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Moran L.M.,University of South Carolina | Fitting S.,University of South Carolina | Fitting S.,Virginia Commonwealth University | Booze R.M.,University of South Carolina | And 3 more authors.
International Journal of Developmental Neuroscience | Year: 2014

Pediatric AIDS caused by human immunodeficiency virus type 1 (HIV-1) remains one of the leading worldwide causes of childhood morbidity and mortality. HIV-1 proteins, such as Tat and gp120, are believed to play a crucial role in the neurotoxicity of pediatric HIV-1 infection. Detrimental effects on development, behavior, and neuroanatomy follow neonatal exposure to the HIV-1 viral toxins Tat1-72 and gp120. The present study investigated the neurobehavioral effects induced by the HIV-1 neurotoxic protein Tat1-86, which encodes the first and second exons of the Tat protein. In addition, the potential effects of HIV-1 toxic proteins Tat1-86 and gp120 on inflammatory pathways were examined in neonatal brains. Vehicle, 25μg Tat1-86 or 100ng gp120 was injected into the hippocampus of male Sprague-Dawley pups on postnatal day 1 (PD1). Tat1-86 induced developmental neurotoxic effects, as witnessed by delays in eye opening, delays in early reflex development and alterations in prepulse inhibition (PPI) and between-session habituation of locomotor activity. Overall, the neurotoxic profile of Tat1-86 appeared more profound in the developing nervous system in vivo relative to that seen with the first exon encoded Tat1-72 (Fitting et al., 2008b), as noted on measures of eye opening, righting reflex, and PPI. Neither the direct PD1 CNS injection of the viral HIV-1 protein variant Tat1-86, nor the HIV-1 envelope protein gp120, at doses sufficient to induce neurotoxicity, necessarily induced significant expression of the inflammatory cytokine IL-1β or inflammatory factors NF-κβ and I-κβ. The findings agree well with clinical observations that indicate delays in developmental milestones of pediatric HIV-1 patients, and suggest that activation of inflammatory pathways is not an obligatory response to viral protein-induced neurotoxicity that is detectable with behavioral assessments. Moreover, the amino acids encoded by the second tat exon may have unique actions on the developing hippocampus. © 2014 ISDN.

Pai A.B.,Hunter Holmes ire Veterans Administration Medical Center | Walker W.C.,Hunter Holmes ire Veterans Administration Medical Center | Walker W.C.,Virginia Commonwealth University
American Journal of Physical Medicine and Rehabilitation | Year: 2014

Objective: The aim of this study was to determine whether either Physical Medicine and Rehabilitation residency performance on core competency evaluations or on practice mock oral examinations is correlated to performance on future American Board of Physical Medicine and Rehabilitation Part 2 board-certifying examination.Design: This is a retrospective cohort study of residents who took part 2 of the American Board of Physical Medicine and Rehabilitation certification examination between 1995 and 2011 (N = 31 or 38 or 67).Results: The postgraduate year 4 mock oral examination average achieved significance in correlation analysis (Spearman Q, 0.0391; P = 0.030). Patient care and a composite average of the other core competencies evaluations were also significantly correlated with performance on part 2 of the board-certifying examination (Spearman Q, 0.329; P = 0.044). The only independent variable that was uniquely predictive was postgraduate year 4 mock oral examinations (χ2 = 7.09; P = 0.029). More specifically, when controlling for rotation performances, residents with higher mock oral examination scores were 9.6 times (Exp B = 9.6;95% confidence interval, 1.2-80; P = 0.036) more likely than those one grade lower to achieve the upper half on oral board examinations vs. either of the lower 2 quartiles.Conclusions: The postgraduate year 4 mock oral examinations and the core competency evaluations composite are each predictive of performance on American Board of Physical Medicine and Rehabilitation part 2 examination. Further research into this area, with a larger sample size and with multiple institutions, would be helpful to allow for a better measurement of these evaluation tools' effectiveness. Copyright © 2014 by Lippincott Williams & Wilkins.

Ingersoll K.S.,University of Virginia | Farrell-Carnahan L.,University of Virginia | Cohen-Filipic J.,Virginia Commonwealth University | Heckman C.J.,Fox Chase Cancer Center | And 3 more authors.
Drug and Alcohol Dependence | Year: 2011

Background: Crack cocaine use undermines adherence to highly active antiretroviral therapy (HAART). This pilot randomized clinical trial tested the feasibility and efficacy of 2 interventions based on the Information-Motivation-Behavioral Skill model to improve HAART adherence and reduce crack cocaine problems. Methods: Participants were 54 adults with crack cocaine use and HIV with <90% HAART adherence. Most participants were African-American (82%) heterosexual (59%), and crack cocaine dependent (92%). Average adherence was 58% in the past 2 weeks. Average viral loads (VL) were detectable (log. VL 2.97). The interventions included 6 sessions of Motivational Interviewing plus feedback and skills building (MI+), or Video information plus debriefing (Video+) over 8 weeks. Primary outcomes were adherence by 14-day timeline follow-back and Addiction Severity Index (ASI) Drug Composite Scores at 3 and 6 months. Repeated measure ANOVA assessed main effects of the interventions and interactions by condition. Results: Significant increases in adherence and reductions in ASI Drug Composite Scores occurred in both conditions by 3 months and were maintained at 6 months, representing medium effect sizes. No between group differences were observed. No VL changes were observed in either group. Treatment credibility, retention, and satisfaction were high and not different by condition. Conclusions: A counseling and a video intervention both improved adherence and drug problems durably among people with crack cocaine use and poor adherence in this pilot study. The interventions should be tested further among drug users with poor adherence. Video interventions may be feasible and scalable for people with HIV and drug use. © 2011 Elsevier Ireland Ltd.

Lolans K.,Rush University Medical Center | Calvert K.,Alverno Laboratories | Won S.,Rush University Medical Center | Won S.,Hunter Holmes ire Veterans Administration Medical Center | And 2 more authors.
Journal of Clinical Microbiology | Year: 2010

Klebsiella pneumoniae carbapenemase (KPC) production in Gram-negative bacilli is an increasing problem worldwide. Rectal swab surveillance is recommended as a component of infection prevention programs, yet few screening methods are published. We compared detection of KPC-producing Klebsiella pneumoniae and Escherichia coli in surveillance specimens by 2 methods: (i) inoculation of swabs in tryptic soy broth containing 2 μg/ml imipenem followed by plating to MacConkey agar (MAC) (method 1) and (ii) streaking swabs on MAC onto which a 10-μg ertapenem disk was then placed (method 2). Simulated rectal swab specimens of challenge isolates from a collection of well-characterized K. pneumoniae and E. coli strains and salvage rectal swab specimens collected from patients at 4 different health care facilities over a 7-month period were tested. The gold-standard comparator was blaKPC PCR testing of isolates. Method 1 detected 4/9 (44%) KPC-positive challenge isolates. By method 2, 9/9 KPC-positive challenge isolates exhibited zones of inhibition of ≤27 mm; all KPC-negative isolates exhibited zones of inhibition greater than 27 mm. The sensitivity and specificity of method 1 for detection of KPC-positive K. pneumoniae and E. coli in 149 rectal swab specimens were 65.6% (95% confidence interval [CI], 46.8% to 80.8%) and 49.6% (95% CI, 40.3% to 58.9%), respectively. With method 2, a zone diameter of ≤27 mm had a sensitivity of 97.0% (95% CI, 82.5% to 99.8%) and specificity of 90.5% (95% CI, 83.3% to 94.9%) for detection of KPC in rectal swab specimens. Direct ertapenem disk testing is simpler, more sensitive, and more specific than selective broth enrichment with imipenem for detection of KPC-producing K. pneumoniae and E. coli in surveillance specimens. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Goehe R.W.,Virginia Commonwealth University | Shultz J.C.,Virginia Commonwealth University | Murudkar C.,Virginia Commonwealth University | Usanovic S.,Virginia Commonwealth University | And 9 more authors.
Journal of Clinical Investigation | Year: 2010

Caspase-9 is involved in the intrinsic apoptotic pathway and suggested to play a role as a tumor suppressor. Little is known about the mechanisms governing caspase-9 expression, but post-transcriptional pre-mRNA processing generates 2 splice variants from the caspase-9 gene, pro-apoptotic caspase-9a and anti-apoptotic caspase-9b. Here we demonstrate that the ratio of caspase-9 splice variants is dysregulated in non-small cell lung cancer (NSCLC) tumors. Mechanistic analysis revealed that an exonic splicing silencer (ESS) regulated caspase-9 pre-mRNA processing in NSCLC cells. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) interacted with this ESS, and downregulation of hnRNP L expression induced an increase in the caspase-9a/9b ratio. Although expression of hnRNP L lowered the caspase-9a/9b ratio in NSCLC cells, expression of hnRNP L produced the opposite effect in non-transformed cells, suggesting a post-translational modification specific for NSCLC cells. Indeed, Ser 52 was identified as a critical modification regulating the caspase-9a/9b ratio. Importantly, in a mouse xenograft model, downregulation of hnRNP L in NSCLC cells induced a complete loss of tumorigenic capacity that was due to the changes in caspase-9 pre-mRNA processing. This study therefore identifies a cancer-specific mechanism of hnRNP L phosphorylation and subsequent lowering of the caspase-9a/9b ratio, which is required for the tumorigenic capacity of NSCLC cells.

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