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

Plasma proteins are of interest from many points of view. Biochemists have separated and purified numerous plasma proteins and studied their physical properties, amino acid composition and sequence, the carbohydrate com- ponents of some, and binding of metals, hormones, and other materials. Much work has also been carried out on the synthesis, rates of turnoverr, and degradation of plasma proteins. Many plasma proteins show inherited variations, some of which (e.g., those of heptoglobins and transferrins) are common in various human popu- lations while others (e.g., absence of lipoproteins or immunoglobins) are rare but important because of their association with clinical syndromes. Since blood is the most accessible bodily constituent, geneticists have made good use of serum protein differences as genetic markers in family and popula- tion studies. Physiologists have long been interested in plasma proteins in relation to colloid osmotic pressure; transport of lipids, iron, hormones, and other ma- terials; the activities of renal glomeruli and tubules; the function of the liver, and many other bodily activities. Plasma proteins are also widely studied in relation to malnutrition and undernutrition, particularly that associated with defective intake of protein.

This volume contains the proceedings of a conference held at the National Institutes of Health in Bethesda on March 21-23. 1988. jointly sponsored by the International Council for Control of Iodine Deficiency Disorders (ICCIDD) and the Fogarty International Center of the National Institutes of Health. Several themes converged to make this meeting timely. The first is an increasing awareness of iodine deficiency disorders as a world-wide problem of public health and a preventable cause of mental deficiency. and as a subject of scientific effort. Increased interest in these problems owes a great deal to accessibility to remote and under developed areas of the world where iodine deficiency persists. As with any subject. greater scrutiny yields unexpected complexity and interest. It is true that provision of iodine. typically as iodized salt, is the necessary and sufficient preventative for iodine deficiency disorders. without including endemic cretinism. This provision is a governmental, economic and social problem. Apart from this, however, the scientific and medical problem of iodine deficiency and its effect on brain development and function is one of great interest and importance for developmental neurology and psychology. Even though the specific preventative agent is known, we do not totally understand the neurobiological questions raised."

This volume represents the first attempt to present in one place the clinical syndromes and the pathophysiologic basis for the "resistance states" to each of the classes of steroid hormones. Glucocorticoids, mineralocorticoids, androgens, estrogens, progesterone and vitamin D have widely diverse roles ranging from the control of homeostasis to reproduction and bone formation. They are similar in that they share a chemical structure and that their action is in the cell nucleus where they induce transcription of specific genes leading to synthesis of function-specific proteins. Clinical syndromes of steroid hormone resistance to androgens (complete and partial testicular feminization), aldosterone (pseudo hypoaldosteronism) and vitamin D (vitamin D-dependent rickets type II) have been known for many years. Progesterone and glucocorticoid resistance syndromes have been described only recently. Resistance to estrogens has not been reported in man or in animals. It is hoped that a detailed reexamination of what is known about each of these conditions at the clinical and molecular levels will enhance our understanding of the function of these hormones and their mechanisms of action. New insight and research initiatives should result. G.P. Chrousos D.L. Loriaus M.B. Lipsett vii ACKNOWLEDGMENTS The contents of this volume are based in part on the proceedings of an International Conference held in Bethesda in the summer of 1984. This conference was sponsored by the National Institute of Child Health and Human Development, Bethesda, Maryland."

Foreword by Walter J. Freeman.

The induction of unconsciousness using anesthetic agents demonstrates that the cerebral cortex can operate in two very different behavioral modes: alert and responsive vs. unaware and quiescent. But the states of wakefulness and sleep are not single-neuron properties---they emerge as bulk properties of cooperating populations of neurons, with the switchover between states being similar to the physical change of phase observed when water freezes or ice melts. Some brain-state transitions, such as sleep cycling, anesthetic induction, epileptic seizure, are obvious and detected readily with a few EEG electrodes; others, such as the emergence of gamma rhythms during cognition, or the ultra-slow BOLD rhythms of relaxed free-association, are much more subtle. The unifying theme of this book is the notion that all of these bulk changes in brain behavior can be treated as phase transitions between distinct brain states.

Modeling Phase Transitions in the Brain contains chapter contributions from leading researchers who apply state-space methods, network models, and biophysically-motivated continuum approaches to investigate a range of neuroscientifically relevant problems that include analysis of nonstationary EEG time-series; network topologies that limit epileptic spreading; saddle--node bifurcations for anesthesia, sleep-cycling, and the wake--sleep switch; prediction of dynamical and noise-induced spatiotemporal instabilities underlying BOLD, alpha-, and gamma-band Hopf oscillations, gap-junction-moderated Turing structures, and Hopf-Turing interactions leading to cortical waves.

This volume contains the text of the presentations delivered at the International Symposium on Rare Diseases "Inherited Neuromuscular Diseases: Translation from Pathomechanisms to Therapies," held in Valencia, Spain, from November 16 to 18, 2008. The symposium represents a part of the continuous efforts on dif- sion of science to the society of the Catedra Santiago Grisolia and the Fundacion Ciudad de las Artes y las Ciencias -Comunitat Valenciana. More than 200 inter- tional scientists from different countries of Europe, the USA, and Australia attended the meeting. The venue was the Auditorium of the Science Museum Principe Felipe. Ten years ago Alan Emery wrote in the preface of Neuromuscular Disorders: Clinical and Molecular Genetics the following comments: "It has been estimated that more than one person in every 3,000 has a serious disabling inherited n- romuscular disorder. The suffering caused by these disorders is considerable, but, until the last decade or so, virtually nothing was known of their pathogenesis. Any rationale approach to treatment was therefore out of the question. However, matters are now changing rapidly. The genes for many of these disorders have been localised and characterised and their gene products identi ed and studied. The detection of preclinical disease, the identi cation of heterozygous carriers and prenatal di- nosis are all becoming possible, and, hopefully, effective treatments may no be too far distant."

An essential element in the development and functional integrity of all organisms is intercellular communication. This is achieved by the secretion of soluble messenger molecules which subsequently interact with receptor-effector pathways in the responsive cells. Hormones are traditionally defined as chemical messengers synthesized by endocrine glands. Unlike hormones produced by endocrine glands, growth factors are hormone-related substances produced by many tissues and play an important role in controlling growth and development. While the exact physiological roles of growth factors have yet to be elucidated, they play important roles in the regulation of cellular proliferation and/or differentiation during ontogenesis, growth and differentiation. During recent years there has been a substantial increase in research related to peptide growth factors, their receptors, and modes of action. With the discovery and characterization of numerous growth factors, it became clear that these growth factors had multiple features in common with classic hormones as well as with oncogenes. Furthermore, there are distinct families of growth factors based either on structural or functional similarities.

Catecholamines are important transmitter substances in the autonomic and central nervous systems. These two volumes provide a comprehensive presentation of the state-of-the-art of catecholamine research and development in the past 15 years. The volumes present in-depth reviews of topical areas of catecholamine research in which substantial progress has been made and which are of current interest to various theoretical and clinical disciplines. Each topic has been dealt with by an established expert. Clinical subjects of relevant importance are included. Catecholamines are of interest in pharmacology, physiology, biochemistry, as well as in neurology, psychiatry, internal medicine (cardiology, hypertension, asthma), ophthalmology and anesthesiology.

Anesthetics produce a reversible state of unconsciousness accompanied by ante- grade amnesia. This remarkable phenomenon brings great relief to surgical patients and wonder to clinicians and scientists. To date, we do not fully understand the mechanisms by which anesthetics ablate conscious sensation and memory. We are, however, making progress. This book presents original results as well as overviews of the current state of knowledge of the problem. It is authored by investigators who know the ?eld well; their research at a number of levels has contributed substantially to our c- rent understanding of anesthetic modulation of memory and consciousness. Most of the contributors were presenters at two workshops organized by Dr. Pearce and Dr. Hudetz at the 40th Annual Winter Conference on Brain Research, held at Snowmass Village, Colorado, from January 27 through February 2, 2007. One workshop focused on anesthetic modulation of consciousness and another on an- thetic modulation of memory. Seven of the chapters are based on material presented at these symposia - appropriately updated with new relevant ?ndings. This infor- tion is supplemented by chapters on anesthesia and sleep, computational analysis of the state of anesthesia, and the clinical phenomenon of "anesthesia awareness," a topic that has recently received much public attention. With these three additional contributions, the book thus includes 10 chapters.

Coronary circulation research is advancing at a rapid rate. Not only are inno vative techniques for studying myocardial perfusion being developed, new mechanisms related to coronary blood flow control and mechanics are also being discovered. The progress in this field justifies an update in the form of this new monograph. The book is divided into the following sections: "Measurement of Coronary Blood Flow and Assessment of Myocardial Per fusion" discusses advances in perfusion measurements in humans as well as nonradioactive microsphere methods. . "Coronary Flow Dynamics" elucidates the effect of heart contraction on coronary flow, perfusion, and reserve distribution as well as systolic-diastolic interaction. Models-a frequent topic of debate-are used to quantify hypotheses. "Models of Coronary Circulation" attempts to elucidate the concept of tissue pressure. "Regulatory Mechanisms of Coronary circulation and its Clinical Relevance" N u.merous mechanisms affecting coronary flow have been defined and studied at the level of isolated vessels and whole organs. The chapters in this section provide an in-depth analysis of a selection of these mechanisms and their inter actions. "Pathophysiology of Coronary Circulation in Ischemic Heart Disease" considers important aspects of factors which restrict perfusion of the myocardium in ischemic heart disease. An understanding these factors is of crucial importance in the management of patients. "Small Vessel Disorder in Coronary Circulation" describes circulatory flow and how it can be influenced by drugs."

The NATO Advanced Study Institute on "Cerebral Blood Flow: Mathematical Models, Instrumentation, and Imaging Techniques" was held in L'Aquila, Italy, June 2-13, 1986. Contributions to this program were received from the University of L'Aquila, Consiglio Nazionale delle Ricerche, Siemens Elettra S.p.A., and Bracco S.p.A. Recent studies of the cerebral blood circulation have lagged behind analysis of other parameters such as glucose utilization, transmitter distribution, and precursors. This Advanced Study Institute tried to fill this gap by analyzing in detail different physical techniques such as Autoradiography (including Double-Tracer Auto radiography and highly specific tracers as Iodoantipyrine, Micro spheres), Single Photon Emission Computed Tomography, Nuclear Magnetic Resonance. Each method was analyzed in regards to its precision, resolution, response time. A considerable part of this Institute was devoted to the mathematics of CBF measurement, in its two aspects, i.e. the modeling of the underlying kinetic system and the statistical analysis of the data. The modeling methods proposed included the development of a differential algebra whereby the differential and integral equations involved could be solved by simple algebraic methods, including graph theoretical ones; the statistical methods proposed included the illustration of different parametrizations of possible use in the interpretation of experimental results.

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

Who said learning A&P can't be fun? The Anatomy and Physiology Learning System, 4th Edition makes it easy to learn normal structure and function of the body, and summarizes the common disorders found in each body system. Written by well-known educator Edith Applegate, this book combines clear, crisp writing with hundreds of vibrant illustrations. This edition includes a stronger emphasis on medical vocabulary, so you understand key terms before you learn anatomy. A wide array of engaging features simplifies physiology concepts, and an Evolve website supports the book with a wealth of new learning opportunities. Even if you have little or no background in science, you will learn the A&P you need to enter your career! A clear and concise writing style makes the book easy to read and understand, even if you have a limited background in science. Quick Check questions let you check your comprehension at various points within a chapter. Chapter quizzes provide recall, thought, and application questions to check your understanding of A&P concepts. An Evolve website includes online tutoring, a Body Spectrum coloring book, Anatomy & Physiology Pioneers boxes with brief biographies of trailblazers in science and medicine, 3-D animations, an audio glossary, Spanish pronunciations of key terms, and frequently asked questions. Outlines and objectives at the beginning of each chapter help you prioritize your study. Key terms are highlighted to help you analyze, pronounce, and spell important medical words. A glossary provides definitions and a pronunciation guide for key terms. Functional Relationships pages illustrate the connection between each individual system and the other body systems, showing how all systems work together. Representative Disorders describe the common health issues associated with each body system. Focus on Aging boxes describe the effects of aging on body systems. Quick Applications boxes connect the material to real-world scenarios. From the Pharmacy boxes describe common medications for each body system and include a brief description of the drug and its action, common uses, and abbreviations. 100 new high-quality illustrations help you visualize anatomical features and physiological processes. Chapter summaries and vocabulary quizzes have been added to the end of each chapter. New Building Your Medical Vocabulary section covers the history of medical words, giving you the building blocks to use and recognize new terms.

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.