P F Binkley

The Ohio State University, Columbus, Ohio, United States

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Publications (166)825.14 Total impact

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    ABSTRACT: The study aims to determine whether the route of insulin administration influences glycemic variability and inflammatory or neurohormonal markers in patients with type 2 diabetes (T2D) and congestive heart failure (CHF) exacerbation.
    Diabetes/Metabolism Research and Reviews 06/2014; · 2.97 Impact Factor
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    ABSTRACT: There has been a steady increase of patients living in the community with Left Ventricular Assist Devices (LVADs). There is a significant gap in our fund of knowledge with respect to the impact that insurance and socioeconomic status has on outcomes for LVAD patients. We thus hypothesize that low neighborhood socioeconomic status and receipt of Medicaid, respectively, lead to earlier readmissions, earlier death, as well as longer time to transplantation among LVAD patients.
    Journal of Surgical Research 05/2014; · 2.02 Impact Factor
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    ABSTRACT: Cardiac function depends on the highly regulated and coordinate activity of a large ensemble of potassium channels that control myocyte repolarization. While voltage-gated K(+) channels have been well-characterized in heart, much less is known about regulation and/or targeting of two-pore K(+) channel (K2P) family members, despite their potential importance in modulation of heart function.Methods and ResultsHere we report a novel molecular pathway for membrane targeting of TREK-1, a mechano-sensitive K2P channel regulated by environmental and physical factors including membrane stretch, pH, and polyunsaturated fatty acids (e.g. arachidonic acid). We demonstrate that βIV-spectrin, an actin-associated protein, is co-localized with TREK-1 at the myocyte intercalated disc, associates with TREK-1 in heart, and is required for TREK-1 membrane targeting. Mice expressing βIV-spectrin lacking TREK-1 binding (qv(4 J)) display aberrant TREK-1 membrane localization, decreased TREK-1 activity, delayed action potential repolarization, and arrhythmia without apparent defects in localization/function of other cardiac potassium channel subunits. Finally, we report abnormal βIV-spectrin levels in human heart failure. These data provide new insight into membrane targeting of TREK-1 in heart and establish a broader role for βIV-spectrin in organizing functional membrane domains critical for normal heart function.
    Cardiovascular Research 01/2014; · 5.81 Impact Factor
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    ABSTRACT: We describe the development and implementation of a randomized controlled trial to investigate the impact of genomic counseling on a cohort of patients with heart failure (HF) or hypertension (HTN), managed at a large academic medical center, the Ohio State University Wexner Medical Center (OSUWMC). Our study is built upon the existing Coriell Personalized Medicine Collaborative (CPMC®). OSUWMC patient participants with chronic disease (CD) receive eight actionable complex disease and one pharmacogenomic test report through the CPMC® web portal. Participants are randomized to either the in-person post-test genomic counseling—active arm, versus web-based only return of results—control arm. Study-specific surveys measure: (1) change in risk perception; (2) knowledge retention; (3) perceived personal control; (4) health behavior change; and, for the active arm (5), overall satisfaction with genomic counseling. This ongoing partnership has spurred creation of both infrastructure and procedures necessary for the implementation of genomics and genomic counseling in clinical care and clinical research. This included creation of a comprehensive informed consent document and processes for prospective return of actionable results for multiple complex diseases and pharmacogenomics (PGx) through a web portal, and integration of genomic data files and clinical decision support into an EPIC-based electronic medical record. We present this partnership, the infrastructure, genomic counseling approach, and the challenges that arose in the design and conduct of this ongoing trial to inform subsequent collaborative efforts and best genomic counseling practices.
    Journal of Personalized Medicine. 01/2014; 4(1):1-19.
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    ABSTRACT: The role of IKCa in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of IKCa blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The IKCa blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n = 5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n = 7). A group of age-matched canine controls were used (n = 8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by IKCa blockade in all of the groups studied. IKCa blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. IKCa blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, IKCa blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for IKCa in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles.
    PLoS ONE 01/2014; 9(10):e108824. · 3.53 Impact Factor
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    ABSTRACT: DEFEAT-PE is a prospective, multi-center study of multiple intrathoracic impedance vectors to detect pulmonary congestion (PC) events. Changes in intrathoracic impedance between the right ventricular (RV) coil and device can (RVcoil→Can) of implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy ICDs (CRT-Ds) are used clinically for detection of PC events, but other impedance vectors and algorithms have not been studied prospectively. An initial 75 patient study was used to derive optimal impedance vectors to detect PC events, with 2 vector combinations selected for prospective analysis in DEFEAT-PE: (ICD vectors: RVring→Can + RVcoil→Can, detection threshold 13 days; CRT-D vectors: LVring→Can + RVcoil→Can, detection threshold 14 days). Impedance changes were considered true positive if detected within 30 days prior to an adjudicated PC event. 162 patients were enrolled (80 ICDs and 82 CRT-Ds), all with > 1 prior PC event. 144 patients provided study data, with 214 patient years of follow-up and 139 PC events. Sensitivity for PC events of the pre-specified algorithms was: ICD: sensitivity 32.3%, False Positive Rate (FPR) 1.28/pt-year; CRT-D: sensitivity 32.4%, FPR 1.66/pt-year. An alternative algorithm, ultimately FDA approved (RVring→Can + RVcoil→Can detection threshold 14 days), resulted in (all patients): sensitivity 21.6%, FPR 0.9/pt-year. The CRT-D thoracic impedance vector algorithm selected in the derivation study was not superior to the ICD algorithm RVring→Can + RVcoil→Can when studied prospectively. In conclusion, to achieve an acceptably low false positive rate, the intra-thoracic impedance algorithms studied in DEFEAT-PE resulted in low sensitivity for prediction of heart failure events.
    The American Journal of Cardiology. 01/2014;
  • Philip F Binkley, Heather C Brod
    The American journal of medicine 09/2013; · 5.30 Impact Factor
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    ABSTRACT: The role of viral infections in the pathogenesis of atherosclerosis remains controversial largely due to inconsistent detection of the virus in atherosclerotic lesions. However, viral infections elicit a pro-inflammatory cascade known to be atherogenic and to precipitate acute ischemic events. We have published in vitro data that provide the foundation for a mechanism that reconciles these conflicting observations. To determine the relation between an early viral protein, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), produced following reactivation of Epstein Barr Virus (EBV) to circulating pro-inflammatory cytokines, intercellular adhesion molecule-1 (ICAM-1) and acute coronary events. Blood samples were obtained from 299 patients undergoing percutaneous coronary intervention for stable angina (SA), unstable angina (UA), or acute myocardial infarction (AMI). Plasma concentrations of pro-inflammatory cytokines and neutralizing antibody against EBV-encoded dUTPase were compared in the three patient groups. AMI was associated with the highest measures of interleukin-6 (ANOVA p<0.05; 4.6±2.6 pg/mL in patients with AMI vs. 3.2±2.3 pg/mL in SA). ICAM-1 was significantly higher in patients with AMI (ANOVA p<0.05; 304±116 pg/mL in AMI vs. 265±86 pg/mL SA). The highest values of ICAM-1 were found in patients having an AMI and who were antibody positive for dUTPase (ANOVA p = 0.008; 369±183 pg/mL in AMI and positive for dUTPase vs. 249±70 pg/mL in SA negative for dUTPase antibody). These clinical data support a model, based on in vitro studies, by which EBV may precipitate AMI even under conditions of low viral load through the pro-inflammatory action of the early protein dUTPase that is produced even during incomplete viral replication. They further support the putative role of viral infections in the pathogenesis of atherosclerosis and coronary artery events.
    PLoS ONE 08/2013; 8(1):e54008. · 3.53 Impact Factor
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    ABSTRACT: Indicated for treating hyperlipidemias and for the prevention of cardiovascular disease (CVD), statins rank among the most commonly prescribed drug classes. While statins are considered to be highly effective in preventing atherosclerotic events, a substantial portion of treated patients still progress to overt CVD. Genetic factors are thought to contribute substantially to treatment outcome. Several candidate genes have been associated with statin dose requirements and treatment outcomes, but a clinically relevant pharmacogenomics test to guide statin therapy has not yet emerged. Here we define basic pharmacogenomics terminology, present strong candidate genes (CETP, HMGCR, SLCO1B1, ABCB1, and CYP3A4/5), and discuss the challenges in developing much-needed statin pharmacogenomics biomarkers for predicting treatment outcomes.
    Discovery medicine 08/2013; 16(86):45-51. · 2.97 Impact Factor
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    ABSTRACT: AIMS: Glycemic variability (GV) is associated with mortality in acutely ill patients, but the mechanism is unknown. The objective of this study is to determine whether common approaches to insulin therapy have distinct effects on GV and autonomic tone. MATERIALS & METHODS: Hospitalized patients with diabetes were randomized to short-term intravenous (IV) or physiologic subcutaneous (SQ) insulin. Heart rate variability (HRV) and cardiac impedance (pre-ejection period, PEP) were used to estimate parasympathetic and sympathetic tone respectively. GV was measured using a continuous glucose monitor. RESULTS: Mean glucose tended to be lower initially in the SQ group (N=16) compared to the IV group (N=17) on day 1 (10.5 vs. 8.6mmol/l, p=0.05), but became nonsignificant during the transition off of the infusion. There was no difference in glycemic lability index (GLI), continuous overlapping net glycemic action (CONGA) or coefficient of variation (CV) on day 1, but by day 2, these measures were higher in the IV group (p<0.05 for all). PEP was higher in the SQ group during (110 vs. 123 ms, p=0.02) and after the intervention (104 vs. 126 ms, p=0.004). Hypoglycemia was similar in both groups. There were only small differences in HRV. Post-treatment PEP was inversely correlated with log GLI (r= -0.41, p=0.03) but not other measures. CONCLUSIONS: Short-term IV insulin is associated with an increase in multiple GV measures compared to optimal SQ insulin. However, GLI was the only predictor of PEP. Further research is needed to determine if interventions that minimize GV improve outcomes in the hospital.
    Diabetes Obesity and Metabolism 01/2013; · 5.18 Impact Factor
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    ABSTRACT: Kinase/phosphatase balance governs cardiac excitability in health and disease. While detailed mechanisms for cardiac kinase regulation are established, far less is known regarding cardiac protein phosphatase 2A (PP2A) regulation. This is largely due to the complexity of the PP2A holoenzyme structure (combinatorial assembly of three subunit enzyme from >seventeen subunit genes) and the inability to segregate global PP2A function from the activities of multiple local holoenzyme populations. Here, we report that PP2A catalytic, regulatory, and scaffolding subunits are tightly regulated at transcriptional, translational, and post-translational levels to tune myocyte function at baseline and in disease. We show that past global read-outs of cellular PP2A activity more appropriately represent the collective activity of numerous individual PP2A holoenzymes, each displaying a specific subcellular localization (dictated by select PP2A regulatory subunits), as well as local specific post-translational catalytic subunit methylation and phosphorylation events that regulate local and rapid holoenzyme assembly/disassembly (via LCMT-1/PME-1). We report that PP2A subunits are selectively regulated between human and animal models, across cardiac chambers, and even within specific cardiac-cell types. Moreover, this regulation can be rapidly tuned in response to cellular activation. Finally, we report that global PP2A is altered in human and experimental models of heart disease, yet each pathology displays its own distinct molecular signature though specific PP2A subunit modulatory events. These new data provide an initial view into the signaling pathways that govern PP2A function in heart, but also establish the first step in defining specific PP2A regulatory targets in health and disease.
    Journal of Biological Chemistry 11/2012; · 4.65 Impact Factor
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    ABSTRACT: Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked to potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia variants remains undefined despite more than a decade of investigation. Posttranslational modulation of membrane proteins is essential for normal cardiac function. Importantly, aberrant myocyte signaling has been linked to defects in cardiac ion channel posttranslational modifications and disease. We recently identified a novel pathway for posttranslational regulation of the primary cardiac voltage-gated Na(+) channel (Na(v)1.5) by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). However, a role for this pathway in cardiac disease has not been evaluated. We evaluated the role of CaMKII-dependent phosphorylation in human genetic and acquired disease. We report an unexpected link between a short motif in the Na(v)1.5 DI-DII loop, recently shown to be critical for CaMKII-dependent phosphorylation, and Na(v)1.5 function in monogenic arrhythmia and common heart disease. Experiments in heterologous cells and primary ventricular cardiomyocytes demonstrate that the human arrhythmia susceptibility variants (A572D and Q573E) alter CaMKII-dependent regulation of Na(v)1.5, resulting in abnormal channel activity and cell excitability. In silico analysis reveals that these variants functionally mimic the phosphorylated channel, resulting in increased susceptibility to arrhythmia-triggering afterdepolarizations. Finally, we report that this same motif is aberrantly regulated in a large-animal model of acquired heart disease and in failing human myocardium. We identify the mechanism for 2 human arrhythmia variants that affect Na(v)1.5 channel activity through direct effects on channel posttranslational modification. We propose that the CaMKII phosphorylation motif in the Na(v)1.5 DI-DII cytoplasmic loop is a critical nodal point for proarrhythmic changes to Na(v)1.5 in congenital and acquired cardiac disease.
    Circulation 09/2012; 126(17):2084-94. · 15.20 Impact Factor
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    ABSTRACT: Ankyrins (ankyrin-R, -B, and -G) are adapter proteins linked with defects in metazoan physiology. Ankyrin-B (encoded by ANK2) loss-of-function mutations are directly associated with human cardiovascular phenotypes including sinus node disease, atrial fibrillation, ventricular tachycardia, and sudden cardiac death. Despite the link between ankyrin-B dysfunction and monogenic disease, there are no data linking ankyrin-B regulation with common forms of human heart failure. Here, we report that ankyrin-B levels are altered in both ischemic and non-ischemic human heart failure. Mechanistically, we demonstrate that cardiac ankyrin-B levels are tightly regulated downstream of reactive oxygen species, intracellular calcium, and the calcium-dependent protease calpain, all hallmarks of human myocardial injury and heart failure. Surprisingly, β(II)-spectrin, previously thought to mediate ankyrin-dependent modulation in the nervous system and heart, is not coordinately regulated with ankyrin-B or its downstream partners. Finally, our data implicate ankyrin-B expression as required for vertebrate myocardial protection as hearts deficient in ankyrin-B show increased cardiac damage and impaired function relative to wild-type mouse hearts following ischemia reperfusion. In summary, our findings provide the data of ankyrin-B regulation in human heart failure, provide insight into candidate pathways for ankyrin-B regulation in acquired human cardiovascular disease, and surprisingly, implicate ankyrin-B as a molecular component for cardioprotection following ischemia.
    Journal of Biological Chemistry 07/2012; 287(36):30268-81. · 4.65 Impact Factor
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    ABSTRACT: Cardioversion (CV) and radiofrequency catheter ablation (RFA) are often used to restore sinus rhythm in patients with atrial fibrillation (AF). These procedures are associated with a risk for stroke. The use of transesophageal echocardiography (TEE) to guide the management of AF is a validated strategy for patients in whom CV is planned, as well patients before RFA. For patients in whom the initial procedure fails, repeat TEE is often performed before repeat CV or RFA. The aim of this study was to test the hypothesis that patients with initial negative results on TEE would be unlikely to have thrombi detected on subsequent TEE and thus may avoid repeat procedures. A total of 2,999 patients with AF were identified via retrospective review who had undergone TEE before CV or RFA, and 418 of these individuals underwent repeat TEE. After excluding patients who underwent repeat TEE >365 days from the initial study (n = 135) and those with thrombi on initial TEE (n = 20), 263 patients who had underwent two or more examinations were identified and analyzed. Of 263 eligible patients, two (0.8%; 95% confidence interval, 0.21-2.7%) had thrombi on subsequent TEE. Fewer than 1% of patients with AF with negative results on baseline TEE had thrombi detected on repeat TEE before subsequent CV or RFA. Thus, it may be possible to selectively screen patients to identify those at low risk for developing thrombi subsequent to negative results on initial TEE, especially if patients are in sinus rhythm. These results suggest the need for a prospective trial to definitively answer the question regarding repeat TEE in low-risk patients.
    Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography 06/2012; 25(10):1106-12. · 2.98 Impact Factor
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    ABSTRACT: Pulmonary edema (PE) is associated with fluid accumulation in the lungs. Device-based impedance measurements have been used to detect fluid overload prior to hospitalization. However, studies have reported a high false positive rate (FPR). The objective of this study was to develop and test a new multivector impedance-based algorithm that reliably tracks PE clinical events. We enrolled patients with implanted CRT-Ds in 23 US centers within 2 weeks of device implant. Six-vector impedance data was collected automatically by the CRT-Ds every 30 min during emergency department visits/hospitalizations and every 2 h at all other times. Detection algorithms for cardiac resynchronization therapy defibrillator (CRT-D) and implantable cardiac defibrillator (ICD) devices were developed using those impedance vectors that would be available in corresponding devices and retrospectively evaluated. There were 75 patients (69 % male), mean age 66 ± 12 years, with a LVEF of 23 ± 6 % and QRS of 149 ± 25 ms. Twenty-one major clinical events occurred over 8.2 ± 2.6 months of follow-up time. CRT-D vector combinations resulted in a sensitivity of 71.4 % (95 % confidence interval 47.8-88.7) and a FPR of 0.56 (0.30-0.94) false positives per patient-year (FPs/pt-yr); ICD vector combinations resulted in a sensitivity of 61.9 % (38.4-81.9) and a FPR of 0.63 (0.36-0.90) FPs/pt-yr. In comparison, the single-vector RVCoil-Can implementation of this algorithm resulted in a sensitivity of 57.1 % (34.0-78.2) and a FPR of 0.74 (0.44-1.12) FPs/pt-yr. This multivector impedance algorithm was effective in tracking PE clinical events in this patient population. Additional studies are needed to prospectively evaluate the performance of this algorithm in a larger population.
    Journal of Interventional Cardiac Electrophysiology 06/2012; 35(2):197-206. · 1.39 Impact Factor
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    ABSTRACT: Electrical and structural remodeling during the progression of cardiovascular disease is associated with adverse outcomes subjecting affected patients to overt heart failure (HF) and/or sudden death. Dysfunction in integral membrane protein trafficking has long been linked with maladaptive electrical remodeling. However, little is known regarding the molecular identity or function of these intracellular targeting pathways in the heart. Eps15 homology domain-containing (EHD) gene products (EHD1-4) are polypeptides linked with endosomal trafficking, membrane protein recycling, and lipid homeostasis in a wide variety of cell types. EHD3 was recently established as a critical mediator of membrane protein trafficking in the heart. Here, we investigate the potential link between EHD3 function and heart disease. Using four different HF models including ischemic rat heart, pressure overloaded mouse heart, chronic pacing-induced canine heart, and non-ischemic failing human myocardium we provide the first evidence that EHD3 levels are consistently increased in HF. Notably, the expression of the Na/Ca exchanger (NCX1), targeted by EHD3 in heart is similarly elevated in HF. Finally, we identify a molecular pathway for EHD3 regulation in heart failure downstream of reactive oxygen species and angiotensin II signaling. Together, our new data identify EHD3 as a previously unrecognized component of the cardiac remodeling pathway.
    Journal of Molecular and Cellular Cardiology 03/2012; 52(5):1183-90. · 5.15 Impact Factor
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    Philip F Binkley
    Journal of the American College of Cardiology 02/2012; 59(8):776; author reply 776-7. · 14.09 Impact Factor
  • Carl V Leier, Alex J Auseon, Philip F Binkley
    The American journal of medicine 10/2011; 124(10):893-5. · 5.30 Impact Factor
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    ABSTRACT: The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a survival benefit. However, the efficacy of this approach is uncertain. In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds. Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval [CI], 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53). The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.).
    New England Journal of Medicine 04/2011; 364(17):1617-25. · 54.42 Impact Factor
  • Philip F Binkley, Stephen S Gottlieb
    Heart Failure Clinics 01/2011; 7(1):xix-xx.

Publication Stats

3k Citations
825.14 Total Impact Points

Institutions

  • 1982–2014
    • The Ohio State University
      • • Division of Cardiovascular Medicine
      • • Department of Pathology
      • • Division of Hospital Medicine
      • • Division of Cardiology
      Columbus, Ohio, United States
  • 2005
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 1986–1991
    • Columbus State University
      Columbus, Georgia, United States
  • 1989–1990
    • University of Tennessee
      • Department of Clinical Pharmacy
      Knoxville, TN, United States