Portland Veterans Affairs Medical Center

Portland, OR, United States

Portland Veterans Affairs Medical Center

Portland, OR, United States
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Perederiy J.V.,Oregon Health And Science University | Luikart B.W.,Oregon Health And Science University | Washburn E.K.,Oregon Health And Science University | Schnell E.,Portland Veterans Affairs Medical Center | Westbrook G.L.,Oregon Health And Science University
Journal of Neuroscience | Year: 2013

Neural plasticity following brain injury illustrates the potential for regeneration in the central nervous system. Lesioning of the perforant path, which innervates the outer two-thirds of the molecular layer of the dentate gyrus, was one of the first models to demonstrate structural plasticity of mature granule cells (Parnavelas et al., 1974; Caceres and Steward, 1983; Diekmann et al., 1996). The dentate gyrus also harbors a continuously proliferating population of neuronal precursors that can integrate into functional circuits and show enhanced short-term plasticity (Schmidt-Hieber et al., 2004; Abrous et al., 2005). To examine the response of adult-generated granule cells to unilateral complete transection of the perforant path in vivo, we tracked these cells using transgenic POMC-EGFP mice or by retroviral expression of GFP. Lesioning triggered a marked proliferation of newborn neurons. Subsequently, the dendrites of newborn neurons showed reduced complexity within the denervated zone, but dendritic spines still formed in the absence of glutamatergic nerve terminals. Electron micrographs confirmed the lack of intact presynaptic terminals apposing spines on mature cells and on newborn neurons. Newborn neurons, but not mature granule cells, had a higher density of dendritic spines in the inner molecular layer postlesion accompanied by an increase in miniature EPSC amplitudes and rise times. Our results indicate that injury causes an increase in newborn neurons and lamina-specific synaptic reorganization indicative of enhanced plasticity. The presence of de novo dendritic spines in the denervated zone suggests that the postlesion environment provides the necessary signals for spine formation. © 2013 the authors.

Wu Y.-N.,Oregon Health And Science University | Johnson S.W.,Oregon Health And Science University | Johnson S.W.,Portland Veterans Affairs Medical Center
Neuroscience | Year: 2011

Rotenone is a mitochondrial poison that causes dopamine cell death and is used as a model of Parkinson's disease in rodents. Recently, we showed that rotenone augments currents evoked by N-methyl-d-aspartate (NMDA) by relieving voltage-dependent Mg 2+ block in rat substantia nigra compacta (SNC) dopamine neurons. Because rotenone is well known to generate reactive oxygen species (ROS), we conducted the present experiments to evaluate the role of ROS in mediating the effect of rotenone on NMDA current augmentation. Using patch pipettes to record whole-cell currents from SNC neurons in slices of rat brain, we found that the ability of rotenone (100 nM) to increase NMDA (3-30 μM) current was antagonized by the antioxidant agent n-acetylcysteine (1 mM). In contrast, mercaptosuccinate (1 mM), which blocks glutathione peroxidase and raises tissue levels of H 2O 2, mimicked rotenone by augmenting inward currents evoked by NMDA. Because oxidation of dopamine can also generate ROS, we explored the role of dopamine on this action of rotenone. We prepared dopamine-depleted midbrain slices from rats that had been pretreated with reserpine (5 mg/kg ip) and alpha-methyl-para-tyrosine (AMPT, 250 mg/kg ip). Dopamine depletion blocked the ability of rotenone (100 nM) to increase inward current evoked by NMDA (30 μM). Rotenone-dependent augmentation of NMDA current was also blocked by the monoamine oxidase inhibitor pargyline (100 μM) in slices prepared from normal rats. In contrast, the dopamine precursor levodopa potentiated the action of rotenone on NMDA current. These results suggest that ROS and/or dopamine oxidation products mediate the ability of rotenone to potentiate NMDA currents. Because excessive NMDA receptor stimulation can produce excitotoxicity, our results suggest that oxidative metabolism of dopamine might facilitate the neurotoxicity of rotenone. © 2011.

Luikart B.W.,Oregon Health And Science University | Schnell E.,Portland Veterans Affairs Medical Center | Schnell E.,Oregon Health And Science University | Washburn E.K.,Oregon Health And Science University | And 3 more authors.
Journal of Neuroscience | Year: 2011

Some cases of autism spectrum disorder have mutations in the lipid phosphatase, phosphatase and tensin homolog on chromosome 10 (Pten). Tissue specific deletion of Pten in the hippocampus and cortex of mice causes anatomical and behavioral abnormalities similar to human autism. However, the impact of reductions in Pten on synaptic and circuit function remains unexplored. We used in vivo stereotaxic injections of lentivirus expressing a short hairpin RNA to knock down Pten in mouse neonatal and young adult dentate granule cells. We then assessed the morphology and synaptic physiology between 2 weeks and 4 months later. Confocal imaging of the hippocampus revealed a marked increase in granule cell size and an increase in dendritic spine density. The onset of morphological changes occurred earlier in neonatal mice than in young adults. We used whole-cell recordings from granule cells in acute slices to assess synaptic function after Pten knockdown. Consistent with the increase in dendritic spines, the frequency of excitatory miniature and spontaneous postsynaptic currents increased. However, there was little or no effect on IPSCs. Thus, Pten knockdown results in an imbalance between excitatory and inhibitory synaptic activity. Because reductions in Pten affected mature granule cells as well as developing granule cells, we suggest that the disruption of circuit function by Pten hypofunction may be ongoing well beyond early development. Copyright © 2011 the authors.

Kinkel R.P.,Beth Israel Deaconess Medical Center | Dontchev M.,Jaeb Center for Health Research | Kollman C.,Jaeb Center for Health Research | Skaramagas T.T.,Cleveland Clinic | And 2 more authors.
Archives of Neurology | Year: 2012

Objective: To determine whether immediate initiation of treatment at the time of a clinically isolated syndrome in patients at high risk for clinically definite multiple sclerosis alters disease course over 10 years. Design: Prospective follow-up study. Setting: Twenty-four Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) sites in the United States and Canada. Participants: A total of 81 patients originally randomly assigned to receive intramuscular interferon beta-1a (the immediate-treatment group) and 74 patients originally randomly assigned to receive placebo (the delayed-treatment group). All patients were from CHAMPS. Intervention: For the immediate-treatment group, treatment was initiated within a month after the onset of a clinically isolated syndrome, and for the delayed-treatment group, treatment was initiated a median of 30 months (interquartile range, 24-35 months) after CHAMPS randomization. Main Outcome Measures: Rate of developing clinically definite multiple sclerosis, annualized relapse rate, disease course classification, disability measures, and magnetic resonance imaging measures. Results: The immediate-treatment group showed a lower 10-year rate of clinically definite multiple sclerosis (unadjusted hazard ratio, 0.64 [95% CI, 0.48-0.87]; P=.004) and a lower annualized relapse rate between years 5 and 10 (P=.03). There was no differential effect on disability, magnetic resonance imaging T2-weighted lesions, or the proportion of patients developing progressive disease at 10 years. Few patients reached the Expanded Disability Status Scale milestone scores of 4.0 or greater (9% of patients) or 6.0 or greater (6% of patients). Conclusions: Immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome in high-risk patients reduces relapse rates over 10 years but does not improve disability outcomes compared with a control group that also initiated therapy relatively early in the disease course. Trial Registration: clinicaltrials.gov Identifier: NCT00179478. ©2012 American Medical Association. All rights reserved.

Subramanya A.R.,University of Pittsburgh | Ellison D.H.,Oregon Health And Science University | Ellison D.H.,Portland Veterans Affairs Medical Center
Clinical Journal of the American Society of Nephrology | Year: 2014

The distal convoluted tubule is the nephron segment that lies immediately downstream of the macula densa. Although short in length, the distal convoluted tubule plays a critical role in sodium, potassium, and divalent cation homeostasis. Recent genetic and physiologic studies have greatly expanded our understanding of how the distal convoluted tubule regulates these processes at the molecular level. This article provides an update on the distal convoluted tubule, highlighting concepts and pathophysiology relevant to clinical practice. Copyright © 2014 by the American Society of Nephrology.

Thompson E.M.,Oregon Health And Science University | Neuwelt E.A.,Oregon Health And Science University | Neuwelt E.A.,Portland Veterans Affairs Medical Center | Frenkel E.P.,University of Texas at Dallas
Neurology | Year: 2011

One rationale behind the use of agents that inhibit vascular endothelial growth factor in the therapy of primary CNS malignancies is based upon the concept that normalization of tumor vasculature with a decrease in tumor interstitial pressure will improve access of cytoreductive drugs and improve radiotherapy efficacy due to increased oxygen delivery. However, several studies have raised the concern that these agents may both rapidly restore the low permeability characteristics of the blood-brain barrier and counteract the beneficial effect of pseudoprogression. The result may be decreased therapeutic efficacy while increasing infiltration by co-opting normal vessels. In this discussion, we examine both histologic and radiographic tumor progression in the context of antiangiogenic agents. Issues dealing with the safety of bevacizumab (Avastin®, Genentech, South San Francisco, CA) and its potential to decrease efficacy of standard radiochemotherapy when used to treat patients with newly diagnosed malignant glioma are emphasized. Copyright © by AAN Enterprisos, Inc.

Qaseem A.,The American College | Barry M.J.,Massachusetts General Hospital | Kansagara D.,Portland Veterans Affairs Medical Center
Annals of Internal Medicine | Year: 2016

Description: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the comparative effectiveness of treatment with second-generation antidepressants versus nonpharmacologic treatments for major depressive disorder in adults. Methods: This guideline is based on a systematic review of published, English-language, randomized, controlled trials from 1990 through September 2015 identified using several databases and through hand searches of references of relevant studies. Interventions evaluated include psychotherapies, complementary and alternative medicines (including acupuncture,-3 fatty acids, S-adenosyl-L-methionine, St. John's wort [Hypericum perforatum]), exercise, and second-generation antidepressants. Evaluated outcomes included response, remission, functional capacity, quality of life, reduction of suicidality or hospitalizations, and harms. The target audience for this guideline includes all clinicians, and the target patient population includes adults with major depressive disorder. This guideline grades the evidence and recommendations using ACP's clinical practice guidelines grading system. Recommendation: ACP recommends that clinicians select between either cognitive behavioral therapy or second-generation antidepressants to treat patients with major depressive disorder after discussing treatment effects, adverse effect profiles, cost, accessibility, and preferences with the patient (Grade: strong recommendation, moderate-quality evidence). © 2016 American College of Physicians.

Turner E.H.,Oregon Health And Science University | Turner E.H.,Portland Veterans Affairs Medical Center | Knoepflmacher D.,Oregon Health And Science University | Shapley L.,Oregon Health And Science University
PLoS Medicine | Year: 2012

Background: Publication bias compromises the validity of evidence-based medicine, yet a growing body of research shows that this problem is widespread. Efficacy data from drug regulatory agencies, e.g., the US Food and Drug Administration (FDA), can serve as a benchmark or control against which data in journal articles can be checked. Thus one may determine whether publication bias is present and quantify the extent to which it inflates apparent drug efficacy. Methods and Findings: FDA Drug Approval Packages for eight second-generation antipsychotics-aripiprazole, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, risperidone long-acting injection (risperidone LAI), and ziprasidone-were used to identify a cohort of 24 FDA-registered premarketing trials. The results of these trials according to the FDA were compared with the results conveyed in corresponding journal articles. The relationship between study outcome and publication status was examined, and effect sizes derived from the two data sources were compared. Among the 24 FDA-registered trials, four (17%) were unpublished. Of these, three failed to show that the study drug had a statistical advantage over placebo, and one showed the study drug was statistically inferior to the active comparator. Among the 20 published trials, the five that were not positive, according to the FDA, showed some evidence of outcome reporting bias. However, the association between trial outcome and publication status did not reach statistical significance. Further, the apparent increase in the effect size point estimate due to publication bias was modest (8%) and not statistically significant. On the other hand, the effect size for unpublished trials (0.23, 95% confidence interval 0.07 to 0.39) was less than half that for the published trials (0.47, 95% confidence interval 0.40 to 0.54), a difference that was significant. Conclusions: The magnitude of publication bias found for antipsychotics was less than that found previously for antidepressants, possibly because antipsychotics demonstrate superiority to placebo more consistently. Without increased access to regulatory agency data, publication bias will continue to blur distinctions between effective and ineffective drugs. Please see later in the article for the Editors' Summary.

Shen K.-Z.,Oregon Health And Science University | Johnson S.W.,Oregon Health And Science University | Johnson S.W.,Portland Veterans Affairs Medical Center
Journal of Neuroscience | Year: 2010

Excessive burst firing of action potentials in subthalamic nucleus (STN) neurons has been correlated with the bradykinesia and rigidity seen in Parkinson's disease. Consequently, there is much interest in characterizing mechanisms that promote burst firing, such as the regulation of NMDA receptor function. Using whole-cell recording techniques in rat brain slices, we report that inward currents evoked by NMDA are greatly potentiated by ATP-sensitive K+ (K-ATP) channel blocking agents in STN neurons but not in dopamine neurons in the substantia nigra. Moreover, we found that the ability of NMDA to evoke K-ATP current was blocked by inhibitors of nitric oxide synthase, guanylyl cyclase, and calcium/calmodulin. By altering firing patterns of STN neurons, this NMDA/K-ATP interaction may exert an important influence on basal ganglia output and thereby affect the clinical expression of Parkinson's disease. Copyright © 2010 the authors.

Kansagara D.,Portland Veterans Affairs Medical Center | Kansagara D.,Oregon Health And Science University | Englander H.,Oregon Health And Science University | Salanitro A.,Geriatric Research | And 6 more authors.
JAMA - Journal of the American Medical Association | Year: 2011

Context: Predicting hospital readmission risk is of great interest to identify which patients would benefit most from care transition interventions, as well as to risk-adjust readmission rates for the purposes of hospital comparison. Objective: To summarize validated readmission risk prediction models, describe their performance, and assess suitability for clinical or administrative use. Data Sources and Study Selection: The databases of MEDLINE, CINAHL, and the Cochrane Library were searched from inception through March 2011, the EMBASE database was searched through August 2011, and hand searches were performed of the retrieved reference lists. Dual review was conducted to identify studies published in the English language of prediction models tested with medical patients in both derivation and validation cohorts. Data Extraction: Data were extracted on the population, setting, sample size, follow-up interval, readmission rate, model discrimination and calibration, type of data used, and timing of data collection. Data Synthesis: Of 7843 citations reviewed, 30 studies of 26 unique models met the inclusion criteria. The most common outcome used was 30-day readmission; only 1 model specifically addressed preventable readmissions. Fourteen models that relied on retrospective administrative data could be potentially used to risk-adjust readmission rates for hospital comparison; of these, 9 were tested in large US populations and had poor discriminative ability (c statistic range: 0.55-0.65). Seven models could potentially be used to identify high-risk patients for intervention early during a hospitalization (c statistic range: 0.56-0.72), and 5 could be used at hospital discharge (c statistic range: 0.68-0.83). Six studies compared different models in the same population and 2 of these found that functional and social variables improved model discrimination. Although most models incorporated variables for medical comorbidity and use of prior medical services, few examined variables associated with overall health and function, illness severity, or social determinants of health. Conclusions: Most current readmission risk prediction models that were designed for either comparative or clinical purposes perform poorly. Although in certain settings such models may prove useful, efforts to improve their performance are needed as use becomes more widespread. ©2011 American Medical Association. All rights reserved.

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