Muscarinic acetylcholine receptors have played a key role in the advancement of knowledge of pharmacology and neurotransmission since the inception of studies in these fields, and the effects of naturally occurring drugs acting on muscarinic receptors were known and exploited for both therapeutic and non-therapeutic purposes for hundreds of years before the existence of the receptors themselves was recognized. This volume presents a broad yet detailed review of current knowledge of muscarinic receptors that will be valuable both to long-time muscarinic investigators and to those new to the field. It describes the detailed insights that have been obtained on the structure, function, and cell biology of muscarinic receptors. This volume also describes physiological analyses of muscarinic receptors and their roles in regulating the function of the brain and of a variety of peripheral tissues. This volume shows how the study of muscarinic receptors continues to provide new and surprising insights not just to the cholinergic system but to the broad areas of neurobiology, cell biology, pharmacology, and therapeutics.

Apoptosis is a fascinating concept for the basic scientist. This is not only because of the multifaceted variety of proposed and discovered mechanisms, but because apoptosis represents a fundamental pathway for cell renewal. The study of apoptosis has resulted in an array of discoveries on signal transduc tion and downstream effects that have facilitated and advanced many fields in biology, including research on cancer and other diseases. Thus, the apoptotic process can be viewed as the largest effort of the scientific community to understand how cells work and tissues assemble or remodel. The most direct consequence of this accumulated knowledge is a greater understanding of disease and pathological mechanisms. The end result of these efforts will be significant contributions to health and the adoption of new, never anticipated, therapeutic approaches. This book represents the summation of considerable effort from a significant group of contributors from all over the world as well as from its editors. In this fashion, many viewpoints have been collected and SUbjected to thorough academic discussion. The concepts contained in this medically important volume will stimulate and renew the ideas of scientists and indeed, will generate additional work to advance biological knowledge even further. The emphasis of this volume cements what has been established, adds what has not been explored fully, and creates a fertile ground for further hypotheses that will lead to a more complete understanding of the apoptotic process."

A review of the current state of the clinical and basic science of the pharmacology of sleep. The information provided ranges from a historical perspective to current concepts of sleep mechanisms, including the interaction between pharmacology and sleep-wake regulation and between chronopahrmacology and sleep-wake rhythms. For the first time in one single volume, both the basic mechanisms of sleep, and the basic and clinical aspects of the pharmacology of sleep are dealt with in a thorough, comprehensive and authoritative manner. The chapters, written by the foremost scientific authorities in this field, integrate the latest information on the basic mechanisms of drugs as they relate to their effects on sleep.

Adopting an interdisciplinary approach to the chemistry and physics of materials, their biocompatibility, and the consequences of implantation of such devices into the human body, this text introduces readers to the principles of polymer science and the study of metals, ceramics and composites, and also to the basic biology required to understand the nature of the host-transplant interface. Topics covered include the macromolecular components of cells and tissues, self-assembly processes, biological cascade systems, microscopic structure of cells and tissues, immunology, transplantation biology, and the pathobiology of wound healing. The materials science section includes the structures and properties of polymers, metals, ceramics and composites, and the processes for forming materials as well as the pathobiology of devices. The final two chapters deal with tissue engineering and the relations between the biology of cells and tissue transplantation, and the engineering of tissue replacements using passaged cells.

A presentation of the most elementary form of pulsatile flow as an important prerequisite for the study of other flow applications in biological systems. The book provides in a single source a complete treatment of the fluid dynamics of flow with the required mathematics and emphasis on the basis mechanics. The style and level of this book make it accessible to students and researchers in biophysics, biology, medicine, bioengineering and applied mathematics working in theoretical and clinical work on the cardiovascular system, as well as in the design of new instrumentation, medical imaging systems, and artificial organs. With problems and exercises.

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.

RNA technologies are the driving forces of modern medicine and biotechnology. They combine the fields of biochemistry, chemistry, molecular biology, cell biology, physics, nanotechnology and bioinformatics. The combination of these topics is set to revolutionize the medicine of tomorrow. After more than 15 years of extensive research in the field of RNA technologies, the first therapeutics are ready to reach the first patients. Thus we are witnessing the birth of a very exciting time in the development of molecular medicine, which will be based on the methods of RNA technologies. This volume is the first of a series. It covers various aspects of RNA interference and microRNAs, although antisense RNA applications, hammerhead ribozyme structure and function as well as non-coding RNAs are also discussed. The authors are internationally highly respected experts in the field of RNA technologies.

This drug is a landmark discovery, which consequently has become the definitive therapy for the treatment of erectile dysfunction (ED). Following the major breakthrough in the field of nitric oxide (NO)-physiology and pharmacology leading to sildenafil being marketed, the most current information is presented in this reference book, including ongoing research from several disparate groups about NO as endothelium-derived relaxing factor (EDRF) and also as a neurotransmitter for nerves innervating erectile tissue in mammals.

The development of sildenafil as an oral phosphodiesterase-5 (PDE5) inhibitor drug for the treatment of ED resulted in one of the first products, which made its way successfully from basic NO research to routine clinical therapy.

This volume addresses all fields of sildenafil application in both men and women. In a highly competitive research environment with a critical medical need for drug improvements the reader will learn more about clinical resistance to sildenafil treatment and the modalities to overcome the failure rates.

The individual chapters cover clinical use, pharmacokinetics, pharmacodynamics, biochemistry, and cultural aspects. They are written by leading experts in their respective fields. Therefore, readers whether professionals in the pharmaceutical industry, physicians treating ED, biochemists, chemists or pharmacologists will find a detailed and up-to-date knowledge base about current research activities and an excellent overview for further research on this compound class and its cultural impact."

Recent research suggests that adult growth hormone (GH) deficiency, whether of pathological or physiological origin, is associated with a dis tinct syndrome that includes alterations in body composition, endocrine metabolic function, immune competence, and physical and psychosocial well-being. Not surprisingly, substantial investigative effort is currently focused on validating the above hypothesis and on determining whether restoration of a normal GH-IGF-I axis in various states of adult GH deficiency is clinically useful, safe, and cost-beneficial. This book contains the proceedings from the Symposium on GHRH, GH, and IGF-I: Basic and Clinical Advances, held December 9 to 12, 1993, in San Diego, California, and sponsored by Serono Symposia USA, Inc. The conference was meant to highlight selected novel and exciting clinical research developments related to possible therapeutic uses of recombinant human GH and IGF-I, GHRH, GH releasing peptides, and related GH secretagogues. This meeting occurred only one year after a similar Serono symposium that was somewhat more oriented to novel basic science discoveries, thus attesting to the current scientific and clinical interest in this area.

Chronic obstructive pulmonary disease (COPD) ranges amongst the commonest diseases in the world. The relentless progression of the disease causes a pressing need for a better understanding of and therapies for COPD. This volume provides state-of-the-art information on the pathophysiology of COPD including an outlook on new therapies. It is of interest to researchers and clinicians in academia as well as in the pharmaceutical industry.

"Nitric Oxide and Free Radicals in Peripheral Neurotransmission" is a welcome addition to the literature and describes current research into the role of nitric oxide in the peripheral nervous system and its associated organs. Topics covered range from general consideration of nitrergic transmission, in its broadest sense, to elaboration of our current understanding of the role of nitric oxide in transmission in individual peripheral organs, including its role as a backup, or alternate as well as chief transmitter. The influence of nitric oxide and related compounds on the more conventional modes of autonomic transmission are also considered. Aimed at students and researchers in the areas of neuroscience and physiology, "Nitric Oxide and Free Radicals in Peripheral Neurotransmission" also covers the emerging role of abnormal nitric oxide function in disease states and, where appropriate, as potential avenues of therapy.

Physiological, pharmacological and molecular biological data generated over the past three decades have demonstrated the existence of two major families of extracellular receptors, the P1, a family of four G-protein coupled receptors and the P2, a family of at least 12 receptors responsive to purine (ATP, ADP) and pyrimidine (UTP) nucleotides through which adenosine and ATP can function as extracellular messengers. The present two-part volume represents an integrated compendium of invited chapters by leading researchers in the area focusing on advances in the understanding of purinergic and pyrimidinergic signaling systems, their role(s) in tissue function and pathophysiology and advances in developing potential new medications based on the modulation of P1 and P2 receptor signaling processes. The volumes will thus provide the reader with a topical, comprehensive and integrated overview of this important area.

Most of the following chapters were presented as plenary lectures or symposium talks at the 1986 XXXth Congress of the International Union of Physiological Sciences in Vancouver, B.C. A distinguished international group of endocrinologists and physiologists have contributed up-to-date reviews of their particular fields. The early chapters are largely concerned with the brain and neuroendocrine mechanisms controlling the secretion of gonadotropin releasing hormone (GnRH) and its action on the anterior pitui- tary gland. Later chapters focus on the gonads themselves and the systemic and intrinsic hormones influencing the functional cytology of ovarian and testicular cells. Such comprehensive subjects as sex differentiation, puberty, placentation and parturition are also discussed authoritatively. According to Pfaff and Cohen and Arai et al., gonadal steroids, especially estrogen, exert multiple effects on certain hypothalamic and preoptic neurons, including growth, protein synthesis and electrical changes, which promote plasticity and facilitate synaptogenesis. The electrophysio- logy of the hypothalamic GnRH pulse generator in the rhesus monkey is reviewed more specifically by Knobil. In ovariectomized ewes, Clarke finds both positive and negative effects of estrogen on hypothalamic release of GnRH as well as on pituitary responsiveness to the peptide. Flerk6 et al.

Pulmonary Biology in Health and Disease was conceived as a companion to a handful of expensive, multivolume textbooks. This is part of the promising trend to publish shorter textbooks on the subjects of lung biology and remodeling. Whoever is familiar with human biology and the far-reaching consequences of the genome and postgenome revolutions is apt to concede that the centerpiece in remodeling lies in the ?eld of m- ecular cardiobiology. The ?eld of molecular cardiobiology includes the syndrome of chronic heart failure as well as ischemic cardioprotection. By analogy, the centerpiece in pulmonobiology is chronic asthma. Key topics in the present volume include s- naling mechanisms regulating the endothelium and smooth muscle cells,in?ammatory cells, mediators, airway surface liquid, and pharmacological therapy that focuses on how in?amed airways are altered. Written primarily for predoctoral and postdoctoral graduates in the basic medical sciences, the medical student and postdoctoral physician, graduates in the allied s- ences, nurses, pulmonologists, and physicians in critical care medicine, this book p- vides many of the fundamentals of contemporary pulmonology. It is divided into several parts devoted to the control of respiration, arterial chemoreceptors,muscles of ventilation, pulmonary physiology, and gas exchange in health, exercise, and disease. Special emphasis is placed on emphysema and its pathobiology, acute lung injury, asthma and inhaled toxicants. Because the ?eld is always evolving, each chapter includes recommended readings that lead the reader to sources of additional information, such as the review on remodeling of the blood gas barrier by West and Mathieu-Costello.

This book offers a mathematical update of the state of the art of the research in the field of mathematical and numerical models of the circulatory system. It is structured into different chapters, written by outstanding experts in the field. Many fundamental issues are considered, such as: the mathematical representation of vascular geometries extracted from medical images, modelling blood rheology and the complex multilayer structure of the vascular tissue, and its possible pathologies, the mechanical and chemical interaction between blood and vascular walls, and the different scales coupling local and systemic dynamics. All of these topics introduce challenging mathematical and numerical problems, demanding for advanced analysis and efficient simulation techniques, and pay constant attention to applications of relevant clinical interest. This book is addressed to graduate students and researchers in the field of bioengineering, applied mathematics and medicine, wishing to engage themselves in the fascinating task of modeling the cardiovascular system or, more broadly, physiological flows.

F. Schweda and A. Kurtz: Regulation of Renin Release by Local and Systemic Factors M. Krauss and V. Haucke: Shaping Membranes for Endocytosis B.M. Jockusch and P.L. Graumann: The Long Journey: Actin on the Road to Pro- and Eukaryotic Cells B. Colsoul, R. Vennekens and B. Nilius: Transient Receptor Potential (TRP) Cation Channels in Pancreatic ss cells

Mathematical modelling of physiological systems promises to advance our understanding of complex biological phenomena and pathophysiology of diseases. In this book, the authors adopt a mathematical approach to characterize and explain the functioning of the gastrointestinal system. Using the mathematical foundations of thin shell theory, the authors patiently and comprehensively guide the reader through the fundamental theoretical concepts, via step-by-step derivations and mathematical exercises, from basic theory to complex physiological models. Applications to nonlinear problems related to the biomechanics of abdominal viscera and the theoretical limitations are discussed. Special attention is given to questions of complex geometry of organs, effects of boundary conditions on pellet propulsion, as well as to clinical conditions, e.g. functional dyspepsia, intestinal dysrhythmias and the effect of drugs to treat motility disorders. With end of chapter problems, this book is ideal for bioengineers and applied mathematicians.

Strong body odor is a condition for which, until now, there have been few treatment methods. The Japanese authors, encouraged by the willingness of Oriental patients to undergo radical treatment, have developed the subcutaneous tissue shaving method, which eliminates the condition in a very short period of time without ugly scarring. The book Human Body Odor not only introduces the completely new subcutaneous tissue shaving method, it also questions conventional theories on the hair cycle itself and throws a new hypothesis about the process of hair generation and regeneration into the scientific arena. This could even lead in the future to a formula for retarding hair loss! Developed over the past twenty years, the authors' new surgical method for the radical treatment of bromidrosis represents a landmark in cosmetic surgery and dermatology!

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."

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."

This volume was originally published in 1982. Ergonomics is the study of people, primarily in relation to their work, but also with reference to transport, sport and leisure activities. The general purposes of this book were to apply to ergonomics the established principles of anatomy, physiology and psychology and to provide a comprehensive textbook and source of information in this area.

The study of membrane traffic in reconstituted cell-free systems has generated an unprecedented amount of new information on the biochemistry, molecular biology and genetics of membrane-based molecular events that underly normal and abnormal cellular function. Many of the individual steps have now been isolated and dissected in simple systems that permit detailed molecular analyses of transport mechanisms and their regulation. Reconstituted events of intercompartment transport include inter-membrane recognition, and controlled membrane fusion-fission reactions. Among the many advances is the growi ng awareness of a remarkabl e evolutionary conservation of many of the components involved in the many steps of membrane traffic, this realization has accelerated greatly the pace of progress in the field. This book provides a collection of participant contributions from the 1992 Summer Research Conference, "Mol ecul ar Mechani sms of Membrane Traffi c, " jointly sponsored with NATO by the American Society of Cell Biology. The conference was held May 9-13, at the Airlie Conference Center in the Virginia countryside, near Warrenton. The conference was attended by 158 scientists. A unique feature was the high proportion of young scientists among the participants. Approximately 65% were students, postdoctoral fe 11 ows and young investigators. Each attendee contri buted to the conference with either a pl atform or poster presentation.

(Chapters 11 to 14) summarise important features of the biological clock at the level of whole animal covering all vertebrate classes (fish to mammal). Chapters 15 and 16 are on long term (seasonal) rhythms in plants and higher vertebrates. Short term rhythms (ultradian rhythms), the significance of having a clock system in animals living in extreme (arctic) environments, and the diversity of circadian responses to melatonin, the key endocrine element involved in regulation of biological rhythms, have been discussed in Chapters 17 to 19. Finally, a chapter on sensitivity to light of the photoperiodic clock is added which, using vertebrate examples, illustrates the importance of wavelength and intensity of light on circadian and non-circadian functions. A well-known expert writes each chapter. When presenting information, the text provides consistent thematic coverage and feeling for the methods of investigation. Reference citation within the body of the text adequately reflects the literature as subject is developed. A chapter begins with an abstract that enables a reader to know at the first glance the important points covered in that chapter. The chapter concludes with a full citation of references included in the text, which could be useful for further reading. The book ends with a comprehensive subject index that may be useful for quick searches.

This book is a survey of some aspects of current knowledge on regional Cerebral Blood Flow (rCBF), mainly as studied by the isotope clearance method. Although both theoretical and methodological problems are discussed, attention is mainly dedicated to data obtained from clinical studies. The papers which make up this book were presented at the International Symposium on the Clinical Applications of Isotope Clearance Measurement of Cerebral Blood Flow, held in Mainz, Western Germany, on April 10-12, 1969. The previous meetings on Cerebral Blood Flow, held in Lund in 1964* and in Lund and Copenhagen 1968**, had shown that the moment had come to concentrate on the possibilities of introducing rCBF measurements into clinical routine. This is why in the Mainz Symposium attention was initially focused on methodological aspects. This is also why theoretical problems of physiology of CBF were not emphasized. Finally, this explains why such topics as cerebrovascular disease, head trauma, coma, carotid surgery, brain tumors and intracranial pressure were given pride of place. However a survey of the clinical aspects of rCBF measurements would not be complete without an account of the application of such measurements to monitor cerebral circulatory changes during anesthesia and therapeutic procedures like, for instance, hyperventilation and hyperbaric treatment. Furthermore, it is now possible to obtain data from correlative rCBF studies per formed before, during and after surgical operations on the human brain."