These Proceedings contain the contributions of the partIcIpants of the Third International Symposium on Dendritic Cells that was held in Annecy, France, from June 19 to June 24, 1994. This symposium represented a follow-up of the first and second international symposia that were held in Japan in 1990 and in the Netherlands in 1992. Dendritic cells are antigen-presenting cells, and are found in all tissues and organs of the body. They can be classified into: (1) interstitial dendritic cells of the heart, kidney, gut, and lung;(2) Langerhans cells in the skin and mucous membranes; (3) interdigitating dendritic cells in the thymic medulla and secondary lymphoid tissue; and (4) blood dendritic cells and lymph dendritic cells (veiled cells). Although dendritic cells in each of these compartments are all CD45+ leukocytes that arise from the bone marrow, they may exhibit differences that relate to maturation state and microenvironment. Dendritic cells are specialized antigen-presenting cells for T lymphocytes: they process and present antigens efficiently in situ, and stimulate responses from naive and memory T cells in the paracortical area of secondary lymphoid organs. Recent evidence also demonstrates their role in induction of tolerance. By contrast, the primary and secondary B-cell follicles contain follicular dendritic cells that trap and retain intact antigen as immune complexes for long periods of time. The origin of follicular dendritic cells is not clear, but most investigators believe that these cells are not leukocytes.

Currently, individuals interested in seeking an in-depth discussion of transplantation immunology must seek individual articles published in several journals, or extrapolate information from various non-transplant immunology textbooks. The purpose of this text is to provide the reader with a single source of information for the basic science of immunobiology of organ transplantation. It is unique that it focuses on immunobiology from the basic research side, with an emphasis on the cellular and molecular levels. The readers will be physicians, scientists, and graduate students interested and engaged in the study of immunology as it relates to allo- and xenotransplantation. This book is designed to be the reference standard for the immunobiology of transplantation.

The title "Stem Cells from Cord Blood, In Utero Stem Cell Develop ment, and Transplantation-Inclusive Gene Therapy" suggests that more than one topic is combined in one workshop. Indeed, at first glance the recovery of stem cells from cord blood has to be seen as separate from the attempts to achieve effective in utero therapy by stem cell trans plantation, because the first issue deals with an innovative stem cell source as an alternative to bone marrow, which is already spreading rapidly in medical practice, whereas the second topic is still strictly ex perimental and only investigated in medical centers with the appropri ate background. It is, however, not only justified, but helpful to com bine the two topics in one workshop and consequently to cover them in the same volume of the Ernst Schering Research Foundation Work shop series, because they are intimately related and both based on the new insights into the biology of stem cells. Professor Werner Arber, the Nobel Laureate from the University of Basel, pointed out in his In- Professor Dr. W. Holzgreve VI Preface The participants of the workshop troductory Lecture that our understanding of hematopoietic stem cells as descendents of totipotent cells and our current approaches to using them in post-and prenatal therapy have been furthered significantly by genetic engineering technologies which are "artificial contributions to the process of biologic evolution.""

Oncology has developed as a subspecialty of medicine with unique and often complex clinical problems. This handbook ofhematologic and oncologic emer gencies provides a compact, concise, yet comprehensive guide to the manage ment of a variety of difficult clinical situations. The authors of the various chapters are all clinicians with experience in the management of these difficult patients. Their efforts provide insight and a ready source of practical infor mation which lends itself to use in the clinic and in the inpatient ward. The authors sincerely hope that this handbook will be of service to house officers and fellows alike, as they develop skills in the management of the emergent problems of patients with hematologic and other neoplasms. Janice P. Dutcher Peter H. Wiernik Bronx, New York;; Contents 1. Syndrome of Inappropriate Antidiuretic Hormone Secretion and Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . 000 . . . . . . . . . . . Stuart L. Marcus, M.D., Ph.D., and Joachim Z. Fuks, M.D. 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2. Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3. Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 2. Acute Tumor Lysis Syndrome: Prevention and Management . . 9 Stuart L. Marcus, M.D., Ph.D., and Avi I. Einz;ig, M.D. 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2. Risk Factors for the Development of Azotemia in Acute Tumor Lysis Syndrome........................................... 10 3. Metabolic Abnormalities That Occur during Acute Tumor Lysis Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 . . . . . . . . . . . . . . 4. Prevention of Acute Tumor Lysis Syndrome: Management prior to Beginning Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . 13 . . . . . . . . . . 5. Posttreatment Management: Indications for Dialysis . . . . . . . . . . 14 . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 . . . . . . . . . . . . . ."

The International Symposium on Heparin, held May 13-15, 1974, in St. Louis, Missouri, as a part of the dedication of the Shoenberg Pavilion of the Jewish Hospital of St. Louis, was conceived as a forum to bring together physicians and scientists with a basic in terest in the structure, function and clinical usefulness of heparin. Few naturally occurring substances have commanded the breadth of interest among members of the biomedical research community as this compound has. Aspects of its covalent and three-dimensional struc ture, its biosynthesis, its interaction with and effect on physio logically important moieties and its use as a therapeutic agent in a variety of disease states have been actively studied for the past several decades. Thus, the present state of these studies seemed to be a timely subject for discussion, not only to gather together in one place representative samples of the myriad of data on heparin but also to underscore the ever increasing necessity for communica tion between basic research and clinical practice."

A description of the latest methods of oncological and hematological diagnostics, such as immunological, molecular genetic and histological essays. All methods are described in principle in their different variations and compared with regard to their effectiveness and cost. Written for scientists, clinicians and personnel in research, specialised and routine diagnostic laboratories in hospitals, this book satisfies the increased demand for information on new methods in hematology and oncology.

380 years ago, in the year 1614, Ubbo Emmius transplanted the gene ofscience from Ostfriesland into the education genome ofthe city ofGroningen as devel- oped by Regnerus Praedinius. He thereby founded the University ofGroningen. It is with great pleasure that the Faculty of Medicine as one of the founding faculties ofour University, welcomes you to this 19th International Symposium ofBloodTransfusion, whichwill coverthe themeofHereditaryDiseasesandtheir relation to Transfusion Medicine, where cell expansion, gene transfer and gene therapy are the read thread. Since the earlydays there has beena specificand sincere interest in inborn errors ofmetabolism and hereditarydisorders. This interest has resulted in a structured research, diagnostic and counselling facilities, and therapeuticapproaches where various disciplines within our faculty work closely together with groups from related faculties of the University of Groningen, as well as other national and international scientific institutions. The field of inborn errors, genetic abnormalities and mutations, and hereditary diseases covers a broad gamma of extremely interesting and exciting scientific aspects,whichrangefrom clearphysicalaberrationstomolecularanalysisofgenes and genomes, coding areas and amino acid sequences. It is intriguing to realise that the balance of life seemingly depends on the position or presence of one single molecule as a part ofthe total complex ofgenetic information in the cell.

Since the first concepts of gene therapy were formulated, the hemopoietic system has been considered the most natural first target tissue for genetic manipulation. The reasons for this include the fact that a very large number of inherited disorders (including some of the most common disorders, such as the hemoglobinopathies) are disorders of the hemopoietic system, and the large amount of experience in hematopoietic transplantation biology. The consequence of this resulted in the first clinical trial of gene therapy in 1989, where two children suffering from severe combined immune deficiency (ADA-SCID) were transplanted with T-cells express ing adenosine deaminase (the defective enzyme in patients with this disorder). The partial success of this treatment was perhaps responsible for undue optimism among those proposing other gene therapy treatments within the hematopoietic system, and it has since become clear that there are a number of technical and biological difficulties to overcome before hematopoietic gene therapy becomes a mainstream therapeutic strategy. The chapters in this book evaluate the need for gene therapy in the hematopoietic system, discuss how efficient gene transfer and expression can be achieved in the target cells, highlight areas of difficulty to be addressed, and examine a number of potential applications of the gene therapy approach. The book begins with a chapter by Testa and colleagues, discussing the various sources of hematopoietic cells for both transplantation and gene therapy.

This book reflects the personal prejudices I have developed in twenty years of reading the scientific literature. I like monographs; good ones assemble a great deal of information in a logical sequence and in enough detail to enable one to see why current beliefs are held. For this purpose, it is entirely useless to write "as Smith has shown21 ,81,117 **** " That only means that one must go to the library and turn up Smith's original papers, and one's object in reading a monograph is precisely to avoid that neces sity. One needs to know what Smith did and why he thought his observa tions proved whatever he claimed. Because life is short, it is impossible to deal with several thousand papers in this way, and the author must there fore select a relatively few papers that he regards as crucial. Often, several papers of equal merit might be quoted, and the selection is then arbitrary. I therefore apologize to authorities who do not find their work discussed. Omission does not mean that I thought their work was not valuable; it means only that I preferred to quote twenty references that people might read rather than two thousand that assuredly no one would read. Another strong prejUdice is that the full understanding of present knowledge requires one to know how present views have developed.

Pocket Reference to Renal Anemia, Second edition, provides a comprehensive overview of anemia in patients with renal disease, including the definition and causes of renal anemia, current management approaches, and the latest clinical practice guidelines. Key learning points are highlighted throughout the book and also listed at the end of the book for a quick reference. The book is useful for general physicians, fellows, and other healthcare professionals wishing to learn more about renal anemia.

Multiple myeloma is currently still an incurable disease, but during the past decade knowledge of its molecular pathogenesis has increased rapidly. This has led to remarkable progress in both diagnosis and therapy, including in particular the approval of novel and first-in-class drugs such as thalidomide, bortezomib, and lenalidomide. This book, written by internationally acknowledged experts, covers a wide range of topics relating to multiple myeloma, including history, epidemiology, pathophysiology, clinical features, staging, and prognostic systems. The principal focus, however, is on therapy, with detailed information on the various promising treatment options which give hope that this cancer will be transformed into a chronic disease or even become curable. Individualized therapy and the variety of supportive treatment options, as described in this volume, will help in achieving this goal, as well as in reducing adverse events and improving quality of life.

Under the broad heading of blood oxygenation there may be specific areas of study, such as the kinetics of the oxygen hemoglobin reaction, diffusion of gases through the red cell, blood preservation, blood chemistry, oxygen electrode design and the design and evaluation of artificial blood oxygenators. ~lood oxygenation is of interest to many disciplines including physicians, chemists, physicists, biologists, physiologists and engineers. The International Symposium on Blood Oxygenation was or ganized in order to bring together the people working in the various areas of blood oxygenation. This multidiscipline meet ing was held at the University of Cincinnati on December 1, 2 and 3 of 1969. It was jOintly sponsored by the U. S. Army Medi cal Research and Development Command and the University of Cin cinnati. Participants came from Australia, England, Israel, Italy, Japan and the United States. There were 122 persons registered for the Symposium. From the nature of the discussion during the meeting, it seemed apparent that the participants were benefiting from the contacts with colleagues in other disciplines. The result was a significant contribution to the present fund of knowledge of blood oxygenation and an enhancement of the future work.

This comprehensive treatise on the reticuloendothelial system is a project jointly shared by individual members of the Reticuloendothelial (RE) Society and bio medical scientists in general who are interested in the intricate system of cells and molecular moieties derived from those cells which constitute the RES. It may now be more fashionable in some quarters to consider these cells as part of what is called the mononuclear phagocytic system or the lymphoreticular sys tem. Nevertheless, because of historical developments and current interest in the subject by investigators from many diverse areas, it seems advantageous to present in one comprehensive treatise current information and knowledge con cerning basic aspects of the RES, such as morphology, biochemistry, phylogeny and ontogeny, physiology, and pharmacology as well as clinical areas including immunopathology, cancer, infectious diseases, allergy, and hypersensitivity. It is anticipated that, by presenting information concerning these apparently het erogeneous topics under the unifying umbrella of the RES, attention will be focused on the similarities as well as interactions among the cell types constitut ing the RES from the viewpoint of various disciplines. The treatise editors and their editorial board, consisting predominantly of the editors of individual vol and enormous task umes, are extremely grateful for the enthusiastic cooperation undertaken by members of the biomedical community in general and especially and Japanese Reticuloen by members of the American as well as European dothelial Societies.

The aim of this book is to introduce the medical student, recent medical graduates involved in postgraduate training and physicians in practice to the role of the platelet in physiology and disease. It is not intended to be an encyclopaedic review of all the literature over the past few decades, but largely represents a personal account, and although resultant prejudices occur, an attempt has been made to emphasize to the reader areas of doubt, and point the way to other sources which may explore these questions more fully in selected references at the end of each chapter. I acknowledge the help of my secretaries, Ms Carolyn Harvey and Mrs Marjorie Brown without whom the book would never have been started, let alone completed. Some illustrations and figures were made by Mr W. Shepherd of Monash University and Ms A. Leaman of the Alfred Hospital. I am indebted to Mrs E. Hagon who read and corrected a number of the chapters, and for the constant help through discussion and debate with my two close collaborators in research, Dr Margaret Howard and Dr Sharron pfueller. Dr Siew Choong, Mrs Maureen Broadway and Ms Ilona Lakatos documented the methods used in our laboratory to study platelets as outlined in the Appendix.

Age is a nonreversible risk factor for atherosclerosis. The atherosclerotic process begins early in life, progresses during the middle years, and usually culminates in clinical disease towards the later years of the life span. Since atherosclerosis is a multifactorial disease, and many of the "risk factors" are time- and age related, it has been difficult to sort out intrinsic aging from environmental factors that operate over many years. Furthermore, the role of genetic factors remains unknown. This workshop has produced much worthwhile information that is helping elucidate the impact of age on atherogenesis. Important strides have been made in understanding the role of changes in the arterial wall and of lipoproteins, platelets, and monocyte-derived macrophages in the disease process. In parallel, our understanding of the biology of aging has increased sufficiently so that these two areas of interest can now profitably intersect. The proceedings of this successful workshop emphasize that there is much to be gained by continued interaction between those scientists interested in the biology of aging at all levels and those interested in the atherosclerotic process. Hopefully, we may eventually progress in our understanding and reach the stage when atherosclerosis will no longer be an inexorable concomitant of human aging. Edwin L. Bierman, M. D. Contents Foreword V Contributors IX Participants in the Workshop XV Introduction and Statement of Research Recommendations Sandra R."

Leading oncologists, hematologists, and nephrologists comprehensively review the role of HGFs in clinical practice, explain the molecular basis of their effects, and consider potential future developments. The authors focus on the use of HGFs in oncology, describing their cutting-edge application to patients with lung cancer, Hodgkin's and nonhodgkin's lymphoma, breast cancer, chronic lymphocytic leukemia, AIDS-related malignancies, myelodysplastic syndromes, and aplastic anemias. Among the HGFs described are granulocyte colony-stimulating factor, erythropoietc factors, thrombopoietic factors, and stem cell factor and its receptor, C-kit. To complete their survey, the contributors also consider the safety and economic implications of HGFs and the future potential for HGF antagonists in oncology.

The Fondazione Lorenzini has been sponsoring Postgraduate Courses for physicians and specialists, in Italy, since 1970. Its aim, as an institution, has been that of promoting post graduate medical education. In these years, recent advances in a wide range of medical fields have been discussed by distinguished experts from many countries throughout the world. Courses dealing with methodo logies and technical problems have been designed to include practical demonstrations of the various methods and techniques in the relevant fields. The Postgraduate Course on "Platelets and Thrombosis: Methods of Study" was held in Milan, at the Fondazione Lorenzini, from February 24th to 26th, 1972. This volume contains the edited and somewhat extended papers presented at the Course, which was sponsored and organized by the Italian Society for the Study of Atherosclerosis. The special contribution of the present volume is that of gathering a large amount of up-to-date information on the formidable problem of the methods used for testing platelet function in thrombosis.

In the summer of 1988, my developmental biology professor announced to the class that hematopoietic stem cells (HSCs) had finally been purified. Somehow, I never forgot the professor's words. When I started working in Dr. Irv Weissman's labo- tory at Stanford as a postdoctoral fellow, I realized that the findings mentioned by the professor were from Weissman's laboratory and had been published in a 1988 edition of the journal Science. It has been over 20 years since the publication of that seminal paper, and since then tremendous advances in understanding the biology and maturation of HSCs, namely the process of hematopoiesis, which includes lymphocyte development, have been made. These discoveries were made possible in part by advancements in technology. For example, recent availability of user friendly fluorescence activated cell sorting (FACS) machines and monoclonal an- bodies with a variety of fluorescent labels has allowed more scientists to sort and analyze rare populations in the bone marrow, such as HSCs. All classes of hematopoietic cells are derived from HSCs. Stem cell biology draws enormous attention not only from scientists, but also from ordinary people because of the tremendous potential for development of new therapeutic application to diseases that currently lack any type of effective therapy. Thus, this type of "regenerative medicine" is a relatively new and attractive field in both basic science and clinical medicine.

This monograph is a collection of invited contributions from a group of investiga tors who share a common interest in the interrelationships between the shape, struc ture, and functional characteristics of normal and pathologic erythrocytes. Most of the authors participated in a workshop on red cell shape held in June, 1972 at the Institute of Cell Pathology, Hopital de Bicetre, Paris. We hope that these various contributions on the physiology, pathology, and ultrastructure of red cell shape will be useful and stimulating for other investigators interested in the correlation of shape and structure with the biochemistry and biophysics of the red cell. The text is divided into four sections. Section I deals with red cell shape, including the presentation of a rational descriptive nomenclature and a discussion of post splenectomy changes. Section II deals with biochemical factors that underlie the disco cyte-echinocyte (crenated) and discocyte-stomatocyte (cup-shaped) transformation. This section includes discussions of plasma factors, and of the biochemical dynamics of erythrocyte lipids and consideration of the effects of such factors as cellular ATP, calcium, aging, and various chemical agents as determinants of shape. Section III, which deals with biophysical measurements, includes studies of the deformability of cells of different shapes, descriptions of ways to define precisely the geometric dimensions of the red cell under various circumstances, and a model of membrane structure, which is proposed to account for the dimensions of red cells that undergo shape change."

In the last decade, remarkable advances have been made in bone marrow transplantation (BMT), which is now becoming a powerful tool in the treatment of diseases such as leukemia, aplastic anemia, and congenital immunodeficiency. In animal experiments, it has been found that BMT can be used to treat not only systemic autoimmune diseases but also organ-specific autoimmune diseases. In humans, it has recently been shown that rheumatoid arthritis, ulcerative colitis, and Crohn's disease can be successfully treated after BMT. This volume contains new information on how to prevent graft rejection, how T cell functions can be completely restored, and how concomitant BMT can prevent the rejection of organ allografts without the use of immunosuppressive agents. BMT will become an increasingly useful and powerful treatment for various currently intractable diseases, and this book will contribute by providing details of the latest research in the field.

This, the third volume of the Blood Cell Biochemistry series, follows the pattern estab- lished in the two previous volumes by containing up-to-date specialist reviews of topics of current interest within the field of study defined by the subtitle. Thus, the topics included can be loosely classified under the broad subtitle "Lymphocytes and Granulocytes," but this does not indicate the full scope of content, scientific interest, and emphasis of the present volume. The opening chapter, by Antonio Bonati, surveys the currently available bio- chemical, immunological, and molecular markers of hemopoietic precursor cells. This is followed, appropriately, by a contribution from Arnold S. Freedman on the cell surface markers in leukemia and lymphoma. In a detailed chapter, Annette Schmitt-Graff and Giulio Gabbiani discuss the cytoskeletal organization of normal and leukemic lympho- cytes and lymphoblasts. John C. Cambier and his colleagues then present a discussion of the signaling events in T-Iymphocyte-dependent B-Iymphocyte activation. Lymphocyte IgE receptors and IgE-binding factors are dealt with by Kwang-Myong Kim and his colleagues, and the role ofgranule mediators in lymphocyte-mediated cytolysis is covered by John Ding-E Young and his associates. A short contribution from James D. Katz deals with the intricacies and difficulties of studies on the complement C3b (CRl) receptor and its cytoskeletal interactions in neutrophils. Arthur K. Sullivan then presents an in-depth survey of the membrane biochemistry surrounding the flow of granule organelles in leukocyte differentiation.

The discussion of some diseases is only occasionally enlivened by the emergence of new worthwhile facts. In the case of others, it would seem that, even if only a few years have passed, each new discussion wears the air of a revolution. Hodgkin's disease, at least from the pathological standpoint, is not so extraordinarily fickle and certainly does not touch either of these two extremes of variability. But it is still a fertile field of study and presents its full share of innovations and practical results. This is perhaps due to the special position it occupies between tumours and inflammatory diseases, or possibly to a lucky series of coincidences; the truth is that events have been on the move for some years now in the case of this disease. There can be no doubt that surprising progress has been made in connec tion with Hodgkin's disease, due, one feels, to close cooperation between several branches of medical science, each of which has had occasion to make new and useful contributions. This does not, however, hide the fact that certain important matters are still not clear, in particular the cause of the disease, its essential nature and, indeed, the best method for its treatment.

Managing infections that complicate care of neutropenic patients with leukemia and hematopoietic stem cell recipients has become a distinct specialty. In Managing Infections in Patients with Hematological Malignancies, the authors and editor draw on their extensive expertise while providing a roadmap for hematologists to efficiently manage the complex infections within their patients. The first section of the text reviews viral, bacterial, and fungal pathogens, and provides brief descriptions of the microbes and diseases they cause in patients with hematological malignancies. The second section is devoted to management of infections in patients with the different underlying hematological malignancies, while the third addresses several important topics that are often ignored in most books about infections and hematological malignancies. Managing Infections in Hematological Malignancies is a useful tool for all clinicians and practicing hematologists who treat individual patients and aspire to build stronger infectious diseases programs within their respective cancer centers.

Recent years have seen great strides in research on the pathogenesis of thromboses, unmatched by progress in other branches of hemostasiology. The orthodox concepts of the mechanisms of thrombus formation described by Virchow have come down to us as a "classical triad" of factors. Now, due to developments in molecular biology, pharmacology, and patho- physiology, they appear in a basically new light. The fruits of modern research, currently being tested or already imple- mented in clinical practice, have opened up the possibility of controlling the hemostatic process and developing effec- tive antithrombotic drugs. Much progress has been achieved in the past years, but much more remains to be achieved in such areas as the patho- genesis of venous and arterial thromboses, early diagnosis, therapy, and control of disorders. Many scientists in the U.S.S.R. are involved in studying these problems. Their data, from years of research carried out in leading laboratories and clinics in the U.S.S.R., are summarized in this monograph. This work is written by experts in various fields of biology and medicine. It deals with new and original con- cepts on the structure and function of the fibrinolytic sys- tem, the role of nonenzymatic fibrinolysis in regulating physiological hemostasis, the heterogeneous and discrete pat- terns of the system regulating blood coagulation, the molecu- lar mechanisms of fibrin polymerization, and the anticoagu- lating effects of fibrinogen/fibrin degradation products.