Veterans Affairs Medical Center
Veterans Affairs Medical Center
Nagahara A.H.,University of California at San Diego |
Tuszynski M.H.,University of California at San Diego |
Tuszynski M.H.,Veterans Affairs Medical Center
Nature Reviews Drug Discovery | Year: 2011
The growth factor brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase receptor type B (TRKB) are actively produced and trafficked in multiple regions in the adult brain, where they influence neuronal activity, function and survival throughout life. The diverse presence and activity of BDNF suggests a potential role for this molecule in the pathogenesis and treatment of both neurological and psychiatric disorders. This article reviews the current understanding and future directions in BDNF-related research in the central nervous system, with an emphasis on the possible therapeutic application of BDNF in modifying fundamental processes underlying neural disease. © 2011 Macmillan Publishers Limited. All rights reserved.
Waxman S.G.,Yale University |
Waxman S.G.,Veterans Affairs Medical Center |
Zamponi G.W.,University of Calgary
Nature Neuroscience | Year: 2014
The transmission and processing of pain signals relies critically on the activities of ion channels that are expressed in afferent pain fibers. This includes voltage-gated channels, as well as background (or leak) channels that collectively regulate resting membrane potential and action potential firing properties. Dysregulated ion channel expression in response to nerve injury and inflammation results in enhanced neuronal excitability that underlies chronic neuropathic and inflammatory pain. Pharmacological modulators of ion channels, particularly those that target channels on peripheral neurons, are being pursued as possible analgesics. Over the past few years, a number of different types of ion channels have been implicated in afferent pain signaling. Here we give an overview of recent advances on sodium, calcium, potassium and chloride channels that are emerging as especially attractive targets for the treatment of pain. © 2014 Nature America, Inc. All rights reserved.
Clark R.E.,Veterans Affairs Medical Center
Neurobiology of Learning and Memory | Year: 2011
Systems consolidation involves a prolonged process of memory reorganization that appears to be distinctly related to declarative memory. Declarative memory can be sharply contrasted with simple delay eyeblink classical conditioning, a prototypical example of nondeclarative memory. Yet inserting a trace interval between the conditioned and unconditioned stimuli endows eyeblink (trace) conditioning with many features of declarative memory. Work in humans has established that trace conditioning requires declarative memory. Recently trace eyeblink conditioning in animals has become one of the most powerful methods to study systems consolidation. Thus, it is ironic that a substantially nondeclarative form of memory has been so instructive concerning the organization of declarative memory. © 2010.
Niewoehner D.E.,Veterans Affairs Medical Center
New England Journal of Medicine | Year: 2010
A 67-year-old man presents with a history of dyspnea, which has progressed for the past several years. He began smoking cigarettes at 15 years of age and continues to smoke one pack per day. Worsening breathlessness forced him to retire as a laborer, and he has sought emergency care for what he calls bronchitis twice in the past year. His physical examination is notable for diminished breath sounds on auscultation, with a prolonged expiratory phase. Spirometry reveals severe airflow obstruction (ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC], 0.43; FEV 1, 34% of the predicted value). How should this case be managed? Copyright © 2010 Massachusetts Medical Society.
Lederle F.A.,Veterans Affairs Medical Center
New England Journal of Medicine | Year: 2012
BACKGROUND: Whether elective endovascular repair of abdominal aortic aneurysm reduces long-term morbidity and mortality, as compared with traditional open repair, remains uncertain. METHODS: We randomly assigned 881 patients with asymptomatic abdominal aortic aneurysms who were candidates for both procedures to either endovascular repair (444) or open repair (437) and followed them for up to 9 years (mean, 5.2). Patients were selected from 42 Veterans Affairs medical centers and were 49 years of age or older at the time of registration. RESULTS: More than 95% of the patients underwent the assigned repair. For the primary outcome of all-cause mortality, 146 deaths occurred in each group (hazard ratio with endovascular repair versus open repair, 0.97; 95% confidence interval [CI], 0.77 to 1.22; P = 0.81). The previously reported reduction in perioperative mortality with endovascular repair was sustained at 2 years (hazard ratio, 0.63; 95% CI, 0.40 to 0.98; P = 0.04) and at 3 years (hazard ratio, 0.72; 95% CI, 0.51 to 1.00; P = 0.05) but not thereafter. There were 10 aneurysm-related deaths in the endovascular-repair group (2.3%) versus 16 in the open-repair group (3.7%) (P = 0.22). Six aneurysm ruptures were confirmed in the endovascular-repair group versus none in the open-repair group (P = 0.03). A significant interaction was observed between age and type of treatment (P = 0.006); survival was increased among patients under 70 years of age in the endovascular-repair group but tended to be better among those 70 years of age or older in the open-repair group. CONCLUSIONS: Endovascular repair and open repair resulted in similar long-term survival. The perioperative survival advantage with endovascular repair was sustained for several years, but rupture after repair remained a concern. Endovascular repair led to increased long-term survival among younger patients but not among older patients, for whom a greater benefit from the endovascular approach had been expected. (Funded by the Department of Veterans Affairs Office of Research and Development; OVER ClinicalTrials.gov number, NCT00094575). Copyright © 2012 Massachusetts Medical Society.
Lederle F.A.,Veterans Affairs Medical Center
European Journal of Vascular and Endovascular Surgery | Year: 2012
In a 1997 report of a large abdominal aortic aneurysm (AAA) screening study, we observed a negative association between diabetes and AAA. Although this was not previously described and negative associations between diseases are rare, the credibility of the finding was supported by consistent results in several previous studies and by the absence of an obvious artifactual explanation. Since that time, a variety of studies of AAA diagnosis, both by screening and prospective clinical follow-up, have confirmed the finding. Other studies have reported slower aneurysm enlargement and fewer repairs for rupture in diabetics. The seeming protective effect of diabetes for AAA contrasts with its causal role in occlusive vascular disease and so provides a strong challenge to the traditional view of AAA as a manifestation of atherosclerosis. Research focused on a protective effect of diabetes has already increased our understanding of the etiology of AAA, and might eventually pave the way for new therapies to slow AAA progression. © 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.
Carabello B.A.,Veterans Affairs Medical Center
Circulation Research | Year: 2013
Aortic stenosis is perhaps the most common of all valvular heart diseases in the developed nations of the world. Once primarily caused by rheumatic fever, the most common pathogenesis today is an active inflammatory process with some features that are similar to atherosclerosis. Because of this shift, the age at onset of severe obstruction has changed from the sixth decade 50 years ago to the eighth decade in most individuals today. The onset of symptoms remains a key determinant of outcome, although the later age at onset may make it difficult to discern if aortic stenosis or other age-related comorbidities is the cause of the symptoms. Once symptoms of aortic stenosis develop, life expectancy is shortened to ≈3 years unless the mechanical obstruction to left ventricular outflow is relieved by aortic valve replacement. Traditionally performed during cardiac surgery, aortic valve replacement now may be performed safely and effectively using transcatheter techniques, potentially revolutionizing the approach to this potentially fatal disease. © 2013 American Heart Association, Inc.
Unemo M.,Örebro University |
Shafer W.M.,Emory University |
Shafer W.M.,Veterans Affairs Medical Center
Clinical Microbiology Reviews | Year: 2014
Neisseria gonorrhoeae is evolving into a superbug with resistance to previously and currently recommended antimicrobials for treatment of gonorrhea, which is a major public health concern globally. Given the global nature of gonorrhea, the high rate of usage of antimicrobials, suboptimal control and monitoring of antimicrobial resistance (AMR) and treatment failures, slow update of treatment guidelines in most geographical settings, and the extraordinary capacity of the gonococci to develop and retain AMR, it is likely that the global problem of gonococcal AMR will worsen in the foreseeable future and that the severe complications of gonorrhea will emerge as a silent epidemic. By understanding the evolution, emergence, and spread of AMR in N. gonorrhoeae, including its molecular and phenotypic mechanisms, resistance to antimicrobials used clinically can be anticipated, future methods for genetic testing for AMR might permit region-specific and tailor- made antimicrobial therapy, and the design of novel antimicrobials to circumvent the resistance problems can be undertaken more rationally. This review focuses on the history and evolution of gonorrhea treatment regimens and emerging resistance to them, on genetic and phenotypic determinants of gonococcal resistance to previously and currently recommended antimicrobials, including biological costs or benefits; and on crucial actions and future advances necessary to detect and treat resistant gonococcal strains and, ultimately, retain gonorrhea as a treatable infection. © 2014, American Society for Microbiology. All Rights Reserved.
Samuel V.T.,Yale University |
Samuel V.T.,Veterans Affairs Medical Center |
Shulman G.I.,Yale University |
Shulman G.I.,Howard Hughes Medical Institute
Cell | Year: 2012
Insulin resistance is a complex metabolic disorder that defies explanation by a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway, and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, these cellular changes may converge to promote the accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, a common final pathway leading to impaired insulin signaling and insulin resistance. © 2012 Elsevier Inc.
Robey R.B.,Veterans Affairs Medical Center
Kidney International | Year: 2014
Severe cyclical dehydration induces chronic renal injury in rodents. This effect is attenuated by global fructokinase deficiency, suggesting possible roles for fructokinase and fructose metabolism in mediating or promoting dehydration-induced injury. Clinical and pathological similarities between this injury model and endemic Mesoamerican nephropathy (MeN) have fueled speculation that dehydration-induced injury and MeN may share common mechanistic underpinnings involving fructokinase that can be targeted to mitigate disease development, progression, and/or severity. © 2014 International Society of Nephrology.