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Annual Review of Medicine - Volume 60, 2009
Volume 60, 2009
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Transcatheter Valve Repair and Replacement
Vol. 60 (2009), pp. 1–11More LessThere is significant interest in developing transcatheter therapy for valvular heart disease (VHD). Numerous devices have been developed for the percutaneous treatment of pulmonary and aortic stenosis as well as mitral regurgitation. Several of these devices have progressed to randomized clinical trials. These ongoing trials for aortic stenosis and mitral regurgitation will provide important insights into the durability of these therapies as well as the results following standard surgical repair. The field of transcatheter valve therapy is rapidly evolving, and this review aims to summarize the current status of the field.
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Role of Endothelin Receptor Antagonists in the Treatment of Pulmonary Arterial Hypertension
Vol. 60 (2009), pp. 13–23More LessPulmonary arterial hypertension (PAH) is a severe disease with marked morbidity and mortality for which therapeutic strategies have been limited. Basic research in vascular biology has implicated endothelin-1 (ET-1) and its receptors (ETA and ETB) in diverse preclinical models of PAH, and ET-1 has been shown to contribute significantly to PAH in human patients. Despite the complexity of roles of the ET receptors in the development or reversal of PAH in the laboratory, the introduction of endothelin receptor antagonists (ETRAs) to clinical medicine has substantially expanded our therapeutic approach toward severe PAH. This article briefly reviews preclinical data and the current status of ETRAs in the clinical management of PAH.
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Oral Iron Chelators
Vol. 60 (2009), pp. 25–38More LessDeferoxamine (DFO) was the standard of care for transfusional iron overload for >40 years, requiring subcutaneous infusion for 8–12 h/day, 5–7 days/week. Oral iron chelators are an important development, offering the potential to improve compliance and patients’ quality of life. The oral, three-times-daily agent deferiprone appeared to be a promising advance; however, its use has been limited owing to serious adverse events, such as neutropenia and agranulocytosis. Therapy combining deferiprone with DFO has proved effective in the management of severe cardiac siderosis. Deferasirox is a novel, orally active agent that provides 24-h chelation with a once-daily dose. An extensive clinical trial program has demonstrated that deferasirox at appropriate doses is effective in reducing or maintaining iron burden in adult and pediatric patients. The clinical program demonstrated that deferasirox has a safety profile that is clinically manageable with regular monitoring.
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The Treatment of Hyperhomocysteinemia
Vol. 60 (2009), pp. 39–54More LessThe unique biochemical profile of homocysteine is characterized by chemical reactivity supporting a wide range of molecular effects and by a tendency to promote oxidant stress–induced cellular toxicity. Numerous epidemiological reports have established hyperhomocysteinemia as an independent risk factor for cardiovascular disease, cerebrovascular disease, dementia-type disorders, and osteoporosis-associated fractures. Although combined folic acid and B-vitamin therapy substantially reduces homocysteine levels, results from randomized placebo-controlled clinical trials testing the effect of vitamin therapy on outcome in these diseases have generally fallen short of expectations. These results have led some to abandon homocysteine monitoring in the management of patients with cardiovascular or cognitive disorders. These trials, however, have generally included patients with only mildly elevated homocysteine levels and have not addressed several clinical scenarios in which homocysteine reduction may be effective, including the primary prevention of atherothrombotic disease in individuals at low or intermediate risk, or those with severe hyperhomocysteinemia.
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Stroke Rehabilitation: Strategies to Enhance Motor Recovery
Vol. 60 (2009), pp. 55–68More LessRecent evidence indicates that the brain can remodel after stroke, primarily through synaptogenesis. Task-specific and repetitive exercise appear to be key factors in promoting synaptogenesis and are central elements in rehabilitation of motor weakness following stroke. Expert medical management ensures a patient is well enough to participate in rehabilitation with minimal distractions due to pain or depression. Contraint-induced motor therapy and body-weight-supported ambulation are forms of exercise that “force use” of an impaired upper extremity. Technologies now in common use include robotics, functional electrical stimulation, and, to a lesser degree, transcranial magnetic stimulation and virtual reality. The data on pharmacological interventions are mixed but encouraging; it is hoped such treatments will directly stimulate brain tissue to recovery. Mitigation of factors preventing movement, such as spasticity, might also play a role. Research evaluating these motor recovery strategies finds them generally good at the movement level but somewhat less robust when looking at functional performance. It remains unclear whether inconsistent evidence for functional improvement is a matter of poor treatment efficacy or insensitive outcome measures.
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Cardiomyopathic and Channelopathic Causes of Sudden Unexplained Death in Infants and Children
Vol. 60 (2009), pp. 69–84More LessIn the past decade there has been an increasing awareness of distinct, potentially lethal heritable cardiomyopathic and channelopathic syndromes as they pertain to sudden cardiac death in infants and children. This review highlights current clinical and molecular findings of two highly relevant structural cardiac abnormalities evident at autopsy, namely hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, as well as the cardiac channelopathies of long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome, which may account for one third of autopsy-negative sudden unexplained deaths (SUDs) during childhood and adolescence. We also explore the role of postmortem genetic analysis (molecular autopsy) in cases of SUD, provide a critical analysis of the current spectrum and prevalence of channelopathies as the pathogenic basis for sudden infant death syndrome (SIDS), and provide a brief synopsis on genetic testing for such potentially lethal cardiac disorders.
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Bisphosphonate-Related Osteonecrosis of the Jaw: Diagnosis, Prevention, and Management
Vol. 60 (2009), pp. 85–96More LessBisphosphonate therapy has been considered standard therapy in the management and care of cancer patients with metastatic bone disease and patients with osteoporosis. The efficacy of these drugs is due to their ability to inhibit osteoclast-mediated bone resorption. However, the postmarketing experience with intravenous and, to a much lesser extent, oral bisphosphonates has raised concerns about potential side effects related to profound bone remodeling inhibition and osteonecrosis isolated to the jaws. We review the risk factors, incidence, pathogenesis, prevention strategies, and management of this new complication.
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IL-23 and Autoimmunity: New Insights into the Pathogenesis of Inflammatory Bowel Disease
Clara Abraham, and Judy H. ChoVol. 60 (2009), pp. 97–110More LessThe intestinal immune system has the challenge of maintaining both a state of tolerance toward intestinal antigens and the ability to combat pathogens. This balance is partially achieved by reciprocal regulation of proinflammatory, effector CD4+ T cells and tolerizing, suppressive regulatory T cells. Inflammatory bowel disease (IBD) comprises Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have linked CD to a number of IL-23 pathway genes, notably IL23R (interleukin 23 receptor). Similar associations in IL-23 pathway genes have been observed in UC. IL23R is a key differentiation feature of CD4+ Th17 cells, effector cells that are critical in mediating antimicrobial defenses. However, IL-23 and Th17 cell dysregulation can lead to end-organ inflammation. The differentiation of inflammatory Th17 cells and suppressive CD4+ Treg subsets is reciprocally regulated by relative concentrations of TGFβ, with the concomitant presence of proinflammatory cytokines favoring Th17 differentiation. The identification of IL-23 pathway and Th17 expressed genes in IBD pathogenesis highlights the importance of the proper regulation of the IL-23/Th17 pathway in maintaining intestinal immune homeostasis.
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Necrotizing Enterocolitis
Vol. 60 (2009), pp. 111–124More LessNecrotizing enterocolitis (NEC) remains a major cause of neonatal morbidity and death. The pathophysiology is poorly understood. Prevailing evidence suggests that NEC is due to an inappropriate inflammatory response of the immature gut to some undefined insult. The mortality rate (15%–25%) for affected infants has not changed appreciably in 30 years. Many infants with NEC recover uneventfully with medical therapy and have long-term outcomes similar to unaffected infants of matched gestational age. Infants with progressive disease requiring surgical intervention suffer almost all of the mortality and morbidity. Of these, ∼30%–40% will die of their disease and most of the remainder will develop long-term neurodevelopmental and gastrointestinal morbidity. Recent randomized trials suggest that the choice of operation does not influence patient outcome. Current work is focusing on developing a better understanding of the pathogenesis and improving means to identify which infants are at greatest risk of disease progression.
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Cancer Screening: The Clash of Science and Intuition*
Vol. 60 (2009), pp. 125–137More LessThe concept of early detection of cancer holds great promise and intuitive appeal. However, powerful biases can mislead clinicians when evaluating the efficacy of screening tests by clinical observation alone. Selection bias, lead-time bias, length-biased sampling, and overdiagnosis are counterintuitive concepts with critical implications for early-detection efforts. This article explains these biases and other common confounders in cancer screening. The most direct and reliable way to avoid being led astray by intuitions is through the use of randomized controlled trials.
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Biomarkers for Prostate Cancer
Vol. 60 (2009), pp. 139–151More LessThe development of biomarkers for prostate cancer screening, detection, and prognostication has revolutionized the management of this disease. Prostate-specific antigen (PSA) is a useful, though not specific, biomarker for detecting prostate cancer. We review the literature on prostate cancer biomarkers, including serum markers (PAP, tPSA, fPSA, proPSA, PSAD, PSAV, PSADT, EPCA, and EPCA-2), tissue markers (AMACR, methylated GSTP1, and the TMPRSS2-ETS gene rearrangement), and a urine marker (DD3PCA3/UPM-3). Future research should focus on validation of already existing biomarkers and the discovery of new markers to identify men with aggressive prostate cancer.
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Management of Breast Cancer in the Genome Era
Vol. 60 (2009), pp. 153–165More LessThe genomic era has been characterized by an exponential increase in the number of targets in the management of breast cancer. Prognostic profiling has helped to determine which tumors are more likely to be associated with poor disease-free survival. Gene expression profiles are being studied in order to improve predictions of response and toxicity. Epigenetics is being evaluated for its ability to influence estrogen receptor expression. However, these fields require further validation. This review discusses the advances in the management of breast cancer through genomic evaluation.
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MicroRNAs in Cancer
Vol. 60 (2009), pp. 167–179More LessMicroRNAs (miRNAs) are small, noncoding RNAs with important functions in development, cell differentiation, and regulation of cell cycle and apoptosis. MiRNA expression is deregulated in cancer by a variety of mechanisms including amplification, deletion, mutation, and epigenetic silencing. Several studies have now shown that miRNAs are involved in the initiation and progression of cancer. In this review, we briefly describe miRNA biogenesis and discuss how miRNAs can act as oncogenes and tumor suppressors. We also address the role of miRNAs in the diagnosis, prognosis, and treatment of cancer.
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Erythropoietin in Cancer Patients
Vol. 60 (2009), pp. 181–192More LessTherapy with erythropoiesis-stimulating agents (ESAs) is associated with well-documented benefits to anemic cancer patients undergoing chemotherapy, most importantly a reduction in the likelihood of needing red cell transfusions. One challenge in supportive cancer care is a relative resistance to ESAs, requiring high doses with a significant rate of nonresponse. Recent advances in our understanding of iron metabolism in patients with chronic illness and the results of clinical trials indicate that parenteral iron improves ESA response in this setting. Another issue is the safety of ESA treatment in cancer patients. There is an increased risk of venous thrombosis that must be considered in clinical decision making. There are also recent data raising concerns that ESAs may enhance tumor progression or decrease patient survival. Although the preponderance of the data suggests that ESAs do not alter survival when used to treat chemotherapy-induced anemia, large well-controlled trials addressing this issue are needed.
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Thrombopoietin and Thrombopoietin Mimetics in the Treatment of Thrombocytopenia
Vol. 60 (2009), pp. 193–206More LessAlthough the thrombopoietin receptor was discovered in 1991 and thrombopoietin (TPO) was purified in 1994, the development of a clinically useful TPO was hampered by the appearance of neutralizing antibodies to some forms of recombinant TPO. However, in 2008 two new drugs that mimic the effect of TPO became available to treat thrombocytopenia. Romiplostim is a TPO peptide mimetic given by subcutaneous injection that activates the TPO receptor by binding to the distal hematopoietic receptor domain just like TPO. Eltrombopag is a TPO nonpeptide mimetic administered orally that activates the TPO receptor by binding to the transmembrane domain. Both increase the platelet count in healthy humans as well as in >80% of patients with immune thrombocytopenic purpura (ITP). Although initially restricted to the second-line treatment of ITP, both agents could help treat many thrombocytopenic disorders. Both agents are well tolerated, with mild headache being the most common complaint. Potential long-term complications include thrombosis, increased bone marrow reticulin, rebound worsening of thrombocytopenia upon discontinuation, and increased blast formation. Ongoing studies should establish the incidence of these complications and determine the efficacy of these new agents in a variety of other thrombocytopenic conditions.
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Evolving Treatment of Advanced Colon Cancer
Vol. 60 (2009), pp. 207–219More LessColorectal cancer is a common malignancy worldwide. Despite significant developments in the treatment of this disease, it still causes considerable morbidity and mortality. Recent advances include both newer cytotoxic chemotherapies and novel biologic agents. Although overall progress has been more modest than had been hoped, substantial benefits have been achieved for some patients, and the number of treatment options has substantially increased. Perhaps most importantly, treatment regimens can now be selected and tailored toward the individual patient following an informed discussion between the patient and the treating oncologist. We present in detail these recent advances and provide some insight into several promising future strategies.
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Barrett's Esophagus and Esophageal Adenocarcinoma
Vol. 60 (2009), pp. 221–231More LessThe incidence of esophageal adenocarcinoma (EAC) has risen dramatically over the past three decades in western countries. The importance of Barrett's esophagus (BE) derives from its potential to transform to adenocarcinoma. BE is characterized by endoscopically recognized displacement of the squamocolumnar junction proximal to the gastroesophageal junction, with replacement of squamous mucosa with columnar lined mucosa. Adenocarcinomas of the esophagus appear to arise from Barrett's mucosa through progressive degrees of dysplasia, but the pathogenesis and natural history of this process are still unclear. Much of our knowledge regarding BE and the risk of EAC is based on observational and cross-sectional analyses, and recommendations regarding management have traditionally represented “expert opinion.” The past few years have seen an explosion in new information and the initiation of longitudinal studies to define the risk of adenocarcinoma in BE, the identification of predictive and prognostic markers of cancer risk, sensitive and cost-effective methods of surveillance, and methods of management of dysplasia and early neoplasia including disease prevention.
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Primary Myelofibrosis: Update on Definition, Pathogenesis, and Treatment
Vol. 60 (2009), pp. 233–245More LessPrimary myelofibrosis (PMF) is a clonal stem cell disorder that manifests clinically as anemia, splenomegaly due to extramedullary hematopoiesis, leukoerythroblastosis, and constitutional symptoms, which are the clinical hallmarks of PMF. Within the past three years it has been determined that a single, recurrent, somatic mutation in the gene encoding the cytoplasmic tyrosine kinase Janus kinase 2 (JAK2) occurs in the majority of patients with PMF, and more recently, activating mutations in the gene encoding the thrombopoietin receptor MPL have also been identified in a subset of PMF patients. These discoveries have yielded important insights into the pathogenesis of PMF and have brought about the first opportunity for rationally targeted therapy for this disorder. Here we present an updated review of the pathogenesis, definition, and treatment of PMF in light of the discovery of JAK2 and MPL mutations, as well as other recent work in the myeloproliferative neoplasm field.
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Nicotine Dependence: Biology, Behavior, and Treatment
Vol. 60 (2009), pp. 247–260More LessDespite great advances in the understanding and treatment of nicotine dependence, close to 21% of adults in the United States continue to smoke. Tobacco use is the single greatest cause of premature and preventable death in the United States. This article reviews the epidemiology, assessment, neurobiology, genetic etiology, and treatment of nicotine dependence. Enhanced understanding of these dimensions of nicotine dependence may help to advance progress toward lowering the prevalence rate of tobacco use in the U.S. and lowering the rate of tobacco-related morbidity and mortality.
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Food Allergy: Recent Advances in Pathophysiology and Treatment
Vol. 60 (2009), pp. 261–277More LessFood allergies, defined as an adverse immune response to food proteins, affect as many as 6% of young children and 3%–4% of adults in westernized countries, and their prevalence appears to be rising. In addition to well-recognized acute allergic reactions and anaphylaxis triggered by IgE antibody–mediated immune responses to food proteins, there is an increasing recognition of cell-mediated disorders such as eosinophilic gastroenteropathies and food protein–induced enterocolitis syndrome. We are gaining an increasing understanding of the pathophysiology of food allergic disorders and are beginning to comprehend how these result from a failure to establish or maintain normal oral tolerance. Many food allergens have been characterized at a molecular level, and this knowledge, combined with an increasing appreciation of the nature of humoral and cellular immune responses resulting in allergy or tolerance, is leading to novel therapeutic approaches. Currently, management of food allergies consists of educating the patient to avoid ingesting the responsible allergen and initiating therapy if ingestion occurs. However, numerous strategies for definitive treatment are being studied, including sublingual/oral immunotherapy, injection of anti-IgE antibodies, cytokine/anticytokine therapies, Chinese herbal therapies, and novel immunotherapies utilizing engineered proteins and strategic immunomodulators.
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Immunomodulation of Allergic Disease
Vol. 60 (2009), pp. 279–291More LessThis review focuses on sublingual immunotherapy (SLIT), toll-like receptor-9 (TLR-9) vaccines using cytosine phosphorothioate guanosine (CpG)–allergen conjugates, and anti-IL-5 as novel immunomodulating therapies in allergy. At present, all three approaches are investigational in the United States and require further study to determine their safety and effectiveness. SLIT provides a novel oral route of administering an allergen to induce tolerance to inhaled allergens. Studies of SLIT in allergic rhinitis demonstrate that it reduces symptoms and medication use and is associated with a low incidence of systemic allergic reactions. Initial phase II studies with TLR-9 vaccines conjugated to a ragweed allergen demonstrate that they reduce symptoms of allergic rhinitis during the ragweed season. Anti-IL-5 is effective as a corticosteroid-sparing agent in the hypereosinophilic syndrome. It has not shown benefit in moderate asthmatics with persistent symptoms but may reduce aspects of airway remodeling in asthma.
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Hypereosinophilic Syndrome: Current Approach to Diagnosis and Treatment*
Vol. 60 (2009), pp. 293–306More LessHypereosinophilic syndrome is a heterogeneous group of rare disorders characterized by marked blood or tissue eosinophilia resulting in a wide variety of clinical manifestations. Although the existence of clinical subtypes (or variants) of HES has been appreciated for some time, the recent characterization of some of these variants at the molecular and immunologic levels has demonstrated dramatic differences in disease pathogenesis, response to treatment, and prognosis depending on the etiology of the eosinophilia. This, together with the availability of novel targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, has fundamentally altered the approach to the diagnosis and treatment of HES.
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Extensively Drug-Resistant Tuberculosis: A New Face to an Old Pathogen
Vol. 60 (2009), pp. 307–320More LessThe presence and consequences of resistance to drugs used for the treatment of tuberculosis have long been neglected. The recent detection and recognition of widespread multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis have raised interest and concern among clinicians and public health authorities globally. In this article, we describe the current global status of drug-resistant tuberculosis. We discuss the development of resistance, current management, and strategies for control.
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Polycystic Kidney Disease
Vol. 60 (2009), pp. 321–337More LessA number of inherited disorders result in renal cyst development. The most common form, autosomal dominant polycystic kidney disease (ADPKD), is a disorder most often diagnosed in adults and caused by mutation in PKD1 or PKD2. The PKD1 protein, polycystin-1, is a large receptor-like protein, whereas polycystin-2 is a transient receptor potential channel. The polycystin complex localizes to primary cilia and may act as a mechanosensor essential for maintaining the differentiated state of epithelia lining tubules in the kidney and biliary tract. Elucidation of defective cellular processes has highlighted potential therapies, some of which are now being tested in clinical trials. ARPKD is the neonatal form of PKD and is associated with enlarged kidneys and biliary dysgenesis. The disease phenotype is highly variable, ranging from neonatal death to later presentation with minimal kidney disease. ARPKD is caused by mutation in PKHD1, and two truncating mutations are associated with neonatal lethality. The ARPKD protein, fibrocystin, is localized to cilia/basal body and complexes with polycystin-2. Rare, syndromic forms of PKD also include defects of the eye, central nervous system, digits, and/or neural tube and highlight the role of cilia and pathways such as Wnt and Hh in their pathogenesis.
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The Kidney and Ear: Emerging Parallel Functions
Elena Torban, and Paul GoodyerVol. 60 (2009), pp. 339–353More LessThe association between renal dysplasia and minor malformations of the external ear is weak. However, there is a remarkable list of syndromes that link the kidney to the inner ear. To organize these seemingly disparate syndromes, we cluster representative examples into three groups: (a) syndromes that share pathways regulating development; (b) syndromes involving dysfunction of the primary cilium, which normally provides critical information to epithelial cells about the fluid in which they are bathed; (c) syndromes arising from dysfunction of specialized proteins that transport ions and drugs in and out of the extracellular fluid or provide structural support.
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The Expanded Biology of Serotonin
Vol. 60 (2009), pp. 355–366More LessSerotonin is perhaps best known as a neurotransmitter that modulates neural activity and a wide range of neuropsychological processes, and drugs that target serotonin receptors are used widely in psychiatry and neurology. However, most serotonin is found outside the central nervous system, and virtually all of the 15 serotonin receptors are expressed outside as well as within the brain. Serotonin regulates numerous biological processes including cardiovascular function, bowel motility, ejaculatory latency, and bladder control. Additionally, new work suggests that serotonin may regulate some processes, including platelet aggregation, by receptor-independent, transglutaminase-dependent covalent linkage to cellular proteins. We review this new “expanded serotonin biology” and discuss how drugs targeting specific serotonin receptors are beginning to help treat a wide range of diseases.
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Advances in Autism
Vol. 60 (2009), pp. 367–380More LessAutism is a common childhood neurodevelopmental disorder with strong genetic liability. It is not a unitary entity but a clinical syndrome, with variable deficits in social behavior and language, restrictive interests, and repetitive behaviors. Recent advances in the genetics of autism emphasize its etiological heterogeneity, with each genetic susceptibility locus accounting for only a small fraction of cases or having a small effect. Therefore, it is not surprising that no unifying structural or neuropathological features have been conclusively identified. Given the heterogeneity of autism spectrum disorder (ASD), approaches based on studying heritable components of the disorder, or endophenotypes, such as language or social cognition, provide promising avenues for genetic and neurobiological investigations. Early intensive behavioral and cognitive interventions are efficacious in many cases, but autism does not remit in the majority of children. Therefore, development of targeted therapies based on pathophysiologically and etiologically defined subtypes of ASD remains an important and achievable goal of current research.
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Chronic Consciousness Disorders
Vol. 60 (2009), pp. 381–392More LessAlthough philosophers and cognitive neuroscientists have struggled to define human consciousness, physicians can identify and assess its two clinical dimensions: wakefulness and awareness. A comatose patient has neither wakefulness nor awareness; a patient in a vegetative state has wakefulness without awareness; and a minimally conscious patient has both, but awareness is impaired. Syndromes of unconsciousness have established diagnostic criteria, but they encompass a spectrum of severity of brain damage and have indistinct boundaries. Functional neuroimaging using PET and fMRI have provided a new and complementary way to assess consciousness. Several recent provocative studies suggest that fMRI in unresponsive patients may detect evidence of conscious awareness when a careful neurological examination cannot. If these findings are verified by future studies, functional neuroimaging technologies will alter clinical practices concerning the diagnosis, classification, and prognosis of unconscious patients, and will lead to a greater understanding of the biology of human consciousness.
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Goals of Inpatient Treatment for Psychiatric Disorders
Vol. 60 (2009), pp. 393–403More LessThe purpose of the psychiatric hospital changed dramatically during the twentieth century. Formerly the primary location for psychiatric treatment, the hospital now plays a more circumscribed role within a community-based system of care. Crisis stabilization, safety, and a focus on rapid discharge are the critical components of the acute inpatient stay. Subspecialized units focus on geriatrics, children, adolescents, dual diagnosis (substance abuse and mental illness), trauma disorders, eating disorders, and forensics. When integrated with the general medical system and a comprehensive base of community-delivered day treatment, residential sevices, and outpatient services, psychiatric hospitalization is a humane alternative to long-term institutional care.
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Understanding and Reducing Variation in Surgical Mortality
Vol. 60 (2009), pp. 405–415More LessSurgical mortality varies widely across hospitals and surgeons, more so than would be predicted by chance alone or differences in case mix. Although a large body of research has suggested the importance of procedure volume, clinical mechanisms underlying variation in surgical mortality remain largely unknown. Payers, policy makers, and professional organizations have implemented a variety of large-scale strategies aimed at improving outcomes. Selective referral, process compliance, and outcomes measurement reflect different philosophies on how best to improve surgical quality and have distinct advantages and disadvantages. The optimal strategy may depend on both the clinical context (e.g., which procedure) and political realities.
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MRI-Guided Focused Ultrasound Surgery
Vol. 60 (2009), pp. 417–430More LessMRI-guided focused ultrasound (MRgFUS) surgery is a noninvasive thermal ablation method that uses magnetic resonance imaging (MRI) for target definition, treatment planning, and closed-loop control of energy deposition. Integrating FUS and MRI as a therapy delivery system allows us to localize, target, and monitor in real time, and thus to ablate targeted tissue without damaging normal structures. This precision makes MRgFUS an attractive alternative to surgical resection or radiation therapy of benign and malignant tumors. Already approved for the treatment of uterine fibroids, MRgFUS is in ongoing clinical trials for the treatment of breast, liver, prostate, and brain cancer and for the palliation of pain in bone metastasis. In addition to thermal ablation, FUS, with or without the use of microbubbles, can temporarily change vascular or cell membrane permeability and release or activate various compounds for targeted drug delivery or gene therapy. A disruptive technology, MRgFUS provides new therapeutic approaches and may cause major changes in patient management and several medical disciplines.
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Genetic Testing in Clinical Practice
Vol. 60 (2009), pp. 431–442More LessIn the practice of internal medicine, the value of genetic testing in common (mono)genetic diseases such as familial hemochromatosis, hypercholesterolemia, Mediterranean fever, and thrombophilia is limited. The genotype insufficiently predicts the phenotype because of the powerful effects of other modifying genes, environmental influences, and lifestyle factors. Many common diseases, including diabetes mellitus, osteoporosis, and cardiovascular disease, have strong genetic influences but are called complex genetic traits. The underlying genetic factors are currently investigated using new molecular tools such as genome-wide association studies, analyzing up to 500,000 markers in huge numbers of patients. Many new (often unexpected) markers have been identified, and in many instances their functional significance is unknown. Genomic profiles play a rapidly growing role in the field of pharmacogenomics. A number of recently identified pharmacogenomic biomarkers are helpful to predict drug-related toxic effects.
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The HapMap and Genome-Wide Association Studies in Diagnosis and Therapy*
Vol. 60 (2009), pp. 443–456More LessThe International HapMap Project produced a genome-wide database of human genetic variation for use in genetic association studies of common diseases. The initial output of these studies has been overwhelming, with over 150 risk loci identified in studies of more than 60 common diseases and traits. These associations have suggested previously unsuspected etiologic pathways for common diseases that will be of use in identifying new therapeutic targets and developing targeted interventions based on genetically defined risk. Here we examine the development and application of the HapMap to genome-wide association (GWA) studies; present and future technologies for GWA research; current major efforts in GWA studies; successes and limitations of the GWA approach in identifying polymorphisms related to complex diseases; data release and privacy polices; use of these findings by clinicians, the public, and academic physicians; and sources of ongoing authoritative information on this rapidly evolving field.
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Prospects for Life Span Extension*
Vol. 60 (2009), pp. 457–469More LessLife expectancy has increased dramatically in the United States and in much of the world in recent years and decades. The factors underlying this increase are incompletely understood and are undoubtedly complex. A question that drives current research is whether life expectancy can be further extended using current knowledge of modifiable risk factors. A still more challenging research focus is on the possibility that life expectancy might be further increased through knowledge gained from studies of the basic biology of aging and its genetic and environmental modifiers.
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Emerging Concepts in the Immunopathogenesis of AIDS*
Vol. 60 (2009), pp. 471–484More LessThere is an intense interplay between HIV and the immune system, and the literature is replete with studies describing various immunological phenomena associated with HIV infection. Many of these phenomena seem too broad in scope to be attributable either to HIV-infected cells or to the HIV-specific immune response. Recently, a more fundamental understanding of how HIV affects various T cells and T cell compartments has emerged. This review covers the role of immune activation in HIV immunopathogenesis, how that activation could be mediated directly by HIV replicating within and damaging the gut mucosal barrier, how HIV affects multiple T cell functions and phenotypes, and how chronic HIV replication induces immune modulatory pathways to negatively regulate certain functions in HIV-specific T cells.
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Lessons Learned from the Natural Hosts of HIV-Related Viruses
Vol. 60 (2009), pp. 485–495More LessThe fact that human immunodeficiency virus (HIV) causes a deadly disease in humans whereas its simian counterparts, the simian immunodeficiency viruses (SIVs), are virtually nonpathogenic in their natural hosts remains a fundamental mystery of modern medicine. Arguably, the pathogenesis of HIV infection will remain poorly understood until the mechanisms responsible for the AIDS resistance of natural SIV hosts are fully explained. Over the past few years, some key features of natural SIV infections have been described in studies conducted predominantly in sooty mangabeys (SMs), African green monkeys (AGMs), and mandrills. Natural SIV hosts are able to avoid the chronic, generalized immune system activation that is associated with disease progression in HIV-infected individuals and have evolved to down-modulate the expression of CCR5 on CD4+ T cells. Better elucidation of the mechanisms underlying the lack of disease progression of natural SIV infections holds promise for the design of novel preventive and therapeutic approaches to HIV infection.
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Previous Volumes
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Volume 75 (2024)
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Volume 74 (2023)
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Volume 73 (2022)
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Volume 72 (2021)
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Volume 71 (2020)
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Volume 70 (2019)
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Volume 69 (2018)
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Volume 68 (2017)
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Volume 67 (2016)
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Volume 66 (2015)
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Volume 65 (2014)
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Volume 64 (2013)
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Volume 63 (2012)
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Volume 62 (2011)
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Volume 61 (2010)
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Volume 60 (2009)
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Volume 59 (2008)
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Volume 58 (2007)
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Volume 57 (2006)
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Volume 56 (2005)
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Volume 55 (2004)
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Volume 54 (2003)
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Volume 53 (2002)
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Volume 52 (2001)
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Volume 51 (2000)
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Volume 50 (1999)
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Volume 49 (1998)
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Volume 48 (1997)
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Volume 47 (1996)
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Volume 46 (1995)
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Volume 45 (1994)
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Volume 43 (1992)
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Volume 42 (1991)
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Volume 35 (1984)
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Volume 33 (1982)
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Volume 32 (1981)
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Volume 31 (1980)
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Volume 30 (1979)
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Volume 29 (1978)
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Volume 28 (1977)
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Volume 27 (1976)
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Volume 26 (1975)
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Volume 25 (1974)
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Volume 24 (1973)
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Volume 23 (1972)
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Volume 22 (1971)
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Volume 21 (1970)
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Volume 20 (1969)
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Volume 19 (1968)
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Volume 18 (1967)
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Volume 17 (1966)
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Volume 16 (1965)
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Volume 15 (1964)
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Volume 14 (1963)
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Volume 13 (1962)
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Volume 12 (1961)
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Volume 11 (1960)
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Volume 10 (1959)
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Volume 8 (1957)
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Volume 7 (1956)
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Volume 6 (1955)
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Volume 3 (1952)
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Volume 2 (1951)
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Volume 1 (1950)
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Volume 0 (1932)