While emphysema and chronic bronchitis are primarily lung di seases, one of their major consequences is to deeply affect the function of the respiratory muscles. Lung hyperinflation shortens the inspiratory muscles due to increased airways resistance, more of their effort is demanded and changes in nutritional status wea ken them further. Their malfunction can lead to severe dyspnea and to failure of the ventilatory pump. Over the last 10 years we have witnessed an explosion of information of how respiratory muscles function in health and disease, new techniques for their evaluation have been created, the concept of fatigue, weakness, and failure was developed, and their rest or training was attemp ted. The implication of respiratory muscles malfunction in respi ratory medicine has reached a prominent place. It seems remarkable that while some aspect of skeletal muscles function requires molecular biology techniques to find new an swers, we still know little on respiratory muscles interaction, stra tegies of coordination, their role in dyspnea, chronic hypercapnia or how to effectively improve their function in patients. This workshop was organized and held at the Medical Center of Rehabilitation in Montescano and represents an attempt to focus on how the newly adquired wealth of information can eventually be trasformed into medical care. The particpants in this workshop brought forward challenging thoughts and we are most grateful for their participation. This book represents a report of the proceedings and also provides the most updated information in this field.

This volume contains the manuscripts of the full papers and posters pre- sented at the conference "Dietary Phenylalanine and Brain Function," which took place at the Park Hyatt Hotel, Washington, D.C., on May 8-10, 1987. The conference was organized by a committee that included Drs. Louis Elsas (Emory University, Atlanta), William Pardridge (UCLA), Timothy Maher (Massachusetts College of Pharmacy), Donald Schomer (Harvard), and Richard Wurtman (MIT). It was sponsored by the Center for Brain Sciences and Metabolism Charitable Trust, a foun- dation which, during the past few years, had also organized seven other conferences related to interactions between circulating compounds (drugs, nutrients, hormones, toxins) and brain function. The Center's most recent other conferences were on "Melatonin in Humans" (Vienna, Austria; November 1985) and "The Pharmacology of Memory Disorders Associ- ated with Aging" (Zurich, Switzerland; January 1987). The decision to organize this conference was based on the perception that major changes had recently occurred in society's uses of phenylalanine and phenylalanine-containing products, and on the belief that a meeting of scientists and physicians who work on the amino acid's neurological effects could both catalyze additional research on these effects and assist regula- tory bodies in formulating appropriate public policies relating to the use of these products: phenylalanine, in both its L- and D-forms, has apparently become a popular sales item at "health-food" stores, and thus is now being consumed by a fairly large number of people, in the absence of the other

Morphology and physiology are two fields which cannot be separated. This statement needs to be amplified: purely factual results of a morphological or physiological nature only have real value when they are gained in the context of certain guiding, embracing questions. By themselves they are mostly of little value, because only a guiding hypothesis or theory is of any importance. Equally, a physiological question will always raise questions as to the morphological substrate, and vice versa. Thus, Wiedemann's discovery, for instance, that the visual cells in each ommatidium of the dipterans have differing fields of vision has revived the question as to what the optical properties of individual visual cells, and the complete ommatidium, might be and how neighboring ommatidia interact. These questions in turn led to that of the morphological, neuronal wiring diagram of the visual cells in the optical ganglia. Within the realm of invertebrates, the morphological and physiological problems of visual perception have been resolved in very different ways on various levels, from the photo receptor to higher centers; despite many investigations, however, there remain unsolved problems. The first chapter of Vol. VII/6B deals with the neuroarchitecture in the visual system of two groups: crustaceans and insects. These systems are best known through recent investigations. The second chapter is devoted to the neural principles in the visual system of insects. It could not have been written without parallel research into morphology."

This volume emphasizes the comparative approach to under standing vertebrate renal function. I am convinced that this approach is of particular value in understanding both the details of renal function at the cellular and subcellular levels and the renal role in regulating fluid volumes and solute concentrations. My exposure to this approach first occurred during a student research experience in the laboratory of Wilbur H. Sawyer, who also provided an introduction to the works of Homer W. Smith and August Krogh. The importance of this approach was reinforced by doctoral and postdoctoral research in the laboratory of Bodil Schmidt-Nielsen. It has been confirmed through years of personal experience since then. My research and my understanding of renal function have been aided through the years by collaboration and discussion with numerous students and associates. Of particular impor tance in developing my views on comparative renal function, and especially on the relationship of structure to function, has been my long association with my colleague and friend, Eldon J. Braun. Donald S. Farner, who suggested the writing of this volume, provided valuable editorial assistance. Much of my personal research in this area has been supported over the years by grants from the United States National Science Foundation and National Institutes of Health. The writing of this volume was completed while I was in Wiirzburg, Federal Republic of Germany, supported by a Senior U.S. Scientist Award from the Alexander von Humboldt Foundation."

Several methods have been used to demonstrate the vasculature of different organs in man and other species. Many attempts to evaluate the precise microangioarchitecture of organ systems remained unproductive, others were controversial. The development of electron microscope in thirties opend new perspectives in researching microvascular systems. Transmission electron microscopy provided a two-dimensional view on microcirculatory system at higher magnifications, however, its standardization was delayed unnecessarily. The use of methyl methacrylate and related compounds for obtaining replicas of vascular beds, and their study in scanning electron microscope opened a new window in micromorphological research. For the first time, a three-dimensional image analysis of the vascular system was possible. The microvascular corrosion casting method has meanwhile attracted the interest of many contemporary scientists. Its application to medical and biological problems justify it to be used as a routine method for microvascular investigations. The first investigators who used this method, focused either on methodological details or they dealt with the normal microanatomy of organs. The advantages of this method in demonstrating pathological microvascular patterns are also evident.

We are pleased to present to our readers the Proceedings of the Second International Symposium "Proteases: Potential Role in Health and Disease" which was held in Rothenburg ob der Tauber (FRG) during May 17-20, 1987. The topics discussed included those dealing with the physiology and pathophysiology of proteases and their inhibitors, the inter- actions of proteases and hormones, the kallikrein-kinin, com- plement and coagulation system, the function of proteases in arthritis, malignoma, pancreatitis, intestinal tract, lung and kidney disease as well as in hypercatabolic states (acute renal failure, multiple trauma and septicemia). Furthermore some reports dealed with the role of proteases during extracorporeal circulation. The papers presented answered many questions, but raised many more concerning the significance of proteases and their in- hibitors in clinical medicine. It was unfortunately impossible in this volume, to include the extended, lively and stimulating discussions which were enjoyed by the participiants during the conference. The meeting has provided a unique framework for close inter- action between scientists from various disciplines, including molecular biology, biochemistry, physiology, surgery, anaesthe- siology, endocrinology, hematology, pneumatology and nephrology.

Having received the invitation from Springer-Verlag to produce a volume on drug-induced birth defects for the Handbook of Experimental Pharmacology, we asked ourselves what new approach could we offer that would capture the state of the science and bring a new synthesis of the information on this topic to the world's literature. We chose a three-pronged approach, centered around those particular drugs for which we have a relatively well established basis for understanding how they exert their unwanted effects on the human embryo. We then supplemented this information with a series of reviews of critical biological processes involved in the established normal developmental patterns, with emphasis on what happens to the embryo when the processes are perturbed by experimental means. Knowing that the search for mechanisms in teratology has often been inhibited by the lack of understanding of how normal development proceeds, we also included chapters describing the amazing new discoveries related to the molecular control of normal morphogenesis for several organ systems in the hope that the experimental toxicologists and molecular biologists will begin to better appreciate each others questions and progress. Several times during the last two years of developing outlines, issuing invitations, reviewing chapters, and cajoling belated contributors, we have wondered whether we made the correct decision to undertake this effort.

It is an exciting task to be the editor of the first monograph covering a new area of the biomedical sciences. Since the first report in 1980 by Robert Furchgott and colleagues (see Chapter 1) of the evidence of endothelium-dependent relaxation in isolated arteries, there are ever increasing numbers of vascular physiologists and pharmacologists who are scraping away the endothelium to look into its role in cardiovascular con trol. And the more one looks, the more one discovers. Not only is the list of substances that can induce endothelium-dependent relaxations im pressively long, but these intriguing cells can also secrete vasoconstrictor substances. The ability of the endothelium to modulate the degree of con traction of the underlying smooth muscle is an ancestral property of the blood vessel wall, illustrating the logic of nature, since the endothelial cells are located in the best possible strategic location to continuously monitor the properties (chemical or physical) of the blood. And more and more data emerge suggesting that in several cardiovascular diseases per turbations in endothelium-dependent responses are one of the early signs of the abnormal process. Thus, the importance of endothelium-dependent responses, triggered by the intellectual curiosity of one of the pioneers of vascular physiology and pharmacology, is now recognized not only by basic scientists, but also by all concerned with the cardiovascular diseases. The purpose of this monograph is to provide them with a reference work, so that they know where to start."

JAMES L. MCGAUGH Understanding of the nature and functions of neurotransmitter systems in the brain has increased enormously in recent decades. Lack of knowledge required us, not too long ago, to use the adjective "putative" when discussing transmitters. Such caution is no longer essential (at least for a number of transmitters). Impressive progress has been achieved in understanding the pharmacology, biochemistry and anatomy of transmitter systems. There has, however, been relatively less progress in understanding the functioning of brain transmitters in regulating and mediating behavior. A simple and certainly correct explanation for this is, of course, that understanding of neurotransmitter functions requires prior detailed knowledge of basic pharmacology, biochemistry and anatomy. Beyond that, it now seems likely that progress in understanding the functions of brain neurotransmitters will proceed only as we examine the interactions of neurotransmitter systems in regulating behavioral functions. This premise is, of course, suggested by the findings of studies of the chemical neuroanatomy of the brain: Neurotransmitter systems are influenced by other neurotransmitter systems and, in tum, influence the same as well as other systems. No system works alone. The chapters in this book explicitly examine the interactions of neurotransmitter systems involved in the regulation of cognitive processes. The facts and interpretations offered provide compelling support for the premise that cognitive processes are orchestrated by interactions among neurotransmitter systems. And, they offer promise that understanding of such interactions will be of critical importance in the develop ment of treatments for brain diseases affecting cognitive functioning."

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.

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.

In recent years, we have witnessed a rapid expansion of our knowledge regarding the role of the endothelium in the control of vascular tone (and organ perfusion) in health and disease. Physiology, pharmacology, and molecular biology have uncovered a wealth of information on structure and function of this heretofore largely neglected "organ". Clinical medicine is now called upon to define the clinical significance of these observa tions that imply the mechanisms of blood coagulation, e.g., the interaction of throm bocytes with the endothelium, vasomotor control, and specifically, the regulation of smooth muscle tone with consequences for vascular resistance and conductance and organ blood flow. Finally, metabolism of lipids with the everlasting problem of athero sclerosis is an important aspect. In a second step, implications regarding the improvement of current therapeutic con cepts, as well as the development of new modalities of pharmacotherapy will have to be discussed. The topic addressed by the 1990 Gargellen Conference: Endothelial Mechanisms of Vasomotor Control, clearly is of interest for both basic scientists and clinicians. It has been the aim of the organizers, the Society for Cooperation in Medical Science (SCMS) with this and the previous symposia to foster and support both basic science and clinical research. Research in medicine today shows two major directions of development: on the one hand, increasing involvement of the basic sciences and their methodology. On the other hand, statistical validation of concepts and therapeutic strategies in large scale population-and multicenter-studies.

"What we call the beginning is often the end, and to make an end is to make a beginning. The end is where we start from." T. S. ELIOT, "Geroniton" The discovery of endothelin-l was both an end and a beginning. It is an end because this discovery has started a plethora of investigations as to endothe1in's sites of production, mode of action, it's normal and abnormal physiological role and its involvement in a variety of pathological conditions ranging from renal failure to myocardial infarction, cardiac hypertrophy, hyperten sion, cyclosporine induced toxicity, mental depression, renal failure, stress related illness, and even stroke and sudden death. It is a beginning because no one can foresee where the investigations will ultimately lead, or how they will end. The discovery of the endothelins was a very recent event and soon specialist books will start to appear dealing in detail with different aspects of their chemistry, physiological role and pathological importance. The present book is intended to act as a guide and primer for those who are becoming intrigued by the many endothelin related articles which are now appearing in the journals but who as yet have not had the time or opportunity to be caught up in the web of enthusiasm and excitement which is motivating those more directly involved in the field of research.

Stress, high blood pressure, smoking, pollution, fast foods, overweight, excessive travelling, surgery, less movement are common features in our modern life. These features are risky for blood clotting disorders. According to WHO, over 29% of the total mortalities worldwide are due to thrombosis. By the year, 2020 cardiovascular diseases (CVDs) may cause an estimated 25 million deaths per year, thus antithrombotic therapy is of great interest.

The available thrombolytic agents such as urokinase are highly expensive, antigenic, quite unspecific, pyretogenic and hemorrhagenic. Therefore, the production of fibrinolysing enzymes, which rapidly dissolute thrombi within the vascular tree, without the detriments by microorganisms, as described in this book, is the desirable aim of today s research. "

The scientific literature has expanded dramatically in recent years, making entry into the structure of any given area extremely difficult; concurrent with this explosion more people are required to become acquainted with information outside their main line of expertise. For this reason there is a need for review articles which give an overall review of circumscribed areas. This volume reviews the subject of respiratory control mechanisms; the authors of each chapter are active research workers engaged in the area covered by their chapter. The first four chapters are concerned with the basic physiological mechanisms which sense changes in the respiratory system, in the standard physiology textbook parlance chemical and neural sensory receptors. The peripheral arterial chemoreceptors sense changes in arterial oxygen tension, carbon dioxide and pH. The first chapter describes the basic responses in the organ produced by changes in blood chemistry. Later chapters discuss changes in activity produced by exercise, chronic hypoxia and the possible role of the chemoreceptors in initiation of respiration in the new-born. In Chapter 1, a section considers the action of drugs on the peripheral chemoreceptors, and finally there is a discussion of the possible mechanisms whereby the organs sense changes in blood chemistry. This pattern is followed in subsequent chapters wherever possible; first a discussion of the basic physiological properties, followed by any clinical application and dis cussion of the mechanism whereby the receptor might operate. The remaining chapters are of a more applied nature.

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."

"Provides analytical chemists and biomedical scientists with an excellent summary of progress...This is a book that can be recommended to all analytical scientists interested in fluorimetry." (Analytical Chimica Acta) "This is a useful overview and gives the nonspecialist a feeling for the advantages and limitations of the methods. Overall this book is a worthwhile read and a good source of references." (TRAC)
The book is divided into chapters on new methods, new appli- cations, fluorescence immunoassays, fluorometric analysis and fluorescence spectroscopy in biomedical sciences. Specific topics are fluorescence spectroscopy using synchrotron radiation, picosecond fluorescence spectroscopy, fluorescence microscopy, fluorescence scattering by synthetic polymers, fluorescence immunoassays, fluorescence for environmental monitoring, fluorescence in flow injection analysis, hydro-geological studies, fluorescence of proteins, lipids and membranes, cell fluorescence, calcium transients.

Though it is a pleasure to write a short foreword to this collection of excellent scientific papers covering a range of biological topics, the rather depressing feature is the small number of papers. All-electronic publishing is developing and your Editors do have great faith in it. One problem for potential authors has been the reluctance of the abstracting journals to pay any attention to electronic journals - perhaps Springer should make a rapid move in this area and start the first all-electronic journal abstracting this type of literature. However, even the paper citation journals are starting to pay attention to the medium. The particular advantages of all-electronic publishing are beginning to emerge more clearly and it is clear that publishing video material is a unique advantage of our format. Several papers took advantage of this - for example those by Riehle and others on cell behaviour in tunnels, by Bereiter-Hahn and Voss on zonation in the plasmalemma and by Pavlikova, Zicha, Chaloupkova and Vesely on cell motility of tumour cells. These papers made essential and extensive use of video material, publishing some material of great originality. The work on cell pola rity and calcium ions in Fucus embryos by Brownlee, Manison and Anning used animation to present their results in an especially clear way. The facility of use of animation is another special advantage of our type of publication that should be more widely used."

This section will consider the structure and function of muscle receptors, as well as the central nervous system mechanisms with which they are concerned. In volume I of this Handbook, receptor mechanisms are discussed in detail. Also, the crustacean stretch receptor and the frog muscle spindle have been considered. The present section will be concerned with vertebrate muscle receptors with an emphasis on mammals. Muscle receptors provide interesting examples of specialized mechanorecep tors. The muscle spindle is a striking case of a receptor which is regulated in its function by the central nervous system in efferent neurons. Muscle receptors have long been known to playa crucial role in the reflex regulation of movement. In recent years it has become apparent that these receptors are also important in sensory phenomena such as the perception of position and movement. St. Louis, July 1974 c.c. HUNT Contents Chapter I The Morphology of Muscle Receptors. By D. BARKER. With 99 Figures . . . . . . . . . . . . . . . .. 1 Chapter II The Physiology of Muscle Receptors. By C.C. HUNT. With 21 Figures . . . . . . . . . . . . . . . . . 191 Chapter III Central Actions of Impulses in Muscle Afferent Fibres. By A. K. McINTYRE. With 8 Figures 235 Author Index 289 Subject Index 299 List of Contributors BARKER, David Department of Zoology, University of Durham, Science Laboratories, South Road, Durham DH1 3LE, Great Britain HUNT, Carlton C. Department of Physiology and Biophysics, Washington University, School of Medicine, 660 South Euclid Avenue, St. Louis, Mo. 63110, USA McINTYRE, A. K."

In 1976, when Springer-Verlag commissioned Professors Giebisch, Tosteson, and Ussing to edit what was destined to become a monumental five-volume Handbuch (" Membrane Transport in Biology", 1978 [Vols I, II, III] and 1979 [Vols IV A, B]), the subject of transepithelial secretion was still in its infancy. Not surprisingly, therefore, their Handbuch concentrated mainly on trans- epithelial absorption, although substantial chapters dealing with some secre- viz. "Ion Transport Across the Choroid Plexus" tory organs were included, (by E. M. Wright), "Sweat Glands" (by J. H. Thaysen), "Lacrimal Gland" (by J. H. Thaysen) and "Transport Across Insect Excretory Epithelia" (by J. P. H. Maddrell) in Volume III and "Transport in Salivary and Salt Glands" (by J. A. Young and E. W. Van Lennep), "Gastric Secretion" (by T. E. Machen and J. G. Forte), "Transport Processes in the Exocrine Pan- creas" (by I. Schulz and K. J. Ullrich), and "Transport of Ions in Liver Cells" (by M. Claret) in Volume IVB. The publication in 1977 of the seminal paper of Silva and his colleagues on the mechanism of secretion of salt and water in the salt excreting gland of the dogfish (American Journal of Physiology 233, F298-F306, 1977) provided physiologists with their first real insight into the mechanisms underlying transepithelial fluid secretion, however, and, in the ensuing years, interest in the topic has exploded as is evidenced by the numerous international symposia on exocrine secretion held since that date.

Since the endothelium plays such an important role in the pathophysiology of the circulatory system, the readers attention is directed here towards the possible involvement of these polypeptides in the aetiology of ischaemic heart disease, cerebrovascular accidents, hypertension, atherosclerosis and renal failure.