Charlie Norwood Veterans Affairs Medical Center

Augusta, GA, United States

Charlie Norwood Veterans Affairs Medical Center

Augusta, GA, United States
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Shams M.E.E.,Mansoura University | Al-Gayyar M.M.H.,Mansoura University | Al-Gayyar M.M.H.,University of Georgia | Al-Gayyar M.M.H.,Charlie Norwood Veterans Affairs Medical Center | Barakat E.A.M.E.,Mansoura University
Scientia Pharmaceutica | Year: 2011

Type 2 diabetes mellitus is associated with dyslipdemia, insulin resistance and non alcoholic fatty liver disease. The purpose of the current study was to assess whether type 2 diabetes mellitus-induced hyperglycemia has an effect on the lipid profile and release of oxidative stress markers and inflammatory mediators in patients with non alcoholic fatty liver disease and normal liver function tests which may in turn lead to enhancing the pathogenicity of this liver disease. For this purpose, one hundred and five outpatients, matched in age and weight, were classified into two groups: the first group consisted of patients with non alcoholic fatty liver disease and the second group consisted of patients with non alcoholic fatty liver disease in conjunction with hyperglycemia due to the presence of type 2 diabetes mellitus. In all patients, lipid profile, oxidative stress, and inflammatory mediators were assessed by measuring serum concentrations of triglycerides, low density lipoprotein, hydrogen preroxide, malondialdehyde, tumor necrosis factor-alpha and interleukin-6, respectively. In the studied population, it was found that the presence of type 2 diabetes mellitus-induced hyperglycemia significantly impaired lipid profile, and significantly enhanced the formation of hydrogen preroxide and malon-dialdehyde as well as significantly increased the release of tumor necrosisfactor-alpha and interleukin-6 in the second group of patients. In addition, plasma glucose level showed significant positive correlation with hydrogen peroxide, malondialdehyde, tumor necrosis factor-alpha and interleukin-6. From the previous results, it was concluded that the presence of type 2 diabetes mellitus-induced hyperglycemia results in significant increase in lipid profile, oxidative stress markers and inflammatory mediators in patients with non alcoholic fatty liver disease and normal liver function tests. For this reason, further research studies may be essential to evaluate the benefit of adding suitable antioxidant and anti-inflammatory drugs to the treatment regimen for this group of patients. In addition, regular monitoring of blood glucose levels and liver function tests should be advised to this category of patients to reduce liver fat deposition and avoid the development of non alcoholic steatohepatitis, cirrhosis or liver cancer and their related complications. © Shams et al.; licensee Österreichische Apotheker-Verlagsgesellschaft m. b. H., Vienna, Austria.


Tu J.,University of Science and Technology of China | Zhang X.,University of Science and Technology of China | Zhu Y.,University of Science and Technology of China | Dai Y.,University of Science and Technology of China | And 6 more authors.
Journal of Neuroscience | Year: 2015

The current study examined efficacy of a small Tat (trans-activator of transcription)-conjugated peptide activator of the Nrf2 (nuclear factor-E2-related factor-2) antioxidant/cell-defense pathway as a potential injury-specific, novel neuroprotectant against global cerebral ischemia (GCI).A competitive peptide, DEETGE-CAL-Tat, was designed to facilitate Nrf2 activation by disrupting interaction of Nrf2 with Keap1 (kelch-like ECH-associated protein 1), a protein that sequesters Nrf2 in the cytoplasm and thereby inactivates it. The DEETGECAL-Tat peptide contained the critical sequence DEETGE for the Nrf2-Keap1 interaction, the cell transduction domain of the HIV-Tat protein, and the cleavage sequence of calpain, which is sensitive to Ca2+ increase and allows injury-specific activation of Nrf2. Using an animal model of GCI, we demonstrated that pretreatment with the DEETGE-CAL-Tat peptide markedly decreased Nrf2 interaction with Keap1 in the rat hippocampal CA1 region after GCI, and enhanced Nrf2 nuclear translocation and DNA binding. The DEETGE-CAL-Tat peptide also induced Nrf2 antioxidant/cytoprotective target genes, reduced oxidative stress, and induced strong neuroprotection and marked preservation of hippocampal-dependent cognitive function after GCI. These effects were specific as control peptides lacked neuroprotective ability. Intriguingly, the DEETGE-CAL-Tat peptide effects were also injury specific, as it had no effect upon neuronal survival or cognitive performance in sham non ischemic animals. Of significant interest, peripheral, post ischemia administration of the DEETGE-CAL-Tat peptide from days 1-9 after GCI also induced robust neuroprotection and strongly preserved hippo campal-dependent cognitive function. Based on its robust neuro protective and cognitive-preserving effects, and its unique injury-specific activation properties, the DEETGE-CAL-Tat peptide represents a novel, and potentially promising new therapeutic modality for the treatment of GCI. © 2015 the authors.


Yin D.-M.,Georgia Regents University | Xiong W.-C.,Georgia Regents University | Mei L.,Charlie Norwood Veterans Affairs Medical Center
Nature Neuroscience | Year: 2013

A study now identifies an unexpected function of the D2 dopamine receptor in synapse maturation during a critical period in mice. The findings may have implications for the onset of schizophrenia in humans. © 2013 Nature America, Inc. All rights reserved.


Wang J.,Georgia Regents University | Wang J.,Charlie Norwood Veterans Affairs Medical Center | Yu R.K.,Georgia Regents University | Yu R.K.,Charlie Norwood Veterans Affairs Medical Center
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013

Mounting evidence supports the notion that gangliosides serve regulatory roles in neurogenesis; little is known, however, about how these glycosphingolipids function in neural stem cell (NSC) fate determination. We previously demonstrated that ganglioside GD3 is a major species in embryonic mouse brain: more than 80% of the NSCs obtained by the neurosphere method express GD3. To investigate the functional role of GD3 in neurogenesis, we compared the properties of NSCs from GD3-synthase knockout (GD3SKO) mice with those from their wild-type littermates. NSCs from GD3S-KO mice showed decreased self-renewal ability compared with those from the wild-type animals, and that decreased ability was accompanied by reduced expression of EGF receptor (EGFR) and an increased degradation rate of EGFR and EGF-induced ERK signaling. We also showed that EGFR switched from the low-density lipid raft fractions in wild-type NSCs to the high-density layers in the GD3S-KO NSCs. Immunochemical staining revealed colocalization of EGFR and GD3, and EGFR could be immunoprecipitated from the NSC lysate with an anti-GD3 antibody from the wild-type, but not from the GD3S-KO, mice. Tracking the localization of endocytosed EGFR with endocytosis pathway markers indicated that more EGFR in GD3S-KO NSCs translocated through the endosomal?lysosomal degradative pathway, rather than through the recycling pathway. Those findings support the idea that GD3 interacts with EGFR in the NSCs and that the interaction is responsible for sustaining the expression of EGFR and its downstream signaling to maintain the selfrenewal capability of NSCs.


Trotman H.D.,Georgia Regents University | Trotman H.D.,Charlie Norwood Veterans Affairs Medical Center | Trotman H.D.,Emory University | Kirkpatrick B.,Georgia Regents University | Compton M.T.,Emory University
Schizophrenia Research | Year: 2011

Patients with schizophrenia who have primary, enduring negative symptoms, or the deficit syndrome, have poorer psychosocial functioning but lesser clinical distress compared with nondeficit patients. Poor awareness of impairment in patients with deficit schizophrenia may contribute to this seeming contradiction. We hypothesized that poor insight would be present early in the course of illness in deficit patients, and that those with deficit features would have greater impairment in insight than those without deficit features. One-hundred one first-episode patients with nonaffective psychotic disorders were categorized into deficit (n = 31) and nondeficit (n = 70) groups. The deficit patients had significantly poorer insight than nondeficit patients when rated using a self-report questionnaire, and nearly significantly poorer insight rated by clinical researchers. Further, this effect remained for self-rated insight and reached statistical significance for researcher-rated insight after controlling for positive, negative, and general psychopathology symptoms. These results suggest that the treatment of deficit patients may be particularly complicated by poor insight. © 2010 Elsevier B.V.


Qin H.,Georgia Regents University | Frohman M.A.,State University of New York at Stony Brook | Bollag W.B.,Georgia Regents University | Bollag W.B.,Charlie Norwood Veterans Affairs Medical Center
Endocrinology | Year: 2010

In primary bovine adrenal glomerulosa cells, the signaling enzyme phospholipase D (PLD) is suggested to mediate priming, the enhancement of aldosterone secretion after pretreatment with and removal of angiotensin II (AngII), via the formation of persistently elevated diacylglycerol (DAG). To further explore PLD's role in priming, glomerulosa cells were pretreated with an exogenous bacterial PLD. Using this approach, phosphatidic acid (PA) is generated on the outer, rather than the inner, leaflet of the plasma membrane. Although PA is not readily internalized, the PA is nonetheless rapidly hydrolyzed by cell-surface PA phosphatases to DAG, which efficiently flips to the inner leaflet and accesses the cell interior. Pretreatment with bacterial PLD resulted in priming upon subsequent AngII exposure, supporting a role of DAG in this process, because the increase in DAG persisted after exogenous PLD removal. To determine the PLD isoform mediating aldosterone secretion, and presumably priming, primary glomerulosa cells were infected with adenoviruses expressing GFP, PLD1, PLD2, or lipase-inactive mutants. Overexpressed PLD2 increased aldosterone secretion by approximately 3-fold over the GFP-infected control under basal conditions, with a significant enhancement to about 16-fold over the basal value upon AngII stimulation. PLD activity was also increased basally and upon stimulation with AngII. In contrast, PLD1 overexpression had little effect on aldosterone secretion, despite the fact that PLD activity was enhanced. In both cases, the lipase-inactive PLD mutants showed essentially no effect on PLD activity or aldosterone secretion. Our results suggest that PLD2 is the isoform that mediates aldosterone secretion and likely priming. Copyright © 2010 by The Endocrine Society.


Bhatt K.,Georgia Regents University | Mi Q.-S.,Ford Motor Company | Dong Z.,Georgia Regents University | Dong Z.,Charlie Norwood Veterans Affairs Medical Center
American Journal of Physiology - Renal Physiology | Year: 2011

MicroRNAs (miRNA) are endogenously produced, short RNAs that repress and thus regulate the expression of almost half of known protein-coding genes. miRNA-mediated gene repression is an important regulatory mechanism to modulate fundamental cellular processes such as the cell cycle, growth, proliferation, phenotype, and death, which in turn have major influences on pathophysiological outcomes. In kidneys, miRNAs are indispensable for renal development and homeostasis. Emerging evidence has further pinpointed the pathogenic roles played by miRNAs in major renal diseases, including diabetic nephropathy, acute kidney injury, renal carcinoma, polycystic kidney disease, and others. Although the field of renal miRNA research is still in its infancy and important questions remain, future investigation on miRNA regulation in kidneys has the potential to revolutionize both the diagnosis and treatment of major renal diseases. © 2011 by the American Physiological Society.


Mohamed I.N.,University of Georgia | Mohamed I.N.,Charlie Norwood Veterans Affairs Medical Center | Hafez S.S.,University of Georgia | Hafez S.S.,Charlie Norwood Veterans Affairs Medical Center | And 7 more authors.
Diabetologia | Year: 2014

Aims/hypothesis: Obesity and hypertension, known pro-inflammatory states, are identified determinants for increased retinal microvascular abnormalities. However, the molecular link between inflammation and microvascular degeneration remains elusive. Thioredoxin-interacting protein (TXNIP) is recognised as an activator of the NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome. This study aims to examine TXNIP expression and elucidate its role in endothelial inflammasome activation and retinal lesions. Methods: Spontaneously hypertensive (SHR) and control Wistar (W) rats were compared with groups fed a high-fat diet (HFD) (W+F and SHR+F) for 8-10 weeks. Results: Compared with W controls, HFD alone or in combination with hypertension significantly induced formation of acellular capillaries, a hallmark of retinal ischaemic lesions. These effects were accompanied by significant increases in lipid peroxidation, nitrotyrosine and expression of TXNIP, nuclear factor κB, TNF-α and IL-1β. HFD significantly increased interaction of TXNIP-NLRP3 and expression of cleaved caspase-1 and cleaved IL-1β. Immunolocalisation studies identified TXNIP expression within astrocytes and Müller cells surrounding retinal endothelial cells. To model HFD in vitro, human retinal endothelial (HRE) cells were stimulated with 400 μmol/l palmitate coupled to BSA (Pal-BSA). Pal-BSA triggered expression of TXNIP and its interaction with NLRP3, resulting in activation of caspase-1 and IL-1β in HRE cells. Silencing Txnip expression in HRE cells abolished Pal-BSA-mediated cleaved IL-1β release into medium and cell death, evident by decreases in cleaved caspase-3 expression and the proportion of live to dead cells. Conclusions/interpretation: These findings provide the first evidence for enhanced TXNIP expression in hypertension and HFD-induced retinal oxidative/inflammatory response and suggest that TXNIP is required for HFD-mediated activation of the NLRP3 inflammasome and the release of IL-1β in endothelial cells. © 2013 Springer-Verlag Berlin Heidelberg.


Kolhe R.,University of Georgia | Reid M.D.,Emory University | Lee J.R.,Charlie Norwood Veterans Affairs Medical Center | Cohen C.,Emory University | And 2 more authors.
International Journal of Clinical and Experimental Pathology | Year: 2013

Background: Merkel cell carcinoma is a high-grade neuroendocrine carcinoma of skin that is characterized by immature cells which, because of its striking morphologic similarity, may be confused with other small round blue cell tumors such as pulmonary small cell carcinoma or lymphoblastic leukemia/lymphoma. Immunohistochemistry is therefore paramount to ensuring accurate diagnostic distinction between these tumors. The aim of our study was to evaluate and compare the expression of PAX5 and Terminal deoxynucleotidyl transferase (TdT), in Merkel cell carcinoma and pulmonary small cell carcinoma. Design: PAX5 and TdT immunohistochemical stains were performed on 27 Merkel cell carcinomas and 10 pulmonary small cell carcinomas. Results: PAX5 was expressed in 24/27 (89%) Merkel cell carcinomas and 0/10 (0%) pulmonary small cell carcinomas. TdT was expressed in 21/27 (78%) Merkel cell carcinomas and 9/10 (90%) pulmonary small cell carcinomas. Conclusions: Our study confirms that PAX5 and TdT expression can be expressed in a high percentage of Merkel cell carcinomas and so when positive are not diagnostic of lymphoblastic leukemia/lymphoma. When dealing with metastatic lesions, PAX5 negativity would favor a diagnosis of pulmonary small cell carcinoma over Merkel cell carcinoma. In addition, TTF-1 negative pulmonary small cell carcinoma is to be differentiated from Merkel cell carcinoma.


Alhusban A.,University of Georgia | Alhusban A.,Charlie Norwood Veterans Affairs Medical Center | Fagan S.C.,University of Georgia | Fagan S.C.,Charlie Norwood Veterans Affairs Medical Center
American Journal Geriatric Pharmacotherapy | Year: 2011

Background: Stroke is a major health problem with significant impact on the affected individuals and the whole community. In light of stroke being the leading cause of disability, the ageing of the population and the high incidence of stroke among the elderly, highlight the importance of primary and secondary prevention interventions among this group. The elderly generally have been underrepresented in clinical trials, creating many uncertainties and less optimal medical care for this group of patients. Objective: This review aims to make evidence-based management recommendations for secondary stroke prevention in the elderly. Methods: Secondary preventionrelated primary literature was identified using MEDLINE and PubMed (1982 to present) with combinations of the following search terms being employed: antiplatelets, aspirin, atrial fibrillation, elderly, geriatrics, hypertension, lipids, secondary prevention, statins, stroke, and warfarin. In addition, the references of these articles were also reviewed. Results: Twenty-three clinical trials were included in this review, covering different aspects of secondary stroke prevention. Many of these trials were not specifically limited to the elderly, but conclusions related to their care can be derived from them. Although the American Heart Association/American Stroke Association guidelines suggest an equal benefit of aspirin, aspirin/dipyridamole, and clopidogrel in secondary prevention, the use of aspirin in the elderly may be preferred for reasons related to compliance and experience. Warfarin was largely avoided in the management of elderly stroke patients in the past, although available evidence demonstrates its efficacy and safety as a first choice for elderly patients with atrial fibrillation and presumed cardiac source of emboli. Lowering blood pressure among the elderly is an important aspect of secondary stroke prevention and can be achieved with the same agents used among younger age groups with a preference for a thiazide diuretic/angiotensin-converting enzyme inhibitor combination that has proven efficacy among elderly patients. Available evidence supports the use of statins among elderly patients with history of stroke or transient ischemic attack (TIA), and the derived benefit of treatment does not differ significantly from that in the younger age group. Elderly patients with 50% to 99% carotid artery stenosis and history of stroke or TIA should be considered for early carotid endarterectomy to reduce recurrent stroke. Conclusion: Age should not be considered a barrier for the provision of optimal secondary prevention interventions. The available evidence supports similar and sometimes superior derived benefit from secondary preventive stroke measures in the elderly compared with that seen in younger patients. © 2011 Elsevier HS Journals, Inc. All rights reserved.

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