First published in 1986, Professor Tonomura's book explains at the molecular level how cells use energy harnessed as adenosine triphosphate to perform the fundamental physiological functions such as muscle contraction and the active transport of cations. In all cases, ATPases enzymes are involved and the detailed reaction mechanisms are carefully described. Young collaborators helped Professor Tonomura to put together the first draft of the book, for he was particularly anxious that the text should be accessible to students who were less familiar with the intricacies of the field than he himself, and should reflect their needs. After his sudden, untimely death, Professor Ebashi and his colleagues at the National Institute of Physiological Sciences, Okazaki, updated and completed the text. The result is a well-written, interesting account of the field and this volume forms a worthy memorial to one of the foremost workers in this area of biochemical research.

In this unique book, Sir Donald Harrison draws on his wide-ranging experience as a surgeon and comparative anatomist to produce an authoritative and detailed account of the anatomy and physiology of the mammalian larynx. His investigation of the larynx has involved the study of over 1400 specimens of mammalian larynges from around the world, as well as using data from his own clinical experiences. The comparative morphology of the larynx is discussed from a developmental and functional perspective and the involvement of the larynx in respiration, locomotion and vocalisation is highlighted. Throughout the book the relationship of structure to function is drawn out and the clinical relevance of features of the human larynx is emphasised. This book will be an invaluable reference for all researchers and clinicians involved in laryngology as well as for anatomists, zoologists and anaesthesiologists.

The human pancreas consists of two organs in one: the exocrine gland made up of pancreatic acinar cells and duct cells that produce digestive enzymes and sodium bicarbonate, respectively; the endocrine gland made up of four islet cells, namely alpha-, beta-, delta- and PP-cells that produce glucagon, insulin, somatostatin and pancreatic polypeptide, respectively. While the physiological role of exocrine p- creas is to secrete digestive enzyme responsible for our normal digestion, absorption and assimilation of nutrients, the endocrine pancreas is to secrete islet peptide h- mones maintaining our glucose homeostasis. The pancreatic functions are nely regulated by neurocrine, endocrine, paracrine and/or intracrine mechanisms. Thus, dysregulation of these pathways should have signi cant impacts on our health and disease. Nevertheless, the underlying mechanisms by which pancreatic functions are regulated remain poorly understood. Recent basic science and clinical studies con rm myriad physiological and pathophysiological roles of the tissue renin-angiotensin systems (RAS). Of parti- lar interest is the recent identi cation of a local and functional RAS in the pancreas, which in uences both its exocrine and endocrine function. Its role in the pat- genesis of pancreatic diseases including diabetes and pancreatitis is increasingly recognized, as is the therapeutic potential of RAS antagonism: RAS blockade l- its disease progression of type 2 diabetes mellitus and impaired glucose tolerance, and may also protect against pancreatic in ammation.

From humble beginnings over 25 years ago as a lipid kinase activity associated with certain oncoproteins, PI3K (phosphoinositide 3-kinase) has been catapulted to the forefront of drug development in cancer, immunity and thrombosis, with the first clinical trials of PI3K pathway inhibitors now in progress. Here we give a brief overview of some key discoveries in the PI3K area and their impact, and include thoughts on the current state of the field, and where it could go from here

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.

Since 1959, the International Society of Arterial Chemoreception (ISAC) has organized in a variety of countries fifteen scientific meetings devoted to the mechanisms of peripheral arterial chemoreception and chemoreceptor reflexes. After the meeting held in Philadelphia with Sukhamay Lahiri as president, ISAC membership elected Lyon (CNRS, University Claude Bernard, France) as the site of the xv" ISAC Symposium. The Symposium was effectively held in Lyon from the 18th to the 22nd of November 2002 and Jean-Marc Pequignot was its president. The organizers were Jean-Marc Pequignot and Yvette Dalmaz Lyon (CNRS, University Claude Bernard, France) and the Scientific Committee was formed by John Carroll (University of Arkansas for Medical Sciences, USA), Constancio Gonzalez (University of Valladolid, Spain), Prem Kumar (University of Birmingham, U. K. ), Sukhamay Lahiri (University of Pennsylvania, Philadelphia, USA), Colin Nurse (McMaster University, Hamilton, Ontario, Canada), and Nanduri Prabhakar (Case Western University, Cleveland, Ohio, USA). The Symposium in Lyon intended to follow the path opened in Philadelphia gathering people working at the interface of cellular and molecular biology with researchers in the more classical topics of chemoreception pathways and reflexes. The aim was to join experts with different perspectives. Along these lines, some participants are engaged in the exploration of the intimate mechanisms of oxygen sensing and cellular responses, with their work centered in a great number of preparations covering a broad spectrum from bacteria, to chemoreceptor cells or to central nervous systems neurons.

and made insignificant in practice, by selecting for study simple kinds of ex periences which are devoid of emotional content and which can be tested for reliability. A simple somatosensory ''raw feel" fulfills these characteristics (see papers nos. 2,5). In any case, if we fail to find ways to use introspective reports in convincingly acceptable studies we would give up the ability to investigate the relation between conscious experience and neural activity, something warned against by William James (Krech, 1969). Another factor in the dearth of direct experimental studies is, of course, the comparative inaccessibility of the human brain for such purposes. Meaningful investigations of the issue in question requires simultaneous study of brain events and introspective reports of experiences in an awake, cooperative human subject. Analysis by neuropsychologists of pathological lesions in the brain and the related disturbances of conscious functions have contributed much to mapping the pos sible representations of these functions. The non-invasive recording of electrical activity with electrodes on the scalp, starting from Berger's initial EEG record ings in 1929, has contributed much to the problems of states of consciousness and to various cognitive features associated with sensory inputs, but not as much to the specific issue of conscious experience."

Knowledge about the structure and function of the inner ear is vital to an understanding of vertebrate hearing. This volume presents a detailed overview of the mammalian cochlea from its anatomy and physiology to its biophysics and biochemistry. The nine review chapters, written by internationally distinguished auditory researchers, provide a detailed and unified introduction to sound processing in the cochlea and the steps by which the ensuing signals are prepared for the central nervous system.

More than 70 years have elapsed since U. S. von Euler and I. H. Gaddum dis- covered an unidentified depressor substance in the brain and gut. The effects of the powdery extracts were marked as 'P' on the kymograph tracings, and the nondescript name of 'substance P' still carries the breath of this adventurous period. In the 1960s, substance P returned in another disguise, staging as a hypothalamic peptide that causes copious salivary secretion (see chapter by F. Lembeck and I. Donnerer). This time, though, the mysterious substance was tracked down by S. E. Leeman and her collaborators as an undecapeptide, after it had eluded its identification for some 40 years. Substance P turned out to be the mammalian counterpart of a family of peptides which had been extracted from amphibian and nonvertebrate species and which had been given the name 'tachykinins' by V. Erspamer. Soon novel members of this peptide family were discovered, and in mammals substance P was joined by neurokinin A and neu- rokinin B. The presence of tachykinins in frog skin as well as in venoms and toxins of microbes and arachnids raises the possibility that these peptides re- present an old system of biological weapons that have been transformed to a particular messenger system in mammals.

This volume explores all aspects of vascular biochemistry and includes chapters that provide an understanding of vascular function with descriptions of tissue components present in the vascular wall as well as an exploration of the hemodynamic and metabolic activities associated with this function. In addition, some chapters explore the vasculature under conditions which mimic various disease states. The information provided in this volume will provide new insights into the mechanisms that control vascular function as well as therapies designed to treat vascular disease.

Hypoxia, defined as reduced oxygen tension, is a common physiological phenomenon in both normal embryonic development and malignancy progression. Although severe hypoxia is generally toxic for both normal tissue and tumors, neoplastic cells gradually adapt to prolonged hypoxia though additional genetic and genomic changes with a net result that hypoxia promotes tumor progression and therapeutic resistance. Hypoxia promotes cancer progression by regulating various aspects of cancer biology, including radiotherapy resistance, metabolism, angiogenesis and invasion/migration.

First published in 1989, this volume presents a detailed series of scientific reviews concerned with most of the key areas of dog and cat nutrition; for example, the volume surveys and provides data on protein and energy requirements, calcium metabolism and essential fatty acids. It shows the substantial developments in knowledge that have occurred in the subject and discusses potential trends. The volume is an expanded, updated and edited version of papers originally presented at the Seventh Waltham Symposium on advances in dog and cat nutrition, held at Queens' College Cambridge in 1985. This is a comprehensively reference volume in a subject which is scientifically challenging and of immense practical importance. The volume will provide an essential source of reference and information for practitioners and students of veterinary medicine and for nutritionists and food research scientists in academia and industry.

Diabetes is an autoimmune, inflammatory disease affecting many different organ systems and exhibiting both primary and secondary defects. Because diabetes affects a wide range of cellular systems, a multidisciplinary effort has been mounted over the past several decades using a wide range of investigative techniques and methodologies in order to identify molecular mechanisms responsible for cellular dysfunction. Because primary defects at various levels of sub-cellular signaling, intracellular calcium handling, protein expression and energy regulation are often a primary consequence of diabetes. This volume is a compilation of new multidisciplinary research that will broaden our current understanding of diabetes and cardiovascular disease as well as provide the basis for the development of novel therapeutic interventions.

This monograph evolved from years of research into the auditory pathway and hearing of many species of marsupials. Its function is to give biologists, in par ticular neurobiologists, a broad description and review of what is known of the auditory sensory capacities and processing mechanisms in this large order of mammals. My initial interest in marsupials developed from collaborative work with Dr. Richard Gates at Monash and Melbourne Universities in the 1970s and by curiosity as to whether concepts about the auditory system was stimulated stemming from experiments mainly on domestic cats could be extended to mam mals of other orders. My subsequent interest in Australian marsupials, aroused by collaboration with Dr. John Nelson at Monash University in the 1980s and 1990s, concerned their auditory systems and behavior per se and not as primitive cousins of eutherians. More recently, I have collaborated with Dr. Bruce Masterton at Florida State University in studies of New World marsupials. His sad death in 1996 has robbed neurobiologists of one of our most provocative thinkers and hypothesis testers. I would like to thank the Department of Physiology at Monash University for making many facilities available to me, the National Health and Medical Research of Australia and the Australian Research Council for providing funds for Council research, and Jill Poynton and Michelle Mulholland, who illustrated this volume."

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.

Parameters such as membrane transport, metabolism and protein incorporation govern the fate of amino acids in living tissue. Is it possible to use positron tomography to measure some of them, and what is their meaning in normal and pathological situations? These questions have been addressed for a long time and no satisfactory answer has yet been given. This book, which derives from an EEC workshop organized in the frame of the Concerted Action on PET Investigation of Cellular Regeneration and Degeneration', held in Lyon in February 1992, gives the present state of knowledge in this field based on the most recent studies. Contributions from 24 leading European and American scientists are presented and discussed in the following four parts: biochemistry and animal studies; amino acids labelling with positron emittors, quality control and metabolites measurement; kinetic modelling of amino acids transport, metabolism, and protein incorporation; clinical use of amino acids. This book will aid and interest biochemists, radiochemists, pharmacologists, neurologists, oncologists and medical imaging scientists.

This, the 148th volume of the Handbook of Experimental Pharmacology series, focuses on the very core of pharmacology, namely receptor theory. It is fitting that the originator of receptor pharmacology, A. J. CLARK, authored the fourth volume of this series 63 years ago. In that volume CLARK further developed his version of receptor theory first described four years earlier in his classic book The Mode of Action of Drugs. An examination of the topics covered in volume 4 reveals a striking similarity to the topics covered in this present volume; pharmacologists today are still as interested in unlocking the secrets of dose-response relationships to reveal the biological and che mical basis of drug action as they were over half a century ago. Sections in that 1937 volume such as "Curves relating exposure to drugs with biological effects" and "Implications of monomolecular theory" show Clark's keen insight into the essential questions that required answers to move pharma cology forward. With the advent of molecular biological cloning of human receptors has come a transformation of receptor pharmacology. Thus the expression of human receptors into surrogate host cells helped unlock secrets of receptor mechanisms and stimulus-transduction pathways. To a large extent, this elim inates the leap of faith required to apply receptor activity of drugs tested on animal receptor systems to the human therapeutic arena. However, a new leap of faith concerning the veracity of the effects found in recombinant systems with respect to natural ones is now required.

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."

The study and modulation of cortical connections is a rapidly growing area in neuroscience. This unique book by prominent researchers in the field covers recent advances in this area. The first section of the book describes studies of cortical connections, modulation of cortical connectivity and changes in cortical connections with activities such as motor learning and grasping in primates. The second section covers the use of non-invasive brain stimulation to study and modulate cortical connectivity in humans. The last section describes changes in brain connectivity in neurological and psychiatric diseases, and potential new treatments that manipulate brain connectivity. This book provides an up-to-date view of the study of cortical connectivity, and covers its role in both fundamental neuroscience and potential clinical applications.

Electric currents and electromagnetic fields have been applied to biological systems, particularly humans, with both therapeutic and pathological results. This text discusses biological responses to electric currents and electromagnetic fields, including medical applications and shock hazards. It covers fundamental physical and engineering principles of responses to short-term electrical exposure and emphasises human reactions, although animal responses are considered as well, and the treatment covers reactions from the just-detectable to the clearly detrimental. An important new chapter discusses standards for human exposure to electromagnetic fields and electric current and demonstrates how these standards have been developed using the principles treated in earlier chapters.

Ghrelin, the endogenous ligand for the growth hormone secretagogue (GHS) receptor, is critical in the control of food intake and energy balance. The ghrelin receptors are now known to have important physiological properties as modulators of growth hormone release, appetite, glucose homeostasis, metabolism, immune function, neurotransmitter activity, cognitive function and neurodegeneration. Bringing all of this information together in the first comprehensive text on the topic, Ghrelin in Health and Disease provides a state-of-the-art synthesis of the latest work in this area for physicians and physician-scientists. This volume addresses the unique property of ghrelin as a modulator of function. Such a property provides potential utility for safe intervention in a wide variety of disease states. Indeed as we learn more about the basic physiology of ghrelin, the potential for treating new disease targets emerge requiring validation in the clinic. Each chapter in this volume is authored by a leading investigator in the field. The introductory chapter sets the background for the book and provides a superb overview of the relevance of ghrelin to physiology, describing how the discovery of ghrelin has prompted us to completely rethink traditional physiology. The authors conclude their chapters by critically addressing the future translational aspects of ghrelin biology and outlining what key basic research and clinical questions remain to be addressed. An invaluable resource, Ghrelin in Health and Disease distinguishes itself as the first comprehensive title covering all of the molecular and clinical issues relating to ghrelin and advancing our clinical understanding of obesity, growth, and reproductive pathogenesis.

Arterial chemoreceptors are unique structures which continuously monitor changes in arterial blood oxygen, carbon dioxide, glucose, and acid. Alterations in these gases are almost instantaneously sensed by arterial chemoreceptors and relayed into a physiological response which restores blood homeostasis. Arterial Chemoreception contains updated material regarding the physiology of the primary arterial chemoreceptor; the carotid body. Moreover, this book also explores tantalizing evidence regarding the contribution of the aortic bodies, chromaffin cells, lung neuroepithelial bodies, and brainstem areas involved in monitoring changes in blood gases. Furthermore this collection includes data showing the critical importance of these chemoreceptors in the pathophysiology of human disease and possible therapeutic treatments. This book is a required text for any researcher in the field of arterial chemoreception for years to come. It is also a critical text for physicians searching for bench-to-bedside treatments for heart failure, sleep apnea, and pulmonary hypertension.

Skeletal muscle consumes significant amounts of oxygen, and its oxygen flux increases significantly under conditions of exercise and muscle contraction. This makes the muscle vulnerable to oxidative stress since concomitantly with the increase of oxygen flow there is an increase of free oxygen radicals which are a byproduct of muscle respiration. A number of studies in the last decade have documented the involvement of free oxygen radicals in exercising muscles. The consequences of muscle oxidative stress have resulted mainly in increased muscle protein oxidation, elevation of lipid peroxidation, and depletion of muscle antioxidants. The mechanisms of this oxidative stress are under extensive investigation in laboratories around the world and are topics of the chapters in this volume. This book is intended for professionals who are interested in muscle function, physiology, pathophysiology and well-being, such as therapists, trainers and medical professionals as well as for researchers in the field of muscle physiology.

"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.

Proceedings of an International Workshop held in Sheffield, UK, September 1-4, 1997