The hematopoietic system plays roles that are crucial for survival of the host: delivery of oxygen to tissues, arrest of accidental blood leaking from blood vessels, and fending off of invading microbes by humoral, cell-mediated, and phagocytic immunity. The activity of the hematopoietic system is staggering: daily, a normal adult produces approximately 2.5 billion erythrocytes, 2.5 billion platelets, and 1 billion granulocytes per kilogram of body weight. This production is adjusted in a timely fashion to changes in actual needs and can vary from nearly none to many times the normal rate depending on needs which vary from day to day, or even minute to minute. In response to a variety of stimuli, the cellular components of the blood are promptly increased or decreased in production to maintain appropriate numbers to optimally protect the host from hypoxia, infection, and hemorrhage. How does this all happen and happen without over or under responding? There has been extraordinary growth in our understanding ofhematopoiesis over the last two decades. Occupying center stage is the pluripotent stern cell and its progeny. Hematopoietic stern cells have been characterized by their capacity for self renewal and their ability to proliferate and differentiate along multiple lineages. Few in number, the stern cell gives rise to all circulating neutrophils, erythrocytes, lymphoid cells, and platelets. In hematopoietic transplantation, the stern cell is capable of restoring long-term hematopoiesis in a lethally irradiated host.

Transfusion medicine provides an excellent bridge connecting the healthy community donors with the patient's needs at the bedside; the dominant philosophy has been on patient care and science, but it is now realised that blood banks manufacture increasing amounts of blood components to administer to patients -- a role analogous to manufacturing functions. The concept of Good Manufacturing Practice (GMP) is therefore relatively new. While quality has always been important, the impact of GMP, Total Quality Management (TQM) and Quality Assurance (QA) will be profound. As the regulatory agencies, like the FDA in the U.S.A. and the EEC Commission in Europe, increase their enforcement activities, doctors, technical experts and managers will have to face many issues of quality assurance including documentation, validation, audit system, regulatory laws, licensing, teaching and training of staff and their job descriptions, standards, processing facilities, procedure validations, automation, record keeping, internal and external quality control of products and their release.The expansion of this philosophy to include Good Clinical Practice (GCP) is an even greater challenge demanding consensus therapy protocols and quality management of transfusion through auditing by the hospital transfusion committees. Such comprehensive plans will profoundly affect the financial and organisational structure of blood transfusion in the future.

This comprehensive book, lavishly illustrated with over 700 colour pictures, addresses the subject of bone in internal medicine. It is based on biopsies of bone and first describes the normal range of physiological findings in iliac crest biopsies in young, middle-aged and elderly individuals. The book then deals systematically with the osseous disorders most frequently encountered in internal medicine, and some that would be considered in the differential diagnosis. Numerous up-to-date references are included. The clinical applications of biopsies of bone are emphasized as well as their clinical interpretation; sections on histomorphometry and functional aspects of bone cells are also included. The book will be of particular interest to specialists in internal medicine, endocrinology, nephrology, haematology and oncology, as well as being a bench manual for the practising pathologist.

Cellular drug resistance is a major limitation to the success of chemotherapy of leu kemia and lymphoma. The importance of this has now been recognized by both clinicians and scientists. It is of utmost importance to bridge the gap between laboratory and clinic in this field of research. This is the main purpose of the series of International Symposia on Drug Resistance in Leukemia and Lymphoma. These are held every three years in Am sterdam, The Netherlands, since 1992. This book contains the proceedings of the third of these meetings, organised in 1998. The book covers all important aspects of drug resistance in leukemia and lymphoma, both in the form of extensive reviews as in manuscripts describing original data. General mechanisms of resistance are discussed, including the drug resistance related proteins p glycoprotein, MRP (multi-drug resistance protein) and LRP (lung resistance protein), and the role of glutathione and glutathione-S-transferases. Moreover, more drug type-specific mechanisms of resistance are a topic, such as for glucocorticoids and antifolates. Much in formation is provided on apoptosis and its regulators, and on the results of cell culture drug resistance assays. Several papers focus on the modulation or circumvention of drug resistance.

In 1868, Ernst Neumann recognized that blood cells re quire continuous replenishment during postnata1life. Before him, the assumption was that cells of the blood, like nerves once formed in the embryo, remain in the body throughout life. Neumann also recognized that this process occurred within the bone marrow, because this tissue provided a fa vorable environment for proliferation and differentiation of blood cell precursors. Vera Danchakoff, the Russian embryologist working in the US, in 1916 made an analogy to the soil and the seed. Bone marrow forms the soil, providing a favorable environment for the growth of seed, the hemopoietic stem cell, and other progenitor cells. Imagine in the remote past a heap of similar tree seeds. These seeds develop in our moderate climate into a tall and many branched tree. Suppose the wind bears a part of the seeds away and brings them to a land possessing different environmental conditions, we will say the arc tic lands. There the seeds may develop but they may pro duce trees no higher than our moss."

All physicians practicing medicine encounter patients suffering from cardiovascular disease. This book has been outlined in such a way that vascular surgeons, general internists, neurologists and cardiologists should be able to use it. The book covers the complete scope of cardiac diseases in addition to chapters on hypertension and atherosclerosis. In many patients there is a family history of cerebrovascular accidents, myocardial infarction or peripheral arterial disease. Also in patients reporting collaps, palpitations and arrhythmias the family is crucial and can provide clues to a genetic cause of the disease. This book is published to guide physicians in the process of determining whether a genetic component is likely to be present. Furthermore, information is provided what the possibilities and limitations of DNA diagnostic techniques are. Finally, the importance of newly identified categories of potential patients, i. e. gene carriers without symptoms or any inducible sign of disease, is highlighted. For some patients a genetic diagnosis is essential to determine appropriate therapy and for counseling? In some other diseases DNA diagnostic tools are available but the relevant for the patients may be less clear. In other families the search for a disease causing gene is ongoing and the possibilities to find genes and to unravel the pathophysiology of the disease is limited by the lack of patients. To give insight into the current state of genetic diagnostics, the authors have classified the cardiovascular diseases.

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.

An up-to-date overview of blood and marrow transplantations, the book discusses in detail Indication to transplantation and pre-transplant considerations. An outlook on the latest developments and their future aspects is included, while problems and pre- and post-transplant complications are fully explored.

Scintigraphic imaging with radiolabeled blood elements has continued to be a useful diagnostic modality. The major trust of recent investigation has been in simplifying labeling techniques and developing new agents that will label blood elements selectively in vitro. The VI Symposium of the International Society of Radiolabeled Blood Elements was held in Barcelona (Spain) during November 23 to 27, 1992.The conference was sponsored by the NATO Scientific Affairs Division, the USA Department of Energy and the Spanish National Health Service. This monograph comprises articles that represent most of the 85 papers (70 oral and 15 posters) presented during the symposium. The meeting was attended by 110 investigators hailed from 21 countries. Although lllIn-oxine and 99mTc-HMPAO remain the choice agents for labeling blood components for routine applications, there was heavy emphasis on developing new labeling agents that will either simplify the in vitro labeling procedure, or, even better, will label blood components selectively in vivo, by injecting the radioactive agents directly into patients. The degree of success in imaging target lesions in humans by using these agents has been excellent.

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 first International Meeting on Apheresis was held in Dyon in 1984. At the congress it became clear that both the technical and therapeutic sides developed very rapidly and it appeared fruitful to bring together the investigators of the different countries working in the areas. At that time immunology had come to pervade many clinical specialities, and hemapheresis, especially plasmapheresis was considered a therapeutic tool in many immunological diseases which hitherto had proved to be fatal. New methods to identify certain antibodies and circulating immune complexes in the serum and the possibilities to remove them from the blood by several techniques (filtration, centrifugation, immunoabsorp tion) led to an almost uncontrolled use of plasma exchange in a variety of diseases. Since then the technical possibilities of this technique were further recognized, as was the impact of immunology on many diseases, and the possibilities to collect specific components for therapeutic pur poses. But also we became aware of the limited contributions of anec dotal data on successes or failures of apheresis as adjuvant treatment. Therefore international prospective studies were initiated to make critical assessment possible of apheresis in various diseases.

This monograph covers the entire field of blood group serology, with its main emphasis on the chemical and biochemical basis of blood group specificity. Full consideration is given to molecular biology investigations, in particular to studies on the structure of blood group genes and the molecular biological basis of alleles and rare blood group variants, whereby relevant literature up to the year 2000 is covered. The text is supplemented by numerous illustrations and tables, and detailed reference lists.

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.""

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."

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.

There should be, and in the best of cases there is, a synergy between basic research and patient care. However, this synergy is hard to develop because the techniques required to be a successful researcher are so different from the skills required to be an outstanding physician. Harold R. Roberts, M.D., of the University of North Carolina at Chapel Hill, is an example of a physician-researcher who has benefited from having his feet in both the world of patient care and the world of the laboratory: he has let clinical problems direct his basic research effort and conversely has adopted research advances in his care of patients. Dr. Roberts's long and continuing career has included many research and clinical advances. He was part of the first group to determine the amino acid sequence of the important thrombin inhibitor hirudin and part of the group that prepared the first cryoprecipitates which were the first alternative to plasma as therapy in hemophilia A. Dr. Roberts has made significant advances in understanding the protein chemistry behind hemophilia B; he was among the first researchers to identify some patients as not being completely deficient but instead as having measurable levels of protein and subsequently demonstrated that this protein was dysfunctional. This important advance led him to a classification scheme for patients into Cross Reacting Material (CRM) positive, negative, and reduced. Dr.

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.

The idea to compile recent results on the ectoenzymes aminopeptidase N/CD13 and dipeptidylpeptidase IV/CD26 arose from the great interest given by readers world-wide to the two proceedings volumes edited by us in 1997 and 2000 (Ansorge and Langner, 1997; Langner and Ansorge, 2000). These volumes contained the presentations at two symposia held in Magdeburg (Germany) in 1996 and 1999 under the title "Cellular peptidases in immune functions and diseases", which was also the name of the Sonderforschungsbereich in Magdeburg, sponsored by the Deutsche Forschungsgemeinschaft between 1995 and 2001. Our groups in Magdeburg and Halle during the last two decades have provided results on these two enzymes in cells of the hematopoietic system that justify a review in an edited monograph like the present one (see the reviews by Kahne et at. , 1999; Lendeckel et at. ,1999; Riemann et at. , 1999). There are, however, many other groups in Europe, US and Japan which made important contributions to this field and particularly in topics improving the understanding of physiological and pathophysiological roles ofAPN/CD13 and DPIV/CD26. Therefore we decided to invite some of them to contribute reviews of their results to this book. Having worked for about 40 years in the field of proteolysis, for both of us to see the development of activities and knowledge from protein chemistry and enzymology to physiology and pathophysiology and even to therapy is very stimulating and fascinating. Of course, this development also reflects the dramatic improvement and refinement of methods.

TheobservationthatabloodclotspontaneouslydissolveswasfirstdescribedbyDenys in1889. Subsequently,thebloodclottingsystemwasshowntobeinvolvedintumor growth. Forexample,asearlyas1925,Fisherreportedthataviantissueexplantstrans- formedtomalignancybyvirusesgeneratedhighlevelsoffibrinolyticactivityundercon- ditionsinwhichculturesofnormalcellsdidnot. In1958,theconceptthatan equilibriumexistedbetweenthetendencyofbloodtoclotandtoremainfluidwaspro- posedbyAstrup. Atthattime,itwasbelievedthatthishemostaticbalancewasexplained bytheabilityofpolymerizingfibrintoorchestrateitsownclearancebystimulatingfib- rinolyticactivity. Sincethesepioneeringstudies,considerableinformationhasaccumu- latedthathasdefinedthecomponentsofthecoagulationandfibrinolyticsystemsand howtheyareinvolvedinphysiologicalandpathophysiologicalprocesses. Plasminogen: Structure, activation, and regulationfocusesonthebasicprinciplesandrecentdevelop- mentsintheplasminogen/plasminresearchfieldandhowtheseresultsprovideacon- ceptualframeworkforanunderstandingofthephysiologicalroleofplasminogenin healthanddisease. Theenzymaticcascadetriggeredbyactivationofplasminogenhasbeenimplicated inavarietyofnormalandpathologicaleventssuchasfibrinolysis,woundhealing,tis- sueremodeling,embryogenesis,angiogenesis,andtheinvasionandmetastasisoftumor cells. Thisimpressivelistofphysiologicalfunctionsforplasminogenreinforcesthewide diversityofrolesthatplasminogenplaysinvariousphysiologicalprocesses. Productive plasmingenerationrequirestheassemblyofbothplasminogenactivatorsandplasmino- genonasolidsupportsuchasthefibrinpolymerorthecellsurface. Theregulationof plasminproductioninvolvesacomplexinterplaybetweentheseplasminogenactivators, plasminogenactivatorinhibitors,andplasmininhibitors. Clearly,theexplosivegrowth inthisresearchfieldandthemanyexcitingdiscoveriessuggeststhattheresearchefforts inthenextdecadewillrevealthemechanismsbywhichthecomponentsoftheplas- minogensysteminteractandregulatebothplasminactivationandfunctionatacellular level. Plasminogen: Structure, activation, and regulationisdividedintotwosections. Thefirstsectiondealswiththestructureandregulationofplasminogen. Thechapters inthissectionrangefromdiscussionsofthestructureofplasminogenandtheregulation oftheplasminogengenetodiscussionsofthestructureandregulationofplasminogen activatorsandplasminogenactivatorinhibitors. Alsoexaminedistherelativelynewdata concerningthegenerationofanti-angiogenicmoleculesfromplasminogen. Thesecond sectiondealswiththephysiologicalandpathophysiologicalrolesofplasminogenaswell astheconsequencesofplasminogengeneknockout. Discussionsinthissectioninclude examinationoftheroleofplasminogeninhematopoieticmalignancies,tumorcell progression,angiogenesis,mammaryglandinvolution,woundhealing,andbone readsorption. xi xii Preface Inclosing,Iwouldliketothankmyadministrativeassistant,Ms. ViSommerfeld,for herinvaluableassistanceandtimelesseffortswiththeorganizationandeditingofthebook. Lastly,Iwouldliketoacknowledgetheeffortsoftheauthorsoftheindividualchapters, whoareauthorities inthisfield,foragreeingtotaketimefrombusyschedulestoprovide thesechaptersinatimelyfashion. DavidMortonWaisman Contents Part I. Plasminogen: Structure and Regulation 1. Human Plasminogen: Structure, Activation, and Function FrancisJ. Castellino and Victoria A. Ploplis 1. Introduction 3 2. StructureofHumanPlasminogen...3 2. 1. PrimaryProteinStructure...3 2. 2. GeneOrganization 5 3. ActivationofHumanPlasminogen...6 3. 1. ActivationbyPhysiologicalActivators 7 3. 1. 1. Urokinase-typePlasminogenActivator...7 3. 1. 2. Tissue-typePlasminogenActivator...8 3. 2. ActivationbyBacterial-derivedPlasminogenActivators...9 3. 2. 1. Streptokinase 9 3. 2. 2. Staphylokinase...9 4. TargetsforPlasminActivity...9 5. DysplasminogenemiasandPhenotypicManifestations 10 6. Conclusions 11 References...11 2. Plasminogen Activators: Structure and Function Vincent Ellis 1. Introduction ...19 2. SerineProteases...20 3. UrokinasePlasminogenActivator,uPA...21 3. 1. SerineProteaseDomain 22 3. 2. N-terminalDomains...24 3. 2. 1. KRModule 24 3. 2. 2. EGModule 24 4. MechanismsRegulatinguPAFunction...25 4. 1. ZymogenActivation...25 4. 2. ZymogenActivity...26 4. 3. ReciprocalZymogenActivation 27 4. 4. uPARStimulationofPlasminogenActivation...27 4. 4. 1. uPAandtheTemplateMechanism 28 4. 4. 2. PlasminogenandtheTemplateMechanism 29 4. 5. AvianuPA,aSpecialCase? 30 xiii xiv Contents 5. TissuePlasminogenActivator,tPA...30 5. 1. SerineProteaseDomain 31 5. 2. N-terminalDomains ,...33 5. 2. 1. KRModules ,. . ,. . ,...33 5. 2. 2. F1-EGSupermodule 33 6.

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.

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.

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.