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- Volume 64, 2013
Annual Review of Medicine - Volume 64, 2013
Volume 64, 2013
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Abiraterone and Novel Antiandrogens: Overcoming Castration Resistance in Prostate Cancer
Vol. 64 (2013), pp. 1–13More LessSuppression of gonadal androgens by medical or surgical castration remains the mainstay of treatment for patients with advanced prostate cancer. However, the response to treatment is not durable, and transition to a “castration-resistant” state is invariable. Recent advances in our understanding of the androgen receptor signaling pathway have led to the development of therapeutic strategies to overcome castration resistance. This article reviews current concepts and challenges behind targeting continued androgen receptor signaling in castration-resistant prostate cancer and provides an overview of recently completed and ongoing clinical trials of novel hormonal agents, with a focus on abiraterone acetate and enzalutamide (MDV3100).
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Antibody-Drug Conjugates in Cancer Therapy
Vol. 64 (2013), pp. 15–29More LessAn antibody-drug conjugate (ADC) provides the possibility of selectively ablating cancer cells by combining the specificity of a monoclonal antibody (mAb) for a target antigen with the delivery of a highly potent cytotoxic agent. ADC target antigens are typically highly expressed on the surface of cancer cells compared to normal cells. The tumor target, the cytotoxic agent, and the manner in which the agent is attached to the antibody are key determinants of clinical activity and tolerability. Recently, several clinical trials have demonstrated that ADCs achieve higher clinical response rates than unconjugated mAbs targeting the same cell surface antigen. Brentuximab vedotin represents one such ADC that has recently been approved for the treatment of relapsed Hodgkin and systemic anaplastic large cell lymphomas—both characterized by high expression of the target antigen, CD30, on the surface of malignant cells. This review summarizes key characteristics of current, clinically active ADCs and highlights recent clinical data illustrating the benefit of antibody-targeted delivery of cytotoxic agents to cancer cells.
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Circulating Tumor Cells: From Bench to Bedside
Vol. 64 (2013), pp. 31–44More LessCirculating tumor cells (CTCs) represent a surrogate biomarker of hematogenous metastases. In recent years, their detection has gained increasing interest. There is ample evidence regarding the ability to detect CTCs and their prognostic relevance, but their demonstrated predictive value in therapeutic response monitoring is clinically even more meaningful. Many clinical trials in the early and metastatic cancer setting now include CTCs as a monitoring parameter, and numerous translational studies attempting their molecular characterization are under way. There has been great progress in defining the clinical importance of CTCs, and it now seems likely that we may expect wider implementation of CTCs as a diagnostic oncology tool to monitor therapeutic response in real time. Novel technologies may further facilitate molecular characterization of CTCs and development of novel therapeutic targets, possibly leading to more powerful treatment strategies for cancer patients. As the detection and evaluation of CTCs are becoming an increasingly important diagnostic and prognostic tool, the goal of this review is to communicate the knowledge obtained through analysis of primary tumors and CTCs to oncologists and medical specialists in managing patients with cancer.
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Cytokines, Obesity, and Cancer: New Insights on Mechanisms Linking Obesity to Cancer Risk and Progression
Vol. 64 (2013), pp. 45–57More LessObesity is a problem of epidemic proportions in many developed nations. Increased body mass index and obesity are associated with a significantly worse outcome for many cancers. Breast cancer risk in the postmenopausal setting and poor disease outcome for all patients is significantly augmented in overweight and obese individuals. The expansion of fat tissue involves a complex interaction of endocrine factors known as adipokines and cytokines. High cytokine levels in primary breast cancers and in the circulation of affected patients have been associated with poor outcome. This review summarizes the how cytokine production in obese adipose tissue creates a chronic inflammatory microenvironment that favors tumor cell motility, invasion, and epithelial-mesenchymal transition to enhance the metastatic potential of tumor cells. Many of the cytokines associated with a proinflammatory state are not only upregulated in obese adipose tissue but may also stimulate the self-renewal of cancer stem cells. Thus, enhanced cytokine production in obese adipose tissue may serve both as a chemoattractant for invading cancers and to augment their malignant potential. These new mechanistic insights suggest that the current obesity epidemic will presage a significant increase in cancer incidence, morbidity, and mortality in the next few decades.
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Glioblastoma: Molecular Analysis and Clinical Implications
Vol. 64 (2013), pp. 59–70More LessGlioblastoma, the most common malignant primary brain tumor, carries an invariably poor prognosis. Targeting underlying biological foundations of the disease will be crucial to developing more effective treatment strategies. Although increasing evidence clearly indicates that glioblastoma is a molecularly heterogeneous disorder, recent large-scale expression profiling has provided a framework for categorizing the tumor into 3 to 4 distinct subclasses, each with its own characteristic genomic alterations. As such, there remains the enticing possibility that glioblastoma subclasses themselves might represent predictive biomarkers, particularly in the context of specific targeted agents. This review focuses on how best to ascertain the functional relevance of molecular subclass in glioblastoma through both preclinical and clinical investigations. The availability of appropriate mouse modeling systems along with expanded molecular profiling capabilities in the clinical setting should aid such efforts. However, significant systematic challenges remain, particularly in the setting of clinical trials.
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Harnessing the Power of the Immune System to Target Cancer
Vol. 64 (2013), pp. 71–90More LessFor many years, immunotherapeutic approaches for cancer held more promise than actual clinical benefit for the majority of patients. However, several recent key advances in tumor immunology have now turned the tide in favor of immunotherapy for the treatment of many different cancer types. In this review, we describe four of the most effective immunotherapeutic approaches currently used in the clinic: cancer vaccines, immunostimulatory agents, adoptive T cell therapy, and immune checkpoint blockade. In addition, we discuss some of the most promising future strategies that aim to utilize multiple immunotherapies or combine them with other approaches to more effectively target cancer.
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Human Papillomavirus Vaccines Six Years After Approval
Vol. 64 (2013), pp. 91–100More LessHuman papillomavirus vaccines were developed beginning in the early 1990s. Two similar vaccines were approved in 2006 and 2009 following extensive clinical testing. Both vaccines prevent HPV infection. Implementation of these vaccines is the next challenge.
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Reduced-Intensity Hematopoietic Stem Cell Transplants for Malignancies: Harnessing the Graft-Versus-Tumor Effect
Saar Gill, and David L. PorterVol. 64 (2013), pp. 101–117More LessAllogeneic hematopoietic cell transplantation combines the power of cytotoxic chemo/radiotherapy with the ability of the new immune system to seek out and destroy tumor cells. However, administration of such myeloablative transplants is fraught with risks, some of which are related to the intensive conditioning regimens. Reductions in the intensity of the administered cytotoxic therapy have demonstrated that under some circumstances, the burden of fighting tumor and enhancing stem cell engraftment can be shouldered mostly by the transplanted immune system. Reduced intensity has allowed a potentially curative therapy for hematologic malignancies to be offered to an expanded patient population. Ongoing research seeks to enhance the safety and power of this form of allogeneic immunotherapy.
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The Need for Lymph Node Dissection in Nonmetastatic Breast Cancer
Vol. 64 (2013), pp. 119–129More LessDetermining whether cancer has spread to locoregional lymph nodes is a critical step in the initial staging of breast cancer patients. Although axillary dissection reliably identifies nodal metastases and prevents the recurrence of cancer in the axilla, there is a significant incidence of long-term side effects, notably lymphedema, and the procedure is of no therapeutic benefit in women without axillary metastases. With the advent of sentinel lymph node biopsy, the axilla can be accurately staged in patients with T1–T3, clinically node-negative breast cancers while avoiding the morbidity of axillary lymph node dissection if the nodes do not contain cancer. Recent clinical trials suggest that for women with metastases to 1 or 2 sentinel nodes, the radiation and systemic therapy that are part of modern multimodality breast cancer treatment can replace axillary dissection when breast-conserving therapy is undertaken. For those with greater disease burden or those undergoing mastectomy, axillary dissection remains standard management.
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The Role of Anti-Inflammatory Drugs in Colorectal Cancer
Vol. 64 (2013), pp. 131–144More LessA large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet, and lifestyle are key risk factors for colorectal cancer (CRC). Prevention of CRC has long been considered a plausible approach for the population and individuals at high risk for developing this disease. A significant effort has been made in the development of novel drugs for both prevention and treatment over the past two decades. This review highlights recent advances in our understanding of the role of nonsteroidal anti-inflammatory drugs in CRC prevention and adjuvant treatment. Moreover, we focus on the molecular mechanisms underlying the antitumor effects of these drugs in CRC. The knowledge of how anti-inflammatory agents inhibit cancer formation and progression may provide a rationale for the development of more effective chemopreventive and chemotherapeutic agents with less toxicity.
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The Human Microbiome: From Symbiosis to Pathogenesis
Vol. 64 (2013), pp. 145–163More LessThe human microbiota is a complex assemblage of the microbes inhabiting many sites in the human body. Recent advances in technology have enabled deep sequencing and analysis of the members and structures of these communities. Two sites, the vagina and gastrointestinal tract, are highlighted to exemplify how technological advances have enhanced our knowledge of the host–microbiota system. These examples represent low- and high-complexity communities, respectively. In each example, certain community structures are identified that can be extrapolated to larger collections representing multiple individuals and potential disease or health states. One common feature is the unexpected diversity of the microbiota at any of these locations, which poses a challenge for relating the microbiota to health and disease. However, we anticipate microbiota compositional measurements could become standard clinical practice in the future and may become diagnostic for certain diseases or increased susceptibility to certain disorders. The microbiota of a number of disease states are currently being examined to identify potential correlations. In line with these predictions, it is possible that existing conditions may be resolved by altering the microbiota in a positive way.
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The Rotavirus Saga Revisited
Vol. 64 (2013), pp. 165–174More LessTwo live oral rotavirus vaccines were approved by the US Food and Drug Administration in 2005 and 2008, following large studies of ∼70,000 each in order to address questions about intussusception triggered by a third earlier vaccine. Both new rotavirus vaccines showed almost identical rates of intussusception in vaccine and placebo recipients. These vaccines have been used extensively in the United States with positive results. Efforts are under way to implement these vaccines in developing countries where the need is greatest.
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Staphylococcal Infections: Mechanisms of Biofilm Maturation and Detachment as Critical Determinants of Pathogenicity*
Vol. 64 (2013), pp. 175–188More LessBiofilm-associated infections are a significant cause of morbidity and death. Staphylococci, above all Staphylococcus aureus and S. epidermidis, are the most frequent causes of biofilm-associated infections on indwelling medical devices. Although the mechanistic basis for the agglomeration of staphylococcal cells in biofilms has been investigated in great detail, we lack understanding of the forces and molecular determinants behind the structuring of biofilms and the detachment of cellular clusters from biofilms. These processes are of key importance for the formation of vital biofilms in vivo with the capacity of bacterial dissemination to secondary sites of infection. Recent studies showed that the phenol-soluble modulins, surfactant peptides secreted by staphylococci in a quorum-sensing controlled fashion, structure biofilms in vitro and in vivo and lead to biofilm detachment with the in vivo consequence of bacterial dissemination. These findings substantiate that quorum sensing and surfactants have widespread importance for biofilm maturation processes in bacteria and establish a novel theory of the molecular determinants driving dissemination of biofilm-associated infection.
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Toward a Universal Influenza Virus Vaccine: Prospects and Challenges
Natalie Pica, and Peter PaleseVol. 64 (2013), pp. 189–202More LessCurrent influenza virus vaccines are annually reformulated to elicit protection by generating an immune response toward the virus strains that are predicted to circulate in the upcoming influenza season. These vaccines provide limited protection in cases of antigenic mismatch, when the vaccine and the circulating viral strains differ. The emergence of unexpected pandemic viruses presents an additional challenge to vaccine production. To increase influenza virus preparedness, much work has been dedicated to the development of a universal vaccine. Focusing on regions of viral proteins that are highly conserved across virus subtypes, vaccine strategies involving the matrix 2 protein, stalk domain of the hemagglutinin, and multivalent approaches have provided broad-based protection in animal models and show much promise. This review summarizes the most encouraging advances in the field with a focus on novel vaccine designs that have yielded promising preclinical and clinical data.
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Host Genetics of HIV Acquisition and Viral Control
Vol. 64 (2013), pp. 203–217More LessSince the discovery of HIV as the cause of AIDS, numerous insights have been gained from studies of its natural history and epidemiology. It has become clear that there are substantial interindividual differences in the risk of HIV acquisition and course of disease. Meanwhile, the field of human genetics has undergone a series of rapid transitions that have fundamentally altered the approach to studying HIV host genetics. We aim to describe the field as it has transitioned from the era of candidate-gene studies and the era of genome-wide association studies (GWAS) to its current state in the infancy of comprehensive sequencing. In some ways the field has come full circle, having evolved from being driven almost exclusively by our knowledge of immunology, to a bias-free GWAS approach, to a point where our ability to catalogue human variation far outstrips our ability to biologically interpret it.
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Systemic and Topical Drugs for the Prevention of HIV Infection: Antiretroviral Pre-exposure Prophylaxis
Jared Baeten, and Connie CelumVol. 64 (2013), pp. 219–232More LessPre-exposure prophylaxis (PrEP), in which HIV-uninfected persons use oral or topical antiretroviral medications to protect against HIV acquisition, is a promising new HIV prevention strategy. The biologic rationale for evaluation of PrEP for sexual HIV prevention included nonhuman primate models and the efficacy of antiretroviral prophylaxis for HIV-exposed infants. Proof-of-concept that PrEP protects against sexual HIV acquisition has been demonstrated in four clinical trials, which used the antiretroviral medication tenofovir, either as a vaginal gel or as daily oral tenofovir disoproxil fumarate, alone or coformulated with emtricitabine. Importantly, however, two trials failed to demonstrate HIV protection with PrEP; low adherence to daily use of PrEP is the leading hypothesis to account for the lack of efficacy. Next steps in the field include rigorous evaluation of uptake and adherence to PrEP in implementation settings and research into next-generation PrEP agents with longer half-life and less user dependence.
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Hyperaldosteronism as a Common Cause of Resistant Hypertension
Vol. 64 (2013), pp. 233–247More LessResistant hypertension affects an estimated 10–15 million American adults and is increasing in prevalence. The etiology of resistant hypertension is almost always multifactorial, including obesity, older age, high dietary salt, chronic kidney disease, and aldosterone excess. Classical primary aldosteronism and lesser degrees of aldosterone excess, possibly originating from visceral adipocytes, contribute broadly to antihypertensive treatment resistance. Treatment of resistant hypertension is predicated on appropriate lifestyle changes and use of effective combinations of antihypertensive agents from different classes. Blockade of aldosterone with spironolactone has been shown to be particularly effective for treatment of resistant hypertension. The antihypertensive benefit of spironolactone is not limited to patients with demonstrable hyperaldosteronism but instead can be effective in resistant hypertensive patients regardless of aldosterone levels. Chlorthalidone is a potent, long-acting thiazide-like diuretic and should be used preferentially to treat resistant hypertension as it is superior to normally used doses of hydrochlorothiazide.
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Mechanisms of Premature Atherosclerosis in Rheumatoid Arthritis and Lupus
Vol. 64 (2013), pp. 249–263More LessRheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), the two most common systemic autoimmune disorders, have both unique and overlapping manifestations. One feature they share is a significantly enhanced risk of atherosclerotic cardiovascular (CV) disease that significantly contributes to morbidity and mortality. The primary mechanisms that drive CV damage in these diseases remain to be fully characterized, but recent discoveries indicate that distinct inflammatory pathways and immune dysregulation characteristic of RA and SLE likely play prominent roles. This review focuses on analyzing the major mechanisms and pathways potentially implicated in the acceleration of atherothrombosis and CV risk in SLE and RA, as well as in the identification of putative preventive strategies that may mitigate vascular complications in systemic autoimmunity.
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Molecular Mechanisms in Progressive Idiopathic Pulmonary Fibrosis
Vol. 64 (2013), pp. 265–276More LessThere is clear evidence that environmental exposures and genetic predisposition contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Cigarette smoking increases the risk of developing IPF several-fold, as do other exposures such as metal-fume and wood-dust exposure. Occupations that increase the risk of IPF are agricultural work, hairdressing, and stone polishing, supporting the role of environmental exposure in disease pathogenesis. Genetic predisposition to IPF is evident from its familial aggregation and the fact that pulmonary fibrosis develops in several rare genetic disorders. Mutations in surfactant proteins lead to pulmonary fibrosis and are associated with endoplasmic reticulum stress in alveolar type II epithelial cells. Mutations in telomerase have been found in several families with IPF, and shortened telomeres are found in sporadic cases of IPF. A common variant in mucin 5B predisposes to both familial and sporadic IPF and is present in the majority of cases, indicating sporadic IPF occurs in those with genetic predisposition.
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Reprogrammed Cells for Disease Modeling and Regenerative Medicine
Vol. 64 (2013), pp. 277–290More LessThe conversion of somatic cells into pluripotent cells is transforming the way diseases are researched and treated. Induced pluripotent stem (iPS) cells' promise may soon be realized in the field of hematology, as hematopoietic stem cell transplants are already commonplace in clinics around the world. We provide a current comparison between induced pluripotent and embryonic stem cells, describe progress toward modeling hematological disorders using iPS cells, and illustrate the hurdles that must be overcome before iPS cell therapies will be available in clinics.
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Application of Metabolomics to Diagnosis of Insulin Resistance
Vol. 64 (2013), pp. 291–305More LessMetabolomics, the global interrogation of the biochemical components in a biological sample, has become an important complement to genomics and proteomics to aid in the understanding of pathophysiology. Major advantages of metabolomics are the size of the metabolome relative to the genome or proteome and the fact that it provides a view of the existing biochemical phenotype. As such, metabolomics is fast becoming an important discovery tool for new diagnostic and prognostic biomarkers. Although many methods exist for performing metabolomics, relatively few have led to successful development of new diagnostic tests. This review will aid the reader in understanding various metabolomic methods and their applications, as well as some of their inherent advantages and disadvantages. In addition, we present one example of the application of metabolomics to the identification of new fasting blood biomarkers for the diagnosis and monitoring of insulin resistance.
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Defective Complement Inhibitory Function Predisposes to Renal Disease
Vol. 64 (2013), pp. 307–324More LessThe role of the complement system in mediating human renal disease has long been recognized in immune-complex excess syndromes such as systemic lupus erythematosus and in dense deposit disease in which no immunoglobulin (Ig) is present. Over the past 15 years, mutations in complement regulatory genes have been demonstrated to predispose to thrombotic microangiopathies including atypical hemolytic uremic syndrome, C3 and C1q glomerulopathies, and preeclampsia. Excessive complement activation on an endothelial cell, due to either an autoantibody or a regulatory protein deficiency, sets up a procoagulant state in these diseases as well as in the antiphospholipid syndrome. Knowledge of the genes involved and the functional consequences of alterations in their structure has led to therapy that blocks complement activation.
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New Therapies for Gout
Vol. 64 (2013), pp. 325–337More LessGout prevalence is increasing, yet management remains suboptimal. Fortunately, new insights into gout biology are permitting the development of novel, potentially more effective strategies for both gouty inflammation and urate lowering. Colchicine, a drug long used for gout, has been recently approved (for the first time ever) by the FDA, based on a new, safer dosing regimen. The recently appreciated centrality of IL-1β in acute gouty inflammation has prompted studies of agents blocking the IL-1β receptor or soluble IL-1β signaling (canakinumab, rilonacept, anakinra). Novel approaches to urate lowering have led to mechanism-based therapies such as urate synthesis inhibitors (febuxostat is already FDA approved and BCX4208 is in development), URAT-1 inhibitors promoting renal uric acid excretion (lesinurad), and recombinant uricase to directly catabolize urate (pegloticase). These new treatments do not obviate the need for lifestyle and dietary management, another area in which significant scientific and clinical progress has recently been made.
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Pathogenesis of Immunoglobulin A Nephropathy: Recent Insight from Genetic Studies
Vol. 64 (2013), pp. 339–356More LessRecent genome-wide association studies (GWAS) have identified multiple susceptibility loci for immunoglobulin A nephropathy (IgAN), the most common form of glomerulonephritis, implicating independent defects in adaptive immunity (three loci on chromosome 6p21 in the MHC region), innate immunity (8p23 DEFA locus, 17p23 TNFSF13 locus, 22q12 HORMAD2 locus), and the alternative complement pathway (1q32 CFH/CFHR locus). In geospatial analysis of 85 populations, a genetic risk score based on the replicated GWAS loci is highest in Asians, intermediate in Europeans, and lowest in Africans, capturing the known difference in prevalence among world populations. The genetic risk score also uncovered a previously unsuspected increased prevalence of IgAN-attributable kidney failure in Northern Europe. The IgAN risk alleles have opposing effects on many immune-mediated diseases, suggesting that selection has contributed to variation in risk allele frequencies among different populations. Incorporating genetic, immunologic, and biochemical data, we present a multistep pathogenesis model that provides testable hypotheses for dissecting the mechanisms of disease.
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Podocyte Biology and Pathogenesis of Kidney Disease
Jochen Reiser, and Sanja SeverVol. 64 (2013), pp. 357–366More LessProteinuric chronic kidney disease (CKD), once a rare affliction believed to be mainly caused by genetic mutations, has become a global pandemic that severely diminishes the quality of life for millions. Despite the changing face of CKD, treatment options and resources remain woefully antiquated and have failed to arrest or reverse the effects of kidney-related diseases. Histological and genetic data strongly implicate one promising target: the podocyte. Podocytes are terminally differentiated cells of the kidney glomerulus that are essential for the integrity of the kidney filter. Their function is primarily based on their intricate structure, which includes foot processes. Loss of these actin-driven membrane extensions is tightly connected to the presence of protein in the urine, podocyte loss, development of CKD, and ultimately renal failure.
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Toward the Treatment and Prevention of Alzheimer's Disease: Rational Strategies and Recent Progress
Vol. 64 (2013), pp. 367–383More LessAlzheimer's disease (AD) is the major cause of late-life brain failure. In the past 25 years, autosomal dominant forms of AD were found to be primariy attributable to mutations in one of two presenilins, polytopic proteins that contain the catalytic site of the γ-secretase protease that releases the amyloid beta (Aβ) peptide. Some familial AD is also due to mutations in the amyloid precursor protein (APP), but recently a mutation in APP was discovered that reduces Aβ generation and is protective against AD, further implicating amyloid metabolism. Prion-like seeding of amyloid fibrils and neurofibrillary tangles has been invoked to explain the stereotypical spread of AD within the brain. Treatment trials with anti-Aβ antibodies have shown target engagement, if not significant treatment effects. Attention is increasingly focused on presymptomatic intervention, because Aβ mismetabolism begins up to 25 years before symptoms begin. AD trials deriving from new biological information involve extraordinary international collaboration and may hold the best hope for success in the fight against AD.
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Psychiatry's Integration with Medicine: The Role of DSM-5
Vol. 64 (2013), pp. 385–392More LessMental disorders represent a significant global burden whose effects are exacerbated by gaps in diagnosis and service provision. A substantial number of individuals seek services not through specialty psychiatric clinics but through primary care. Thus, the interface between psychiatry and the rest of medicine represents an appropriate area of focus in which to improve the detection and treatment of mental disorders. Development of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) can play a key role in this process. DSM-5 is expected to include specific revisions in diagnostic criteria, chapter organization, text structure, and classification approach that are designed to improve use of DSM by nonpsychiatrist physicians. Furthermore, revisions to DSM-5 will inform development of the primary care version of DSM-5. The goal is to publish a manual that enhances clinical utility in a manner that is concise and more amenable to use in primary care.
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Update on Typical and Atypical Antipsychotic Drugs
Vol. 64 (2013), pp. 393–406More LessAntipsychotic drugs (APDs) are best classified as typical or atypical. The distinction is based solely on their ability to cause extrapyramidal side effects (EPS), including tardive dyskinesia (TD). The two classes differ in mechanism of action, with atypical APDs providing important modulation of serotonergic neurotransmission. TD increases the death rate and can be minimized by limiting use of typical APDs. Clozapine is unique among the atypical APDs in its efficacy for ameliorating psychosis in patients with treatment-resistant schizophrenia (TRS), for reduction of suicide, and for improving longevity. The typical and atypical APDs do not differ in improving psychopathology in non-TRS. The atypicals vary in metabolic side effects: some have little burden. Cognitive benefits of the atypical APDs may be superior for some domains of cognition and require less use of anticholinergic drugs, which impair memory, for treatment of EPS. Overall, choosing among the atypical APDs as first-line treatment represents the best course for schizophrenia and most likely other disorders for which APDs are used.
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Ataluren as an Agent for Therapeutic Nonsense Suppression
Vol. 64 (2013), pp. 407–425More LessThe interplay of translation and mRNA turnover has helped unveil how the regulation of gene expression is a continuum in which events that occur during the birth of a transcript in the nucleus can have profound effects on subsequent steps in the cytoplasm. Exemplifying this continuum is nonsense-mediated mRNA decay (NMD), the process wherein a premature stop codon affects both translation and mRNA decay. Studies of NMD helped lead us to the therapeutic concept of treating a subset of patients suffering from multiple genetic disorders due to nonsense mutations with a single small-molecule drug that modulates the translation termination process at a premature nonsense codon. Here we review both translation termination and NMD, and our subsequent efforts over the past 15 years that led to the identification, characterization, and clinical testing of ataluren, a new therapeutic with the potential to treat a broad range of genetic disorders due to nonsense mutations.
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Treating the Developing Brain: Implications from Human Imaging and Mouse Genetics
Vol. 64 (2013), pp. 427–439More LessA fundamental issue in psychiatric medicine is the lack of empirical evidence indicating when, during development, a treatment will be most effective for a patient. We review behavioral and brain changes that occur across development, focusing on the period of adolescence, when there is a peak in diagnosis of many psychiatric disorders. We use anxiety disorders as an example because of their high prevalence in youth (affecting as many as 1 in 10). Basic forms of fear learning, which are at the core of anxiety disorders and are the targets of behavioral therapeutics, are examined as a function of age. We also discuss how fear learning has been genetically modulated in mice and humans. Based on these findings, we provide future directions for determining the efficacy of innovative therapies and preventive strategies for anxiety disorders as a function of age and potential genetic effects inferred from mice and humans.
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Genetic Basis of Intellectual Disability
Vol. 64 (2013), pp. 441–450More LessIn the past decade, we have witnessed a flood of reports about mutations that cause or contribute to intellectual disability (ID). This rapid progress has been driven in large part by the implementation of chromosomal microarray analysis and next-generation sequencing methods. The findings have revealed extensive genetic heterogeneity for ID, as well as examples of a common genetic etiology for ID and other neurobehavioral/psychiatric phenotypes. Clinical diagnostic application of these new findings is already well under way, despite incomplete understanding of non-Mendelian transmission patterns that are sometimes observed.
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Sickle Cell Disease, Vasculopathy, and Therapeutics
Vol. 64 (2013), pp. 451–466More LessSickle cell disease (SCD) is caused by a mutation in both beta globin genes, resulting in chronic hemolysis and multiorgan disease that ultimately leads to premature death. Although hemoglobin S (HbS) polymerization and vaso-occlusion are central to the pathogenesis of SCD, overlapping pathways implicated in SCD-related endothelial dysfunction include hemolysis, defects in nitric oxide metabolism, ischemia-reperfusion injury, oxidative stress, increased cell-to-cell adhesion, and proinflammatory and coagulation mediators. Progression of organ-specific vasculopathy often precedes organ dysfunction and may provide targets for therapeutic intervention. SCD-related vasculopathies include, but are not limited to, moyamoya that often precedes cerebral infarcts or hemorrhage, proliferative retinopathy prior to loss of eyesight, pulmonary vasculopathy associated with pulmonary hypertension, and renal vasculopathy prior to the onset of chronic renal disease. This review evaluates evidence that SCD vasculopathy is a harbinger for organ dysfunction and reviews the potential for targeted antivasculopathy therapies.
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Duty-Hour Limits and Patient Care and Resident Outcomes: Can High-Quality Studies Offer Insight into Complex Relationships?
Vol. 64 (2013), pp. 467–483More LessLong hours are an accepted component of resident education, yet data suggest they contribute to fatigue that may compromise patient safety. A systematic review confirms that limiting duty hours increases residents' hours of sleep and improves objective measures of alertness. Most studies of operative experience for surgical residents found no effect, and there is evidence of a limited positive effect on residents' mood. We find a mixed effect on patient safety, although problems with supervision, rather than the limits, may be responsible or contibute; evidence of reduced continuity of care and reduced continuity in residents' clinical education; and evidence that increased workload under the limits has a negative effect on patient and resident outcomes. We highlight specific areas for research and offer recommendations for national policy.
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Quality Measurement in Healthcare
Vol. 64 (2013), pp. 485–496More LessMeasurement is the basis for assessing potential improvements in healthcare quality. Measures may be classified into four categories: volume, structure, outcome, and process (VSOP). Measures of each type should be used with a full understanding of their cost and benefit. Although volume and structure measures are easily collected, impact on healthcare results is not always clear. Process measures are generally more difficult and expensive to collect, and the relationship between process and outcomes is only recently being explored. Knowledge of measure types and relationships among them, as well as emerging evidence on the role of patient satisfaction, must be used to guide improvements and ultimately for demonstrating value in healthcare.
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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 43 (1992)
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Volume 26 (1975)
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Volume 23 (1972)
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Volume 22 (1971)
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Volume 18 (1967)
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Volume 2 (1951)
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Volume 0 (1932)