Showing papers in "Annual Review of Medicine in 1999"
TL;DR: Exploitation of the antigen-presenting properties of DCs offers promise for the development of effective cancer immunotherapies.
Abstract: Human tumors express a number of protein antigens that can be recognized by T cells, thus providing potential targets for cancer immunotherapy. Dendritic cells (DCs) are rare leukocytes that are uniquely potent in their ability to present antigens to T cells, and this property has prompted their recent application to therapeutic cancer vaccines. Isolated DCs loaded with tumor antigen ex vivo and administered as a cellular vaccine have been found to induce protective and therapeutic anti-tumor immunity in experimental animals. In pilot clinical trials of DC vaccination for patients with non-Hodgkin's lymphoma and melanoma, induction of anti-tumor immune responses and tumor regressions have been observed. Additional trials of DC vaccination for a variety of human cancers are under way, and methods for targeting tumor antigens to DCs in vivo are also being explored. Exploitation of the antigen-presenting properties of DCs thus offers promise for the development of effective cancer immunotherapies.
534 citations
TL;DR: HRV in combination with other risk stratifiers, e.g. ejection fraction, can identify cardiac patients at especially high risk of mortality and many but not all interventions associated with increased HRV are also associated with better survival rates.
Abstract: Indices of heart rate variability (HRV) provide a window onto autonomic modulation of the heart. HRV indices, determined in either the time or frequency domain, are closely related and reflect parasympathetic, mixed sympathetic, and parasympathetic and circadian rhythms. In population studies, decreased HRV has had predictive value for mortality among healthy adults. It is a well-established risk factor for arrhythmic events and mortality among post-myocardial-infarction patients but has only moderate sensitivity and specificity. Decreased HRV has had mixed predictive success in congestive heart failure. Reduced HRV identifies diabetic patients with autonomic neuropathy. HRV in combination with other risk stratifiers, e.g. ejection fraction, can identify cardiac patients at especially high risk of mortality. Many but not all interventions associated with increased HRV are also associated with better survival rates.
519 citations
TL;DR: The ubiquitin-proteasome pathway plays a pivotal role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation.
Abstract: ▪ Abstract The ubiquitin-proteasome pathway plays a pivotal role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway involves an enzymatic cascade through which multiple ubiquitin molecules are covalently attached to the protein substrate, which is then degraded by the 26S proteasome complex. The pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman's syndroome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting. The molecular mechanisms that underlie these processes are being unraveled at present.
457 citations
TL;DR: Coagulase-negative staphylococci are by far the most common cause of bacteremia related to indwelling devices and their important role as pathogens and their increasing incidence have been recognized and studied in recent years.
Abstract: Coagulase-negative staphylococci have long been regarded as apathogenic but their important role as pathogens and their increasing incidence have been recognized and studied in recent years. Although specific virulence factors are not as clearly established as they are in Staphylococcus aureus, it seems clear that factors such as bacterial polysaccharide components are involved in attachment and/or persistence of bacteria on foreign materials. Coagulase-negative staphylococci are by far the most common cause of bacteremia related to indwelling devices. Most of these infections are hospital-acquired, and studies over the past several years suggest that they are often caused by strains that are transmitted among hospitalized patients. Other important infections due to coagulase-negative staphylococci include central nervous system shunt infections, native or prosthetic valve endocarditis, urinary tract infections, and endophthalmitis. Intravenous treatment of systemic infections is usually required because ...
437 citations
TL;DR: Reports on homozygous deletion of p16 and p15 genes suggest the value of larger, prospective studies with standardized treatment protocols to definitively establish the prognostic utility of p15/p16 deletions in acute leukemias.
Abstract: Progression through the cell cycle is governed by cyclin-dependent kinases (cdks), whose activity is inhibited by the cdk inhibitors. Cyclins, cdks, and cdk inhibitors are frequently deregulated in cancers. This chapter reviews the prognostic significance of alterations in cdk inhibitors. Loss of p27 protein provides independent prognostic information in breast, prostate, colon, and gastric carcinomas, and immunohistochemical (IHC) staining for p27 may eventually become part of routine histopathologic processing of cancers. Loss of IHC staining for p21 may be prognostic in certain cancers but conflicting results are reported in breast cancer. Reports on homozygous deletion of p16 and p15 genes suggest the value of larger, prospective studies with standardized treatment protocols to definitively establish the prognostic utility of p15/p16 deletions in acute leukemias. Larger trials and the development of a consensus on methods for deletion analysis, IHC staining, and tumor scoring will be needed to move these molecular assays from bench to bedside.
331 citations
TL;DR: This work has shown that targeting specific chemokines and chemokine receptors may have therapeutic utility in both inflammation and infectious disease.
Abstract: Chemokines constitute a large family of chemotactic cytokines that act at G protein-coupled receptors to regulate diverse biological processes, including leukocyte trafficking, angiogenesis, hematopoiesis, and organogenesis. They are believed to be both beneficial in host defense against infectious agents and harmful in diseases marked by pathologic inflammation; however, actual clinical roles in these areas have not yet been established. Recently, unexpected ways have been discovered in which medically important pathogens, including HIV-1, exploit or subvert the chemokine system. These and other recent results suggest that targeting specific chemokines and chemokine receptors may have therapeutic utility in both inflammation and infectious disease.
291 citations
TL;DR: Hantaviruses chronically infect rodents without apparent disease, but when they are spread by aerosolized excreta to humans, two major clinical syndromes result: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS).
Abstract: Hantaviruses chronically infect rodents without apparent disease, but when they are spread by aerosolized excreta to humans, two major clinical syndromes result: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Both diseases appear to be immunopathologic, and inflammatory mediators are important in causing the clinical manifestations. In HPS, T cells act on heavily infected pulmonary endothelium, and it is suspected that gamma interferon and tumor necrosis factor are major agents of a reversible increase in vascular permeability that leads to severe, noncardiogenic pulmonary edema. HFRS has prominent systemic manifestations. The retroperitoneum is a major site of vascular leak and the kidneys suffer tubular necrosis. Both syndromes are accompanied by myocardial depression and hypotension or shock. HFRS is primarily a Eurasian disease, whereas HPS appears to be confined to the Americas; these geographic distinctions correlate with the phylogenies of the rodent hosts and the viruses that coevolved with them.
256 citations
TL;DR: Therapeutic naps, medications, and supportive therapy are recommended for narcolepsy and hypersomnia; continuous positive airway pressure, weight loss, surgery, and oral devices are the common treatments for sleep apnea.
Abstract: Sleep disorders are very prevalent in the general population and are associated with significant medical, psychological, and social disturbances. Insomnia is the most common. When chronic, it usually reflects psychological/behavioral disturbances. Most insomniacs can be evaluated in an office setting, and a multidimensional approach is recommended, including sleep hygiene measures, psychotherapy, and medication. The parasomnias, including sleepwalking, night terrors, and nightmares, have benign implications in childhood but often reflect psychopathology or significant stress in adolescents and adults and organicity in the elderly. Excessive daytime sleepiness is typically the most frequent complaint and often reflects organic dysfunction. Narcolepsy and idiopathic hypersomnia are chronic brain disorders with an onset at a young age, whereas sleep apnea is more common in middle age and is associated with obesity and cardiovascular problems. Therapeutic naps, medications, and supportive therapy are recommended for narcolepsy and hypersomnia; continuous positive airway pressure, weight loss, surgery, and oral devices are the common treatments for sleep apnea.
220 citations
TL;DR: This chapter reviews the epidemiology, clinical spectrum, diagnosis, treatment, and prevention of infections with E. coli O157:H7.
Abstract: Escherichia coli O157:H7 is an increasingly common cause of a variety of illnesses, including bloody diarrhea and the hemolytic uremic syndrome. This emerging infectious agent was first identified in 1982 and has been isolated with increasing frequency since then. This chapter reviews the epidemiology, clinical spectrum, diagnosis, treatment, and prevention of infections with E. coli O157:H7.
212 citations
TL;DR: It is becoming increasingly important for clinicians to recognize the clinical syndromes suggestive of a mitochondrial disorder, and to understand the unique features of mitochondrial genetics that complicate diagnosis and genetic counseling.
Abstract: Virtually all cells in humans depend on mitochondrial oxidative phosphorylation to generate energy, accounting for the remarkable diversity of clinical disorders associated with mitochondrial DNA mutations. However, certain tissues are particularly susceptible to mitochondrial dysfunction, resulting in recognizable clinical syndromes. Mitochondrial DNA mutations have been linked to seizures, strokes, optic atrophy, neuropathy, myopathy, cardiomyopathy, sensorineural hearing loss, diabetes mellitus, and other clinical features. Mitochondrial DNA mutations also may play an important role in aging, as well as in common age-related neurodegenerative disorders such as Parkinson's disease. Therefore, it is becoming increasingly important for clinicians to recognize the clinical syndromes suggestive of a mitochondrial disorder, and to understand the unique features of mitochondrial genetics that complicate diagnosis and genetic counseling.
142 citations
TL;DR: The extraordinary success of DLI demonstrates that it is now possible to harness the GVL potential of the human immune system for clinical benefit, and the necessary effector cells and target antigens required for GVL reactivity are poorly defined but are the subject of intensive investigation.
Abstract: Until recently, the only cure for relapse after allogeneic bone marrow transplantation (BMT) has been a second BMT. Recently, infusions of leukocytes collected from the original transplant donor have been used to induce a direct graft-versus-leukemia (GVL) reaction in patients with relapsed disease. Adoptive immunotherapy with donor leukocyte infusions (DLI) results in complete remission for 60-80% of patients with relapsed chronic-phase CML; therapy is also effective for relapse of diseases other than CML, although response rates are lower. Adoptive immunotherapy induces remissions for the majority of patients with post-transplantation Epstein-Barr virus-related lymphomas and other viral-associated illnesses. The extraordinary success of DLI demonstrates that it is now possible to harness the GVL potential of the human immune system for clinical benefit. The necessary effector cells and target antigens required for GVL reactivity are poorly defined but are the subject of intensive investigation. Future trials will investigate strategies that retain and enhance the GVL effects while limiting toxicity from this therapy, and they may define methods of successful allogeneic adoptive immunotherapy outside the setting of allogeneic BMT.
TL;DR: Thrombin generation helps to explain the strong association between HIT and thrombosis, including the newly recognized syndrome of warfarin-induced venous limb gangrene, and provides a rationale for the use of anticoagulants that reduce throm bin generation (danaparoid) or inhibit thrombin (lepirudin).
Abstract: The past decade has seen many important advances in the pathogenesis, clinical and laboratory diagnosis, and management of heparin-induced thrombocytopenia (HIT), one of the most common immune-mediated adverse drug reactions. HIT is caused by IgG antibodies that recognize complexes of heparin and platelet factor 4, leading to platelet activation via platelet Fc gamma IIa receptors. Formation of procoagulant, platelet-derived microparticles, and, possibly, activation of endothelium generate thrombin in vivo. Thrombin generation helps to explain the strong association between HIT and thrombosis, including the newly recognized syndrome of warfarin-induced venous limb gangrene. This syndrome occurs when acquired protein C deficiency during warfarin treatment of HIT and deep venous thrombosis leads to the inability to regulate thrombin generation in the microvasculature. The central role of HIT antibodies in causing HIT, as well as refinements in laboratory assays to detect these antibodies, means that HIT should be considered a clinicopathologic syndrome. The diagnosis can be made confidently when one or more typical clinical events (most frequently, thrombocytopenia with or without thrombosis) occur in a patient with detectable HIT antibodies. The central role of thrombin generation in this syndrome provides a rationale for the use of anticoagulants that reduce thrombin generation (danaparoid) or inhibit thrombin (lepirudin).
TL;DR: There is an imperative need for cheap, well-tolerated drugs that can be used in short courses, and for strategies to delay the onset of drug resistance.
Abstract: Malaria still kills some 0.5-2.5 million people per year in the tropics. Resistance to the cheap, most commonly used antimalarials continues to spread alarmingly and could outpace drug development. The artemisinin derivatives have had an important clinical impact both on the treatment of resistant falciparum malaria and on the incidence of disease in low-transmission areas. A few promising new antimalarials are being tested clinically but there is an imperative need for cheap, well-tolerated drugs that can be used in short courses, and for strategies to delay the onset of drug resistance. Bed nets have been shown to reduce the incidence of severe malaria in many areas but an effective vaccine is urgently needed.
TL;DR: Practical concepts regarding the treatment of gastroesophageal reflux disease are developed, based on a review of studies on the natural history of the disease and the long-term outcome of therapy.
Abstract: This chapter reviews the biology of gastroesophageal reflux disease, relating pathophysiology to medical and surgical therapy. Various definitions of the disease are presented and workable criteria are developed to identify patients with the disease. The central importance of the lower esophageal high-pressure zone as a barrier to reflux is emphasized, along with an analysis of its biomechanical alteration in disease. The composition of the refluxed gastric juice is characterized in regard to its potential for mucosal injury. Evidence is provided that cardiac-type mucosa is an acquired sequel to acid-induced squamous mucosal injury in the terminal esophagus. A hypothesis regarding the process of intestinalization of cardiac-type mucosa to form Barrett's esophagus is presented. An integrated concept of the pathophysiology of gastroesophageal reflux disease is constructed. Practical concepts regarding the treatment of gastroesophageal reflux disease are developed, based on a review of studies on the natural...
TL;DR: The development of red cell substitutes affords a deeper insight into how oxygen is delivered to tissues in the microcirculation and how blood-flow distribution is regulated within and between organs.
Abstract: Red cell substitutes are solutions that can potentially be used in emergencies or during surgery when rapid expansion of the blood volume with an oxygen carrier is needed. The three main types of products in development are based on cell-free hemoglobin, perfluorocarbon emulsions, or liposome-encapsulated hemoglobin. None is currently approved for clinical use, but several are in advanced clinical trials. Outside the red blood cell, hemoglobin is subject to degradation and heme loss. It readily diffuses in the plasma space and effectively scavenges nitric oxide. These properties must be understood and controlled if hemoglobin-based products are to fulfill their promise. The development of red cell substitutes affords us a deeper insight into how oxygen is delivered to tissues in the microcirculation and how blood-flow distribution is regulated within and between organs. As red cell substitutes become available to clinicians and scientists, clinical applications are expected to expand.
TL;DR: The life-long nature of many of the mood disorders is described, as is the consequent role of the primary care physician in their management, and recent advances in the treatment of bipolar disorder are described.
Abstract: This chapter focuses on recent developments in our understanding of the etiology, epidemiology, and treatment of recurrent mood disorders. It addresses the changing relationship between endogenous ...
TL;DR: A combination of nonpharmacological and pharmacological measures is needed in the management of neurogenic postural hypotension.
Abstract: Postural hypotension may result from various neurogenic and non-neurogenic causes. It may be a key feature of certain disorders, such as the primary chronic autonomic failure syndromes; it can complicate a variety of diseases, such as diabetes mellitus; and its prevalence increases with advancing age. When symptomatic, it may result in loss of consciousness and thus cause injury. Postural hypotension can be suspected from the patient's history and is readily documented in the clinic by measuring lying and standing blood pressure. The diagnosis ideally should be confirmed in the laboratory with additional tests to determine the cause and evaluate the functional deficit, so as to aid treatment. Treatment of the causative disorder is often curative when there are non-neurogenic causes. A combination of nonpharmacological and pharmacological measures is needed in the management of neurogenic postural hypotension.
TL;DR: The roles of intestinal pacemakers (interstitial cells of Cajal) and genetic mutations in the etiology of pseudo-obstruction, as well as the cost-benefit ratio of transplantation, will be clarified in the future.
Abstract: Pseudo-obstruction syndromes are increasingly recognized in clinical practice. They result from impairment of intrinsic neuromuscular or extrinsic control of gut motility. Typically, pseudo-obstruction syndromes result in features suggestive of mechanical obstruction and bowel dilatation in the absence of any demonstrable obstruction or mucosal disease. The syndrome may affect any region of the gut. Less severe variants without bowel dilatation are diagnosed by measurement of gastrointestinal transit and pressure profiles. The aims of treatment are restoration of nutrition and hydration, symptom relief, normalization of intestinal propulsion with prokinetics, and suppression of bacterial overgrowth. Surgery plays a limited role, adjunctive to medical treatment, facilitating enteral nutrition and decompression by means of jejunostomy. Infrequently, resection of localized disease or intestinal transplantation are indicated. The roles of intestinal pacemakers (interstitial cells of Cajal) and genetic mutations in the etiology of pseudo-obstruction, as well as the cost-benefit ratio of transplantation for pseudo-obstruction, will be clarified in the future.
TL;DR: Understanding of these disorders has progressed from the description of the clinical phenotypes and delineation of the electrophysiologic and pathologic features to the identification of disease genes and elucidation of the underlying molecular mechanisms.
Abstract: Hereditary peripheral neuropathies, among the most common genetic disorders in humans, are a complex, clinically and genetically heterogeneous group of disorders that produce progressive deterioration of the peripheral nerves. This group of disorders includes hereditary neuropathy with liability to pressure palsies, Charcot-Marie-Tooth disease, Dejerine-Sottas syndrome, and congenital hypomyelinating neuropathy. Our understanding of these disorders has progressed from the description of the clinical phenotypes and delineation of the electrophysiologic and pathologic features to the identification of disease genes and elucidation of the underlying molecular mechanisms.
TL;DR: 13C NMR spectroscopy has shown that muscle glycogen synthesis accounts for the majority of insulin-stimulated muscle glucose uptake in normal volunteers and that defects in this process are chiefly responsible for insulin resistance in type 1 and type 2 diabetes mellitus.
Abstract: Prior to the advent of nuclear magnetic resonance (NMR) spectroscopy, human glucose metabolism was studied through tracer and tissue biopsy methodology. NMR spectroscopy now provides a noninvasive means to monitor metabolic flux and intracellular metabolite concentrations continuously. 13C NMR spectroscopy has shown that muscle glycogen synthesis accounts for the majority of insulin-stimulated muscle glucose uptake in normal volunteers and that defects in this process are chiefly responsible for insulin resistance in type 1 and type 2 diabetes mellitus, as well as in other insulin resistant states (obesity, insulin-resistant offspring of type 2 diabetic parents, elevation of plasma FFA concentrations). Furthermore, using 31P NMR spectroscopy to measure intracellular glucose-6-phosphate, it has been shown that defects in insulin-stimulated glucose transport/phosphorylation activity are primarily responsible for the insulin resistance in these states.
TL;DR: Three interferon beta preparations (Betaseron, Avonex, and Rebif) have shown efficacy in the treatment of relapsing-remitting multiple sclerosis, and Copaxone, a basic copolymer of four amino acids, lessens MS attack frequency and disease activity as measured by gadolinium-enhanced MRI scanning.
Abstract: Three interferon β preparations (Betaseron®, Avonex®, and Rebif®) have shown efficacy in the treatment of relapsing-remitting multiple sclerosis (MS). Attack frequency is reduced by 30% and major attacks to an even greater extent. Accumulating disease burden as measured by annual T2-weighted magnetic resonance imaging is markedly lessened, and disease activity as measured by serial gadolinium-enhanced MRI scanning is reduced by over 80%. A fourth preparation, Copaxone®, a basic copolymer of four amino acids, lessens MS attack frequency by 30% and also lessens disease activity as measured by gadolinium-enhanced MRI. Betaseron® lessens accumulation of disability in MS patients with secondary progressive disease regardless of the severity of disability at the time treatment is commenced. MS is now a treatable disease.
TL;DR: Recent large randomized double-blind studies show the efficacy of these agents in reducing skeletal complications in patients with bone metastases from both breast cancer and multiple myeloma.
Abstract: Tumor-induced osteolysis or lytic bone disease is mediated by osteoclast activation. Osteoclasts can be activated directly by products produced by tumors or indirectly through other nonmalignant cells. By reducing osteoclastic activity, bisphosphonates inhibit bone resorption. Since these agents were shown effective in treating other diseases associated with increased bone resorption, including cancer-related hypercalcemia and Paget's disease of bone, studies have been initiated to explore the use of bisphosphonates in patients with osteolytic bone metastases. Recent large randomized double-blind studies show the efficacy of these agents in reducing skeletal complications in patients with bone metastases from both breast cancer and multiple myeloma.
TL;DR: Ventricular tachycardias range from the common to the exotic, but all represent syndromes with which the internist and general cardiologist should be familiar.
Abstract: Most ventricular tachycardias encountered in clinical practice occur in patients who have structural heart disease. Idiopathic ventricular tachycardia refers to those arrhythmias that occur in patients without structural heart disease, metabolic/electrolyte abnormalities, or the long QT syndrome. Three commonly recognized forms of idiopathic ventricular tachycardia include: (a) ventricular tachycardia associated with mitral valve prolapse, (b) ventricular tachycardia originating from the right ventricular outflow tract, and (c) ventricular tachycardia originating from the left ventricle. Recently, a fourth type of idiopathic ventricular tachycardia, termed the Brugada syndrome, has been identified as responsible for some cases of cardiac arrest in persons without apparent structural heart disease. Each form of ventricular tachycardia may be considered a discrete syndrome based on its electrocardiographic characteristics, mechanisms, responses to pharmacologic intervention, and prognosis (good in most cases). Ventricular tachycardias range from the common to the exotic, but all represent syndromes with which the internist and general cardiologist should be familiar.
TL;DR: Hibernating myocardium is a state of persistently impaired myocardial and left ventricular function at rest due to reduced coronary blood flows, and Revascularization, either by surgery or by interventional catheter techniques, has been shown to improve or normalize the abnormal left vents at rest.
Abstract: Hibernating myocardium is a state of persistently impaired myocardial and left ventricular function at rest due to reduced coronary blood flows. It can be defined as an exquisitely regulated tissue successfully adapting its activity to prevailing circumstances. It has been documented in patients with angina (chronic stable and/or unstable), acute myocardial infarction, heart failure and/or severe left ventricular dysfunction, and anomalous left coronary artery from the pulmonary artery. The diagnosis of hibernating myocardium involves (a) documenting left ventricular dysfunction at rest and (b) documenting that there is viable myocardium in the area of dysfunction. Tests commonly used for the latter are dobutamine echocardiography, 201Tl isotope studies, and positron image tomography. Revascularization, either by surgery or by interventional catheter techniques, has been shown to improve or normalize the abnormal left ventricular function at rest.
TL;DR: Cyclosporine-A demonstrates some efficacy in treating proliferative lupus nephritis and, based on pilot study data, membranous l upus as well, and should be used only in combination with azathioprine and steroids, assuming cytotoxic therapy has failed.
Abstract: Cyclosporine-A is primary therapy for organ transplantation. Its immunosuppressive effect might suggest a therapeutic role in autoimmune diseases, including several idiopathic and secondary glomerular conditions. Various forms of idiopathic nephrotic syndrome, including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), and membranous nephropathy (MN), may respond well to cyclosporine in selected patients. However, frequent relapse limits its use to those who have failed to respond to, or were intolerant of, steroids or cytotoxics. Cyclosporine's efficacy in other glomerulopathies, such as IgA nephropathy (IgAN) and membranoproliferative glomerulonephritis (MPGN) remains poorly studied and, given the risk of nephrotoxicity, cannot be recommended for treatment of these entities until further data are available. Cyclosporine demonstrates some efficacy in treating proliferative lupus nephritis and, based on pilot study data, membranous lupus as well. Again, given relapse rates and potential nephrotoxicity, it should be used only in combination with azathioprine and steroids, assuming cytotoxic therapy has failed. Finally, cyclosporine toxicity is briefly reviewed.
TL;DR: Physicians need to develop their own goals for staying current, systematically and periodically search the literature for high-quality material relevant to the topics on their agendas, become facile with critical appraisal of the literature, and schedule time for reading.
Abstract: Keeping one's personal fund of knowledge current is one of the most formidable challenges that physicians face. This article considers a few strategies that may help physicians as they struggle to keep their knowledge up-to-date. Physicians need to develop their own goals for staying current, systematically and periodically search the literature for high-quality material relevant to the topics on their agendas, become facile with critical appraisal of the literature, and schedule time for reading. One of the responsibilities of any professional is to maintain expertise, and this responsibility is probably nowhere more critical, or more difficult, than in the profession of medicine.
TL;DR: The role of HFE in the process of normal iron metabolism has yet to be clearly defined and Mechanisms by which C282Y and H63D may disrupt the normal functioning of H FE have been suggested.
Abstract: Hereditary hemochromatosis (HHC) is a common autosomal recessive disorder of iron metabolism that results in progressive iron overload and can be fatal if untreated The hemochromatosis gene (HFE) was identified by positional cloning in 1996 Two missense mutations have been described in HFE The majority of HHC patients are homozygous for a cysteine-to-tyrosine substitution (C282Y); however, a small number are homozygous for a histidine-to-aspartic-acid substitution (H63D) or are heterozygous for both of these mutations Mechanisms by which C282Y and H63D may disrupt the normal functioning of HFE have been suggested, but the role of HFE in the process of normal iron metabolism has yet to be clearly defined
TL;DR: The regulation of virulence factors at the different stages of the infection is considered, and a general model for the pathogenesis of urinary tract infection is proposed.
Abstract: Cystitis is caused by a relatively small number of bacterial species. To colonize and grow in the urinary tract, these organisms have developed and acquired special properties (virulence factors) that allow them to overcome the defences of the urinary tract, particularly clearance by urine flow. These virulence factors are unlikely to be required during transmission from host to host, and sometimes their constitutive expression may actually be disadvantageous. Such factors are therefore regulated by the environment and in a coordinate manner to ensure their most appropriate expression for the conditions encountered. This review focuses on the biology of the urinary tract and the bacterial properties necessary to cause cystitis. The regulation of virulence factors at the different stages of the infection is considered, and a general model for the pathogenesis of urinary tract infection is proposed.
TL;DR: Individual patients who could benefit from screening should be informed about the potential benefits and harms and invited to make a personal choice based on their priorities and concerns.
Abstract: Controversy over screening for prostate cancer involves both scientific and policy considerations. The principal scientific questions are whether tumors detected by screening are clinically significant, whether screening generates too many false-positive results, and whether early detection lowers morbidity or mortality. Both screening and treatment of prostate cancer can be harmful, making the tradeoff between benefits and risks especially relevant. Studies suggest that this judgment is highly personal, depending on the relative importance that individuals assign to potential outcomes. Opinions and policy considerations also influence views about the appropriateness of screening. Chief among these are personal beliefs about benefits and harms, medicolegal concerns, patient expectations, resource constraints, and opportunity costs. Appropriate policy must discriminate between what is best for populations and for individual patients. The lack of evidence of benefit and the potential harms argue against a societal policy of routine screening. Individual patients who could benefit from screening should be informed about the potential benefits and harms and invited to make a personal choice based on their priorities and concerns.
TL;DR: Patients with mild or repaired problems, who function normally or nearly so and may fully participate; those with severe functional deficit or known high risk, for whom strenuous exertion must be strictly proscribed; and those who fall in between, with some limitations and some risk.
Abstract: Advances in the diagnosis and early management of congenital heart disease in recent decades have led to increasing numbers of individuals being sufficiently well to participate in social as well as truly competitive sports Physicians are increasingly asked whether such participation is safe, advisable, and efficacious, yet few guidelines exist to help them make these decisions There are three apparent subgroups of patients: (a) those with mild or repaired problems, who function normally or nearly so and may fully participate; (b) those with severe functional deficit or known high risk, for whom strenuous exertion must be strictly proscribed; and (c) those who fall in between, with some limitations and some risk—these patients present a great challenge to the wisdom and clinical skill of the physician