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APS Physiology in Medicine reviews, 1998-2011

Review articles explicating basic science for clinicians. From the American Physiological Society.

Physiology in Medicine: 1998 - 2000

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Andreoli, T. E. (2000). "Free radicals and oxidative stress." The American Journal of Medicine 108(8): 650-651.

This series of “Physiology in Medicine” will deal with oxidative stress produced by free radicals. It is fair to say that the field was opened in 1969 by Joe M. McCord, the author of the first article in this series, working in collaboration with Irwin Fridovich at Duke University. McCord and Fridovich discovered an enzyme entitled superoxide dismutase (SOD) that catalyzed the conversion of the reactive oxygen species O2 to hydrogen peroxide [...]: From the above reaction, one can see that the reactive oxygen species O2 can be converted to hydrogen peroxide (H2O2) by the enzyme superoxide dismutase. Now if one has sufficient quantities of the enzyme catalase on hand, the H2O2 can be broken down to water plus oxygen. In practical terms, reactive oxygen species include two compounds that are free radicals, O2 and OH·, both of which are characterized by having a single unpaired electron; and H2O2, which is not a free radical but which can, in the absence of catalase, lead to the formation of the free radical OH·. The consequences of the formation of these free radicals, or of H2O2 formation in excess of the rate at which it can be converted to oxygen and water, are precisely the issues to be considered in this series of articles. Stated briefly, it now seems clear that oxidative stress, particularly when free radicals are generated by leukocytes in inflammatory reactions, can lead to the formation of the noxious free radicals O2 and OH· as well as H2O2 which, as I noted above, can under certain circumstances lead to the formation of OH·. In turn, these reactive oxygen species harm tissues in a variety of ways, including DNA damage, impairment of mitochondrial respiration, and direct parenchymal impairment. The series begins with an article by McCord, who provides a global overview of the evolution of free radicals and oxidative stress. Among other things, McCord stresses the remarkable interplay between O2, obviously a gas necessary for life, and the pejorative consequences of free radicals. Next, B. M. Babior considers the role of oxidative stress associated with the activation of phagocytes in inflammatory responses. The remaining articles focus on a series of particular examples of oxidative stress, the ways in which oxidative stress damages various parenchymal organs, and diseases in which oxidative stress plays a key developmental role: P. Kubes considers diseases of the gastrointestinal tract, D. N. Granger focuses on cardiac disease, C. E. Cross discusses the relations of oxidative stress and pulmonary disease, N. Delanty deals with oxidative stress and diseases of the central nervous system, and finally, K. A. Nath considers the role of oxidative stress in acute renal failure.It is, as McCord points out in the first article of the PIM series in this issue of AJM, a remarkable paradox that oxygen is a mixed blessing. It is obvious that the gas O2 is necessary for life but under pernicious circumstances, oxygen can be transformed into the reactive oxygen species O2 and OH·, which have pernicious consequences. The same can be said for H2O2, the product of the free radical scavenger superoxide dismutase, when catalase is unavailable.

Babior, B. M. (2000). "Phagocytes and oxidative stress." The American Journal of Medicine 109(1): 33-44.

Neutrophils and other phagocytes manufacture O2- (superoxide) by the one-electron reduction of oxygen at the expense of NADPH. Most of the O2- reacts with itself to form H2O2 (hydrogen peroxide). From these agents a large number of highly reactive microbicidal oxidants are formed, including HOCl (hypochlorous acid), which is produced by the myeloperoxidase-catalyzed oxidation of Cl- by H2O2; OH· (hydroxyl radical), produced by the reduction of H2O2 by Fe++ or Cu+; ONOO- (peroxynitrite), formed by the reaction between O2- and NO·; and many others. These reactive oxidants are manufactured for the purpose of killing invading microorganisms, but they also inflict damage on nearby tissues, and are thought to be of pathogenic significance in a large number of diseases. Included among these are emphysema, acute respiratory distress syndrome, atherosclerosis, reperfusion injury, malignancy and rheumatoid arthritis.

Grodzicky, T. and K. B. Elkon (2000). "Apoptosis in rheumatic diseases." The American Journal of Medicine 108(1): 73-82.

Honig, L. S. and R. N. Rosenberg (2000). "Apoptosis and neurologic disease." The American Journal of Medicine 108(4): 317-330.

Many neurological disorders involve cell death. During development of the nervous system, cell death is a normal feature. Elimination of substantial numbers of initially generated cells enables useful pruning of "mismatched" or excessive cells produced by exuberance during the proliferative and migratory phases of development. Such cell death, occurring by "programmed" pathways, is termed apoptosis. In mature organisms, cells die in two major fashions, either by necrosis or apoptosis. In the adult nervous system, because there is little cell production during adulthood, there is little normal cell death. However, neurological disease is often associated with significant neural cell death. Acute disorders, occurring over minutes to hours, such as brain trauma, infarction, hemorrhage, or infection, prominently involve cell death, much of which is by necrosis. Chronic disorders, with relatively slow central nervous system degeneration, may occur over years or decades, but may involve cell losses. Such disorders include motor neuron diseases such as amyotrophic lateral sclerosis (ALS), cerebral dementing disorders such as Alzheimer's disease and frontotemporal dementia, and a variety of degenerative movement disorders including Parkinson's disease, Huntington's disease, and the inherited ataxias. There is evidence that the mechanism of neuronal cell death in these disorders may involve apoptosis. Direct conclusive evidence of apoptosis is scarce in these chronic disorders, because of the swiftness of cell death in relation to the slowness of the disease. Thus, at any particular time point of assessment, very few cells would be expected to be undergoing death. However, it is clearly of importance to define the type of cell death in these disorders. Of significance is that while treating the underlying causes of these conditions is an admirable goal, it may also be possible to develop productive therapies based on alleviating the process of cell death. This is particularly likely if this cell loss is through apoptosis, a programmed process for which the molecular cascade is increasingly understood. This article reviews our understanding of apoptosis in the nervous system, concentrating on its possible roles in chronic neurodegenerative disorders.

Kubes, P. and D.-M.McCafferty (2000)."Nitric oxide and intestinal inflammation." The American Journal of Medicine 109(2): 150-158.

Inflammation of the intestinal tract remains a very serious concern in the clinical setting. Unfortunately, to date, the mechanisms underlying many inflammatory conditions such as sepsis or inflammatory bowel diseases are poorly understood and our therapeutic interventions are less than ideal. Over the past decade, an abundance of research has been directed toward the role of nitric oxide (NO) in intestinal inflammation. It has become apparent that NO might have a dichotomous role as both a beneficial and detrimental molecule. Nitric oxide is a weak radical produced from L-arginine via the enzyme nitric oxide synthase (NOS). NOS exists in three distinct isoforms; constitutively (cNOS) expressed neuronal NOS (NOS1 or nNOS) and endothelial NOS (NOS3 or eNOS) or an inducible isoform (NOS2 or iNOS) capable of high production output of NO during inflammation. Constitutively expressed NOS has been shown to be critical to normal physiology and inhibition of these enzymes (nNOS or eNOS) caused damage. It has been proposed that the high output production of NO from iNOS causes injury, perhaps through the generation of potent radicals such as peroxynitrite and hence may explain the apparent dichotomous role of NO. However, recent studies have challenged this simple paradigm providing evidence that iNOS may have some protective role in some inflammatory models. Moreover, the importance of peroxynitrite has been questioned. In this review we discuss the role of cNOS and iNOS in intestinal inflammation and provide an overview of peroxynitrite in intestinal inflammation, highlighting some of the controversy that exists.

Lefer, D. J. and D. N. Granger (2000). "Oxidative stress and cardiac disease." The American Journal of Medicine 109(4): 315-323.

Reactive oxygen species (ROS) are formed at an accelerated rate in postischemic myocardium. Cardiac myocytes, endothelial cells, and infiltrating neutrophils contribute to this ROS production. Exposure of these cellular components of the myocardium to exogenous ROS can lead to cellular dysfunction and necrosis. While it remains uncertain whether ROS contribute to the pathogenesis of myocardial infarction, there is strong support for ROS as mediators of the reversible ventricular dysfunction (stunning) that often accompanies reperfusion of the ischemic myocardium. The therapeutic potential of free radical-directed drugs in cardiac disease has not been fully realized.

McCord, J. M. (2000). "The evolution of free radicals and oxidative stress." The American Journal of Medicine 108(8): 652-659.

The superoxide free radical has come to occupy an amazingly central role in a wide variety of diseases. Our metabolic focus on aerobic energy metabolism in all cell types, coupled with some chemical peculiarities of the oxygen molecule itself, contribute to the phenomenon. Superoxide is not, as we once thought, just a toxic but unavoidable byproduct of oxygen metabolism. Rather it appears to be a carefully regulated metabolite capable of signaling and communicating important information to the cell's genetic machinery. Redox regulation of gene expression by superoxide and other related oxidants and antioxidants is beginning to unfold as a vital mechanism in health and disease.

Nath, K. A. and S. M. Norby (2000). "Reactive oxygen species and acute renal failure." The American Journal of Medicine 109(8): 665-678.

Acute renal failure is commonly due to acute tubular necrosis (ATN), the latter representing an acute, usually reversible loss of renal function incurred from ischemic or nephrotoxic insults occurring singly or in combination. Such insults instigate a number of processes--hemodynamic alterations, aberrant vascular responses, sublethal and lethal cell damage, inflammatory responses, and nephron obstruction--that initiate and maintain ATN. Eventually, reparative and regenerative processes facilitate the resolution of renal injury and the recovery of renal function. Focusing mainly on ischemic ATN, this article reviews evidence indicating that the inordinate or aberrant generation of reactive oxygen species (ROS) may contribute to the initiation and maintenance of ATN. This review also discusses the possibility that ROS may instigate adaptive as well as maladaptive responses in the kidney with ATN, and raises the possibility that ROS may participate in the recovery phase of ATN.

Praticò, D. and N. Delanty (2000). "Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease." The American Journal of Medicine 109(7): 577-585.

Alzheimer's disease is one of the most challenging brain disorders and has profound medical and social consequences. It affects approximately 15 million persons worldwide, and many more family members and care givers are touched by the disease. The initiating molecular event(s) is not known, and its pathophysiology is highly complex. However, free radical injury appears to be a fundamental process contributing to the neuronal death seen in the disorder, and this hypothesis is supported by many (although not all) studies using surrogate markers of oxidative damage. In vitro and animal studies suggest that various compounds with antioxidant ability can attenuate the oxidative stress induced by beta-amyloid. Recently, clinical trials have demonstrated potential benefits from treatment with the antioxidants, vitamin E, selegiline, extract of Gingko biloba, and idebenone. Further studies are warranted to confirm these findings and explore the optimum timing and antioxidant combination of such treatments in this therapeutically frustrating disease.

Rust, C. and G. J. Gores (2000). "Apoptosis and liver disease." The American Journal of Medicine 108(7): 567-574.

Considering the important role of apoptosis in a growing number of physiological and pathophysiological conditions, it is interesting to note that research in this field is surprisingly young. Although the term apoptosis was first introduced by Kerr in 1972 [1], little was known about apoptosis until the mid-1980s. However, in the last 15 years things have changed considerably, and by now papers published on apoptosis are growing exponentially each year. Especially in the past few years, significant advances have been made in our understanding of cell death by apoptosis. Indeed, apoptosis has now emerged as a fundamental process in tissue homeostasis and is vital for the necessary balance between cell loss and cell gain in normal tissue [2]. In normal tissue, rates of mitosis are therefore counterbalanced by rates of apoptosis [3]. Of equal importance, apoptosis is nature’s way of eliminating unwanted, senescent, and damaged cells from multicellular organisms [4]. Given the pivotal role of apoptosis in cell homeostasis, it is not surprising that basic apoptotic mechanisms are highly conserved in evolution [5]. Any kind of dysregulation of apoptosis is potentially deleterious and can have profound consequences. The liver is no exception, and we now realize that dysregulation of apoptosis is a principal mechanism contributing to many liver diseases. Indeed, excessive apoptosis can lead to severe liver damage, as can be exemplified by fulminant hepatic failure seen after experimental induction of apoptosis in mice [6]. On the other hand, failure of apoptosis has been implied as a major determinant in development of hepatocellular carcinoma such as occurs with mutations of p53 [7]. Treatment strategies to moderate apoptosis are therefore desirable to inhibit apoptosis in liver injury and selectively induce apoptosis in malignant liver tumors. Apoptosis is not only important in the pathophysiology of humanliver diseases, it is also on the edge of entering clinical practice by providing new treatment opportunities. Our intention is to provide a useful overview of the current knowledge of apoptosis in liver diseases, especially for the reader new to the field of apoptosis. Although apoptosis has been identified in a variety of humanliver diseases [8], in this review we will focus on alcoholic liver disease, viral hepatitis, cholestatic liver diseases, and hepatocellular carcinoma (HCC).

der Vliet, A. and C. E. Cross (2000). "Oxidants, nitrosants, and the lung." The American Journal of Medicine 109(5): 398-421.

The respiratory tract is subjected to a variety of environmental stresses, including oxidizing gases, particulates, and airborne microorganisms, that together, may injure structural and functional lung components and thereby jeopardize the primary lung function of gas exchange. To cope with such various environmental threats, the lung has developed elaborate defense mechanisms that include inflammatory-immune pathways as well as several antioxidant systems. These defense systems operate largely in extracellular spaces, thus protecting underlying bronchial and alveolar epithelial cells from injury, although these cells themselves are also active participants in such (inflammatory) defense mechanisms. Although potentially harmful, oxidants are increasingly recognized as pathophysiologic mediators produced primarily by inflammatory-immune cells as a host defense mechanism, but also by various other cell types as an intracellular mediator in various cell responses, thus affecting inflammatory-immune processes or inducing resistance. The molecular mechanisms and signaling pathways involved in such processes are the focus of much current investigation. Nitric oxide, a messenger molecule produced by many lung cell types, also modulates oxidant-mediated processes, thereby giving rise to a new family of reactive nitrogen species ("nitrosants") with potentially unique signaling properties. The complex role of oxidants and nitrosants in various pathophysiologic processes in the lung haveconfounded the design of therapeutic approaches with antioxidant substrates. This review discusses current knowledge regarding extracellular antioxidant defenses in the lung, and oxidant/nitrosant mechanisms operating under inflammatory-immune conditions and their potential contribution to common lung diseases. Finally, some recent developments in antioxidant therapeutic strategies are discussed.

Weinstein, R. S. and S. C. Manolagas (2000). "Apoptosis and osteoporosis." The American Journal of Medicine 108(2): 153-164.

During normal bone remodeling, the rate of supply of new osteoblasts and osteoclasts and the timing of the death of osteoclasts, osteoblasts, and osteocytes by apoptosis are critical determinants of the initiation of new BMUs and the extension or reduction of the lifetime of existing ones. Disruption of the fine balance among these processes may be an important mechanism behind the deranged bone turnover found in most metabolic disorders of the adult skeleton. Like most armies, the amount 5 of work done by bone cells is far more dependent on numbers than vigor. Therapeutic agents that alter the prevalence of apoptosis of osteoblasts and osteoclasts can correct the imbalance in cell numbers that is the basis of the diminished bone mass and increased risk of fractures in osteoporosis.

Adler, S. and H. R. Brady (1999). "Cell adhesion molecules and the glomerulopathies." The American Journal of Medicine 107(4): 371-386.

The kidney possesses a unique architecture that allows it to carry out its function of purifying the blood through filtration and tubular reabsorption and secretion. This structure is established and maintained through the interactions of renal cells with the extracellular matrix (ECM) consisting of the glomerular, Bowman’s capsular, tubular and other vascular basement membranes, and the mesangial and tubulointerstitial matrices. These ECMs and basement membranes form a supporting scaffolding for renal cells that help guide the formation, function, and repair of renal structures. Cells, however, do not passively occupy a site on the ECM but interact with it through specific cell adhesion molecules that mediate attachment to the ECM. Work over the past decade has demonstrated that these receptors function as a two-way conduit between the cell and the ECM. Thus, the ECM influences cellular morphology, proliferative, synthetic, and metabolic states, and responsiveness to several extracellular factors while events in the cell can affect how matrix receptors bind to the ECM. Other cell adhesion molecules mediate interactions between cells, playing a role in renal morphogenesis and maintenance of tubular epithelial polarity, as well as providing a foothold for circulating leukocytes and platelets to gain access to areas of injury and inflammation. These receptors help determine the extent and type of inflammation in the kidney in response to diverse injuries, as well as modulating some of the inflammatory mediators that are produced. In this review we will initially discuss receptors that mediate cell-matrix interactions and their roles in the normal kidney and in the response to injury. The second part will concentrate on cell-cell interactions that play an important role in leukocyte and platelet recruitment in inflammation and thrombosis.

Andreoli, T. E. (1999). "The Apoptotic Syndromes". The American Journal of Medicine 107(5): 488-488.

Boonyapisit, K., H. J. Kaminski, et al. (1999). "Disorders of neuromuscular junction ion channels." The American Journal of Medicine 106(1): 97-113.

Ion channel defects produce a clinically diverse set of disorders that range from cystic fibrosis and some forms of migraine to renal tubular defects and episodic ataxias. This review discusses diseases related to impaired function of the skeletal muscle acetylcholine receptor and calcium channels of the motor nerve terminal. Myasthenia gravis is an autoimmune disease caused by antibodies directed toward the skeletal muscle acetylcholine receptor that compromise neuromuscular transmission. Congenital myasthenias are genetic disorders, a subset of which arecaused by mutations of the acetylcholine receptor. Lambert-Eaton myasthenic syndrome is an immune disorder characterized by impaired synaptic vesicle release likely related to a defect of calcium influx. The disorders will illustrate new insights into synaptic transmission and ion channel structure that are relevant for all ion channel disorders.

Brown, E. M. (1999). "Physiology and pathophysiology of the extracellular calcium-sensing receptor." The American Journal of Medicine 106(2): 238-253.

The system governing extracellular calcium (Ca2+o) homeostasis maintains near constancy of Ca2+o so as to ensure continual availability of calcium ions for their numerous intracellular and extracellular roles. In contrast to the intracellular ionized calcium concentration (Ca2+i), which varies substantially during intracellular signaling via this key second messenger, Ca2+o remains nearly invariant. Yet there must be a mechanism that senses small changes in Ca2+o so as to set into motion the homeostatic responses that return Ca2+o to its normal level. The recent identification and molecular cloning of the mechanism through which parathyroid cells and a number of other cell types sense Ca2+o, a G protein-coupled Ca2+o-sensing receptor (CaR), has proven unequivocally that extracellular calcium ions serve in an informational capacity. The CaR permits Ca2+o to function in a hormone-like role as an extracellular first messen-ger through which parathyroid, kidney, and other cells communicate with one another via the CaR. The identification of inherited human hypercalcemic and hypocalcemic disorders arising from inactivating and activating mutations of the CaR, respectively, has provided additional proof of the essential, nonredundant role of the CaR in mineral ion homeostasis. Moreover, CaR-active drugs are currently in clinical trials for the treatment of primary and uremic hyperparathyroidism, disorders in which there are acquired, tissue-specific reductions in CaR expression and, in turn, defective Ca2+o-sensing by pathological parathyroid cells. No doubt further studies of Ca2+o-sensing by the CaR will reveal additional functions of Ca2+o, not only as a systemic "hormone" but also in local, paracrine, and autocrine signaling through this novel Ca2+o-sensing receptor.

James, T. N. (1999). "Apoptosis in cardiac disease." The American Journal of Medicine 107(6): 606-620.

Kevil, C. G. and D. C. Bullard (1999). "Roles of leukocyte/endothelial cell adhesion molecules in the pathogenesis of vasculitis." The American Journal of Medicine 106(6): 677-687.

Vasculitis is defined simply as blood vessel inflammation. Many different inflammatory diseases that damage vascular tissue have been described (Table 1). The pathogenetic mechanisms that lead to localized vascular injury and inflammation have been actively studied. Much of this work has been devoted to identifying the stimuli that initiate lesion formation in various vasculitic diseases. These stimuli include antineutrophil cytoplasmic antibodies (ANCA), anti-endothelial antibodies (AECA), immune complex deposition, complement activation, and infectious agents. How do such diverse stimuli induce the destruction of specific segments of the vasculature? Studies using both in vivo and in vitro systems suggest that they induce the expression of adhesion molecules on leukocytes and endothelial cells, which mediate leukocytic interactions and damage to the blood vessel. This review highlights some of the experimental evidence implicating adhesion molecules as important determinants in both the initiation and progression of vasculitic lesions.

Malloy, P. J. and D. Feldman (1999). "Vitamin D resistance." The American Journal of Medicine 106(3): 355-370.

This review will discuss the syndrome of hereditary hypocalcemic rickets due to generalized resistance to the action of the active vitamin D hormone, 1α,25-dihydroxyvitamin D. Historically, this entity usually has been refered to as “vitamin D–dependent rickets, type II (VDDR II). However, now that the biochemical basis of the disease is understood, we prefer the terminology “hereditary vitamin D–resistant rickets ” (HVDRR). In order to describe the syndrome of HVDRR, we will first briefly discuss the vitamin D endocrine system, the mechanism of action of 1,25(OH)2D, and the nature of the vitamin D receptor (VDR). After this background is presented, we will then portray the syndrome of HVDRR and detail the heterogeneous mutations in the VDR that cause the vitamin D–resistant state. Various aspects of vitamin D metabolism and action as well as the syndrome of HVDRR recently have been reviewed in the volume entitled Vitamin D [1].

Molitoris, B. A. and J. Marrs (1999). "The role of cell adhesion molecules in ischemic acute renal failure." The American Journal of Medicine 106(5): 583-592.

Ischemia remains the primary cause of acute renal failure in adults. Following the development and practical application of dialysis, little progress has been made in the treatment of ischemic acute renal failure (ARF) to significantly affect patient outcome. However, excellent advancement has occurred in the understanding of the cellular consequences of ischemic injury. This has occurred through an integrated approach using complementary in vivo and in vitro models of ischemic cell injury. Fundamental insights into the physiology, biochemistry, cell biology, and molecular biology of ischemic cell injury have now resulted in new clinical trials and renewed optimism. These combined basic science and clinical research approaches to design and test new therapies were recently reviewed to identify priorities by a NIH supported conference (1). Since substantial progress has been made in the pathophysiologic aspects of cell adhesion molecules in the injury and recovery phases of ischemic ARF, the purpose of this review is to delineate and synthesize these findings. Although brief introductions will be given to the different classes of cell adhesion molecules (CAMs), the reader is referred to the original article in this series, which dealt exclusively with the structure and cellular function of these molecules (2).

Paine, R. and P. A. Ward (1999). "Cell adhesion molecules and pulmonary fibrosis." The American Journal of Medicine 107(3): 268-279.

Pulmonary fibrosis comprises a group of conditions with common pathologic and physiologic responses in the lung. Pulmonary fibrosis results from a very wide variety of causes, listed in the Table [1]. These include inhalational exposure to inorganic and organic agents (eg, cadmium, asbestos fibers, thermophillic actinomycetes, etc), inflammatory response to infectious agents, collagen vascular diseases, and late responses to the acute respiratory distress syndrome. Up to one half of the cases are idiopathic, with no specific etiology or associated condition identified despite thorough evaluation. Pulmonary fibrosis is a major source of morbidity and mortality. Patients typically present with symptoms of cough and dyspnea; when the condition progresses, chronic respiratory failure and cor pulmonale often ensue. Although some forms of pulmonary fibrosis of known origin may have a better prognosis, idiopathic pulmonary fibrosis (IPF) is a progressive condition that rarely, if ever, remits spontaneously [2]. In large series, the 5-year survival of patients with IPF was less than 50%. Unfortunately, despite intensive investigation, the results of therapy for IPF have remained poor. First-line therapy with corticosteroids offers only a 15% to 20% response rate despite very significant side effects. More aggressive immunosuppressive therapy with cytotoxic agents has had only a modest impact on the outcome of the disease. This pessimistic picture regarding treatment for IPF has spurred increased interest in investigations into the pathogenesis of pulmonary fibrosis. A better understanding of the mechanisms responsible for the initiation and maintenance of the fibrotic process may lead to new approaches to therapy that will improve the outcome of this devastating condition. It is clear that cell–cell interactions as well as cell–extracellular matrix interactions are critical for the pathogenesis of pulmonary fibrosis. One of the essential mechanisms by which cells interact with the microenvironment is through the expression of cell adhesion molecules (CAMs). Recent progress in our understanding of the biology of CAMs has suggested that there are several points at which these molecules play critical roles in the pathogenesis of pulmonary fibrosis, and offers hope for new therapeutic modalities.

Petruzzelli, L., M. Takami, et al. (1999). "Structure and function of cell adhesion molecules." The American Journal of Medicine 106(4): 467-476.

The ability of cells to adhere through specific molecular interactions plays a critical role in a wide array of biologic processes that include hemostasis, the immune response, inflammation embryogenesis, and development of neuronal tissue [1, 2, 3, 4, 5, 6, 7, 8, 9 and 10]. Over the last decade there has been a rapid progression in our understanding of the molecules that mediate cell–cell adhesion and adhesion of cells to proteins within the extracellular matrix [3, 8, 10 and 11]. With the elucidation of specific molecular components and the classification of these moieties based on their structural or functional similarities has come the observation that this process is complex, well orchestrated, and under sophisticated regulatory control [8 and 10]. The adhesive interactions between cells and the interactions of cells with extracellular matrix proteins play a role in embryonic and organ development, in host defense, and in the maintenance of vascular and epithelial integrity [1]. The loss of adhesive interactions as well as a stimulation of adhesion may result in disease states (Table 1A and Table 1B). In this review we will first describe the classes of molecules involved in cellular adhesion and then discuss how adhesive interactions can be modulated in several biologic models. The choices of adhesive phenomena included in this presentation by no means cover the vast array of systems for which the molecular components are known. We have chosen several examples to provide an overall understanding and characterization of the molecular events involved in cellular adhesion.

Price, D. T. and J. Loscalzo (1999). "Cellular adhesion molecules and atherogenesis." The American Journal of Medicine 107(1): 85-97.

Atherosclerosis as manifested by coronary, cerebral, and peripheral arterial vascular disease is the leading cause of morbidity and mortality in the United States. Our understanding of the process of atherogenesis has evolved from the epidemiologic identification of cardiac risk factors to an increasing understanding of the molecular basis of vascular pathobiology. Evidence for the role of chronic inflammation in atherogenesis has been accumulating over the last decade and suggests that a generalized cellular and humoral inflammatory response promotes the formation of the atherosclerotic plaque. To target potential sites of intervention by which to inhibit or arrest the progression of atherosclerosis, an understanding of the molecular determinants of inflammation in the vasculature is critical. Localization of the cellular inflammatory response and regulation of the humoral inflammatory response are both mediated through the interactions of a group of specialized molecules, collectively referred to as cellular adhesion molecules. The cell-surface expression of these molecules in response to pathophysiological stimuli mediates the interaction between the endothelium and blood cells central to the development of atherosclerosis. As initially described, adhesion molecules serve as mediators of cell–cell and cell–matrix interactions. More recently, these molecules have been shown to participate in cell emigration, signaling functions, and other vascular physiological responses. The structure, function, and regulation of these specialized molecules in atherogenesis are the focus of this review.

Rabb, H. and J. V. Bonventre (1999). "Leukocyte adhesion molecules in transplantation." The American Journal of Medicine 107(2): 157-165.

Dramatic developments in organ transplantation have revolutionized the care of the patient with a failing organ. Despite these advances, however, acute and chronic rejection remain important clinical problems. As reflected by the contributions in this series, in the past decade there have been great advances in our knowledge of characteristics of cellular adhesion molecules and the contributions of those molecules to disease processes. The ground work has been laid for a better understanding of the mechanisms involved in allograft rejection, detection of early rejection, and development of therapies that will extend graft survival and improve the care of the transplant patient. We will review some of the roles played by adhesion molecules in pathophysiology, diagnosis, and treatment in organ transplantation. At the present time, the organ most commonly transplanted is the kidney. Thus, kidney transplantation will be the focus for much of the discussion. Because of the pivotal role of the leukocyte in the immune response to transplantation, we will limit this review to the leukocyte–endothelial adhesion molecules (LAMs). Because of space limitations, this review cannot be exhaustive and will, by necessity, leave out important contributions.

Saikumar, P., Z. Dong, et al. (1999). "Apoptosis: definition, mechanisms, and relevance to disease." The American Journal of Medicine 107(5): 489-506.

Andreoli, T. E. (1998). "Diseases of receptors: introductory comments." The American Journal of Medicine 105(3): 242-243.

This issue of The American Journal of Medicine begins the second group of articles in the Series “Physiology in Medicine” (PIM), cosponsored by The Journal and the American Physiological Society (APS). As with the prior series on channel disorders, this series focuses on a particular topic, in this case, diseases of receptors, and attempts to show how this ecumenical biologic theme crosses many traditional departmental lines.

Bichet, D. G. (1998). "Nephrogenic diabetes insipidus." The American Journal of Medicine 105(5): 431-442.

In nephrogenic diabetes insipidus, the kidney is unable to concentrate urine despite normal or elevated concentrations of the antidiuretic hormone arginine vasopressin (AVP). In congenital nephrogenic diabetes insipidus (NDI), the obvious clinical manifestations of the disease, that is polyuria and polydipsia, are present at birth and need to be immediately recognized to avoid severe episodes of dehydration. Most (>90%) congenital NDI patients have mutations in the AVPR2 gene, the Xq28 gene coding for the vasopressin V2 (antidiuretic) receptor. In <10% of the families studied, congenital NDI has an autosomal recessive inheritance and mutations of the aquaporin-2 gene (AQP2), ie, the vasopressin-sensitive water channel, have been identified. When studied in vitro, most AVPR2 mutations lead to receptors that are trapped intracellularly and are unable to reach the plasma membrane. A minority of the mutant receptors reach the cell surface but are unable to bind AVP or to trigger an intracellular cyclic adenosine-monophosphate (cAMP) signal. Similarly AQP2 mutant proteins are trapped intracellularly and cannot be expressed at the luminal membrane. The acquired form of NDI is much more common than the congenital form, is almost always less severe, and is associated with downregulation of AQP2. The advances described here are examples of "bedside physiology" and provide diagnostic tools for physicians caring for these patients.

Bodenner, D. L. and R. W. Lash (1998). "Thyroid disease mediated by molecular defects in cell surface and nuclear receptors." The American Journal of Medicine 105(6): 524-538.

Guay-Woodford, L. M. (1998). "Bartter syndrome: unraveling the pathophysiologic enigma." The American Journal of Medicine 105(2): 151-161.

Familial hypokalemic, hypochloremic metabolic alkalosis, or Bartter syndrome, is not a single disorder but rather a set of closely related disorders. These Bartter-like syndromes share many of the same physiologic derangements, but differ with regard to the age of onset, the presenting symptoms, the magnitude of urinary potassium (K) and prostaglandin excretion, and the extent of urinary calcium excretion. At least three clinical phenotypes have been distinguished: (1) classic Bartter syndrome; (2) the hypocalciuric-hypomagnesemic Gitelman variant; and (3) the antenatal hypercalciuric variant (also termed hyperprostaglandin E syndrome). The fundamental pathogenesis of this complex set of disorders has long fascinated and stymied investigators. Physiologic investigations have suggested numerous pathogenic models. The cloning of genes encoding renal transport proteins has provided molecular tools to begin testing these hypotheses. To date, molecular genetic analyses have determined that mutations in the gene encoding the thiazide-sensitive sodium-chloride (Na-Cl) cotransporter underlie the pathogenesis of the Gitelman variant. In comparison, the antenatal variant is genetically heterogeneous with mutations in the genes encoding either the bumetanide-sensitive sodium-potassium-chloride (Na-K-2Cl) cotransporter or the luminal, ATP-regulated, K channel. With these data, investigators have begun to unravel the pathophysiologic enigma of the Bartter-like syndromes. Further studies will help refine pathogenic models for this set of disorders as well as provide new insights into the normal mechanisms of renal electrolyte transport.

Hebert, S. C. (1998). "General Principles of the Structure of Ion Channels." The American Journal of Medicine 104(1): 87-98.

Hunter, S. J. and W. T. Garvey (1998). "Insulin action and insulin resistance: diseases involving defects in insulin receptors, signal transduction, and the glucose transport effector system." The American Journal of Medicine 105(4): 331-345.

Katz, A. M. (1998). "Selectivity and Toxicity of Antiarrhythmic Drugs: Molecular Interactions with Ion Channels." The American Journal of Medicine 104(2): 179-195.

Disorders of cardiac rate and rhythm, the arrhythmias, represent major causes of mortality and morbidity in the developed world. Sudden cardiac death, defined as death within 1 hour of a sudden and unexpected change in cardiovascular status, kills more than 300,000 each year in the United States [1]. Nonlethal arrhythmias account for additional disability. Atrial fibrillation, which is a major cause of cerebrovascular accidents, occurs in more than 1% of patients over the age of 60, and as many as 10% in those over 70 years of age [2]. The most effective strategy to deal with sudden cardiac death is obviously prevention, whereas for chronic arrhythmias that are not life-threatening, therapeutic goals are less clear. In atrial fibrillation, treatment includes conversion to sinus rhythm and rate control, as well as anticoagulation to prevent stroke. Management of other arrhythmias, notably paroxysmal tachycardias and premature systoles, is more problematical because, as discussed below, drug therapy for nonlethal arrhythmias can increase the likelihood of a lethal arrhythmia. Only a few years ago, the goals of both arrhythmia prevention and arrhythmia treatment were met largely by the use of antiarrhythmic drugs. It is both good and bad news, however, that use of this once-common approach to therapy has been seriously curtailed in recent years. The good news is that advances in ablation therapy allow a growing number of arrhythmias to be cured permanently, and that implantation of cardiac defibrillators can prevent sudden death in patients at high risk for lethal arrhythmias. The bad news, however, is that antiarrhythmic drugs are far more dangerous than had been believed. Especially dramatic was the Cardiac Arrhythmia Suppression Trial (CAST) [4], which examined several antiarrhythmic drugs, each of which reduced the frequency of premature ventricular beats known to herald a high risk of subsequent lethal arrhythmia. In this trial, not only did these drugs not prevent sudden death, but in the high-risk population studied, all dramatically increased total mortality. The present article addresses the mechanisms responsible for these important clinical findings, and seeks to explain why a given drug can, at the same time, be both antiarrhythmic and proarrhythmic. As emphasis is on basic mechanisms rather than clinical practice, the article begins with a discussion of the ion channels responsible for the heart’s electrical activity. The molecular structures of these membrane proteins are described, after which interactions between antiarrhythmic drugs and ion channels are reviewed. This information is then analyzed in an effort to explain why a given drug can, on the one hand, suppress some arrhythmogenic mechanisms while at the same time increase the risk of other, and often more dangerous, arrhythmias.

Loke, J. and D. H. MacLennan (1998). "Malignant Hyperthermia and Central Core Disease: Disorders of Ca2 Release Channels." The American Journal of Medicine 104(5): 470-486.

Palmer, B. F. and R. J. Alpern (1998). "Liddle's Syndrome." The American Journal of Medicine 104(3): 301-309.

Ptácek, L. (1998). "The familial periodic paralyses and nondystrophic myotonias." The American Journal of Medicine 105(1): 58-70.

The periodic paralyses are divided into hypokalemic, hyperkalemic, and paramyotonic forms [1]. A normokalemic form has been included in the literature but most (if not all) patients with this disorder have hyperkalemic periodic paralysis. Over the past decade, a combination of electrophysiologic and molecular biologic studies have led to reclassification of the disease (Table 1). All forms of periodic paralysis are either autosomal dominantly inherited or occur as sporadic cases that are probably the result of new mutations. It has become apparent that there are two broad categories of disease, each resulting from mutations in a distinct gene: hyperkalemic periodic paralysis (hyperKPP) and hypokalemic periodic paralysis (hypoKPP). In hyperKPP, the disease results from mutations in a skeletal muscle, voltage-gated sodium channel gene.