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."

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.

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.

The International Scientific Symposium on Fibrinogen, Thrombosis, Coagulation, and Fibrinolysis was held in Academia Sinica, Taipei, Taiwan, Republic of China, on August 30 - September 1, 1989. This Symposium has provided a forum for the free exchange of information in this important and rapidly advancing research field. This proceedings volume provides a published record of 46 papers presented at the Symposium. The sponsors have exerted no influence on the scientific opinions or positions of the participants in the Symposium. It is hoped that this Symposium will stimulate further worldwide cooperation and collaboration in these vital fields for the benefit of all human kind. This volume is composed of four parts. The first part consists of 8 papers on Fibrinogen and Fibrin: Biochemistry, Molecular Biology, and Physiology. The second part contains 16 papers on Coagulation and Fibrinolysis: Biochemistry, Molecular Biology, and Physiology. The third part has 10 papers on Cardiovascular Cell Biology: Biochemistry, Molecular Biology, and Physiology. The fourth part comprises 12 papers on Clinical Studies of the Cardiovascular System: Thrombotic and Bleeding Disorders and Thrombolytic Therapy. The Author Index with addresses of all contributors and the Subject Index of all 46 papers are arranged at the end of this volume.

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.

th It is a great pleasure for me to open the jubilee 25 International Symposium on Blood Transfusion here in Groningen. This symposium is co-sponsored by the World Health Organization and is being held under the auspices of the ISBT and the Secretary General of the Council of Europe, Mr Walter Schwimmer. The patronage was granted with great pleasure for several reasons. First of all, Dutch experts are very active in our Committees and have largely contributed in developing the Council of Europe principles in the blood area. Secondly, the Council of Europe is active today in the area of blood transfusion due to a tragic event, which occurred in 1953 in the Netherlands; following a flooding many of the blood products given for assistance' could not be used due to incompatibilities and differences in labelling. Some words to present the Council of Europe since the organisation is sometimes confused with institutions ofthe European Union: The organisation has been founded in 1949 to establish the principles of democracy and rule of law all over Europe. Since 1989, the year of the fall of the Berlin wall and the opening up of the iron curtain, these principles could be extended to the countries of Central and Eastern Europe. Today this makes the Council of Europe the only pan-European organisation with 41 Member States thus representing more than 750 million people.

A variety of metabolic processes are known to be intimately involved in the maintenance of cellular structure and function. It has also become clear that metabolic events involved in the synthesis and hydrolysis of ATP as well as for the synthesis of proteins and phospholipids are essential for cellular health. The regulation of cell function is generally achieved through participation of a wide variety of hormones and different signal transduction mechanisms for the activation/deactivation of some specific metabolic processes. In this regard cyclic AMP and calcium seem to play a crucial role. Various hormones are also known to affect the genetic machinery of all the cell; however, the exact signals for genetic control of cellular function are not well defined. In particular, the sequence of events concerned with remodelling of different types of cells under various pathological situations is poorly understood. In this book we have therefore dealt with some of these issues from biochemical, molecular biological, physiological, and pharmacological viewpoints. Special emphasis has been laid on understanding heart function and metabolism in health and disease in general, and cardiac hypertrophy, heart failure, and ischemic heart disease in particular. It is hoped that this multidisciplinary information will be of value to basic scientists and clinical investigators.

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.

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 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.""

Coronary heart disease remains the leading cause of death for men and women in the United States and other industrialized nations. Acute myocardial infarction accounts for a majority of these deaths, approaching 750,000 yearly. Thrombolytic therapy has revolutionized the treatment of myocardial infarction, saving lives to a greater extent than any treatment developed to date. The identification of patients best suited for thrombolytic therapy has been a challenging task, as has the ideal adjuvant strategy. Further, the noninvasic diagnosis of treatment successes and failures, as well as the expeditious triaging of patients requiring mechanical/surgical revascularization have been difficult to define, but progress has been made recently. The emergence of information vital for patient care has appeared at an extraordinary pace, with hundreds of articles being published yearly. Unfortunately, a resource devoted to the area of thrombolysis does not exist, making the dissemination of information to physicians, scientists and health care providers problematic. The Modern Era of Coronary Thrombolysis is designed to bring the medical and scientific communities up to date. It will serve as a foundation for future investigation, as well as a resource which can be referred to for many years to come.

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.

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.

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.

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.

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.

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."