Hypoxia is a constant threat throughout life. International experts from many different fields, including clinicians, clinical researchers, and basic scientists, have contributed to this volume, presenting state-of-the-art information regarding normal and abnormal (pathophysiological) responses to hypoxia. The topics covered include visitors to high altitude, the latest developments on high-altitude cerebral and pulmonary edema, the brain in hypoxia, high-altitude headache, and similarities between ischemic and hypoxic injury to the brain. In addition topics are covered such as blood-brain barrier in hypoxia, hypoxia interactions with vascular growth, and how humans adjust to extreme hypoxia.

This volume contains refereed manuscripts prepared from presentations made at the 2ih annual meeting of the International Society on Oxygen Transport to Tissue (ISOTT). The meeting was held in Hanover, NH, USA, at Dartmouth Medical School, the 3rd oldest medical school in the USA. ISOTT attempts to produce high quality pUblications on cutting edge topics relating to oxygen in living systerns. The goal is to allow contributors to contribute original data, as with a main-stream journal article, but also to voice individual opinions and ideas in a more relaxed scientific forum. The meeting brought together an international group of scientists who share a common interest in the measurement and role of oxygen in living systems. The organizers of ISOTT99 made a special effort to bring together people from industry, medicine, and basic sciences in order to improve the links in the chain of discovery through to application. As a result, this volume contains publications on a range of subjects. There are contributions from companies on modifiers of oxygen carrying capacity (allosteric modifiers of hemoglobin and infusible oxygen carriers or blood substitutes); technical reports on oxygen measurement devices including advances in near-infrared spectroscopy and imaging, oxygen electrodes, magnetic resonance spectroscopy and imaging, and fluorescence based measurements. There are medically related sections on modifying and measuring tumor oxygenation in order to improve therapy, assessment and interpretation of oxygenation in the central nervous system, and general issues relating oxygen to pathological conditions.

Numerous studies have proven the biological basis of memory formation and have begun to identify the biochemical traces and cellular circuits that are formed by experience, and which participate int the storage of information in the brain, its retention for long durations, and its retrieval upon demand. Cells in the nervous system have the capability of undergoing extremely long-lasting alterations in response to hormonal, pharmacological, and environmental stimulations. The mechanisms underlying this neuronal plasticity are activated by experiential inputs and operate in the process of learning and the formation of memories in the brain. This volume presents research areas which have not been highlighted in the past. In addition to studies on the involement of functional proteins in neuronal adaptation, this volume presents recent developments on the critical roles of bioactive lipids and nucleotides in these processes. In addition to the widely studied role of second messengers, a review of studies on extracellular phosphorylation systems operating on the surface of brain neurons is presented.The first section of the volume presents studies of basic mechanisms operating in a wide range of adaptive processes. The second section presents recent advances in investigations that have demonstrated the clinical implications of this research. These include: state of the art use of transgenic models in studies of molecular and cellular mechanisms implicated in familial Alzheimer's disease and Amyotrophic Lateral Sclerosis; studies of specific proteins implicated in Alzheimer's disease, including an adapter that binds to the beta-amyloid precurser protein (beta-APP) and the microtubular protein Tau and its membrane-bound counterpart. The advantages of using cell culture models for elucidating the causes of neuronal degeneration and for identifying mechanisms of neuroprotection are also presented among the chapters in the section on clinical implications.

Recently, attention has been called to the role that microvascular organization plays in the functional morphology of all organs and tissues, both in normal and pathological conditions. Since its development by Murakami, the corrosion cast method for scanning electron microscopy has come to be considered one of the most efficient means in clarifying the three-dimensional features of the microcirculation of organs and tissues. Scanning Electron Microscopy of Vascular Casts: Methods and Applications was planned to supply fundamental and new information regarding microcirculation studies to general biologists, anatomists, pathologists and clinicians. The contributions to this volume, contain original findings and excellent electron micrographs obtained by using recently improved corrosion cast methods. The rich variety of papers in this book will be useful to many, and will provide both the basic and clinically oriented readers with good ideas, suggestions, and original and worthwhile information.

The 'Formation of the Heart and its Regulation' reviews in considerable detail the major events in heart development and their control via genes, cell-cell interactions, growth factors and other contributing elements. In addition, there is an extensive and useful overview of the field of heart development taken as a whole. The book will appeal to all students and researchers working on cardiovascular development and to pediatric cardiologists.

We have considered it to be a demanding assignment to provide a complete exposition dealing with the nature of radiation, its effects, and protection against it to workers in health-related activities. "Radiation" (and more precisely "ionizing radiation") is emitted by X-ray machines, nuclear reactors, and nuclear weapons, but also comes from natural sources to which we are all exposed. It would have been easier to deal with this subject area with the terminology and mathematics employed by specialists. However, although most of the potential readers probably have obtained further pertinent knowledge, we assume no more than a high school education in science and mathematics and the challenge was to provide maximum information within this constraint. This book contains five sections: (A) Radiation Physics, (B) Radiological Physics, (C) Radiation Biology, (D) Radiation Effects on Human Populations, and (E) Radiation Protection. Each section is preceded by a synopsis covering its essential features. It provides sufficient information to enable readers to obtain a general under standing of the subject of the section and an adequate background for comprehension of other sections. The more detailed presentation in the bulk of each section is followed by appendixes that generally contain more advanced topics. This scheme necessarily involves some repetition but permits a more flexible approach for readers who are especially interested in the contents of particular sections.

The overall scope of this new series will be to evolve an understanding of the genetic basis of (1) how early mesoderm commits to cells of a heart lineage that progressively and irreversibly assemble into a segmented, primary heart tube that can be remodeled into a four-chambered organ, and (2) how blood vessels are derived and assembled both in the heart and in the body. Our central aim is to establish a four-dimensional, spatiotemporal foundation for the heart and blood vessels that can be genetically dissected for function and mechanism. Since Robert DeHaan's seminal chapter "Morphogenesis of the Vertebrate Heart" published in Organogenesis (Holt Rinehart & Winston, NY) in 1965, there have been surprisingly few books devoted to the subject of cardiovascular morpho genesis, despite the enormous growth of interest that occurred nationally and inter nationally. Most writings on the subject have been scholarly compilations of the proceedings of major national or international symposia or multi authored volumes, without a specific theme. What is missing are the unifying concepts that can often make sense out of a burgeoning database of facts. The Editorial Board of this new series believes the time has come for a book series dedicated to cardiovascular mor not only as an important archival and didactic reference phogenesis that will serve source for those who have recently come into the field but also as a guide to the evo lution of a field that is clearly coming of age.

If one were to design the ideal nuisance for cell cultures, the resultant might well be similar to mycoplasmas. These micro organisms are very prevalent in nature, being found in the oral cavity, blood, the mucous membranes of the respiratory and uro genital tract and other tissues of both man and animals. They are relatively difficult to detect microbiologically and chemically. Lacking cell walls, they do not routinely produce turbidity in cell cultures and are resistant to antibiotics that act on cell walls. Mycoplasmas grow to high titers in cell cultures. Concen 7 8 trations of 10-10 colony forming units per ml of supernatant medium are representative. Additionally, more numbers are attached to cell membranes. Further, mycoplasmas have been shown to mimic in vitro effects of viruses and toxic chemicals. In various cell culture systems, mycoplasmas have been known to cause cell death, decrease or increase cell growth, affect virus tite s, induce interferon, cause chromosome damage, induce transformation, cyto pathic effects, alter phenotypic expression, and significantly alter metabolic pathways and products of cells. The presence of such high concentrations of mycoplasmas in cell cultures constitutes a true in vitro infection. Such infected cell cultures, with a 8 9 total of 10 _10 or more actively metabolizing mycoplasmas, have no place in controlled, standardized cell culture procedures. Numerous reports have been published on mycoplasma assay pro cedures, effects of infection, and preventive and elimination measures."

Compact and portable, Netter's Surgical Anatomy Review P.R.N. is the easiest and most convenient way to refresh need-to-know anatomy for surgeons-in-training. Vibrant, detailed artwork by preeminent medical illustrator Frank H. Netter, MD makes it easy to visualize the anatomy that underlies the procedures and clinical conditions you see during a surgical residency or clerkship. This concise, instant review of anatomy and clinical correlates is perfect for "just in time" use. Updates include new chapters on heart and lung anatomy, diagnoses, and procedures. Expert Consult eBook version included with purchase. This enhanced eBook experience allows you to search all of the text, figures, images, and references from the book on a variety of devices.

Heme oxygenase is rapidly taking its place as the centerpiece of multiple inter acting metabolic systems. Only 25 years ago heme oxygenase and its metabolic prod ucts appeared to be merely a simple metabolic system-one substrate, heme; one enzyme, heme oxygenase; and one set of products, iron to be recycled, and bilirubin and carbon monoxide to be disposed. From a group of about 25 people in 1974, as judged by attendance at various Gordon conferences, heme oxygenase has, in the year 2000, attracted working scientists-and clinicians I might add-by the hundreds and has produced referenced publications by the thousands. It is well-deserved attention. Heme oxygenase system is now similar to the metabolic networks surrounding glucose in those complex maps of glycolytic and non-glycolytic metabolic pathways, which we had to memorize as students. The relevance of heme oxygenase to regulatory biology was recognized many years ago, but the work conducted over the past five years has created a new wave of emphasis focusing on genetic manipulation to alter heme oxygenase gene expression, the regulatory actions of heme oxygenase products including carbon monoxide, and the significance of changes in the heme oxygenase system. The physiological and pathological relevance of heme oxygenase in the brain, heart, liver, bone marrow, organ transplant, lung and kidney, opens many areas of investigation in various dis ciplines. Advances in the pharmacology of bilirubin and its ability as an antioxidant have provided a new avenue in clinical research.

Over the last twenty-five years, there has been an extensive effort, still growing for that matter, to explore and understand the organization of extrastriate cor tex in primates. We now recognize that most of caudal neocortex is visual in some sense and that this large visual region includes many distinct areas. Some of these areas have been well defined, and connections, neural properties, and the functional consequences of deactivations have been studied. More recently, non invasive imaging of cortical activity patterns during visual tasks has led to an expanding stream of papers on extrastriate visual cortex of humans, and results have been related to theories of visual cortex organization that have emerged from research on monkeys. Against this backdrop, the time seems ripe for a review of progress and a glance at the future. One caveat important to emphasize at the very onset is that the reader may be puzzled or confused by the use of different terminologies. Individual investi gators commonly tend to favor different terminologies, but in general some prove more advantageous than others. As discussed by Rowe and Stone (1977) as well as by others, there is an unfortunate tendency for role-indicating names to lead to fixed ideas about function, in contrast to those that are more neutral and adaptable to new findings.

The discovery of the human T cell leukemia virus type I in the late 1970s heralded a new era in retrovirology. For the first time, it was demonstrated that a retrovirus could play a role in the development of a human disease, in this case adult T cell leukemia (ATL). Several years later, the acquired immunodeficiency syndrome (AIDS) epidemic began, and it was dem- strated that a retrovirus, originally designated the human T cell lymp- tropic virus type 3, was the causal agent of this syndrome. This virus, later named the human immunodeficiency virus type 1 (HIV-1), has since been extensively studied in terms of its pathogenesis as well as its ability to elicit immune responses. In that time, a tremendous amount of information has been obtained about the virus. Although recent drug regimens have been useful in significantly lowering viral loads and perhaps maintaining an asymptomatic state among individuals infected with HIV-1, an established "cure" for AIDS eludes us. In addition, the effective drug therapies are very expensive, and are not available to infected people in the third world, where greater than 90% of new infections occur. Furthermore, the development of viral resistance against the drug therapies is an additional concern. Despite extensive study, no effective vaccine has been developed. One of the problems in developing an effective vaccine against HIV-1 is the ability of the virus, particularly in the immunogenic envelop glycoprotein, to undergo amino acid hypervariability.

The Eighth Annual Research Conference of the American Institute for Cancer Research, held in Washington, D.C., September 3-4, 1998, was on the subject "Colon Cancer Prevention: Dietary Modulation of Cellular and Molecular Mechanisms," with participants representing various disciplines interested in this area. One of the speak ers provided an appropriate quote from 17th century physician Thomas Adams: "Pre vention is better than healing because it saves the labor of being sick," which aptly describes the need for the prevention of cancer. An overview of normal and abnormal colonic development emphasized that although the typical human colon undergoes 1013 cell divisions by age 60, with the asso ciated possibilities for error, relatively few colon tumors develop. Since dietary modu lation leads to extremely small changes in colonic cells over a long period, animal models are useful to time, observe, and delineate the events associated with colon cancer. In the development colon cancer, the inactivation of the adenomatous polyposis coli (Apc) gene is one of the earliest known events. Normally Apc downregulates the cellular protein beta-catenin, but this is lost during cancer development. Beta-catenin may itself be an oncogene; it has a short half-life, but it is stabilized by binding to is more prevalent in the cell nucleus, the gene shuttles caherin. Although the Apc between the nucleus and the cytoplasm."

The NATO Advanced Study Institute on "Cellular and Molecular Control of Direct Cell Interactions in Developing System" has been attended by 15 invited main lecturers and 60 participants. According to its purpose senior scientists, postdoctoral trainees and graduate students working in areas like biology, biochemistry, electrophysiology, medicine etc . . . could discuss their common interest in the various structural, ultrastructural, molecular and functional aspects of cell interactions in developing in vivo and in vitro systems. Whereas the topics of the first week have been mostly concerned with the general aspects of cell interactions in embryogenesis (section I and II of this book), the second week has been mainly devoted to the structures and functions of the direct cell contact sites at the membrane level as gap junctions, including electrophysiological aspects, dye coupling and selective cell-cooperation in some model systems as the neuro-muscular junctions (section III-V of this book). A multidisciplinary and stepwise approach, from initial cell contacts in early embryogenesis up to well defined selective cell cooperation, appeared to be an efficient means to provide answers to the question of how cells control, in a dynamic system as given in a differentiating embryo, their multiple temporary and permanent interactions so necessary for ordered cell positioning, cell linking and well established cell-to-cell communication.

During October 18-31, 1980, the first course of the Inter- national School of Pure and Applied Biostructure, a NATO Advanced Study Institute was held at the "Et tore Majorana Center for Scien- tific Culture" in Erice, Sicily, co-sponsored by national and international agencies. The subject of the course was "Cell Growth", with participants (from 16 different countries) selected worldwide. The study of cell growth has been one of humanity's most challenging problems and it has been approached from many differ- ent points of view, such as biochemistry, genetic engineering, cell biology, zoology, oncology, immunology, biophysics and a few other fields. It has been very difficult to keep such varied points of view all in one room and in one audience, because of the heterogeneity of background and inherent difficulty of communica- tion, with occasional nominalistic rather than factual debates. This Institute aimed to bypass those limitations by approaching in a structured and tutorial fashion the problem of cell growth in three dimensions: (1) in terms of the various disciplines involv- ed, from molecular to cellular biology, from genetic engineering to clinical oncology, from biophysics to immunology; (2) in terms of the system studied, from prokaryotes to eukaryotes and cancer cells; (3) in terms of the various levels of macromolecular orga- nization, from membrane to cytoskeleton and chromatin.

Advances in Cell Biology has been initiated as a continuing, multi-volume series to report on the progress of a wide spectrum of problems of cell structure and cell func tion. In arranging these volumes individual contributors are asked not only to review the major new information, but especially to present the state of a given problem or area by discussing the current central issues, speculations, concepts, hypotheses, and technical problems. We intend, in addition, that these volumes will not be concerned with comprehensive reviews of the recent literature but will consist rather of presenta tions of an interpretative and integrative nature, based on selection of major research advances. It is our aim that these volumes should provide the means whereby cell biologists may keep themselves reasonably well informed about the current progress in research areas in cell biology in which they are not immediately or directly involved themselves. The articles, nevertheless, are expected to bring into focus the experimental objectives of the specialists in a given research area. D.M.P. L. G. E. M. vii Contents v Contributors Preface vii Bacterial Chromosome Replication 3 I. Peter L. Kuempel 57 2. Structure and Replication of Eukaryotic Chromosomes David M. Prescott Ultrastructure and Interaction of the Kinetochore and Centriole 3.

This volume documents the proceedings of a symposium on "Lung in its Environment" held at the Ettore Majorana 'Center for Scientific Culture, in Erice, Sicily, between 16th June and 21st June 1980. This was attended by about 200 participants drawn from Europe as a whole, but the majority were from Southern Europe. The discussion was recorded either in English or Italian and the tapes were reduced to a verbatim typescript by the Ente Nazionale Interpreti Congresso. The verbatim typescript has been edited using a few guiding principles as follows: - 1. Titles and honorifics have been eliminated unless the statement is addressed to a specific person. 2. The style of the speakers in the discussion has been preserved as far as possible and not reduced to a strictly grammatical format. 3. Where references to illustrations (e.g., on the blackboard) are made, the comments have been left unaltered and many are understandable. Removing them detracted from the sense. 4. The air of informality in the proceedings has been preserved so far as possible. 5. The responsibility for the discussion rests solely with the editors, and no contributor has had the opportunity of correcting what he said. 6. No manuscript was received from two participants, but the discussion of their presentations has been included since it contains some points of substance. 7.

Many factors may influence the release of neurotransmitters from airway nerves 1]. This is likely to be important in physiological control of airway functions and may be particularly relevant in airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Neural elements in airways interact in a complex manner and the activation of certain neural pathways may profoundly influence the release of transmitters from other neural pathways. Similarly inflamma tory mediators released from inflammatory cells in the airways may also modulate neurotransmitter release. There are marked differences be tween species in airway innervation and in neuromodulatory effects and, wherever possible, studies in human airways have been emphasised, although information on neuromodulation in human airways is some what limited at present. Release of neurotransmitters from nerve terminals occurs via a Ca2+ dependent secretion evoked by a nerve action potential, but may also be evoked experimentally by a high extracellular K + concentration which directly depolarises the nerve terminal membrane. Modulation refers to the alteration of neurotransmitter release, which may either be increased (facilitation) or reduced (inhibition) by the action of a particular agent, thus changing the magnitude of the neurally-mediated response. Such agents would normally act on receptors on the nerve terminal which are referred to as pre-junctional (or presynaptic) receptors, in contrast to post-junctional (or post-synaptic) receptors located on the target cells which are influenced by that particular transmitter."

Prior to the emergence of the sliding filament model, contraction theories had been in abundance. In the absence of the kinds of structural and biochemical information available today, it has been a simple matter to speculate about the possible ways in which tension generation and shortening might occur. The advent of the sliding filament model had an immediate impact on these theories; within several years they fell by the wayside, and attention was redirected towards mechanisms by which the filaments might be driven to slide by one another. In terms of identifying the driving mechanism, the pivotal observa tion was the electron micrographic indentification of cross-bridges extending from the thick filaments. It was quite naturally assumed that such bridges, which had the ability to split ATP, were the molecular motors, i.e., that they were the sites of mechanochemical transduction. Out of this presumption grew the cross-bridge model. in which filament sliding is presumed to be driven by the cyclic interaction of cross-bridges with complementary actin sites located along the thin filaments."

The brine shrimp Artemia has become an important experimental system for studies of the developmental process. In recent years the shrimp has yielded considerable information on the pattern of development, bio chemistry, and gene structure and expression of crustaceans. This book is a compilation of research activity from twenty five of the most active re search laboratories working with brine shrimp in the above areas. It also represents the proceedings of a NATO Advanced Research Workshop held in Montreal, Canada, August 11-13, 1988. The book contains twenty nine full papers covering the major areas discussed at the workshop. In addition, one page abstracts representing seventeen poster presentations which were given at the workshop, and which were deemed to be most relevant to the theme of the book, are included. These are designated with an al in the Table of Contents following the title of each paper. A considerable amount of discussion which took place during the workshop has not been included in the book because of space limitations. However, the editors will endeavour to make some of this in formation available at a later date through the Artemia Newsletter. In addition to the high percentage of invited speakers who attended and contributed to the workshop, the organizers would like to thank a number of participants who made valuable contributions to the major dis cussion sessions. These include: John Freeman, Michael Horst, Herman Slegers, Jack Vaughn, Frank Conte, Sandy McLennan, Clive Trotman and Patrick Sorgeloos."

vi The word ppotein, coined one and a half century ago from the 1TpOTE:toa ("proteios" = of primary importance), underlines the "primary importance" ascribed to proteins from the time they were described as biochemical entities. But the unmatched compl~xity of the process involved in their biosynthesis was (understandably) overlooked. Indeed, protein biosynthesis was supposed to be nothing more than the reverse of protein degradation, and the same enzymes known to split a protein into its constituent amino acids were thought to be able, under adequate conditions, to reconstitute the peptide bond. This oversimplified view persisted for more than 50 years: It was just in 1940 that Borsook and Dubnoff examined the thermodynamical aspects of the process, and concluded that protein synthesis could not be the reverse of protein degradation, such an "uphill task being thermody- namically impossible *** * " The next quarter of a century witnessed the unravelling of the basic mechanisms of protein biosynthesis, a predictable aftermath of the Copernican revolution in biology which followed such dramatic de- velopments as the discovery of the nature of the genetic material, the double helical structure* of DNA, and the determination of the ge- netic code. Our present understanding of the sophisticated mechan- isms of regulation and control is a relatively novel acquisition, and recent studies have shed some light into the structure and organi- zation of the eukaryotic gene.

The fetal period of human growth and development has become an area of intense study in recent years, due in large part to the development of diagnostic ultrasound. More than 2,000 articles have been published in the last five years describing anatomy and pathology in utero, as reflected in sonographic images. Yet, no stan dard reference exists to correlate these images with fetal gross anatomy and at tempts to draw parallels from adult structure have often led to false assumptions. The dictum "the newborn is not a miniature adult" is all the more valid for the fetus. This text aims to provide a comprehensive reference for normal sectional anat omy correlated with in utero ultrasound images. In addition, magnetic resonance images of therapeutically aborted or stillborn fetuses are paired with similar gross sections to serve as a foundation upon which current in vivo studies may build. Lastly, a miscellaneous section illustrates several anatomic points useful in the understanding of fetal anatomy. These points include the changing anatomy of the fetal brain during gestation and the anatomy of the meninges, the fetal heart, and ductus venosus. It is our hope that this atlas will provide a clear picture of fetal anatomy, rectify some of the confusion which exists in antenatal diagnosis, and stimulate further interest in fetal development."

In 1980, the IVth International Cyclic Nucleotide Conference was held in Brussels. As this meeting attracted many investigators involved in cyclic nucleotides and calcium role in intracellular regulation, it was thought that this opportunity could be used to organize, prior to the Congress, an in-depth introductory course on the subject. This was carried out as a NATO Advanced Study Institute. The participants included Ph. D. students and M. D. s engaged in a research training, but also fully trained and well known researchers who wanted a refresher course on the whole subject. During the course, most of the participants and lecturers asked to be provided with a text summarizing the basic lectures of the course. This book was therefore conceived as a basic textbook on the regulation and action of intracellular signal molecules, concentrating mainly on cyclic nucleotides and calcium. It was deliberately kept at a basic level. We would therefore be happy if it could be used as an introduction for interested M. D. s or Ph. D. s working in other fields or entering this field and as a general refresher for researchers interested in the subject. For this reason, very general schemes have been asked of the authors, along with reading lists of available reviews rather than extensive bibliographies. The editors should like to thank the NATO Scientific Affairs Committee for having supported the course and Mrs. Gh. Wilmes who prepared the manuscripts. S. SWILLENS J. E.

Since the appearance of photosynthesis on our planet, all living organisms have been facing a new abundant, extremely reactive element, oxygen. This element is used for the synthesis of highly energetic compounds, but can also generate molecules capable of damaging constituents of living structures, including proteins, nucleic acids and lipids. It is therefore no surprise that all biological organisms have evolved multiple and sophisticated ways to reduce the detrimental effects of oxygen. For cells and tissues of highly organized animals, particularly cells of the immune system, superoxidation products play an important role, via oxidative stress, in activation, inflammation and viral and bacterial infections. We must be grateful to Drs. C. Pasquier, C. Auclair, L. Packer and R. Olivier for having brought together many specialists in an international meeting held in Paris in March 1993, at the Ministry of Research. This book comprises an impressive amount of recent knowledge, a real mine for the reader in this fast developing field of research. Furthermore, we should not forget that this basic research may lead in the future to new therapeutic approaches to the most important pathologies of the latter part of this century, including AIDS.