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Characterization of binding mode of action of a blocking anti-platelet-derived growth factor (PDGF)-B monoclonal antibody, MOR8457, reveals conformational flexibility and avidity needed for PDGF-BB to bind PDGF receptor-Î². - Biochemistry
Platelet derived growth factor-BB (PDGF-BB) is an important mitogen and cell survival factor during development. PDGF-BB binds PDGF receptor-Î² (PDGFRÎ²) to trigger receptor dimerization and tyrosine kinase activation. We present the pharmacological and biophysical characterization of a blocking PDGF-BB monoclonal antibody, MOR8457, and contrast this to PDGFRÎ². MOR8457 binds to PDGF-BB with high affinity and selectivity, and prevents PDGF-BB induced cell proliferation competitively and with high potency. The structural characterization of the MOR8457-PDGF-BB complex indicates that MOR8457 binds with a 2:1 stoichiometry, but that binding of a single MOR8457 moiety is sufficient to prevent binding to PDGFRÎ². Comparison of the MOR8457-PDGF-BB structure with that of the PDGFRÎ²-PDGF-BB complex suggested the potential reason for this was a substantial bending and twisting of PDGF-BB in the MOR8457 structure, relative to the structures of PDGF-BB alone, bound to a PDGF-BB aptamer or PDGFRÎ², which makes it nonpermissive for PDGFRÎ² binding. These biochemical and structural data offer insights into the permissive structure of PDGF-BB needed for agonism as well as strategies for developing specific PDGF ligand antagonists.
Clinical Oncology Society of Australia position statement on the use of complementary and alternative medicine by cancer patients. - Asia-Pacific journal of clinical oncology
Health professionals involved in the clinical management of cancer are becoming increasingly aware that their patients use complementary and alternative medicine (CAM). As cancer incidence and survival rates increase, use of CAM is also likely to increase. This paper outlines the position of the Clinical Oncology Society of Australia (COSA) on the use of CAM by cancer patients and provides guidance for health professionals involved with the treatment of cancer patients who are using or wish to use CAM. Key definitions and common communication scenarios are presented along with evidence-based recommended steps for health professionals when discussing CAM use. COSA encourages health professionals to focus on open discussion with their patients regarding CAM, to become familiar with reputable resources for CAM information, to discuss with patients the concept of evidence-based medicine, to recognize limitations to their knowledge of CAM and seek further advice when necessary, and to be respectful of the patients' right to autonomy.Â© 2014 Wiley Publishing Asia Pty Ltd.
Impact of denervated myocardium on improving risk stratification for sudden cardiac death. - Transactions of the American Clinical and Climatological Association
Between 184,000 and 462,000 Americans die suddenly each year. Fifty percent to 70% of these deaths are due to ventricular tachycardia/fibrillation (VT/VF). We tested whether hibernating myocardium or myocardial sympathetic denervation identifies patients at high-risk for developing VT/VF independently of ejection fraction (EF). Positron emission tomography (PET) was used to quantify myocardial sympathetic denervation ((11)C-meta-hydroxyephedrine [(11)C-HED]), perfusion ((13)N-ammonia), and viability (insulin-stimulated (18)F-2-deoxyglucose [(18)FDG]) in patients with ischemic cardiomyopathy (EF < 35%) eligible for a primary prevention implantable cardioverter defibrillator (ICD). The primary end-point was sudden cardiac arrest (SCA) defined as arrhythmic death or ICD discharge for VT/VF > 240 bpm. Volumes of total denervated (P = .001) and viable denervated myocardium ((11)C-HED-(18)FDG mismatch, P = .03) predicted SCA, whereas hibernating and infarcted myocardium did not. Multivariate analysis identified four independent predictors of SCA: denervated myocardium > 37.6% of left ventricule (LV), LV end-diastolic volume > 98 mL/m(2), creatinine level > 1.49 mg/dL, and no angiotensin- inhibition therapy. Denervated myocardium had a hazard ratio of 3.5 for SCA (10.3%/year vs. 3.0%/year, p=0.001). Absence of all four factors predicted low risk (44% of cohort; SCA <1%/y) whereas two or more factors identified subjects at high-risk (20% of cohort; SCA 12%/y). Denervated myocardium quantified using PET strongly predicts risk of SCA, and is independent of EF, infarct volume, and other clinical variables.
Transposition of the great arteries--outcomes and time interval of early neonatal repair. - World journal for pediatric & congenital heart surgery
This study evaluates the relationship of morbidity and resource utilization with the timing of early neonatal repair of transposition of the great arteries and intact ventricular septum (d-TGA/IVS).All patients with d-TGA/IVS who underwent arterial switch in the first 14 days of life, between January 2000 and May 2011, were reviewed. Patients undergoing repair at â‰¤ 4 days of age were categorized as group I, 5 to 7 days as group II, and 8 to 14 days as group III. Outcomes included mortality, morbidity, and resource utilization.Hospital survival was 69 (98.6%) of 70. The length of stay (LOS) and total charges were lowest in group I--15.5 days compared to group II--18.0 days and group III--23.5 days (P = .005); group I--US$128,219 compared to group II--US$141,729 and group III--US$217,427 (P = .0006). Using regression analysis to account for potentially confounding effects of multiple variables and treating time as a continuous variable demonstrated that age at surgery was significantly associated with total LOS (P = .029), hospital charges (P = .029) and intensive care unit charges (P = .002). Younger age at repair was not associated with worse outcomes for any measure of morbidity.Earlier repair of d-TGA/IVS was associated with decreased resource utilization and no detriment to clinical outcomes. Further analysis based on a larger cohort of patients is needed to verify these results that have important implications for improving the value of care.
Interventional radiology workflow management in the electronic medical record. - Journal of digital imaging
The electronic medical record (EMR) has significantly improved efficiency in many areas of radiology workflow. Following implementation of an electronic protocol selection process for cross-sectional imaging at the University of Colorado Hospital, the interventional radiology (IR) division desired to have a similar tool. Evaluation of the IR workflow demonstrated the need for a multilayered solution, which accounted for consultation, physician review, authorization and scheduling, pre-procedural nursing evaluation, physician rounding, and resource allocation and prioritization. This paper outlines the rationale for and components of this process.
Regional myocardial sympathetic denervation predicts the risk of sudden cardiac arrest in ischemic cardiomyopathy. - Journal of the American College of Cardiology
The PAREPET (Prediction of ARrhythmic Events with Positron Emission Tomography) study sought to test the hypothesis that quantifying inhomogeneity in myocardial sympathetic innervation could identify patients at highest risk for sudden cardiac arrest (SCA).Left ventricular ejection fraction (LVEF) is the only parameter identifying patients at risk of SCA who benefit from an implantable cardiac defibrillator (ICD).We prospectively enrolled 204 subjects with ischemic cardiomyopathy (LVEF â‰¤35%) eligible for primary prevention ICDs. Positron emission tomography (PET) was used to quantify myocardial sympathetic denervation ((11)C-meta-hydroxyephedrine [(11)C-HED]), perfusion ((13)N-ammonia) and viability (insulin-stimulated (18)F-2-deoxyglucose). The primary endpoint was SCA defined as arrhythmic death or ICD discharge for ventricular fibrillation or ventricular tachycardia >240 beats/min.After 4.1 years follow-up, cause-specific SCA was 16.2%. Infarct volume (22 Â± 7% vs. 19 Â± 9% of left ventricle [LV]) and LVEF (24 Â± 8% vs. 28 Â± 9%) were not predictors of SCA. In contrast, patients developing SCA had greater amounts of sympathetic denervation (33 Â± 10% vs. 26 Â± 11% of LV; p = 0.001) reflecting viable, denervated myocardium. The lower tertiles of sympathetic denervation had SCA rates of 1.2%/year and 2.2%/year, whereas the highest tertile had a rate of 6.7%/year. Multivariate predictors of SCA were PET sympathetic denervation, left ventricular end-diastolic volume index, creatinine, and no angiotensin inhibition. With optimized cut-points, the absence of all 4 risk factors identified low risk (44% of cohort; SCA <1%/year); whereas â‰¥2 factors identified high risk (20% of cohort; SCA âˆ¼12%/year).In ischemic cardiomyopathy, sympathetic denervation assessed using (11)C-HED PET predicts cause-specific mortality from SCA independently of LVEF and infarct volume. This may provide an improved approach for the identification of patients most likely to benefit from an ICD. (Prediction of ARrhythmic Events With Positron Emission Tomography [PAREPET]; NCT01400334).Copyright Â© 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Mortality risk associated with bundle branch blocks and related repolarization abnormalities (from the Women's Health Initiative [WHI]). - The American journal of cardiology
Electrocardiographic bundle branch block (BBB) has higher cardiac and all-cause death. However, reports on the association between BBBs and mortality in the general populations are conflicting. The aim of this study was to evaluate the risk for coronary heart disease (CHD) and all-cause death associated with left BBB (LBBB) and right BBB (RBBB) during 14 years of follow-up in 66,450 participants from the Women's Health Initiative (WHI) study. Cox proportional-hazards regression was performed for mortality risk in Women with LBBB (n = 714) and those with RBBB (n = 832). In risk models adjusted for demographic and clinical risk factors in women with cardiovascular disease (CVD), hazard ratios for CHD death were 2.92 (95% confidence interval 2.08 to 4.08, p <0.001) for LBBB and 1.62 (95% confidence interval 1.08 to 2.43, p <0.05) for RBBB, and only LBBB was a significant predictor of all-cause death (hazard ratio 1.43, 95% confidence interval 1.11 to 1.83, p <0.01). In CVD-free women, only LBBB was a significant predictor of CHD death (fully adjusted hazard ratio 2.17, 95% confidence interval 1.37 to 3.43, p <0.01), and neither blocks was predictive of all-cause death. From several repolarization variables that were significant mortality predictors in univariate risk models, after adjustment for other electrocardiographic covariates and risk factors, ST J-point depression in lead aVL â‰¤-30 Î¼V in women with LBBB was an independent predictor of CHD death, with a more than fivefold increase in risk. None of the repolarization variables were independent predictors in women with RBBB. In conclusion, prevalent LBBB in CVD-free women and LBBB and RBBB in women with CVD were significant predictors of CHD death. In women with LBBB, ST J-point depression in lead aVL was a strong independent predictor of CHD death.Copyright Â© 2012 Elsevier Inc. All rights reserved.
Estrogen-related receptor Î± regulates osteoblast differentiation via Wnt/Î²-catenin signaling. - Journal of molecular endocrinology
Based on its homology to the estrogen receptor and its roles in osteoblast and chondrocyte differentiation, the orphan nuclear receptor estrogen-related receptor Î± (ERRÎ± (ESRRA)) is an intriguing therapeutic target for osteoporosis and other bone diseases. The objective of this study was to better characterize the molecular mechanisms by which ERRÎ± modulates osteoblastogenesis. Experiments from multiple systems demonstrated that ERRÎ± modulates Wnt signaling, a crucial pathway for proper regulation of bone development. This was validated using a Wnt-luciferase reporter, where ERRÎ± showed co-activator-dependent (peroxisome proliferator-activated receptor gamma co-activator 1Î±, PGC-1Î±) stimulatory effects. Interestingly, knockdown of ERRÎ± expression also enhanced WNT signaling. In combination, these data indicated that ERRÎ± could serve to either activate or repress Wnt signaling depending on the presence or absence of its co-activator PGC-1Î±. The observed Wnt pathway modulation was cell intrinsic and did not alter Î²-catenin nuclear translocation but was dependent on DNA binding of ERRÎ±. We also found that expression of active ERRÎ± correlated with Wnt pathway effects on osteoblastic differentiation in two cell types, consistent with a role for ERRÎ± in modulating the Wnt pathway. In conclusion, this work identifies ERRÎ±, in conjunction with co-activators such as PGC-1Î±, as a new regulator of the Wnt-signaling pathway during osteoblast differentiation, through a cell-intrinsic mechanism not affecting Î²-catenin nuclear translocation.
Divergent activities of osteogenic BMP2, and tenogenic BMP12 and BMP13 independent of receptor binding affinities. - Growth factors (Chur, Switzerland)
Ectopic expression of recombinant human bone morphogenetic protein 2 (rhBMP2) induces osteogenesis, while ectopic expression of rhBMP12 and rhBMP13 induces the formation of tendon-like tissue. Despite their different in vivo activities, all three ligands bound to the type I bone morphogenic protein receptors (BMPRs), activin receptor-like kinase (ALK)-3 and ALK6, and to the type II BMPRs, activin receptor type-2A, activin receptor type-2B, and BMPR2, with similar affinities. Treatment of C3H10T1/2 cells with rhBMP2 activated SMAD signaling and induced expression of osteoblast markers including osteocalcin mRNA (Ocn). In contrast, treatment with rhBMP12 or rhBMP13 resulted in a dose-dependent induction of a tendon-specific gene (Thbs4) expression with no detectable activation of SMAD 1, 5, and 8. Differential regulation of Thbs4 and Ocn has potential utility as an in vitro biomarker for induction of tenogenic signaling. Such an assay also permits the ability to distinguish between the activities of different BMPs and may prove useful in studies on the molecular mechanisms of BMP tenogenic activity.
Interface of Candida albicans biofilm matrix-associated drug resistance and cell wall integrity regulation. - Eukaryotic cell
Candida albicans frequently infects medical devices by growing as a biofilm, i.e., a community of adherent organisms entrenched in an extracellular matrix. During biofilm growth, Candida spp. acquire the ability to resist high concentrations of antifungal drugs. One recently recognized biofilm resistance mechanism involves drug sequestration by matrix Î²-1,3 glucan. Using a candidate gene approach, we investigated potential C. albicans Î²-1,3-glucan regulators, based on their homology to Saccharomyces cerevisiae, including SMI1 and protein kinase C (PKC) pathway components. We identified a role for the SMI1 in biofilm matrix glucan production and development of the associated drug resistance phenotype. This pathway appears to act through transcription factor Rlmp and glucan synthase Fks1p. The phenotypes of these mutant biofilms mimicked those of the smi1Î”/smi1Î” biofilm, and overexpression of FKS1 in the smi1Î”/smi1Î” mutant restored the biofilm resistant phenotype. However, control of this pathway is distinct from that of the upstream PKC pathway because the pkc1Î”/pkc1Î”, bck1Î”/bck1Î”, mkk2Î”/mkk2Î”, and mkc1Î”/mkc1Î” biofilms retained the resistant phenotype of the parent strain. In addition, resistance to cell-perturbing agents and gene expression data do not support a significant role for the cell wall integrity pathway during the biofilm formation. Here we show that Smi1p functions in conjunction with Rlm1p and Fks1p to produce drug-sequestering biofilm Î²-glucan. Our work provides new insight into how the C. albicans biofilm matrix production and drug resistance pathways intersect with the planktonic cell wall integrity pathway. This novel connection helps explain how pathogens in a multicellular biofilm community are protected from anti-infective therapy.
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Gru College Of Dental Medicine 1430 John Wesley Gilbert Dr
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