Perron N.R.,Medical University of South Carolina |
Beeson C.,Medical University of South Carolina |
Rohrer B.,Ralph hnson Medical Center
Journal of Bioenergetics and Biomembranes | Year: 2013
Although genetic and environmental factors contribute to neurodegenerative disease, the underlying etiology common to many diseases might be based on metabolic demand. Mitochondria are the main producer of ATP, but are also the major source of reactive oxygen species. Under normal conditions, these oxidants are neutralized; however, under environmental insult or genetic susceptibility conditions, oxidative stress may exceed cellular antioxidant capacities, leading to degeneration. We tested the hypothesis that loss in mitochondrial reserve capacity plays a causative role in neuronal degeneration and chose a cone photoreceptor cell line as our model. 661W cells were exposed to agents that mimic oxidant stress or calcium overload. Real-time changes in cellular metabolism were assessed using the multi-well Seahorse Biosciences XF24 analyzer that measures oxygen consumption (OCR) and extracellular acidification rates (ECAR). Cellular stress resulted in an early loss of mitochondrial reserve capacity, without affecting basal respiration; and ECAR was increased, representing a compensatory shift of ATP productions toward glycolysis. The degree of change in energy metabolism was correlated with the amount of subsequent cell death 24-hours post-treatment, the concentration-dependent loss in mitochondrial reserve capacity correlated with the number of live cells. Our data suggested first, that loss in mitochondrial reserve capacity is a major contributor in disease pathogenesis; and second, that the XF24 assay might represent a useful surrogate assay amenable to the screening of agents that protect against loss of mitochondrial reserve capacity. In future experiments, we will explore these concepts for the development of neuroprotective agents. © 2012 Springer Science+Business Media New York.
Schacht J.P.,Medical University of South Carolina |
Anton R.F.,Medical University of South Carolina |
Voronin K.E.,Medical University of South Carolina |
Randall P.K.,Medical University of South Carolina |
And 4 more authors.
Neuropsychopharmacology | Year: 2013
Variation at a single nucleotide polymorphism in the μ-opioid receptor gene (OPRM1), A118G (Asn40Asp), may moderate naltrexone (NTX) effects in alcohol dependence. Both NTX and A118G variation have also been reported to affect alcohol cue-elicited brain activation. This study investigated whether sub-acute NTX treatment and A118G genotype interacted in their effects on cue-elicited activation of the ventral striatum (VS), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). Secondarily, variation at a variable number tandem repeat polymorphism in the dopamine transporter gene (DAT1/SLC6A3), which has been associated with increased reward-related activation in VS, was analyzed as a moderator of medication and A118G effects. Seventy-four non-treatment-seeking alcohol-dependent individuals, half preselected to carry at least one copy of the A118G G (Asp) allele, were randomized to NTX (50 mg) or placebo for 7 days, and performed an fMRI alcohol cue reactivity task on day 6. Region-of-interest analyses indicated no main effects of medication or A118G genotype. However, these factors interacted in their effects on OFC activation, such that, among NTX-treated individuals, G-allele carriers had less activation than A-allele homozygotes. DAT1 variation also moderated medication/A118G effects. There was a three-way interaction between medication and A118G and DAT1 genotypes on VS activation, such that, among G-allele carriers who received NTX, DAT1 10-repeat-allele (10R) homozygotes had less activation than 9-repeat-allele (9R) carriers. Further, 10R homozygotes who received NTX had less mPFC activation than 9R carriers. Polymorphic variation in OPRM1 and DAT1 should be considered in future studies of NTX, particularly regarding its effects on reward processing. © 2013 American College of Neuropsychopharmacology. All rights reserved.
Alge J.L.,Medical University of South Carolina |
Karakala N.,Medical University of South Carolina |
Neely B.A.,Medical University of South Carolina |
Janech M.G.,Medical University of South Carolina |
And 3 more authors.
Critical Care | Year: 2013
Introduction: Acute kidney injury (AKI) is commonly observed in the intensive care unit (ICU), where it can be caused by a variety of factors. The objective of this study was to evaluate the prognostic value of urinary angiotensinogen, a candidate prognostic AKI biomarker identified in post-cardiac surgery patients, in this heterogeneous population.Methods: Urinary angiotensinogen was measured by ELISA and corrected for urine creatinine in 45 patients who developed AKI in the ICU. Patients were grouped by AKI etiology, and the angiotensinogen-to-creatinine ratio (uAnCR) was compared among the groups using the Kruskal-Wallis test. The ability of uAnCR to predict the following endpoints was tested using the area under the ROC curve (AUC): the need for renal replacement therapy (RRT) or death, increased length of stay (defined as hospital discharge > 7 days or death ≤ 7 days from sample collection), and worsening AKI (defined as an increase in serum creatinine > 0.3 mg/dL after sample collection or RRT).Results: uAnCR was significantly elevated in patients who met the composite outcome RRT or death (89.4 vs 25.4 ng/mg; P = 0.01), and it was a strong predictor of this outcome (AUC = 0.73). Patients with uAnCR values above the median for the cohort (55.21 ng/mg) had increased length of stay compared to patients with uAnCR ≤ 55.21 ng/mg (22 days vs 7 days after sample collection; P = 0.01). uAnCR was predictive of the outcome increased length of stay (AUC = 0.77). uAnCR was also a strong predictor of worsening of AKI (AUC = 0.77). The uAnCR of patients with pre-renal AKI was lower compared to patients with AKI of other causes (median uAnCR 11.3 vs 80.2 ng/mg; P = 0.02).Conclusions: Elevated urinary angiotensinogen is associated with adverse events in AKI patients in the ICU. It could be used to identify high risk patients who would benefit from timely intervention that could improve their outcomes. © 2013 Alge et al.; licensee BioMed Central Ltd.
Price M.,Medical University of South Carolina |
Davidson T.M.,Medical University of South Carolina |
Andrews J.O.,Medical University of South Carolina |
Ruggiero K.J.,Ralph hnson Medical Center
Journal of Telemedicine and Telecare | Year: 2013
African-Americans and Hispanics are disproportionally affected by disasters. We evaluated differences in the use and completion of a web-based mental health intervention, Disaster Recovery Web (DRW), by White, African-American and Hispanic adults in the aftermath of Hurricane Ike. Approximately one year after the hurricane, a telephone survey was carried out with adults from Galveston and Chambers counties. A total of 1249 adults participated in the survey (80% White, 14% African-American and 6% Hispanic). Mental health and mental health service utilization were assessed. Whites were more likely to have previously used the Internet to obtain general health information than African-Americans or Hispanics (P, 0.001). A logistic regression was used to identify differences in the use of the Internet intervention after controlling for covariates. There were no differences in rates of non-use and dropout attrition between Whites, African-Americans and Hispanics. Thus the findings suggest that web-based mental health interventions can be used to reach African-American, Hispanic and White adults at similar rates after a disaster.
George M.S.,Medical University of South Carolina |
George M.S.,Ralph hnson Medical Center
Expert Review of Neurotherapeutics | Year: 2010
Repeated daily left prefrontal transcranial magnetic stimulation (TMS) was first proposed as a potential treatment for depression in 1993. Multiple studies from researchers around the world since then have repeatedly demonstrated that TMS has antidepressant effects greater than sham treatment, and that these effects are clinically meaningful. A large industry-sponsored trial, published in 2007, resulted in US FDA approval in October 2008. Most recently, a large NIH-sponsored trial, with a more rigorous sham technique, found that a course of treatment (3-5 weeks) was statistically and clinically significant in reducing depression. However, consistently showing statistically and clinically significant antidepressant effects, and gaining regulatory approval, is merely the beginning for this new treatment. As with any new treatment involving a radically different approach, there are many unanswered questions about TMS, and the field is still rapidly evolving. These unanswered questions include the appropriate scalp location, understanding the mechanisms of action, refining the 'dose (frequency, train, number of stimuli/day and pattern of delivery), understanding whether and how TMS can be combined with medications or talking/exposure therapy, or both, and how to deliver maintenance TMS. This article summarizes the available clinical information, and discusses key areas where more research is needed. TMS reflects a paradigm shift in treating depression. It is a safe, relatively noninvasive, focal brain stimulation treatment that does not involve seizures or implanted wires, and does not have drug-drug interactions or systemic side effects. © 2010 Expert Reviews Ltd.
Arthur J.M.,Ralph hnson Medical Center |
Arthur J.M.,Medical University of South Carolina |
Hill E.G.,Medical University of South Carolina |
Alge J.L.,Medical University of South Carolina |
And 8 more authors.
Kidney International | Year: 2014
Biomarkers for acute kidney injury (AKI) have been used to predict the progression of AKI, but a systematic comparison of the prognostic ability of each biomarker alone or in combination has not been performed. In order to assess this, we measured the concentration of 32 candidate biomarkers in the urine of 95 patients with AKIN stage 1 after cardiac surgery. Urine markers were divided into eight groups based on the putative pathophysiological mechanism they reflect. We then compared the ability of the markers alone or in combination to predict the primary outcome of worsening AKI or death (23 patients) and the secondary outcome of AKIN stage 3 or death (13 patients). IL-18 was the best predictor of both outcomes (AUC of 0.74 and 0.89). L-FABP (AUC of 0.67 and 0.85), NGAL (AUC of 0.72 and 0.83), and KIM-1 (AUC of 0.73 and 0.81) were also good predictors. Correlation between most of the markers was generally related to their predictive ability, but KIM-1 had a relatively weak correlation with other markers. The combination of IL-18 and KIM-1 had a very good predictive value with an AUC of 0.93 to predict AKIN 3 or death. Thus, a combination of IL-18 and KIM-1 would result in improved identification of high-risk patients for enrollment in clinical trials. © 2013 International Society of Nephrology.
Griffin Iii W.C.,Medical University of South Carolina |
Haun H.L.,Medical University of South Carolina |
Hazelbaker C.L.,Medical University of South Carolina |
Ramachandra V.S.,Medical University of South Carolina |
And 2 more authors.
Neuropsychopharmacology | Year: 2014
Using a well-established model of ethanol dependence and relapse, this study examined adaptations in glutamatergic transmission in the nucleus accumbens (NAc) and their role in regulating voluntary ethanol drinking. Mice were first trained to drink ethanol in a free-choice, limited access (2 h/day) paradigm. One group (EtOH mice) received repeated weekly cycles of chronic intermittent ethanol (CIE) exposure with intervening weeks of test drinking sessions, whereas the remaining mice (CTL mice) were similarly treated but did not receive CIE treatment. Over repeated cycles of CIE exposure, EtOH mice exhibited significant escalation in drinking (up to ∼3.5 g/kg), whereas drinking remained relatively stable at baseline levels (2-2.5 g/kg) in CTL mice. Using in vivo microdialysis procedures, extracellular glutamate (GLU EX) levels in the NAc were increased approximately twofold in EtOH mice compared with CTL mice, and this difference was observed 7 days after final CIE exposure, indicating that this hyperglutamatergic state persisted beyond acute withdrawal. This finding prompted additional studies examining the effects of pharmacologically manipulating GLU EX in the NAc on ethanol drinking in the CIE model. The non-selective glutamate reuptake antagonist, threo-β- benzyloxyaspartate (TBOA), was bilaterally microinjected into the NAc and found to dose-dependently increase drinking in nondependent (CTL) mice to levels attained by dependent (EtOH) mice. TBOA also further increased drinking in EtOH mice. In contrast, reducing glutamatergic transmission in the NAc via bilateral injections of the metabotropic glutamate receptor-2/3 agonist LY379268 reduced drinking in dependent (EtOH) mice to nondependent (CTL) levels, whereas having a more modest effect in decreasing ethanol consumption in CTL mice. Taken together, these data support an important role of glutamatergic transmission in the NAc in regulating ethanol drinking. Additionally, these results indicate that ethanol dependence produces adaptations that favor elevated glutamate activity in the NAc which, in turn, promote excessive levels of ethanol consumption associated with dependence. © 2014 American College of Neuropsychopharmacology.
Vistamehr A.,University of Texas at Austin |
Kautz S.A.,Medical University of South Carolina |
Kautz S.A.,Ralph hnson Medical Center |
Neptune R.R.,University of Texas at Austin
Clinical Biomechanics | Year: 2014
Background In post-stroke hemiparetic subjects, solid polypropylene ankle-foot-orthoses are commonly prescribed to assist in foot clearance during swing while bracing the ankle during stance. Mobility demands, such as changing walking speed and direction, are accomplished by accelerating or decelerating the body and maintaining dynamic balance. Previous studies have shown that the ankle plantarflexors are primary contributors to these essential biomechanical functions. Thus, with ankle-foot-orthoses limiting ankle motion and plantarflexor output during stance, execution of these walking subtasks may be compromised. This study examined the influence of a solid polypropylene ankle-foot-orthosis on forward propulsion and dynamic balance in healthy adults. Methods Kinematic and kinetic data were recorded from 10 healthy adults walking with and without a unilateral ankle-foot-orthosis at steady-state slow (0.6 m/s) and moderate (1.2 m/s) speeds, and during accelerated (0-1.8 m/s at 0.06 m/s2) and decelerated (1.8-0 m/s at - 0.06 m/s2) walking. Propulsion was quantified by propulsive and braking impulses (i.e., time integral of the anterior-posterior ground reaction force) while dynamic balance was quantified by the peak-to-peak range of whole-body angular momentum. Findings The propulsive impulses decreased in the leg with ankle-foot-orthosis compared to the contralateral leg and no ankle-foot-orthosis condition. Further, the ankle-foot-orthosis resulted in a greater range of angular momentum in both the frontal and sagittal planes, which were correlated with the reduced peak hip abduction and reduced ankle plantarflexor moments, respectively. Interpretation Solid ankle-foot-orthoses limit the successful execution of important mobility subtasks in healthy adults and that the prescription of ankle-foot-orthosis should be carefully considered. © 2014 Elsevier Ltd. All rights reserved.
Garrett-Mayer E.,Medical University of South Carolina |
Wagner C.L.,Medical University of South Carolina |
Hollis B.W.,Medical University of South Carolina |
Kindy M.S.,Medical University of South Carolina |
And 3 more authors.
American Journal of Clinical Nutrition | Year: 2012
Background: African Americans suffer disproportionately from diabetes and cardiovascular disease and are significantly more likely to have suboptimal concentrations of circulating 25-hydroxyvitamin D [25(OH)D]. The results of epidemiologic and observational studies suggest that there is a link between vitamin D deficiency and the risk of cardiometabolic disorders, which underscores the importance of maintaining healthy concentrations of 25(OH)D. Objective: The objective was to investigate whether daily supplementation with 4000 IU vitamin D3 for 1 y would eliminate any disparities in circulating concentrations of 25(OH)D between African American and white men. Design: Serum concentrations of 25(OH)D were measured every 2 mo in 47 subjects who received a daily oral dose of 4000 IU vitamin D3 for 1 y. Results: More than 90% of African Americans had serum concentrations of 25(OH)D <32 ng/mL, and approximately two-thirds had serum concentrations <20 ng/mL. Furthermore, there were significant disparities in serum concentrations of 25(OH)D between African American and white men. Supplementation with 4000 IU/d for 1 y eliminated any significant differences in circulating concentrations of 25(OH)D between African American and white men. Conclusion: The results of this clinical study show the feasibility and efficacy of this approach in the elimination of hypovitaminosis D, which is a widespread health disparity among African Americans. This trial was registered at clinicaltrials.gov as NCT01045109. © 2012 American Society for Nutrition.
Nott C.R.,Medical University of South Carolina |
Neptune R.R.,University of Texas at Austin |
Kautz S.A.,Medical University of South Carolina |
Kautz S.A.,Ralph hnson Medical Center
Gait and Posture | Year: 2014
Stroke has significant impact on dynamic balance during locomotion, with a 73% incidence rate for falls post-stroke. Current clinical assessments often rely on tasks and/or questionnaires that relate to the statistical probability of falls and provide little insight into the mechanisms that impair dynamic balance. Current quantitative measures that assess medial-lateral balance performance do not consider the angular motion of the body, which can be particularly impaired after stroke. Current control methods in bipedal robotics rely on the regulation of angular momentum (H) to maintain dynamic balance during locomotion. This study tests whether frontal-plane H is significantly correlated to clinical balance tests that could be used to provide a detailed assessment of medial-lateral balance impairments in hemiparetic gait. H was measured in post-stroke (n= 48) and control (n= 20) subjects. Post-stroke there were significant negative relationships between the change in frontal-plane H during paretic single-leg stance and two clinical tests: the Dynamic Gait Index (DGI) (r= -0.57, p< 0.001) and the Berg Balance Scale (BBS) (r= -0.54, p< 0.001). Control subjects showed timely regulation of frontal-plane H during the first half of single-leg stance, with the level of regulation depending on the initial magnitude. In contrast, the post-stroke subjects who made poorer adjustments to frontal-plane H during initial paretic leg single stance exhibited lower DGI and BBS scores (r= 0.45, p= 0.003). We conclude that H is a promising balance indicator during steady-state hemiparetic walking and that paretic single-leg stance is a period with higher instability for stroke patients. © 2013.