structure and dynamics, biomembranes, molecular recognition, nucleic acids and other biomolecules and biological systems containing specific chromophors. Biomedical applications of vibrational spectroscopy are expanding rapidly. On the other hand, a significant number of the papers describe applications of other methods, such as NMR, circular dichroism, optical absorption and fluorescence, X-ray absorption and diffraction and other theoretical methods. One aim has been to achieve a well balanced, critically comparative review of recent progress in the field of biomolecular structure, bonding and dynamics based on applications of the above spectroscopic methods. A great part of the contributions included in this volume are devoted to biomedical and biotechnological applications and provide a broadly based account of recent applicationS in this field. The content of this book has been organized in sections corresponding mainly to the different types of biological molecules investigated. This book includes also another section related to theoretical methods where MO calculations of vibrational frequencies dominate clearly the topic.

The localized attachment of circulating leukocytes to endothelium has been recognized as the cellular hallmark of the inflammatory response. This adhesive interaction, a necessary antecedent to the emigration of leukocytes from the blood into the tissues, is mediated by vascular adhesion molecules. Leukocyte Recruitment, Endothelial Cell Adhesion Molecules and Transcriptional Control: Insights for Drug Discovery outlines some of the cellular and molecular mechanisms of inflammation with contributions from top researchers. This volume provides an overview of three of these endothelial adhesion molecules, as examples of key mediators of leukocyte recruitment. It reviews the structure and regulation of these cell surface proteins and focus on the rapidly expanding field of transcriptional regulation of these inducible proteins, and closes with a discussion of drug discovery possibilities that target the regulation of leukocyte recruitment. This book will be of interest for any researchers, in academia or industry, looking for an overview of leukocyte recruitment or novel approaches to drug discovery.

Alzheimer disease (AD) has become the most common form of dementia in industrialized countries and represents an increasing burden at the economic, social and medical level. In discussing both the biological aspects of AD as well as the cognitive functions involved, Alzheimer Disease - Neuropsychology and Pharmacology presents a comprehensive picture of the pathology and approaches to diagnosis and treatment. Basic research including animal models, molecular and genetic aspects is also taken into consideration. In part I, the biological correlates of AD are discussed. In part II the neuropsychological aspects such as cognitive impairment, loss of functional autonomy and emergence of neuropsychiatric disturbances of AD are outlined. In part III, strategies for effective treatment and prevention of AD are discussed. This book will be a useful source of information for clinicians as well as researchers in the area of neuropharmacology.

Aging represents a physiological and "per se" non-pathological and multifactorial process involving a set of key genes and mechanisms being triggered by different endogenous and exogenous factors. Since aging is a major risk factor in connection with a variety of human disorders, it is increasingly becoming a central topic in biochemical and medical research. The plethora of theories on aging some of which have been discussed for decades are neither isolated nor contradictory but instead can be connected in a network of pathways and processes at the cellular and molecular levels. This book summarizes the most prominent and important approaches, focusing on telomeres, DNA damage and oxidative stress as well as on the possible role of nutrition, the interplay between genes and environment (epigenetics) and intracellular protein homeostasis and introduces some genes that have actually extended life spans in animal models. Linking these different determinants of aging with disease, this volume aims to reveal their multiple interdependencies. We see that there is no single perfect theory of aging and that instead it is possible to define what the authors call the "molecular aging matrix" of the cell. A better knowledge of its key mechanisms and the mutual connections between its components will lead to a better understanding of age-associated disorders such as Alzheimer s disease."

In the front material of this book both a foreword and a preface appear. What the content of a preface should be is well understood. It is the author's retrospective account of intent, of the labors to accomplish that intent, and of the content of the book that resulted. What a foreword should be is less obvious. Most properly, it is perhaps the brief testimony of one who knows the accomplishments of the author and the scope of the field and who may direct readers to the book. On some basis, the writer is assumed to have earned the right to undertake such a task. To undertake the writing of a foreword for so considerable a researcher, teacher, and scholar as Alfred Evans can be seen not only as an honor but also as a daunting one. My first thought, in truth, is that this wine needs no blush and that no foreword is needed. As John Rodman Paul Professor of Epidemiology at Yale, Alfred Evans has an established reputation in the field of causality. We have learned from his insights about the evolution of causal thinking as epidemiology passed from the era of the germ theory into that of the search for causes of chronic noncontagious diseases. It was he who drew attention to the effect of specific context in that evolution.

Historically we have separated the disciplines of Chemistry and Biochemistry by recognizing that the distinguishing characteristic of Biochemistry is the catalysis of reactions by enzymes. Enzymes permit metabolic reactions which would otherwise require extremes of temperature, pressure or pH, often associated with Chemistry, to proceed under ambient conditions of the body. Under some conditions chemical reactions occur in vivo in which products of enzymatic reactions proceed to undergo further reactions non- enzymatically with cellular macromolecules. The results can often be seen as toxic or carcinogenic responses. The chemicals that initiate these reactions are termed "biological reactive intermediates. " The International Symposia on Biological Reactive Intermediates (BRI) began in 1975 at the University of Turku, Finland and have since convened at the University of Surrey, Guildford, The United Kingdom (1980), the University of Maryland, College Park, Maryland (1985), the University of Arizona, Tucson, Arizona (1990), the GSF Forschungszentrum and Technical University of Munich (1995) and, most recently, at the Universite Rene Descartes, Paris, France (2000). The Symposium was organized by an International Planning Committee co-chaired by P. Dansette (Paris, France) and TJ. Monks (Austin, Texas). The committee included: P. H. Beaune (Paris, France), M. De\aforge (Saclay, France), G. P. Gervasi (Pisa, Italy), G. G. Gibson (Guildford, UK), H. Greim (Munich, Germany), DJ. Jollow (Charleston, South Carolina), P. Moldeus (Sodertalje, Sweden), I. G. Sipes (Tucson, Arizona), R. Snyder PJ. van Bladderen (Zeist, The Netherlands). They were (Piscataway, New Jersey), and assisted by an International Scientific Program Advisory Committee which included: TJ.

Metastases determine malignancy. The main attention so far has been focused upon organ metastases. The molecular mechanisms thereof, while far from being totally elucidated, are increasingly well understood. Modern diagnostic tools now enable detection and precise localization of small lesions. In contrast, our knowl edge and diagnostic capabilities regarding metastatic spread to the'lymphatic system are rather limited. However, there have re cently been a number of interesting advances. It is the aim of this volume to submit these developments to detailed analysis. The therapeutic relevance of enhanced sensitivity in detection of lymph node metastases has to be considered in the light of in creased morbidity versus eventual prognostic improvements by modification of therapy. An interesting concept which might im prove diagnostic accuracy while reducing operative morbidity is the "sentinel node" technique. Surgical standards are lacking, however, and many fundamental questions pertaining to precise lymphatic mapping remain unanswered. Whether the sentinel node concept is of general relevance or whether it is applicable in only a few organs remains to be determined. This book offers intensive discussion of the concept from methodological and tu mor biological viewpoints. World-renowned experts with long term involvement in related basic and clinical research provide the reader with a broad survey of actual knowledge together with a critical appraisal of recent and future developments. We sincerely hope this book succeeds in providing an outlook as a reference for all clinicians on future prospects and serving and researchers in this extremely important field.

The study of cultured human tumor cells is a most obvious approach in experimental human cancer research. For many techniques in virology, immunology, biochemistry, and biophysics, for example, large amounts of cells may be required and such quantities are usually provided only when the cultures develop into established cell lines; when this happens, thorough characterization also becomes possible. The development of cell lines, therefore, is of prime importance. Recent major advances in research with animal cell systems see m to be a prologue for present and future efforts directed toward work with human tumor cells in culture. Conceivably, the most significant results in cancer research may develop from work with such cells, and so the time seemed right to define the present state of our knowledge. This is the first book dedicated exclusively to the subject: human tumor cells in vitro. Although so me of the fundamental aspects in the cultivation of human tumor ceIls, and the extent to which they represent human cancer in vivo are still unclear, I asked a number of the leading investigators in this area of research to collect and evaluate previous and present contributions, and to offer their thoughts on the questions to which answers are not yet available. Many of the chapters are concerned with techniques of cultivation. Cultures from some types of tumors have grown weIl; in many cases they have given rise to established cell lines.