This volume presents the proceedings of the Fourth Annual Symposium on the Molecular Biology of Hemopoiesis, held in Reno, Nevada, November 1 and 2, 1988. Its focus on erythropoiesis represents an attempt to cover a rapidly expanding field, which has gone from elegant studies of erythro poietin physiology, to molecular biology, to clinical applications and again to physiology. The rapid development has been made possible by cloning of erythropoietin gene and the availability of recombinant hormone. The regulation of heme and its derivatives has also been aided by techniques of molecular biology; there is now a concerted effort to better understand how these enzymes contribute to proliferation, differentiation and maturation of the erythron. Globin gene derrangements have been targets of recent research in an attempt to correct the defect by genetic engineering. In the chapters of this book, several groups "expressed" their views on this subject. Finally, we analyze various regulators of erythropoiesis, both in vivo and in vitro. Dr. Richard Levere was a pioneer in many studies of heme metabolism and of erythropoiesis. He has been a generous supporter of research in this field and of our past meetings. It is only. fitting that this volume should be dedicated to him."

Cytokines are cellular growth factors which also provide communication between cells and their milieu. This clearly is an exciting area in modern medicine that will have significant impact on various facets of transfusion. Erythropoietin therapy stimulates red cell production while thrombopoietin seems to positively affect megakaryopoiesis and can be an added armamentarium for the thrombocytopenic patient. Using haematnopoietic growth factors, stem cells could be mobilized early to the peripheral blood for collection and subsequent transplantation into haemato-oncology patients instead of bone marrow transplantation. Using a cocktail of cytokines in cell culture, stem cells could be expanded and selected for therapy. Cytokines and growth factors can even be modified, which may lead to successful gene therapy in malignancies, including solid tumour vaccines. However, the presence of cytokines in certain blood products could have biological effects following transfusion, although its clinical relevance needs to be ascertained. There is much potential for the use of cytokines in the treatment of infections. Early diagnostic methods are now available to monitor their levels and relevance. It is likely that cytokines will increasingly play a role in therapy and could develop our fundamental knowledge about the development of T-cells. An ethical dilemma remains, however, regarding the use of cytokines in healthy donors for harvesting suitable specific cells. Longer clinical observation will be necessary to gather the necessary information. Cytokines and growth factors in blood transfusion was the theme of the 21st International Symposium in Blood Transfusion, where twenty clinicians and scientists, experts in their own fields, were invited to update the above information. Their findings are presented in four sections in this volume: Fundamental aspects - cytokines in development of T-cells, growth factors in haematopoiesis, growth factor receptors and signal transduction, cytokine response in platelet and whole blood transfusions. Function, production and diagnosis &endash; laboratory diagnostics of cytokines and growth factors, cytokines in blood components, cytokines and growth factors in cell expansions, cytokines for genetic modification towards gene therapy, progenitor cells from healthy donors. Application in clinical medicine &endash; clinical relevance of cytokines in transfusion products, cytokines and growth factors in solid tumours, gene therapy in malignancies, vaccine strategies inducing T-cell immunity against tumours, cytokines in the treatment of infections, thrombopoietin and megakaryopoiesis. Future potential use in transfusion medicine &endash; erythropoietin, immunotherapy, ethical aspects of the use of cytokines and growth factors in donors, potential of cytokines and growth factors in transfusion medicine.

All medical specialists who must contend with the possibility of thrombosis will be interested in Anticoagulation. This book evaluates anticoagulation procedures from various points of view - from Current Trends in Anti-thrombotic Drugs, to Treatment of Ischemic Vascular Disorders; from Anticoagulants in Pregnancy, to Anticoagulation in the Elderly, from the Effects of Anticoagulant Therapy on the Heart, to Anticoagulation in various Surgical Procedures. Anticoagulation is a resource of approaches to the management of this common medical problem.

A comprehensive collection of classic and innovative methodologies used in many laboratories for the investigation of multiple myeloma. These readily reproducible techniques range from the standard Plasma Cell Labeling Index methodology to a final chapter on making sense of microarrays, and include the full spectrum of cytogenetic and molecular diagnostic methods. The protocols follow the successful Methods in Molecular Medicine (TM) series format, each offering step-by-step laboratory instructions, an introduction outlining the principle behind the technique, lists of the necessary equipment and reagents, and tips on troubleshooting and avoiding known pitfalls. These proven techniques are ideal for studying the pathogenesis of multiple myeloma and identifying new therapeutic targets.

During the past few decades, technical and conceptual breakthroughs have led to a virtual revolution in developmental biology. In part through cross-species compa- sons and multidisciplinary approaches (combining, for example, classical embry- ogy, genetics, molecular biology, and systems biology), major questions have often been redefined and examined from new angles and with innovative tools. Analyses using such model systems as Drosophila, Xenopus, zebrafish, chick, human, and mouse have underscored the remarkable extent to which molecular and genetic pa- ways are conserved across species and throughout embryonic, fetal, and adult dev- opment. What we learn from the embryo, then, is not only of fundamental interest, but may well have future practical applications in the clinic. A number of excellent volumes, including several in this series (e. g. , Hema- poietic Stem Cell Protocols, Klug and Jordan, eds. , 2002), have surveyed methods used in the study of hematopoiesis-the processes by which the multiple lineages of the blood form from stem and progenitor cells during ontogeny and throughout the entire life of the animal. These collections of protocols have focused largely on the postnatal cells of mouse and human. Our understanding of hematopoietic devel- ment, however, has benefitted enormously from investigations in a variety of org- isms at different stages of ontogeny.

12 The average human body has on the order of 10 circulating platelets. They are crucial for hemostasis, and yet excessive platelet activation is a major cause of m- bidity and mortality in Western societies. It is therefore not surprising that platelets have become one of the most extensively investigated biological cell types. We are, however, far from understanding precisely how platelets become activated under physiological and pathophysiological conditions. In addition, there are large gaps in our knowledge of platelet production from their giant precursor cell, the megakar- cyte. Understanding megakaryocyte biology will be crucial for the development of platelet gene targeting. The aim of Platelets and Megakaryocytes is therefore to bring together established and recently developed techniques to provide a comprehensive guide to the study of both the platelet and the megakaryocyte. It consists of five s- tions split between two volumes. The more functional assays appear in Volume 1, whereas Volume 2 includes signaling techniques, postgenomic methods, and a n- ber of key perspectives chapters. Part I of Volume 1, Platelets and Megakaryocytes: Functional Assays, describes many well-established approaches to the study of platelet function, including aggregometry, secretion, arachidonic acid metabolism, procoagulant responses, pla- let adhesion under static or flow conditions, flow cytometry, and production of microparticles. Although one would ideally wish to perform experiments with human platelets, studies within the circulation using intravital microscopy require the use of animal models, which are described in Chapter 16, vol. 1.

Our understanding of the function of natural killer (NK) cells has dramatically changed in recent years. The discovery of NK receptors specific for MHC class I molecules, and the study of the role of co-stimulatory and adhesion molecules have led to an understanding of how NK cells recognize tumor and virally infected cells that have lost expression of MHC class I molecules or have altered distribution of normal cell surface molecules. Such recognition events lead to intracellular signals which can be either stimulatory or inhibitory. This book provides an insight into how NK cells develop, how they learn to distinguish altered cells from normal cells, and into their biological role in controlling infections and tumors.

Mr. Chairman, ladies and gentlemen, with great pleasure I like to welcome you in the cityofGroningen and hope that you will have an enriching and enlighten ing discussion on the conference theme on risk management in blood trans fusion. The organisation of this symposium aims at scientific networking by discussing in an international forum the most important themes of current interest in relation to the state of the art in transfusion medicine. Dr. Cees Smit Sibinga took the initiative in 1976 to start organising the blood bank symposia as they were named in the beginning. Without doubt these symposia have contributed considerably to the development of transfusion medicine. To illustrate the fact that these symposia came to my attention I recollect that I have attended the symposium in 1978, chaired by Dr. Leo Vroman, in my capacity in those days of alderman deputy mayor of the city. So, it has been a long time since. After having been away from Groningen for 18 years I have been inaugurated last week as a mayor and it is a plcasure to be again in your midst. The scries of annual symposia on blood transfusion have contributed to mark the city of Groningen on the map of the international scientific world. A great number of prestigious institutes all over the world involved in the development of transfusion medicine have linked to Groningen and we are proud of that."

Recent developments in recombinant DNA technology have led to the large-scale production of human erythropoietin and to the demonstration that it is effective in the treatment of renal and possibly some other anaemias. This has lent a new impetus to studies of the pathophysiology and pharmacology of the hormone which is reflected in this report of the proceedings of a meeting held in Liibeck in June 1988. In 15 papers, all from European centres, the broad topics covered are erythropoietin's physiology and chemistry, the patho- physiology of erythropoiesis and the use of erythropoietin in the treatment of anaemia. Several of the papers include up-to-date reviews of the literature. The field is now expanding rapidly, and this volume, though not comprehensive, usefully points up many areas of recent understanding as well as others of continuing un- certainty. Overall, it contains material likely to be of interest to biochemists and experimental haematologists as well as to phar- macologists, clinical haematologists and nephrologists.

Edited by two leading orthopedic surgeons who are specialists in the treatment of hemophilia, Orthopedic Surgery in Patients with Hemophilia shows all the surgical techniques needed for surgical treatment of musculoskeletal complications of hemophilia. A practical guide, designed for use on the ward or in the office, this book draws on the experience of numerous specialists worldwide, from developed and developing countries. As well as orthopedic surgery, it also covers research, hematology, and rehabilitation. Although of primary interest to the orthopedic surgeon, rheumatologist, and physiotherapist, this book will also be relevant to the hematologist responsible for the care of the hemophiliac patient.

Active specific immunotherapy is a promising but investigational modality in the management of cancer patients. Currently, several different cancer vaccine formulations such as peptides, proteins, antigen-pulsed dendritic cells, whole tumor cells, etc. in combination with various adjuvants and carriers are being evaluated in clinical trials (1-3). To determine the optimal cancer vaccine strategy, a surrogate immunological end-point that correlates with clinical outcome needs to be defined, since it would facilitate the rapid comparison of these various formulations. Traditional immunological assays such as ELISA, proliferation and cytotoxicity assays can detect immune responses in vaccinated patients but are not quantitative. In contrast, novel assays such as enzyme-linked immunospot (ELISPOT) assay, intracellular cytokine assay and tetramer assay can quantitate the frequency of antigen-specific T cells. Of these, the ELISPOT assay has the 5 lowest detection limit with 1/10 peripheral blood mononuclear cells (PBMC) and has been determined to be one of the most useful assays to evaluate immune response to cancer vaccines (4). However, the IFN-? ELISPOT assay is not an exclusive measure of cytotoxic T-lymphocyte (CTL) activity as non-cytotoxic cells can also secrete IFN-?. Additionally, CTL with lytic activity do not always secrete IFN-? (5). A more relevant approach to assess functional activity of cytotoxic lymphocytes would be to measure the secretion of molecules that are associated with lytic activity. One of the major mechanisms of cell-mediated cytotoxicity involves exocytosis of cytoplasmic granules from the effector toward the target cell.

What we now call 'deep venous thrombosis' (DVT) has been elucidated by a diversity of investigative approaches during the past four centuries. The authors of this book survey the history of the field and ask: why has one of these perspectives - the haematological/biochemical - come to dominate research into the causation of DVT during the past 50 years and to exclude alternatives? In answering this question, the authors show that the current consensus model is conceptually flawed.

A large number of chemical agents are known which affect blood and blood-forming organs. The purpose of this volume is to review the sig- nificant advances made over the past several years regarding such chemical agents. The purification, biological action, and therapeutic implications of several widely used hematopoietic growth factors such as interleukin 3 (IL-3 or multi-CSF), granulocyte/macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), colony stimu- lating factor (CSF-I or M-CSF), thrombopoietin, and erythropoietin are included in this volume. These factors are important in regulating several hematopoietic cell lines such as neutrophils, monocytes, eosinophils, macrophages, megakaryocytes, platelets, and erythrocytes. People are exposed daily to numerous toxic chemical substances present in our environment which produce a suppression of erythropoiesis, myelo- poiesis, lymphocytopoiesis, and megakaryocytopoiesis. Attempts have been made in this volume to assess the therapeutic role of some of the hematopoietic factors such as erythropoietin in the anemia of end stage renal disease, as well as colony stimulating factors in other hematopoietic abnormalities. In addition, some of the chemical factors in our environment which suppress major hematopoietic lineages stimulated by erythropoietin, macrophage colony stimulating factor, granulocyte colony stimulating factor, interleukin I-alpha, interleukin I-beta, and interleukins 2, 3, 4, 5, 6, 7, and 9 are also included. An updating of the mechanism of action of each of these factors on the major hematopoietic lineages is covered.

The cloning of hemopoietic cells in semisolid medium began some 12 years ago, and when colonies of T = and B = lymphocytes were grown by several groups last year, the last major subclasses of hemopoietic cells had been successfully cultured in vitro. The time seemed appropriate to write a short general account of this exciting new area of hematology, emphasizing particularly the potential value of these new techniques for direct studies on patients with leukemia and allied diseases. I had hoped to refer to, or at least record, every paper published in this field, but the literature proved to be larger than I had realized, and furthermore, some areas were so active that chapters had to be rewritten over a period of less than a year. I regret that .what follows is an incomplete account and no doubt, by the time this book becomes available, the material will be even more out of date. However, I have described the basic techniques in some detail and have tried, where possible, to explain how and why the techniques can fail. It is already possible to see patterns, perhaps even principles, emerging from this work which may well be applicable to other cell populations. These have been emphasized in the text in an attempt to make this review as creative as possible."

MSC (mesenchymal stem cells) have been reported to initiate revascularization after injury, to facilitate engraftment of blood-forming stem cells, and to reduce the incidence of graft-vs. host disease through their immune-suppressive qualities. Finally, bone marrow-derived MSC have been reported to home to areas of solid tumor revascularization, and thus may be used as delivery vehicles to target ablative agents into dividing tumor cells. Recently the characteristics of human MSC from adipose (fat) tissue have also been identified. The possibility of repairing tissues, speeding stem cell engraftment, and targeting solid tumors for specific killing, using MSC easily harvested from bone marrow, or better yet, from unwanted fat tissue, holds broad appeal, and is an intriguing possibility that could have dramatic effect on health care.

This book has information on how to isolate, grow, and characterize MSC from marrow and fat, and gives important insight into how these cells may be used for gene delivery and cellular therapies in the future. Updates on emerging clinical trials are given.

Leading international experts contribute to this selection of reviews covering the merging fields of growth factors, differentiation factors, and cytokines. These appear to play fundamental roles in a wide variety of physiological and pathophysiological processes that include the regulation of growth in normal and malignant cells, embryogenesis, the immune response, wound healing, inflammation, and atherogenesis. The major aspects of recent research and development are discussed, providing an important update in this pioneering field.

th This book contains most of the papers presented at the Iy Inter- national Symposium on Bone Circulation which was held in Tou- louse, France, in September of1987. The symposium was attended by over 200 specialists from 17 different countries. Some of them were in Toulouse for the fourth time to discuss their favourite topic of study and research: bone circulation, its exploration, its pathol- ogy. Many, including a group of Japanese orthopaedic surgeons, were present for the first time, delighted to meet the authors of papers they had read. There were more than 100 oral presentations and posters, but many meaningful informal discussions took place both in and outside of the auditorium, in the hall and during meals. The organizers wished to maintain a balance between funda- mental themes and subjects of clinical and practical interest. This balance was accomplished: recent developments including scintig- raphy, magnetic resonance imaging and bone grafts played just as important a part as more sophisticated topics such as the evalua- tion of the blood flow rate in animal bone tissue. Thus, as did the previous symposia, this book aims to present a progress report on developments during the last 5 years in the study of bone circulation. We wish to thank all those who helped and encouraged us throughout the organization of the congress, especially C. Ar- noldi, M. Brookes, R. Burkhardt, L. Coutelier, S.P.F. Hughes, P. Kehr, J.P. Jones, A. Trias, K.Ono, T. Yizkelety and G.J.

Contents: Introduction and Overview Lymphopoietic Growth Factors: Pathophysiology of T-Cell Mediated Shock Induced by Bacterial Superantigens - Natural Killer Cells and Interleukin-2-Activated Killer Cells - TumourImmunogenicity Induced by Exogenous Interleukins - Cytokine Gene Therapy of Cancer - Analysis of T-Cell Receptor Variability in Tumour Infiltrating Lymphocytes - Clinical Studies with Interleukin-2: An Overview - Clinical Trials with Local Administration of Lymphopoietic Growth Factors - Clinical Trials with Interlaukin-2. The Rome Experience. Haematopoietic Growth Factors: Lymphohaematopoietic Growth Factor Use in Lung Cancer Patients - Clinical Trials with Haematopoietic Growth Factors and Peripheral Blood Stem Cells

One of the most fascinating tools at the disposal of the molecular biologist is the medical clinic. The responsibilities of those who provide health care do not stop when they give optimal care to the individual patient and train their successors adequately. They also are under the obligation to obtain maximal information from every case they treat in order to reach a better understanding of the underlying illness in order to improve therapeutic results in the next patient. Fundamental research in pathological material is therefore a medical must as well as an opportunity for scientific work. The scientist working in this field can profit from nature's unasked for experiments, which are encountered by his medical colleagues in their clinical material. There are many examples of subjects of study - for instance hemoglobins and immunoglobulins - which started in a medical context and gradually developed into a field of prime interest for the molecular biologist. The study of blood coagulation is one of the younger areas of this kind.

An overview of diagnosis and current management of myelodysplastic syndromes.

- Reviews the performance of the pharmacological treatments currently available and analyses the potential for new treatments
- High quality clinical photos and figures to enhance descriptions and improve reader comprehension
- Useful reference text for healthcare professionals needing to know more about myelodysplastic syndromes

David Kuter and a host of leading international researchers summarize in one volume all the knowledge of thrombopoietins (TPO) available today. The distinguished experts review the history of the search to discover TPO, describe the molecular and biological characteristics of this new molecule, and present the results of the preclinical animal experiments that will guide clinical use of this new hormone. Along the way they provide the most recent and comprehensive guide to the biology of megakaryocytes and platelets.

This unique publication explores diverse themes relating to thrombosis and embolism, from basic research at cell and molecular level to the actual care, prevention, and treatment of diverse categories of patients suffering from such diseases. Chapters cover a variety of topics including thrombosis and embolism in surgical patients, cancer patients, pregnant women and children and adolescents, as well as treatment of the conditions by traditional anticoagulants, novel oral anticoagulants, thrombolytic therapy, endovascular treatment and embolectomy. Readers may explore cutting edge research, recommendations from major societies, contemporary guidelines, areas of controversy and directions for ongoing and future research. The book features comprehensive information ranging from molecular mechanisms of diseases to the clinical features, diagnosis, and therapeutic regimens for treating a variety of clinical conditions. It has a broad appeal to scientists and research students as well as busy clinicians engaged in patient care, who will all find something important and useful amongst these carefully selected chapters.

Welcome to the City of Groningen, the center of the North of the Netherlands. Groningen is proud of the long lasting tradition of scientific symposia organised by the Sanquin Blood Bank. These Sanquin International Symposia on Blood Transfusion have become a true traditional event in Groningen, marking the early academic year and have contributed to the specific reputation of Groningen and its University in the scientific field of Transfusion Medicine. The growing tradition has also contributed to initiatives of both University, Province and the City of Groningen to bring science and industry together - BioMedCity Groningen. Such repu- tion does not just happen, but is the result of creative and scientific leadership, of vision and an open mind, to explore in a team spirit horizons. Groningen is particularly proud of this reputation thanks to its leadership, the Sanquin Blood Bank North-East. This year in particular the theme chosen some two years ago is extremely timely as it illustrates the activities and scientific interest of an integrated team which includes our regional Sanquin Blood Bank North-East and fits in the City initiatives within the concept of BioMedCity, Groningen.

This is a comprehensive textbook of Hodgkin's and non-Hodgkin's lymphomas written by leaders in the field of childhood lymphomas. It includes clinical, pathologic and molecular biology of each subtype of lymphoma. The pathology chapters are comprehensive and include excellent photographs. The book is at the level of subspecialists in pediatric hematology and oncology, radiation oncology, pediatric surgery and hematopathology.