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APS Physiology in Medicine reviews, 1998-2011: Home

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

Physiology in Medicine

Physiology in Medicine: Review articles from the American Physiological Society

The aim of this series is to provide practicing MD’s and/or researchers an up-to-date physiological understanding of disease with the proper application of new molecular models and tools. Articles published in this series are intended to provide a thoughtful and lucid linkage of science to the patient.

This page provides links to all articles in the series from 1998-2011.

From 1998-2001, the reviews were published in the American Journal of Medicine. From 2001-2011, these articles were published in the Annals of Internal Medicine.

Note: as of 2011, the APS Publications Committee has launched an initiative to continue the series. Future PIM articles will be published in the various APS journals, with each journal soliciting PIM articles in their area of focus.

Physiology in Medicine: 1998 - present (scroll down for earlier reviews)

Looking for a particular review? Use Find in Page (Ctrl + F)

Afshar, M., M. Raju, et al. (2011). "Narrative review: tetanus-a health threat after natural disasters in developing countries." Annals of Internal Medicine 154(5): 329-335.

Tetanus is an expected complication when disasters strike in developing countries, where tetanus immunization coverage is often low or nonexistent. Collapsing structures and swirling debris inflict numerous crush injuries, fractures, and serious wounds. Clostridium tetani infects wounds contaminated with dirt, feces, or saliva and releases neurotoxins that may cause fatal disease. Clusters of infections have recently occurred after tsunamis and earthquakes in Indonesia, Kashmir, and Haiti. The emergency response to clusters of tetanus infections in developing countries after a natural disaster requires a multidisciplinary approach in the absence of an intensive care unit, readily available resources, and a functioning cold-chain system. It is essential that injured people receive immediate surgical and medical care of contaminated, open wounds with immunization and immunoglobulin therapy. Successful treatment of tetanus depends on prompt diagnosis of clinical tetanus, treatment to ensure neutralization of circulating toxin and elimination of C. tetani infection, control of spasms and convulsions, maintenance of the airway, and management of respiratory failure and autonomic dysfunction.

Druey, K. M. and P. R. Greipp (2010). "Narrative review: the systemic capillary leak syndrome." Annals of Internal Medicine 153(2): 90-98.

The systemic capillary leak syndrome (SCLS) is a rare disease of reversible plasma extravasation and vascular collapse accompanied by hemoconcentration and hypoalbuminemia. Its cause is unknown, although it is believed to be a manifestation of transient endothelial dysfunction due to endothelial contraction, apoptosis, injury, or a combination of these. Fewer than 150 cases of SCLS have been reported, but the condition is probably underrecognized because of its nonspecific symptoms and signs and high mortality rate. Patients experience shock and massive edema, often after a nonspecific prodrome of weakness, fatigue, and myalgias, and are at risk for ischemia-induced organ failure, rhabdomyolysis and muscle compartment syndromes, and venous thromboembolism. Shock and edema reverse almost as quickly as they begin, at which time patients are at risk for death from flash pulmonary edema during rapid fluid remobilization. Diagnosis is made clinically and by exclusion of other diseases that cause similar symptoms and signs, most notably sepsis, anaphylaxis, and angioedema. Acute episodes are treated with vasopressor therapy and judicious fluid replacement, possibly with colloid solutions for their osmotic effects, to prevent the sequelae of underperfusion. Between episodes, patients may be treated with theophylline and terbutaline, which clinical experience suggests may reduce the severity and frequency of acute episodes. Prognosis is uncertain, but patients who survive an initial severe SCLS episode are estimated to have a 10-year survival rate greater than 70%. Much remains to be learned about SCLS, and clinicians should consider the diagnosis in patients with unexplained edema, increased hematocrit, and hypotension. [References: 90]

Flaherty, K. T. (2010). "Narrative review: BRAF opens the door for therapeutic advances in melanoma." Annals of Internal Medicine 153(9): 587-591.

Patients with metastatic melanoma have a poor prognosis and limited treatment options. In about one half of analyzed patients with metastatic melanoma, a mutated signal transduction molecule has been identified: v-raf murine sarcoma viral oncogene homolog B1 (BRAF). This molecule is part of an intracellular signaling cascade and may play a role in many different types of cancer. This article provides an overview of the current treatment options for metastatic melanoma and describes the pathophysiology underlying the development of therapies based on inhibition of BRAF. It summarizes findings of phase 1 and phase 2 studies of BRAF inhibitor therapy primarily in patients with metastatic melanoma, who have shown objective response rates of 70% to 80%. However, initial responses have not been sustained, with a median time to relapse of approximately 9 months. Clinicians should be aware of phase 3 trials of these agents and trials combining these therapies with other novel therapies because, at a minimum, BRAF inhibitors seem to be valuable as palliative therapy for metastatic melanoma.

Kelesidis, T., I. Kelesidis, et al. (2010). "Narrative review: the role of leptin in human physiology: emerging clinical applications." Annals of Internal Medicine 152(2): 93-100.

Leptin is a hormone secreted by adipose tissue in direct proportion to amount of body fat. The circulating leptin levels serve as a gauge of energy stores, thereby directing the regulation of energy homeostasis, neuroendocrine function, and metabolism. Persons with congenital deficiency are obese, and treatment with leptin results in dramatic weight loss through decreased food intake and possible increased energy expenditure. However, most obese persons are resistant to the weight-reducing effects of leptin. Recent studies suggest that leptin is physiologically more important as an indicator of energy deficiency, rather than energy excess, and may mediate adaptation by driving increased food intake and directing neuroendocrine function to converse energy, such as inducing hypothalamic hypogonadism to prevent fertilization. Current studies investigate the role of leptin in weight-loss management because persons who have recently lost weight have relative leptin deficiency that may drive them to regain weight. Leptin deficiency is also evident in patients with diet- or exercise-induced hypothalamic amenorrhea and lipoatrophy. Replacement of leptin in physiologic doses restores ovulatory menstruation in women with hypothalamic amenorrhea and improves metabolic dysfunction in patients with lipoatrophy, including lipoatrophy associated with HIV or highly active antiretroviral therapy. The applications of leptin continue to grow and will hopefully soon be used therapeutically. [References: 70]

Levine, S. J. and S. E. Wenzel (2010). "Narrative review: the role of Th2 immune pathway modulation in the treatment of severe asthma and its phenotypes." Annals of Internal Medicine 152(4): 232-237.

New therapeutic approaches are needed for patients with severe asthma who are refractory to standard therapy comprising high doses of inhaled corticosteroids plus long-acting beta(2)-agonists. Current treatment guidelines for patients with severe asthma from the National Asthma Education and Prevention Program recommend the addition of oral corticosteroids, which are associated with substantial morbidity, and, for those with allergic asthma, anti-IgE. Genetic and translational studies, as well as clinical trials, suggest that in a subgroup of patients, the pathobiology of severe asthma is mediated by immune pathways driven by T-helper 2 (Th2)-type CD4(+) T cells, which produce a characteristic repertoire of interleukins (ILs), including IL-4, IL-5, and IL-13. Therefore, biological modifiers of Th2-type ILs, such as monoclonal antibodies, soluble receptors, and receptor antagonists, are a rational strategy for developing new treatment approaches but will need to be targeted to selected patients in whom the appropriate Th2 immune pathway is "active." The benefits of immune-modifier therapies targeting Th2-type cytokines, however, need to be weighed against the toxicities associated with inhibition of key biological pathways, as well as the expense of future medications. Therefore, future clinical trials need to clearly establish the efficacy and safety of biological modifiers of Th2 immune pathways before these approaches can enter routine clinical practice for the treatment of severe asthma. [References: 44]

Rosenbloom, J., S. V. Castro, et al. (2010). "Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies." Annals of Internal Medicine 152(3): 159-166.

Abnormal and exaggerated deposition of extracellular matrix is the hallmark of many fibrotic diseases, including systemic sclerosis and pulmonary, liver, and kidney fibrosis. The spectrum of affected organs, the usually progressive nature of the fibrotic process, the large number of affected persons, and the absence of effective treatment pose an enormous challenge when treating fibrotic diseases. Delineation of the central role of transforming growth factor-beta (TGF-beta) and identification of the specific cellular receptors, kinases, and other mediators involved in the fibrotic process have provided a sound basis for development of effective therapies. The inhibition of signaling pathways activated by TGF-beta represents a novel therapeutic approach for the fibrotic disorders. One of these TGF-beta pathways results in the activation of the nonreceptor tyrosine kinase cellular Abelson (c-Abl), and c-Abl inhibitors, including imatinib mesylate, diminishing the fibrogenic effects of TGF-beta. Thus, recently acquired basic knowledge about the pathogenesis of the fibrotic process has enabled the development of novel therapeutic agents capable of modifying the deleterious effects of the fibrotic diseases. [References: 117]

Spivak, J. L. (2010). "Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation." Annals of Internal Medicine 152(5): 300-306.

The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus. [References: 59]

Tobin, M. J., F. Laghi, et al. (2010). "Narrative review: ventilator-induced respiratory muscle weakness." Annals of Internal Medicine 153(4): 240-245.

Clinicians have long been aware that substantial lung injury results when mechanical ventilation imposes too much stress on the pulmonary parenchyma. Evidence is accruing that substantial injury may also result when the ventilator imposes too little stress on the respiratory muscles. Through adjustment of ventilator settings and administration of pharmacotherapy, the respiratory muscles may be rendered almost (or completely) inactive. Research in animals has shown that diaphragmatic inactivity produces severe injury and atrophy of muscle fibers. Human data have recently revealed that 18 to 69 hours of complete diaphragmatic inactivity associated with mechanical ventilation decreased the cross-sectional areas of diaphragmatic fibers by half or more. The atrophic injury seems to result from increased oxidative stress leading to activation of protein-degradation pathways. Scientific understanding of ventilator-induced respiratory muscle injury has not reached the stage where meaningful controlled trials can be done, and thus, it is not possible to give concrete recommendations for patient management. In the meantime, clinicians are advised to select ventilator settings that avoid both excessive patient effort and excessive respiratory muscle rest. The contour of the airway pressure waveform on a ventilator screen provides the most practical indication of patient effort, and clinicians are advised to pay close attention to the waveform as they titrate ventilator settings. Research on ventilator-induced respiratory muscle injury is in its infancy and portends to be an exciting area to follow. [References: 36]

Wang, L., J. G. Seidman, et al. (2010). "Narrative review: harnessing molecular genetics for the diagnosis and management of hypertrophic cardiomyopathy." Annals of Internal Medicine 152(8): 513-520, W181.

Unexplained cardiac hypertrophy, the diagnostic criterion for hypertrophic cardiomyopathy (HCM), occurs in 1 in 500 adults. Insights into the genetic cause and molecular pathophysiology of HCM are reshaping clinical paradigms for diagnosis and treatment of this common myocardial disorder. Human genetic studies have established that dominant mutations in the proteins that make up the contractile apparatus (the sarcomere) cause HCM. With the current availability of clinical gene-based diagnostics, pathogenic mutations in affected patients can be defined, which can suggest a clinical course and allow definitive preclinical identification of family members at risk for HCM. Genetic discoveries have also fostered mechanistic investigations in model organisms that are engineered to carry human HCM mutations. Novel therapeutic targets have emerged from these fundamental studies and are currently under clinical assessment in humans. The combination of contemporary gene-based diagnosis with new strategies to attenuate disease development and progression is changing the natural history of lifelong cardiac symptoms, arrhythmias, and heart failure from HCM. [References: 70]

Greenlee, M., C. S. Wingo, et al. (2009). "Narrative review: evolving concepts in potassium homeostasis and hypokalemia." Annals of Internal Medicine 150(9): 619-625.

Humans are intermittently exposed to large variations in potassium intake, which range from periods of fasting to ingestion of potassium-rich meals. These fluctuations would abruptly alter plasma potassium concentration if not for rapid mechanisms, primarily in skeletal muscle and the liver, that buffer the changes in plasma potassium concentration by means of transcellular potassium redistribution and feedback control of renal potassium excretion. However, buffers have capacity limits, and even robust feedback control mechanisms require that the perturbation occur before feedback can initiate corrective action. In contrast, feedforward control mechanisms sense the effect of disturbances on the system's homeostasis. This review highlights recent experimental insights into the participation of feedback and feedforward control mechanisms in potassium homeostasis. New data make clear that feedforward homeostatic responses activate when decreased potassium intake is sensed, even when plasma potassium concentration is still within the normal range and before frank hypokalemia ensues, in addition to the classic feedback activation of renal potassium conservation when plasma potassium concentration decreases. Given the clinical importance of dyskalemias in patients, these novel experimental paradigms invite renewed clinical inquiry into this important area. [References: 41]

Joy, T. R. and R. A. Hegele (2009). "Narrative review: statin-related myopathy." Annals of Internal Medicine 150(12): 858-868.

Statin-related myopathy is a clinically important cause of statin intolerance and discontinuation. The spectrum of statin-related myopathy ranges from common but clinically benign myalgia to rare but life-threatening rhabdomyolysis. Observational studies suggest that myalgia can occur in up to 10% of persons prescribed statins, whereas rhabdomyolysis continues to be rare. The mechanisms of statin-related myopathy are unclear. Options for managing statin myopathy include statin switching, particularly to fluvastatin or low-dose rosuvastatin; nondaily dosing regimens; nonstatin alternatives, such as ezetimibe and bile acid-binding resins; and coenzyme Q10 supplementation. Few of these strategies have high-quality evidence supporting them. Because statin-related myopathy will probably become more common with greater numbers of persons starting high-dose statin therapy and the increasing stringency of low-density lipoprotein cholesterol level targets, research to better identify patients at risk for statin myopathy and to evaluate management strategies for statin-related myopathy is warranted. [References: 87]

Sowers, J. R., A. Whaley-Connell, et al. (2009). "Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension." Annals of Internal Medicine 150(11): 776-783.

The prevalence of obesity, diabetes, hypertension, and cardiovascular and chronic kidney disease is increasing in developed countries. Obesity, insulin resistance, and hypertension commonly cluster with other risk factors for cardiovascular and chronic kidney disease to form the metabolic syndrome. Emerging evidence supports a paradigm shift in our understanding of the renin-angiotensin-aldosterone system and in aldosterone's ability to promote insulin resistance and participate in the pathogenesis of the metabolic syndrome and resistant hypertension. Recent data suggest that excess circulating aldosterone promotes the development of both disorders by impairing insulin metabolic signaling and endothelial function, which in turn leads to insulin resistance and cardiovascular and renal structural and functional abnormalities. Indeed, hyperaldosteronism is associated with impaired pancreatic beta-cell function, skeletal muscle insulin sensitivity, and elevated production of proinflammatory adipokines from adipose tissue, which results in systemic inflammation and impaired glucose tolerance. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated in part by aldosterone acting on the mineralocorticoid receptor. Although we have known that mineralocorticoid receptor blockade attenuates cardiovascular and renal injury, only recently have we learned that mineralocorticoid receptor blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation. In summary, aldosterone excess has detrimental metabolic effects that contribute to the metabolic syndrome and endothelial dysfunction, which in turn contribute to the development of resistant hypertension as well as cardiovascular disease and chronic kidney disease. [References: 56]

Vetter, M. L., S. Cardillo, et al. (2009). "Narrative review: effect of bariatric surgery on type 2 diabetes mellitus." Annals of Internal Medicine 150(2): 94-103.

Bariatric surgery leads to substantial and durable weight reduction. Nearly 30% of patients who undergo bariatric surgery have type 2 diabetes, and for many of them, diabetes resolves after surgery (84% to 98% for bypass procedures and 48% to 68% for restrictive procedures). Glycemic control improves in part because of caloric restriction but also because gut peptide secretion changes. Gut peptides, which mediate the enteroinsular axis, include the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, as well as ghrelin and peptide YY. Bariatric surgery (particularly bypass procedures) alters secretion of these gut hormones, which results in enhanced insulin secretion and sensitivity. This review discusses the various bariatric procedures and how they alter the enteroinsular axis. Familiarity with these effects can help physicians decide among the different surgical procedures and avoid postoperative hypoglycemia.

Brodsky, R. A. (2008). "Narrative review: paroxysmal nocturnal hemoglobinuria: the physiology of complement-related hemolytic anemia." Annals of Internal Medicine 148(8): 587-595.

Clinical Principles: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem-cell disorder caused by a somatic mutation in a gene known as phosphatidylinositol glycan class A (PIGA). It may arise de novo or in the setting of acquired aplastic anemia. Clinical presentation can include hemolytic anemia, hemoglobinuria, thrombosis, severe fatigue, abdominal pain, and esophageal spasm. Thrombosis, the leading cause of death from PNH, most commonly occurs in abdominal and cerebral veins. Therapeutic options include supportive care, bone marrow transplantation, and monoclonal antibody therapy with the terminal complement inhibitor eculizumab. Pathophysiologic Principles:The product of the PIGA gene is required for the biosynthesis of a glycolipid anchor that attaches a class of membrane proteins known as glycosylphosphatidylinositol (GPI)– anchored proteins to the cell surface. The absence of GPI-anchored proteins leads to complement- mediated intravascular hemolysis, because 2 important complement regulatory proteins (CD55 and CD59) are missing from PNH cells. Hemolysis in PNH occurs intravascularly. This leads to release of free hemoglobin, a potent nitric oxide scavenger. Depletion of nitric oxide at the tissue level contributes to fatigue, esophageal spasm, thrombosis, and male erectile dysfunction. Eculizumab decreases hemolysis in PNH by binding to C5 and blocking the terminal portion of the complement cascade.

LeGrand, S. B., D. Leskuski, et al. (2008). "Narrative review: furosemide for hypercalcemia: an unproven yet common practice." Annals of Internal Medicine 149(4): 259-263.

Although primary hyperparathyroidism is the most common cause of hypercalcemia, cancer is the most common cause requiring inpatient intervention. An estimated 10% to 20% of all patients with cancer have hypercalcemia at some point in their disease trajectory, particularly in advanced disease. Aggressive saline hydration and varying doses of furosemide continue to be the standard of care for emergency management. However, a review of the evidence for the use of furosemide in the medical management of hypercalcemia yields only case reports published before the introduction of bisphosphonates, in contrast to multiple randomized, controlled trials supporting the use of bisphosphonates. The use of furosemide in the management of hypercalcemia should no longer be recommended. [References: 49]

McDonnell, W. M. and E. Guenther (2008). "Narrative review: do state laws make it easier to say "I'm sorry?"." Annals of Internal Medicine 149(11): 811-816.

Initiatives intended to reduce the frequency and impact of medical errors generally rely on recognition and disclosure of medical errors. However, fear of malpractice liability is a barrier to physician disclosure. Some U.S. state legislatures have attempted to encourage physicians to disclose medical errors by enacting "apology laws." The authors reviewed the codified statutes of each of the 50 states and the District of Columbia to determine the prevalence and characteristics of such apology laws. They found that many states have recently adopted apology laws and that there is variability in these laws. The authors review some of the important differences in these laws and explore the potential impact of apology laws. [References: 66]

Newman, J. H., J. A. Phillips, 3rd, et al. (2008). "Narrative review: the enigma of pulmonary arterial hypertension: new insights from genetic studies." Annals of Internal Medicine 148(4): 278-283.

Pulmonary arterial hypertension (PAH) occurs as an idiopathic disease (formerly called primary pulmonary hypertension) and as a consequence of other illnesses. These illnesses include connective tissue diseases, portal hypertension, diet and stimulant drug use, HIV infection, and congenital heart disease. Inherited susceptibility to PAH occurs in families and is almost always due to mutations in genes of the TGF-beta family of receptors. The most common mutation leading to PAH is in bone morphogenetic protein receptor type 2 (BMPR2), originally discovered to be involved in bone healing. Mutations in BMPR2 have also been found in patients with idiopathic PAH, although the true prevalence of this susceptibility has not been determined. About 20% of individuals with a BMPR2 mutation develop symptomatic pulmonary hypertension. Evidence is growing that imbalanced activation of other TGF-beta receptors coupled with reduced activity of mutated BMPR2 increases the likelihood of development of PAH. Many signaling systems have been found to participate in PAH, including K channels, serotonin, angiopoietin, and cyclooxygenases. An interaction of these signaling systems with BMPR2 is a focus of research in PAH. Approaches to altering the imbalance of activation of BMPR2 and other TGF-beta receptors may yield future therapies for PAH. [References: 47]

Sullivan, L. E. and D. A. Fiellin (2008). "Narrative review: buprenorphine for opioid-dependent patients in office practice." Annals of Internal Medicine 148(9): 662-670.

The profile of opioid dependence in the United States is changing. Abuse of prescription opioids is more common than that of illicit opioids: Recent data indicate that approximately 1.6 million persons abuse or are dependent on prescription opioids, whereas 323,000 abuse or are dependent on heroin. Despite this prevalence, nearly 80% of opioid-dependent persons remain untreated. One option for expanding treatment is the use of buprenorphine and the buprenorphine-naloxone combination. Buprenorphine is a partial opioid agonist that can be prescribed by trained physicians and dispensed at pharmacies. This article addresses the clinical presentation of a patient with opioid dependence and describes the relatively new practice of office-based treatment with buprenorphine-naloxone. The different components of treatment; the role of the physician who provides this treatment; and the logistics of treating this growing, multifaceted patient population are also examined. [References: 86]

Abeles, A. M., M. H. Pillinger, et al. (2007). "Narrative review: the pathophysiology of fibromyalgia." Annals of Internal Medicine 146(10): 726-734.

Primary fibromyalgia is a common yet poorly understood syndrome characterized by diffuse chronic pain accompanied by other somatic symptoms, including poor sleep, fatigue, and stiffness, in the absence of disease. Fibromyalgia does not have a distinct cause or pathology. Nevertheless, in the past decade, the study of chronic pain has yielded new insights into the pathophysiology of fibromyalgia and related chronic pain disorders. Accruing evidence shows that patients with fibromyalgia experience pain differently from the general population because of dysfunctional pain processing in the central nervous system. Aberrant pain processing, which can result in chronic pain and associated symptoms, may be the result of several interplaying mechanisms, including central sensitization, blunting of inhibitory pain pathways, alterations in neurotransmitters, and psychiatric comorbid conditions. This review provides an overview of the mechanisms currently thought to be partly responsible for the chronic diffuse pain typical of fibromyalgia. [References: 111]

Ali, B. and A. M. Zafari (2007). "Narrative review: cardiopulmonary resuscitation and emergency cardiovascular care: review of the current guidelines." Annals of Internal Medicine 147(3): 171-179.

Calabrese, L. H., D. W. Dodick, et al. (2007). "Narrative review: reversible cerebral vasoconstriction syndromes." Annals of Internal Medicine 146(1): 34-44.

Reversible cerebral vasoconstriction syndromes (RCVS) comprise a group of diverse conditions, all characterized by reversible multifocal narrowing of the cerebral arteries heralded by sudden (thunderclap), severe headaches with or without associated neurologic deficits. Reversible cerebral vasoconstriction syndromes are clinically important because they affect young persons and can be complicated by ischemic or hemorrhagic strokes. The differential diagnosis of RCVS includes conditions associated with thunderclap headache and conditions that cause irreversible or progressive cerebral artery narrowing, such as intracranial atherosclerosis and cerebral vasculitis. Misdiagnosis as primary cerebral vasculitis and aneurysmal subarachnoid hemorrhage is common because of overlapping clinical and angiographic features. However, unlike these more ominous conditions, RCVS is usually self-limited: Resolution of headaches and vasoconstriction occurs over a period of days to weeks. In this review, we describe our current understanding of RCVS; summarize its key clinical, laboratory, and imaging features; and discuss strategies for diagnostic evaluation and treatment. [References: 97]

Clarke, J. T. R. (2007). "Narrative review: Fabry disease." Annals of Internal Medicine 146(6): 425-433.

Fabry disease is an X-linked, hereditary, lysosomal storage disease caused by deficiency of the enzyme alpha-galactosidase A, which results in the accumulation of the neutral glycosphingolipid globotriaosylceramide (Gb3) in the walls of small blood vessels, nerves, dorsal root ganglia, renal glomerular and tubular epithelial cells, and cardiomyocytes. It is a complex, multisystem disorder that is characterized clinically by chronic pain and acroparesthesia, gastrointestinal disturbances, characteristic skin lesions (angiokeratomata), progressive renal impairment, cardiomyopathy, and stroke. Enzyme replacement therapy (ERT) with intravenous infusions of recombinant human alpha-galactosidase A consistently decreases Gb3 levels in plasma and clears lysosomal inclusions from vascular endothelial cells. The effects of ERT on other tissues are not as obvious, suggesting that treatment must be initiated early in the course of the disease to be optimally effective or that some complications of the disease are not responsive to enzymes delivered intravenously. [References: 112]

Cohen, M. S., C. Gay, et al. (2007). "Narrative review: antiretroviral therapy to prevent the sexual transmission of HIV-1." Annals of Internal Medicine 146(8): 591-601.

Antiretroviral therapy (ART) has prolonged and improved the lives of persons infected with HIV. Theoretically, it can also be used to prevent the transmission of HIV. The pharmacology of ART in the male and female genital tract can be expected to affect the success of the intervention, and ART agents differ considerably in their ability to concentrate in genital tract secretions. Emergency ART is considered to be the standard of care after occupational exposures to fluids or tissues infected with HIV. More recently, ART for prophylaxis after nonoccupational HIV exposures has been widely used and most countries have developed specific guidelines for its implementation. However, developing clinical trials to prove the efficacy of ART postexposure prophylaxis has not been possible. Experiments with rhesus macaques suggest that therapy must be offered as soon as possible after exposure (within 72 hours) and must be continued for 28 days. Additional nonhuman primate experiments have demonstrated protection from HIV infection with ART preexposure prophylaxis, and several clinical trials are under way to evaluate the safety and efficacy of this approach. The degree to which ART offered to infected persons reduces infectiousness is of considerable public health importance, but the question has not been sufficiently answered. This article provides a review of the data on the use of ART to prevent the sexual transmission of HIV and identify challenges to improving and clarifying this approach. [References: 106]

Kado, D. M., K. Prenovost, et al. (2007). "Narrative review: hyperkyphosis in older persons." Annals of Internal Medicine 147(5): 330-338.

Hyperkyphosis is a widely recognized yet largely ignored condition. Although there are no uniform diagnostic criteria for hyperkyphosis, current studies estimate its prevalence among older adults at 20% to 40%. The causes and consequences of hyperkyphosis are not well understood. Some physicians think that fractures cause hyperkyphosis and that management strategies should focus solely on diagnosis and treatment for osteoporosis. Recent studies, however, demonstrate that many older adults who are most affected by hyperkyphosis do not have vertebral fractures. Hyperkyphosis may be independently associated with an increased risk for adverse health outcomes, including impaired pulmonary function, decreased physical function capabilities, and future fractures. With the growing older population, we now need research that leads to a deeper understanding of the causes, consequences, and treatment of this common condition. [References: 103]

Physiology in Medicine: 2001 - 2006

Bartlett, J. G. (2006). "Narrative review: the new epidemic of Clostridium difficile-associated enteric disease." Annals of Internal Medicine 145(10): 758-764.

Antibiotic-associated diarrhea and colitis were well established soon after antibiotics became available. Early work implicated Staphylococcus aureus, but in 1978 Clostridium difficile became the established pathogen in the vast majority of cases. In the first 5 years (1978 through 1983), the most common cause was clindamycin, the standard diagnostic test was the cytotoxin assay, and standard management was to withdraw the implicated antibiotic and treat with oral vancomycin. Most patients responded well, but 25% relapsed when vancomycin was withdrawn. During the next 20 years (1983 through 2003), the most commonly implicated antibiotics were the cephalosporins, which reflected the rates of use; the enzyme immunoassay replaced the cytotoxin assay because of speed of results and technical ease of performance; and metronidazole replaced vancomycin as standard treatment, and principles of containment hospitals became infection control and antibiotic control. During the recent past (2003 to 2006), C. difficile has been more frequent, more severe, more refractory to standard therapy, and more likely to relapse. This pattern is widly distributed in the United States, Canada, and Europe and is now attributed to a new strain of C. difficile designated BI, NAP1, or ribotype 027 (which are synonymous terms). This strain appears more virulent, possibly because of production of large amounts of toxins, and fluoroquinolones are now major inducing agents along with cephalosporins, which presumably reflects newly acquired in vitro resistance and escalating rates of use. The recent experience does not change principles of management of the individual patient, but it does serve to emphasize the need for better diagnostics, early recognition, improved methods to manage severe disease and relapsing disease, and greater attention to infection control and antibiotic restraint. [References: 77]

Committee, U. S. P. M. G. E. and U. S. Pharmacopeia (2006). "Narrative review: the U.S. Pharmacopeia and model guidelines for Medicare Part D formularies." Annals of Internal Medicine 145(6): 448-453.

The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 includes a provision directing the Secretary of the U.S. Department of Health and Human Services to request that the U.S. Pharmacopeia (USP) develop a list of categories and classes (the USP Model Guidelines) that can be used by prescription drug plans in developing their formularies for the Part D prescription drug benefit. The Centers for Medicare & Medicaid Services (CMS) used the Model Guidelines and USP's related listing, termed the Formulary Key Drug Types, to evaluate prescription drug plan formularies submitted by prescription drug plan sponsors intending to provide the new Part D benefit. This article recounts how USP's all-volunteer Model Guidelines Expert Committee developed the USP Model Guidelines and Formulary Key Drug Types, working under a cooperative agreement with CMS in response to the Secretary's request. The Model Guidelines and Formulary Key Drug Types are updated annually to reflect advances in evidence-based medicine, thereby offering timely guidance to CMS and to prescription drug plans based on USP's demonstrated expertise in setting standards. [References: 22]

Hayward, R. A., T. P. Hofer, et al. (2006). "Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem." Annals of Internal Medicine 145(7): 520-53

Recent national recommendations have proposed that physicians should titrate lipid therapy to achieve low-density lipoprotein (LDL) cholesterol levels less than 1.81 mmol/L (<70 mg/dL) for patients at very high cardiovascular risk and less than 2.59 mmol/L (<100 mg/dL) for patients at high cardiovascular risk. To examine the clinical evidence for these recommendations, the authors sought to review all controlled trials, cohort studies, and case-control studies that examined the independent relationship between LDL cholesterol and major cardiovascular outcomes in patients with LDL cholesterol levels less than 3.36 mmol/L (<130 mg/dL). For those with LDL cholesterol levels less than 3.36 mmol/L (<130 mg/dL), the authors found no clinical trial subgroup analyses or valid cohort or case-control analyses suggesting that the degree to which LDL cholesterol responds to a statin independently predicts the degree of cardiovascular risk reduction. Published studies had avoidable limitations, such as a reliance on ecological (aggregate) analyses, use of analyses that ignore statins' other proposed mechanisms of action, and failure to account for known confounders (especially healthy volunteer effects). Clear, compelling evidence supports near-universal empirical statin therapy in patients at high cardiovascular risk (regardless of their natural LDL cholesterol values), but current clinical evidence does not demonstrate that titrating lipid therapy to achieve proposed low LDL cholesterol levels is beneficial or safe. [References: 54]

Lloyd-Jones, D. M., K. Liu, et al. (2006)."Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease." Annals of Internal Medicine 145(1): 35-42.

Some experts propose C-reactive protein (CRP) as a screening tool for prediction of cardiovascular disease (CVD). Many epidemiologic studies show positive associations between elevated CRP levels and incident CVD. Assessment of the value of new prognostic tests, however, must rely on understanding of test characteristics rather than on associations measured by relative risks. In the case of CRP, test characteristics must be judged in the context of currently available CVD risk prediction algorithms. In this review of literature published before January 2006, the authors describe what is known about the additional utility of CRP in risk prediction. They find no definitive evidence that, for most individuals, CRP adds substantial predictive value above that provided by risk estimation using traditional risk factors for CVD. Use of CRP may add to risk estimation in a limited subset of individuals who are at intermediate predicted risk according to the Framingham risk score. The authors propose that many questions still must be addressed before CRP is incorporated into risk prediction algorithms and before universal screening with CRP can be recommended. [References: 49]

Mooradian, A. D., M. Bernbaum, et al. (2006). "Narrative review: a rational approach to starting insulin therapy." Annals of Internal Medicine 145(2): 125-134.

BACKGROUND: The emergence of multiple insulin products has provided new opportunities to achieve diabetes control. However, the number of options has raised concerns about the optimal choices of products. PURPOSE: To briefly review the pharmacologic characteristics of currently available insulin products and to suggest an initial insulin regimen based on common blood glucose profiles among patients with diabetes. DATA SOURCES: Relevant manuscripts were identified through a MEDLINE search (1996 to 25 February 2006) of the English-language literature. The key phrase used was therapeutic use of insulin. The literature search was limited to core clinical journals that have accessible full texts. STUDY SELECTION: Clinical trials and authoritative reviews published between 1996 and February 2006 were selected. A total of 420 manuscripts wasreviewed. DATA EXTRACTION: The authors independently reviewed the relevant available literature. This literature, along with the authors' clinical experience, was used to construct practical suggestions. DATA SYNTHESIS: Several new insulin and insulin analogue preparations are now available for clinical use. Used as prandial insulin (for example, insulin lispro, insulin aspart, or insulin glulisine) and basal insulin (for example, insulin glargine or insulin detemir), the analogues simulate physiologic insulin profiles more closely than the older conventional insulins. There is currently no strong rationale favoring glargine, neutral protamine Hagedorn insulin, insulin detemir, or fixed-ratio insulin preparations as the preferred agent for initiating insulin therapy. LIMITATIONS: This was a retrospective review of previously published manuscripts chosen at the authors' discretion. CONCLUSIONS: The advent of recombinant DNA technology made it possible to overcome limitations in the time-action profiles of conventional insulins. Insulin therapy must be individualized. Nevertheless, certain subgroups of patients with diabetes can be differentiated from each other according to the pattern of blood glucose changes during the day. On the basis of the blood glucose profile, the authors suggest an initial insulin regimen that can be used to evaluate individual responsiveness and plan a long-term regimen. [References: 54]

Reinstein, E. and A. Ciechanover (2006). "Narrative review: protein degradation and human diseases: the ubiquitin connection." Annals of Internal Medicine 145(9): 676-684.

Between the 1950s and 1980s, many scientists focused on the process by which the genetic code is translated into proteome. However, little attention was devoted to the mechanism responsible for protein degradation. When researchers discovered the organelle lysosome, they assumed that cellular proteins were degraded within it. However, several independent lines of evidence strongly suggested that intracellular proteolysis was largely nonlysosomal. The discovery of the ubiquitin proteasome system (UPS) resolved this enigma. It is now recognized that degradation of intracellular proteins by the UPS is involved in the regulation of a broad array of cellular processes, including cell-cycle division; DNA repair, growth, and differentiation; quality control; and regulation of membrane receptors and ion channels. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of numerous human diseases, and it seems that pharmacologic manipulation of the UPS might alter the outcome of many diseases, especially malignant conditions and possibly neurodegenerative and chronic inflammatory diseases. These findings have led to increasing efforts to develop mechanism-based drugs that modulate UPS activity, one of which is already on the market. In the near future, one can expect to see the development of new, potent, and highly specific drugs that target the degradation pathways of a single or a few proteins without affecting other proteins. [References: 76]

Shanafelt, T. D., J. C. Byrd, et al. (2006). "Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia." Annals of Internal Medicine 145(6): 435-447.

Chronic lymphocytic leukemia is one of the most common malignant lymphoid diseases in the western world and is frequently diagnosed by internists. There have been clinically significant changes in method of diagnosis, prognostic tools, supportive care, and treatment over the past 2 decades. Most patients with chronic lymphocytic leukemia now have Rai stage 0 or I disease at diagnosis. Patients with early-stage disease are a heterogeneous group: Approximately 30% to 50% will have accelerated disease progression, and the remainder may live for decades and possibly never require therapy. Recent insights into the biological characteristics of leukemic B cells have led to the discovery of new prognostic tools (immunoglobulin variable-region heavy chain gene mutation status, cytogenetic abnormalities assessed by fluorescent in situ hybridization, and Z-chain-associated protein kinase-70 protein expression) that can identify patients with early-stage disease who are at high risk for early disease progression. These tools allow physicians to individualize counseling, follow-up, and management on the basis of disease risk. In addition, new treatments developed over the past 2 decades (purine nucleoside analogues, monoclonal antibodies, and combination chemoimmunotherapy regimens) have dramatically improved response rates and appear to prolong survival. In this review, the authors discuss the current work-up of lymphocytosis and highlight how to use recently identified prognostic tools to stratify risk in patients with newly diagnosed, early-stage chronic lymphocytic leukemia. Recommendations for patient counseling, follow-up, supportive care, and initial treatment are presented for each risk category. [References: 90]

Spies, C. and R. G. Trohman (2006). "Narrative review: Electrocution and life-threatening electrical injuries." Annals of Internal Medicine 145(7): 531-537.

The authors reviewed the mechanisms and pathophysiology of typically encountered electrical injuries by searching English-language publications listed in MEDLINE and reference lists from identified articles. They included relevant retrospective studies, case reports, and review articles published between 1966 and 2005. The authors also searched the Internet for information related to electrocution and life-threatening electrical injuries. They found that familiarity with basic principles of physics elucidates the typical injuries sustained by patients who experience electrical shock. Death due to electrocution occurs frequently. However, patients successfully resuscitated after cardiopulmonary arrest often have a favorable prognosis. Approximately 3000 patients who survive electrical shock are admitted to specialized burn units annually. Patients with serious electrical burns admitted to the intensive care unit are trauma patients and should be treated accordingly. Initial prediction of outcome for patients who have experienced electrical shock is difficult, as the full degree of injury is often not apparent. [References: 65]

Steinman, M. A., L. A. Bero, et al. (2006). "Narrative review: the promotion of gabapentin: an analysis of internal industry documents." Annals of Internal Medicine 145(4): 284-293.

BACKGROUND: Internal documents from the pharmaceutical industry provide a unique window for understanding the structure and methods of pharmaceutical promotion. Such documents have become available through litigation concerning the promotion of gabapentin (Neurontin, Pfizer, Inc., New York, New York) for off-label uses. PURPOSE: To describe how gabapentin was promoted, focusing on the use of medical education, research, and publication. DATA SOURCES: Court documents available to the public from United States ex. rel David Franklin vs. Pfizer, Inc., and Parke-Davis, Division of Warner-Lambert Company, mostly from 1994-1998. DATA EXTRACTION: All documents were reviewed by 1 author, with selected review by coauthors. Marketing strategies and tactics were identified by using an iterative process of review, discussion, and re-review of selected documents. DATA SYNTHESIS: The promotion of gabapentin was a comprehensive and multifaceted process. Advisory boards, consultants meetings, and accredited continuing medical education events organized by third-party vendors were used to deliver promotional messages. These tactics were augmented by the recruitment of local champions and engagement of thought leaders, who could be used to communicate favorable messages about gabapentin to their physician colleagues. Research and scholarship were also used for marketing by encouraging "key customers" to participate in research, using a large study to advance promotional themes and build market share, paying medical communication companies to develop and publish articles about gabapentin for the medical literature, and planning to suppress unfavorable study results. LIMITATIONS: Most available documents were submitted by the plaintiff and may not represent a complete picture of marketing practices. CONCLUSION: Activities traditionally considered independent of promotional intent, including continuing medical education and research, were extensively used to promote gabapentin. New strategies are needed to ensure a clear separation between scientific and commercial activity. [References: 124]

Ting, H. H., E. H. Yang, et al. (2006). "Narrative review: reperfusion strategies for ST-segment elevation myocardial infarction." Annals of Internal Medicine 145(8): 610-617.

Optimal treatment for ST-segment elevation myocardial infarction depends on early diagnosis and rapid selection of the appropriate reperfusion strategy. Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy at PCI-capable hospitals. For hospitals without PCI capability, there are 2 reperfusion strategies, primary PCI and thrombolytic therapy, which are both supported by clinical evidence and national guidelines. Transferring patients for primary PCI may cause delays and requires established, proven protocols, systems, and networks to achieve minimal door-to-balloon times. The authors review the available data and present a systematic, evidence-based approach in a simple framework to enable noncardiovascular and cardiovascular physicians to select the optimal reperfusion strategy. The framework is based on available data from clinical trials and local circumstances from clinical practice by incorporating duration of symptoms (fixed ischemia time) and anticipated transport delays to a PCI-capable facility (incurred ischemia time). [References: 72]

Tung, R., S. Kaul, et al. (2006). "Narrative review: drug-eluting stents for the management of restenosis: a critical appraisal of the evidence." Annals of Internal Medicine 144(12): 913-919.

Interventional cardiologists have quickly replaced bare metal stents with intravascular drug-eluting stents for treating and preventing restenosis, largely on the basis of empirical evidence that shows profound reduction in angiographic and clinical restenosis. A critical reassessment of the published evidence, however, suggests that the putative superiority of intravascular drug-eluting stents is founded on questionable premises, including 1) overestimation of restenosis benefit, 2) underestimation of the risk for stent thrombosis, 3) overreliance on "soft" rather than "hard" outcomes (need for repeated revascularization vs. death or myocardial infarction), and 4) the attendant overestimation of cost-effectiveness. Because the long-term incremental risks, benefits, and costs of drug-eluting stents have not yet been optimally evaluated in a broad spectrum of patient and lesion cohorts, the rational role of these devices in clinical management warrants reappraisal. [References: 34]

Umpierrez, G. E., D. Smiley, et al. (2006). "Narrative review: ketosis-prone type 2 diabetes mellitus." Annals of Internal Medicine 144(5): 350-357.

Several investigators have reported that more than half of African-American persons with new diagnoses of diabetic ketoacidosis have clinical, metabolic, and immunologic features of type 2 diabetes during follow-up. These patients are usually obese, have a strong family history of diabetes, have a low prevalence of autoimmune markers, and lack a genetic association with HLA. Their initial presentation is acute, with a few days to weeks of polyuria, polydipsia, and weight loss and lack of a precipitating cause of metabolic decompensation. At presentation, they have markedly impaired insulin secretion and insulin action, but intensified diabetic management results in significant improvement in beta-cell function and insulin sensitivity sufficient to allow discontinuation of insulin therapy within a few months of follow-up. On discontinuation of insulin therapy, the period of near-normoglycemic remission may last for a few months to several years. The absence of autoimmune markers and the presence of measurable insulin secretion have proven useful in predicting near-normoglycemic remission and long-term insulin dependence in adult patients with a history of diabetic ketoacidosis. This clinical presentation is commonly reported in African and African-American persons but is also observed in Hispanic persons and those from other minority ethnic groups. The underlying mechanisms for beta-cell dysfunction in ketosis-prone type 2 diabetes are not known; however, preliminary evidence suggests an increased susceptibility to glucose desensitization. [References: 76]

Alaedini, A. and P. H. R. Green (2005). "Narrative review: celiac disease: understanding a complex autoimmune disorder." Annals of Internal Medicine 142(4): 289-298.

Celiac disease is a common autoimmune disorder that has genetic, environmental, and immunologic components. It is characterized by an immune response to ingested wheat gluten and related proteins of rye and barley that leads to inflammation, villous atrophy, and crypt hyperplasia in the intestine. The disease is closely associated with genes that code for human leukocyte antigens DQ2 and DQ8. Transglutaminase 2 appears to be an important component of the disease, both as a deamidating enzyme that can enhance the immunostimulatory effect of gluten and as a target autoantigen in the immune response. Sensitive and specific serologic tests, including those for anti-transglutaminase antibody, are facilitating fast and noninvasive screening for celiac disease. Thus, they are contributing to a more accurate estimate of the prevalence of the disease and its association with other disorders. Celiac disease is associated with increased rates of anemia, osteoporosis, cancer, neurologic deficits, and additional autoimmune disorders. A gluten-free diet is the mainstay of safe and effective treatment of celiac disease, although its effect on some of the extraintestinal manifestations of the disease remains to be determined. [References: 122]

Eisen, G. M. and D. S. Weinberg (2005). "Narrative review: screening for colorectal cancer in patients with a first-degree relative with colonic neoplasia." Annals of Internal Medicine 143(3): 190-198.

Many patients and providers are aware that colorectal cancer (CRC) "runs in families." A patient with 1 first-degree relative with CRC has approximately twice the personal risk for CRC as a similar person without this family history. Colorectal cancer is the third most common type of cancer in the United States. When providers neglect to collect information on family history, they may fail to appropriately tailor recommendations for screening for CRC for many patients. This review considers the existing data and summarizes an evidence-based approach to the common clinical problem of how and when to implement screening for CRC in a patient with a family history of colonic neoplasia. The authors discuss the varying risks for CRC given the patient's age, health habits, and personal and family histories. In the context of a clinical case that focuses on the effect of a single affected first-degree relative, the authors weigh the risks and benefits of various screening alternatives and briefly address chemoprevention, genetic testing, and future directions in screening for CRC.

Falagas, M. E. and P. I. Vergidis (2005). "Narrative review: diseases that masquerade as infectious cellulitis." Annals of Internal Medicine 142(1): 47-55.

For cellulitis that does not respond to conventional antimicrobial treatment, clinicians should consider, among other explanations, several noninfectious disorders that might masquerade as infectious cellulitis. Diseases that commonly masquerade as this condition include thrombophlebitis, contact dermatitis, insect stings, drug reactions, eosinophilic cellulitis (the Wells syndrome), gouty arthritis, carcinoma erysipelatoides, familial Mediterranean fever, and foreign-body reactions. Diseases that uncommonly masquerade as infectious cellulitis include urticaria, lymphedema, lupus erythematosus, sarcoidosis, lymphoma, leukemia, Paget disease, and panniculitis. Clinicians should do an initial diagnostic work-up directed by the findings from a detailed history and complete physical examination. In many cases, skin biopsy is the only tool that helps identify the correct diagnosis. Special tests may also be needed. [References: 126]

Jeremias, A. and C. M. Gibson (2005). "Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded." Annals of Internal Medicine 142(9): 786-791.

Current guidelines for the diagnosis of non-ST-segment elevation myocardial infarction are largely based on an elevated troponin level. While this rapid and sensitive blood test is certainly valuable in the appropriate setting, its widespread use in a variety of clinical scenarios may lead to the detection of troponin elevation in the absence of thrombotic acute coronary syndromes. Many diseases, such as sepsis, hypovolemia, atrial fibrillation, congestive heart failure, pulmonary embolism, myocarditis, myocardial contusion, and renal failure, can be associated with an increase in troponin level. These elevations may arise from various causes other than thrombotic coronary artery occlusion. Given the lack of any supportive data at present, patients with nonthrombotic troponin elevation should not be treated with antithrombotic and antiplatelet agents. Rather, the underlying cause of the troponin elevation should be targeted. However, troponin elevation in the absence of thrombotic acute coronary syndromes still retains prognostic value. Thus, cardiac troponin elevations are common in numerous disease states and do not necessarily indicate the presence of a thrombotic acute coronary syndrome. While troponin is a sensitive biomarker to "rule out" non-ST-segment elevation myocardial infarction, it is less useful to "rule in" this event because it may lack specificity for acute coronary syndromes. [References: 48]

Sanderson, S., J. Emery, et al. (2005). "Narrative review: aspirin resistance and its clinical implications." Annals of Internal Medicine 142(5): 370-380.

Aspirin is currently the most cost-effective drug for the secondary prevention of cardiovascular disease, but treatment failures are relatively common. Several factors have been linked to these recurrent vascular events in patients prescribed aspirin, including smoking, drug interactions, nonadherence, comorbid conditions, and aspirin resistance. The term aspirin resistance has been used to describe not only an absence of the expected pharmacologic effects of aspirin on platelets but also poor clinical outcomes, such as recurrent vascular events, in patients treated with aspirin. Aspirin resistance is perhaps more precisely understood as the phenomenon of measurable, persisting platelet activation that occurs in patients prescribed a therapeutic dose of aspirin and may underlie an unknown proportion of aspirin treatment failures. Key challenges for future research are to standardize a definition of aspirin resistance and to compare whether different measures of platelet activation, either alone or in combination, independently predict cardiovascular events. These challenges must be met before researchers conduct studies to assess the clinical utility of testing on patient outcomes and cost-effective prescribing. [References: 68]

Yan, A. T., R. T. Yan, et al. (2005). "Narrative review: pharmacotherapy for chronic heart failure: evidence from recent clinical trials." Annals of Internal Medicine 142(2): 132-145.

Heart failure is an important cause of morbidity and mortality. Clinical trials over the past 2 decades have revolutionized the care of patients with systolic heart failure, and substantial data support the use of angiotensin-converting enzyme inhibitors, beta-blockers, angiotensin-receptor blockers, and aldosterone blockers in the management of this serious condition. This article reviews the evidence on the pharmacologic treatment of heart failure, with a focus on recent clinical trials. [References: 149]

Tolman, K. G., V. Fonseca, et al. (2004). "Narrative review: hepatobiliary disease in type 2 diabetes mellitus." Annals of Internal Medicine 141(12): 946-956.

Diabetes mellitus is the fifth leading cause of death in the United States; 17 million people are affected. Liver disease is one of the leading causes of death in persons with type 2 diabetes. The standardized mortality rate for death from liver disease is greater than that for cardiovascular disease. The spectrum of liver disease in type 2 diabetes ranges from nonalcoholic fatty liver disease to cirrhosis and hepatocellular carcinoma. The incidence of hepatitis C and acute liver failure is also increased. Nonalcoholic fatty liver disease is now considered part of the metabolic syndrome, and, with alcohol and hepatitis C, is the most common cause of chronic liver disease in the United States. Weight reduction and exercise are the mainstays of treatment for nonalcoholic fatty liver disease, but there are promising results with the new thiazolidinediones (pioglitazone and rosiglitazone) as well as metformin and 3-hydroxy-3-methylglutaryl coenzyme A inhibitors. [References: 150]

Andreoli, T. E. (2001). "Arrhythmias: introductory comments." The American Journal of Medicine 110(1): 49-49.

This issue of the American Journal of Medicine contains the first of a group of articles in the “Physiology in Medicine” series that will focus on arrhythmias. About a century ago, little was known about arrhythmias except for the notion of so-called “circus movements.” The earliest examples of the latter were drawn from experiments on the Portuguese man-of-war. A burn on the mantle of a man-of-war followed by electrical stimulation of the mantle produced what are now recognized as the requisite characteristics for a circus, or reentrant, arrhythmia: a single excitatory beat with different rates of radial propagation so that annular conduction occurs. In his classic 1933 textbook Diseases of the Heart(New York: MacMillan), Sir Thomas Lewis described circus rhythm as accounting for atrial fibrillation, but no information was available about the actual pathways for conduction.It is reasonable to argue that modern electrophysiology began with the triumphant experiments of Hodgkin and Huxley, culminating in their classic series of papers (for which they were awarded the Nobel Prize) in 1952 in which they described voltage-gated ionic channels and the ways in which these channels produced impulse propagation in excitable tissues. The channels Hodgkin and Huxley dealt with in exquisitely quantitative detail were sodium channels and potassium channels. There followed Sir Bernard Katz’ description of voltage-gated calcium channels, thus setting much of the stage, again at a membrane but not molecular level, for understanding arrhythmias. By the early 1970s, it was well known that impulse formation in the sinus node and in the atrioventricular node was regulated by voltage-gated calcium channels, while the spread of the cardiac impulse in atrial musculature and in the Purkinje system occurred by way of voltage-gated sodium channels.In the last 2 decades, the explosion of knowledge at the molecular level with the cloning and description of the structure of, in particular, voltage-gated sodium channels, potassium channels, and calcium channels has provided us with insights into the molecular mechanisms of arrhythmia formation. Thus, this series provides an overview of the molecular biology of some of these channels; their role in arrhythmias; some specific derangements in channel molecular biology in certain arrhythmias; and the development of devices such as automatic implantable cardiac defibrillators (AICDs) for the treatment of cardiac arrhythmias.The series begins with an article by M. G. Sanguinetti from the University of Utah on the role of calcium channels in the pathogenesis of cardiac arrhythmias. The second article, a close companion to the first, is by C. W. Balke of the University of Maryland School of Medicine and focuses on the molecular biology of calcium channels. The third article, by A. O. Grant of Duke University, considers the molecular biology of sodium channels and how sodium channels are involved directly in cardiac arrhythmias.The fourth article in the series, by J. A. Towbin of the Baylor College of Medicine, deals with the family of disorders grouped under the term “prolonged QT syndromes,” and the molecular biology of some of these disorders. In subsequent articles, G. V. Naccarelli of Penn State University discusses the molecular biology of the Brugatta syndrome, and E. N. Prystowsky of St. Vincent Hospital, Indianapolis, provides an overview of derangements of channel biology in arrhythmias.Finally, the series closes with an article by M. Estes of Tufts University on implantable devices such as AICDs in the management of arrhythmias. This article will also provide insights into the emerging new strategies for the therapy of arrhythmias.

Grant, A. O. (2001). "Molecular biology of sodium channels and their role in cardiac arrhythmias." The American Journal of Medicine 110(4): 296-305.

The sodium channel is an integral membrane protein that plays a central role in conduction of the cardiac impulse in working cardiac myocytes and cells of the His-Purkinje system. The channel has two fundamental properties, ion conduction and gating. Specific domains of the channel protein control each of these functions. Ion conduction describes the mechanisms of the selective movement of sodium ion across the pore in the cell membrane. The selectivity of the channel for sodium ions is at least 10 times greater than that for other monovalent cations; the channel does not normally conduct divalent cations. Gating describes the opening and closing of the sodium channel pore. Sodium channels open transiently during membrane depolarization and close by a process termed inactivation. The cardiac sodium channel protein is a multimeric complex consisting of an [alpha] and an auxiliary [beta]-subunit. The genes encoding the sodium channel have been cloned and sequenced. The [alpha] subunit gene, SCN5A is sufficient to express a functional channel. However, [beta] subunit co-expression increases the level of channel expression and alters the voltage dependence of inactivation. Mutations of the sodium channel may result in incomplete inactivation during maintained depolarization, a decrease in the level of channel expression or acceleration of inactivation. The resulting clinical phenotypes include long QT syndrome, type III (LQT III), Brugada syndrome, and heart block. LQT III and Brugada syndromes have a high case fatality rate and are best treated with an implantable defibrillator.

Naccarelli, G. V. and C. Antzelevitch (2001). "The Brugada syndrome: clinical, genetic, cellular, and molecular abnormalities." The American Journal of Medicine 110(7): 573-581.

The Brugada syndrome is an arrhythmic syndrome characterized by a right bundle branch block pattern and ST segment elevation in the right precordial leads of the electrocardiogram in conjunction with a high incidence of sudden death secondary to ventricular tachyarrhythmias. No evidence of structural heart disease is noted during diagnostic evaluation of these patients. In 25% of families, there appears to be an autosomal dominant mode of transmission with variable expression of the abnormal gene. Mutations have been identified in the gene that encodes the alpha subunit of the sodium channel (SCN5A) on chromosome 3. This genetic defect causes a reduction in the density of the sodium current and explains the worsening of the above electrocardiographic abnormalities when patients are treated with sodium channel blocking antiarrhythmic agents, which further diminish the already reduced sodium current. The prognosis is poor with up to a 10% per year mortality. Antiarrhythmic drugs including beta-blockers and amiodarone have no benefit in prolonging survival. The treatment of choice is the insertion of an implantable cardioverter-defibrillator.

Shorofsky, S. R. and C. W. Balke (2001). "Calcium currents and arrhythmias: insights from molecular biology." The American Journal of Medicine 110(2): 127-140.

Calcium channels are critical to normal cardiac function. They are involved in the generation and conduction of the action potential and in contraction. Three surface membrane channels have been identified. The L-type Ca channel is most abundant and is responsible for Ca entry into the cell that triggers contraction. T-type Ca channels are most prevalent in the conduction system and are probably involved in automaticity. A newly described TTX-sensitive calcium current may be important in "boosting" or enhancing conduction and contraction. The main intracellular Ca channel resides in the sarcoplasmic reticulum and is responsible for the release of the Ca that activates contraction. Oscillatory behavior of this channel influences the sarcolemmal membrane, causing delayed aftercontractions and arrhythmias such as those seen in digoxin toxicity. The on-going molecular characterization of these channels will enhance our knowledge of their normal function and dysfunction in disease states, leading to the development of new therapeutic agents to treat arrhythmias and contractile dysfunction.

Towbin, J. A. and M. Vatta (2001). "Molecular biology and the prolonged QT syndromes." The American Journal of Medicine 110(5): 385-398.

The prolonged QT syndromes are characterized by prolongation of the QT interval corrected for heart rate (QTc) on the surface electrocardiogram associated with T-wave abnormalities, relative bradycardia, and ventricular tachyarrhythmias, including polymorphic ventricular tachycardia and torsades de pointes. These patients tend to present with episodes of syncope, seizures, or sudden death typically triggered by exercise, emotion, noise, or, in some cases, sleep. These disorders of cardiac repolarization are commonly inherited, with the autosomal dominant form, Romano-Ward syndrome, mostcommon. A rare autosomal recessive form associated with sensorineural deafness, Jervell and Lange-Nielsen syndrome, in which the cardiac disorder is autosomal dominant and deafness is a recessive trait, also occurs. The underlying genetic causes of these forms of prolonged QT interval syndromes are heterogeneous, with at least seven genes responsible for the clinical syndromes. All of the five genes identified to date encode ion channel proteins, suggesting this to be an ion channelopathy. In this review, the genetic basis of the prolonged QT interval syndromes will be discussed, genotype-phenotype correlations identified, and the approaches to genetic testing and treatments will be outlined.

Tristani-Firouzi, M., J. Chen, et al. (2001). "Molecular biology of K+ channels and their role in cardiac arrhythmias." The American Journal of Medicine 110(1): 50-59.

The configuration of cardiac action potentials varies considerably from one region of the heart to another. These differences are caused by differential cellular expression of several types of K+ channel genes. The channels encoded by these genes can be grouped into several classes depending on the stimulus that permits the channels to open and conduct potassium ions. K+ channels are activated by changes in transmembrane voltage or binding of ligands. Voltage-gated channels are normally the most important players in determining the shape and duration of action potentials and include the delayed rectifiers and the transient outward potassium channels. Ligand-gated channels include those that probably have only minor roles in shaping repolarization under normal conditions but, when activated by extracellular acetylcholine or a decrease in the intracellular concentration of ATP, can substantially shorten action potential duration. Inward rectifier K+ channels are unique in that they are basically stuck in the open state but can be blocked in a voltage-dependent manner by intracellular Mg2+, Ca2+, and polyamines. Other K+ channels have been described that provide a small background leak conductance. Many of these cardiac K+ channels have been cloned in the past decade, permitting detailed studies of the molecular basis of their function and facilitating the discovery of the molecular basis of several forms of congenital arrhythmias. Drugs that block cardiac K+ channels and prolong action potential duration have been developed as antiarrhythmic agents. However, many of these same drugs, as well as other common medications that are structurally unrelated, can also cause long QT syndrome and induce ventricular arrhythmia.

Physiology in Medicine: 1998 - 2000

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.

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.