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Caveolae (latin for little caves) are small structures found at the surface of cells. They are responsible for the regulation of important metabolic pathway. As a consequence, they may play a critical role in several human diseases such as atherosclerosis, cancer, diabetes, and muscular dystrophies. This book analyzes the role and function of caveolae in these aspects and serves as the first textbook currently available on caveolae/caveolin.

The Liver in Biology and Disease was conceived as a sequel in the series Principles of Medical Biology, whose general aim continues to be the integration of human biology and molecular cell biology into modern molecular medicine. It is a volume molded by the Information Revolution which few will deny has forced the teaching faculties in our medical schools to curtail and prune the teaching load and focus on fundamentals and principles. With this intention in mind, a volume of this nature takes into account the close dependence of progress in the medical sciences on bioinformatics (gene and protein analysis) or more precisely, computational biology and of course, the Internet. In general, it follows the pattern of its predecessors.•Chapters are illustrated with numerous figures and references are current•Clear, concise and accurate text about a large number of liver diseases•Describes the liver's histology, biochemistry, and pathology in molecular terms

It is now widely recognised that biological psychiatry is rapidly coming into its own. For over the last three decades dramatic advances in this young discipline have been made, all of which attest to the staying power of the experimental method. Those who made this revolution in knowledge happen are a breed of investigators availing themselves of the tools of molecular biology, pharmacology, genetics, and perhaps, above all, the technology of neuroimaging. The introduction of the interdisciplinary method of approach to the study of psychopathology had made it very clear that neuroimaging, as a set of techniques, is unique in that it is gradually providing us with evidence supporting Kraepelin's original view that mental illness is closely associated with abnormal changes in the brain.Broadly speaking, there are presently two structural techniques in neuroimaging - computed tomography and magnetic resonance imaging (MRI) - and three functional techniques - single photon emission tomography (SPECT), positron emission tomography and magnetic resonance imaging (fMRI). Through PET technology, for example, we have learned that, in early brain development, the primitive areas, mostly the brain stem and thalamus, are the first to show high activity in an infant. This is followed by the development of cortical areas by year one. Between the ages of four to 10, the cortex is almost twice as active in the child as in the adult. This information alerts us to what might happen in the way of trauma in abused children, especially those under the age of three. Child abuse increases the risk of physical changes, not only in the stress systems, but also in brain development (Glaser and Weissman). In addition to the difficult problem of post-traumatic stress disorder (PTSD), we have to take into account the possibility of other types of mental illness as the consequences of child abuse. These include depression, eating disorders, and drug and alcohol problems.The combination of PET and fMRI represents a more remarkable example of the power of neuroimaging since the two have made it feasible to map accurately in vitro identifiable cortical fields, or networks. In a landmark NIH investigation of human cortical reorganization (plasticity), persuasive evidence was brought forward showing that the process of learning as a motor task involves a specific network of neurons. These neurons occur in the cortical field that is responsible for that particular task. Such findings are important partly because they provide evidence supporting the current notion that labor in the cortex is divided among ensembles of specialized neurons that cooperate in the performance of complex tasks. Cooperation, then, in this, sense implies crosstalk among ensembles and that signals are both processed and retransmitted to neighbouring ensembles. To understand the workings of these ensembles, much better spatial and temporal resolution in functional brain mapping is required. This can be achieved with an NMR instrument whose magnet is 4.1 Tesla or more.

The first section of this volume consists of five chapters to the nature of membrane transport systems. A chapter on secondary active glucose transport has been omitted because this topic is slated to appear in the Nephrobiology module. Chapter 6 deals with oxidase control of plasma membrane proton transport, while chapter 7 addresses the question of how cell volume is regulated. Although we chose not to have a separate chapter covering additional co-transport systems namely, Na+ -K+ -2CI-, KCI, -HCO-3, as well as CI- -HCO-3 exchange and K+ and CI- movements through channels, the role of each in cell volume regulation is emphasized in Chapter 7. Instead of devoting an entire section to the thermodynamics of metabolism, we thought it desirable to have the subjects of medical imaging and NMR of cell metabolism discussed in some detail in two chapters. These are followed by a chapter on the thermodynamic instrument - the calorimeter. Calrimetry allows the measurement of net changes of heat in cells, tissues, organs and whole body. As will be recognized, heat dissipation does not arise only from chemical reactions but also from interactions between macromolecules and conformational changes in protein complexes and mass Ca2+ movement such as that occurring in contracting skeletal muscle. The last chapter provides an account of equilibrium and non-equilibrium thermodynamics and the enthalpy balance method. It reveals that calometric measurements are useful in studies of clinical and toxicological problems.

The tools of molecular biology have revolutionised our understanding of gene structure and function and changed the teaching of genetics in a fundamental way. The transition from classical genetics to molecular genetics was initiated by two discoveries. One was the discovery that DNA has a complementary double helix structure and the other that a universal genetic code does exist. Both led to the acceptance of the central dogma that RNA molecules are made on DNA templates. The last twenty years have seen remarkable growth in our knowledge of molecular genetics, most of which is the outcome of recombinant DNA technology. This technology which is not limited to cloning, sequencing, and expression has created a biotechnology industry of its own, the purpose of which is to develop new diagnostic and therapeutic approaches in medicine. Both industries in collaboration with the biomedical community are now engaged in laying down the foundation of molecular medicine. The present volume seeks to provide a coherent account of the new science of molecular genetics. Its content however is by no means exhaustive, partly because of the publication explosion but more because of space restrictions. A rudimentary knowledge of genetics on the reader's part is assumed. Quite understandably, considerable emphasis is placed on major technical advances but not without expounding numerous new ideas and phenomena including alternative splicing, POR, DNA methylation, genomic imprinting, and so on.

The present volume is the first in the advances in oncobiology series. It is meant to be useful not only to clinical and non-clinical oncologists but also to graduate students and medical students. The individual chapters are presented as self-contained summaries of current knowledge rather than as reviews. The last chapter deals with the subject of chemotherapy.

This volume illustrates the extent to which the traditional distinction between biochemical and physiological processes is being obliterated by molecular biology. It can hardly be doubted that the revolution in cell and molecular biology is leading to core knowledge that provides an outline of the integrative and reductionist approach. We view this as the beginning of a new era, that of the integration of learning.As in the preceding volumes, the choice of topics has been deliberate not only because of the need to keep the volume within reasonable bounds but also because of the need to avoid information over-load. Several relevant topics are dealt with in other modules; for example, the role of G proteins in transmembrane signalling is covered in the Membranes and Cell Signalling module (i.e., Volume 7). Omissions are of course inevitable but they are minor. A case in point is the subject of phosphatases, the treatment of which does not take into account calcineurin. One of the key functions of this Ca2+ -activated protein phosphatase that is also regulated by calmodulin is to desphosphorylate voltage-dependent Ca2+ channels. The mere recognition of such omissions before or after consulting textbooks and journals should be a spur to a more complete discussion by the student of the subject in a small group teaching setting.

The purpose of this volume is to provide a synopsis of present knowledge of the structure, organisation, and function of cellular organelles with an emphasis on the examination of important but unsolved problems, and the directions in which molecular and cell biology are moving. Though designed primarily to meet the needs of the first-year medical student, particularly in schools where the traditional curriculum has been partly or wholly replaced by a multi-disciplinary core curriculum, the mass of information made available here should prove useful to students of biochemistry, physiology, biology, bioengineering, dentistry, and nursing.It is not yet possible to give a complete account of the relations between the organelles of two compartments and of the mechanisms by which some degree of order is maintained in the cell as a whole. However, a new breed of scientists, known as molecular cell biologists, have already contributed in some measure to our understanding of several biological phenomena notably interorganelle communication. Take, for example, intracellular membrane transport: it can now be expressed in terms of the sorting, targeting, and transport of protein from the endoplasmic reticulum to another compartment. This volume contains the first ten chapters on the subject of organelles. The remaining four are in Volume 3, to which sections on organelle disorders and the extracellular matrix have been added.

This volume is in two parts. The first contains the remaining chapters on cellular organelles and several chapters relating to organelle disorders. An account of mitochondriopathis is given in the chapter on the mitochondrion rather than in a separate one. The subject matter of this part of the volume shows quite clearly that the interdisciplinary approach to the study of organelles has shed considerable light on the nature of the mechanisms underlying the etiology and pathobiology of many of these disorders. As an example, mutations in the genes encoding integral membrane proteins are found to lead to disturbances in peroxisome assembly. It is also interesting and significant that mistargeting of protein is now thought to be another cause. It will be revealing to see whether mistargeting is the result of mutations in the genes encoding chaperones.The second part of the volume is concerned with the extracellular matrix. It sets out to show that a vast body of new knowledge of the extracellular matrix is available to us. Take for example the integrin family of cell adhesion receptors. It turns out that integrins play a key role not only in adhesion but also in coupling signals to the nucleus via the cytoskeleton. As for fibronectins, they seem to link the matrix with the cytoskeleton by interacting with integrins.Collagen molecules are dealt with in the last two chapters. The boundaries of collagen in disease are defined by drawing a clear line of demarcation between systemic connective tissue disorders (e.g., scleroderma), better known as autoimmune diseases, and the heritable, and the heritable diseases such as osteogenesis imperfect and the Marfan syndrome. This classification takes into account a second group of acquired disorders of collagen forming tissues in which regional fibrosis is the hallmark. Liver cirrhosis and pulmonary fibrosis are prime examples.The decision to place Volumes 2 and 3 before those dealing with cell chemistry was not easily made. It was based on the view that most students will have had an undergraduate course in biochemistry of cell biology or both courses, and that they could go to Volumes 4-7 in which the subject of cell chemistry is covered, and then return to Volumes 2 and 3.

There is a need in small group teaching for a readable module that provides a balanced treatment of the four main areas of medical microbiology-bacteriology, mycology, virology and parasistology. It need not be encyclopedic in scope nor didactic, but it should emphasise principles and concepts. Any existing gaps in this type of presentation are, of course, left for the student to fill.Some subject material has been excluded. An example is a chapter on laboratory procedures including PCR for rapid bacterial and viral diagnosis. The discussion of bacterial sexually transmitted diseases does not cover goncoccal infections. This is not a serious matter because the tutor can assign the topic to the students. Moreover, we have reluctantly omitted a separate chapter on anaerobic bacteria. The subject of nosocomial pathogens is touched upon but not in sufficient detail (e.g., control). These bacteria (e.g., S. aureus, E. coli and pseudomonas) are found in hospitals and are resistant to disinfectants and antibiotics. A new but serious problem is the emergence of resistance to antiviral agents.Without question, molecular biology owes more to the study of viruses than bacteria. The fact remains, however, that effective therapy against most viral diseases is not yet available. Perhaps one of the most dramatic examples of this situation is the fight against the AIDS virus and the search for a vaccine. The public health challenge of AIDS remains formidable in spite of the recent encouraging results obtained with protease inhibitor therapy. At the moment at least six receptors for HIV are known to be present in human cells. One of them is the CCR5 receptor in the absence of which cells fail to get infected with the virus. Drugs that can interrupt CCR5 binding sites on the virus envelope are being vigorously sought. Thus, Volume 9B gives a large place to HIV disease.The last group of chapters highlight several features of microbiology which are also of clinical importance and heuristic value. The chapter on fever of unknown origin provides fertile soil for problem based learning.

It should not come as too much of a surprise that biological membranes are considerably more complex than lipid bilayers. This has been made quite clear by the fluid-mosaic model which considers the cell membrane as a two-dimensional solution of a mosaic of integral membrane proteins and glycoproteins firmly embedded in a fluid lipid bilayer matrix. Such a model has several virtues, chief among which is that it allows membrane components to diffuse in the plane of the membrane and orient asymmetrically across the membrane. The model is also remarkable since it provokes the right sort of questions. Two such examples are: Does membrane fluidity influence enzyme activity? Does cholesterol regulate fluidity? However, it does not go far enough. As it turns out, there is now another version of this model, the so-called post-fluid mosaic model which incorporates two concepts, namely the existence in the membrane of discrete domains in which specific lipid-lipid, lipid-protein and protein-protein interactions occur and ordered regions that are in motion but remain separate from less ordered regions. We must admit that both are intriguing problems and of importance in guiding our thinking as to what the next model might be.We have chosen not to include the subject of membrane transport in the present volume. This obviously represents a break with convention. However, the intention is to have the topic covered subsequent volumes relating to organ systems. It would be right to regard this as an attempt to strengthen the integrated approach to the teaching of medicine.

This volume is intended to complete the Cell Chemistry and physiology module. It is about how the traditional boundaries of cell chemistry and physiology are being erased by molecular biology. We do not think it necessary to elaborate on this theme, particularly since the body of core knowledge found in this volume brings us a stage closer to answering the question,'what makes cell biology into a new discipline?'The first part of the volume deals with the chemistry of actin and myosin and is followed by chapters on cell motility, ATP synthesis in muscle, and contraction in smooth and skeletal muscle. Here the reader is immediately made aware of the contributions molecular biology is making to our understanding of the molecular mechanisms underlying muscle contraction. It is perhaps enough to point out that Huxley's concept of the cross-bridge cycle and generation of force can now be explained in molecular terms. Topics such as muscle fatigue and muscle disorders, as well as malignant hyperthermia are bound to arouse active learning in the student and set the stage for problem-based learning.Most medical students look askance at thermobiology. We think this is a mistake; hence, we have included a section dealing with this subject. This brings us to the chapter on the heat shock response, which at the very outset makes clear that many stressors besides heat are known to result in heat shock gene expression. Many of the heat shock proteins occur in unstressed cells and some of them behave as chaperones. These proteins also reach high levels in a wide range of diseases including neurodegenerative disorders. Whether certain diseases are the result of mutations in the heat shock genes is not yet known. As will be appreciated, much of the work done in this field involved the use of cultured cells. Animal cells in culture are the subject of the last chapter.

This is the first of a 4-volume module that is an introduction to the study of cell chemistry and physiology. It is not intended to be encyclopedic in nature but rather a general survey of the subject with an emphasis on those topics that are central to an understanding of cell biology and those that are certain to become of increasing importance in the teaching of modern medicine.We have followed what appeared to as to be the logical divisions of the subject beginning with proteins. Allewell and her colleagues stress the point that proteins fold spontaneously to form complex three-dimensional structures and that some of them unfold with the help of proteins called chaperones. Michaelis-Menten kinetics are shown by Nelsestuen to describe the behaviour of enzymes in the test tube. The formalism is particularly useful in the search for agents of therapeutic value, as exemplified by methotrexate. Uptake by mammalian cells of substrates and their metabolic conversions are discussed by van der Vusse and Reneman. However, both Welch and Savageau expound the view that the cell is not simply a bagful of enzymes. The biologist is urged by Savageau to abandon Michaelis-Menten formalism and apply the Power Law. The biologist is also told that the approach to arriving at a theory of metabolic control would have to be one of successive approximations requiring the use of the computer. Information gained from comparative biochemistry is shown by Storey and Brooks to have shed new light on mechanisms of metabolic rate depression and freeze tolerance, and to be applicable to organ transplantation technology. We are reminded that enzyme adaptation is partly the result of the presence of a hydrating shell of vicinal water that stabilises conformation of the enzyme. Vicinal water, according to Drost-Hausen and Singleton, lies adjacent to most solids and protein interfaces. The kinks or breaks observed in the slope of the Arrhenius plot are attributed to structural changes in vicinal water. Regulation of cell volume is shown by Hempling to involve regulation of cell water. It could be that the osmo-receptor or volume detection system is a protein that links the cytoskeleton to specific K and C1 channels. Additionally, it is interesting that aquaporins, which are water channel-forming membrane proteins, are now known to exist in both renal and extra-renal tissues. One of the renal porins is affected by vasopressin. We then pass on to protein synthesis (Rattan) and other important topics including protein glycosylation (Hounsell), methylation (Clarke), ADP-ribosylation (Pearson) and prenylation (Gelb). Among the four types of lipids attached to membrane proteins are the prenyl groups. Ford and Gross in their chapter on lipobiology drive home the point that there is an accumulation of acyl carnitine and lysophospholipids during myocardial infarction.

We have now reached the mid-point of our editorial task of putting together the compendium, Principles of Medical Biology, which is supposed to be composed of twenty-five modules. The present single-volume module on reproductive endocrinology and biology is in more than one respect a continuation of Module 10 (in two volumes) dealing with molecular and cellular endocrinology. In addition, it intersects, as it should, with various parts of obstetrics and gynaecology, both of which are abetted by technology. One has only to recall that the practical benefits of ultrasound in perinatal medicine and in vitro fertilisation are the outcome of the technological revolution in biomedicine. Whether we are approaching a new era in reproductive biology following the invention of animal cloning is still hard to tell. For some people, it remains an article of faith that cloning of the human being is highly probable. For others, asexual reproduction is anathema. It should surely be obvious to us all that somatic cell nuclear transfer technology (SCNTT) is going to be at its strongest in dealing with husbandry. Whether this and several social forces will alter our modern outlook, there can be little doubt.As in diverse clinical and basic research, so in obstetrics, animals are used as a model. The data thus obtained is extrapolated, if valid, to the mother and foetus. The success of this approach is exemplified in studies carried out on sheep as a model. On the whole, it is also quite apparent that progress in the field of reproductive biology is to a large extent ascribable to the discovery in other disciplines of new hormones, as well as the introduction of new tools and recent improvements in laboratory methods including measurement of hormones.

Molecular and Cellular Pharmacology

The purpose of this module is to provide a survey of the rapidly expanding field of developmental biology and to introduce it to the student in a unifying way. In medical schools where courses in biochemistry, physiology, and pharmacology are already considerably intersecting, there is not surprisingly a rising demand in modern medical education for books emphasizing the interdisciplinary approach. In recent years, developmental biology has become a very vibrant and exciting field. The adoption of the interdisciplinary approach in this field has yielded enormous information about how DNA is able to produce a living organism from a fertilized egg. The discovery of'master'genes in Drosophila that control spatial organization and share a segment of DNA, the so-called homeobox, and the discovery in C. elegans of genes controlling the timing of branching off of cell lineages are today recognized as milestones in molecular developmental biology.Because of space limitations and because of the information explosion, we have continued to pursue the policy of selecting broad topics but not in every case. This time, for example, though guided by the principle that a close connection exists between genes, adhesion, and morphogenesis, we opted to include certain topics such as cadherin - an adhesion molecule - rather than have the whole subject of adhesion dealth with in a single chapter. Substrate-adhering molecules (e.g., fibronectnin) are touched upon in Chapter 5. In a similar manner, only one type of junction is discussed at length. Chapters 8, 9, and 10 border on the extraordinary, for they are together absorbingly interesting. The last chapter makes things more pragmatic. The attention of the reader is drawn to the fact that several previous volumes of the compendium impinge on the present one. Chapters 25 and 26 in Volume 7B, in particular, have much to say on the subjects of extracellular matrix adhesion and intercellular communication.

As this volume demonstrates, immunobiology is a young science which is undergoing explosive growth. Judged by results, it is already an elaborate discipline which cuts across every other area in biomedical research and even has its own vocabolary (e.g., the'veto'effect). Rather than inculcate the habit of superficial learning by having the student go through a maze of details, we have sought to gather together sixteen essays that range from T-cells to psyhoneuroimmunology. This is keeping with the growing understanding that the student is expected to read and think far more for herself/himself.Next to nothing is known about innate immunity. However, recent evidence suggests that collectins might bridge the gap between innate immunity and specific clonal immune responses. Collectins are soluble effector proteins that include serum mannose-binding protein, and lung surfactants A and D. They are considered to be ante-antibodies.