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Lopes-Virella M.F.,Medical University of South Carolina | Baker N.L.,Medical University of South Carolina | Hunt K.J.,Medical University of South Carolina | Cleary P.A.,George Washington University | And 2 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-The current study aimed to determine in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications cohort whether or not abnormal levels of markers of inflammation and endothelial dysfunction measured in samples collected at DCCT baseline were able to predict the development of macroalbuminuria. RESEARCH DESIGN AND METHODS-Levels of inflammation and endothelial cell dysfunction biomarkers were measured in 1,237 of 1,441 patients enrolled in the DCCT study who were both free of albuminuria and cardiovascular disease at baseline. To test the association of log-transformed biomarkers with albuminuria, generalized logistic regression models were used to quantify the association of increased levels of biomarkers and development of abnormal albuminuria. Normal, micro-, and macroalbuminuria were the outcomes of interest. RESULTS-In the logistic regression models adjusted by DCCT treatment assignment, baseline albumin excretion rate, and use of ACE/angiotensin receptor blocker drugs, one unit increase in the standardized levels of soluble E-selectin (sE-selectin) was associated with an 87% increase in the odds to develop macroalbuminuria and one unit increase in the levels of interleukin-6 (IL-6), plasminogen activator inhibitor 1 (PAI-1; total and active), and soluble tumor necrosis factor receptors (TNFR)-1 and -2 lead to a 30-50% increase in the odds to develop macroalbuminuria. Following adjustment for DCCT baseline retinopathy status, age, sex, HbA1c, and duration of diabetes, significant associations remained for sE-selectin and TNFR-1 and -2 but not for IL-6 or PAI-1. CONCLUSIONS-Our study indicates that high levels of inflammatory markers, mainly E-selectin and sTNRF-1 and -2, are important predictors of macroalbuminuria in patients with type 1 diabetes. © 2013 by the American Diabetes Association.


Wangelin B.C.,Ralph hnson Va Medical Center | Tuerk P.W.,Medical University of South Carolina
Journal of Law, Medicine and Ethics | Year: 2014

In this paper, we consider ethical issues related to the treatment of posttraumatic stress disorder (PTSD) in combat zones, via exposure therapy. Exposure-oriented interventions are the most well-researched behavioral treatments for PTSD, and rigorous studies across contexts, populations, and research groups provide robust evidence that exposure therapy for PTSD is effective and can be widely disseminated. Clinical procedures for Prolonged Exposure therapy, a manualized exposure-oriented protocol for PTSD, are reviewed, and we illustrate the potential benefits, as well as the potential difficulties, associated with providing this treatment in combat zones. Several ethical considerations are identified: (1) Assuming successful treatment, is it ethical to send individuals with a known risk of developing PTSD back into combat? (2) If treatment is unsuccessful in theater (perhaps due to the confounding factor of ongoing danger), could that impact treatment effectiveness for soldiers who attempt therapy again post-deployment? (3) If the military finds combat-zone treatment effective and useful in maintaining an efficient work force, will treatment become mandatory for those diagnosed with PTSD? (4) What unintended consequences might be associated with large-scale dissemination of exposure therapy in or near combat, outside of mental health care infrastructures? (5) How would genetic variations known to be associated with PTSD risk influence decisions regarding who receives treatment or returns to combat? We conclude with a review of the personal and societal costs associated with not providing evidence-based PTSD treatments wherever possible. © 2014 American Society of Law, Medicine & Ethics, Inc.


Taylor J.J.,Medical University of South Carolina | Borckardt J.J.,Medical University of South Carolina | George M.S.,Medical University of South Carolina | George M.S.,Ralph hnson Va Medical Center
Pain | Year: 2012

The concurrent rise of undertreated pain and opiate abuse poses a unique challenge to physicians and researchers alike. A focal, noninvasive form of brain stimulation called repetitive transcranial magnetic stimulation (rTMS) has been shown to produce acute and chronic analgesic effects when applied to dorsolateral prefrontal cortex (DLPFC), but the anatomical and pharmacological mechanisms by which prefrontal rTMS induces analgesia remain unclear. Data suggest that DLPFC mediates top-down analgesia via gain modulation of the supraspinal opioidergic circuit. This potential pathway might explain how prefrontal rTMS reduces pain. The purpose of this sham-controlled, double-blind, crossover study was to determine whether left DLPFC rTMS-induced analgesia was sensitive to μ-opioid blockade. Twenty-four healthy volunteers were randomized to receive real or sham TMS after either intravenous saline or naloxone pretreatment. Acute hot and cold pain via quantitative sensory testing and hot allodynia via block testing on capsaicin-treated skin were assessed at baseline and at 0, 20, and 40 minutes after TMS treatment. When compared to sham, real rTMS reduced hot pain and hot allodynia. Naloxone pretreatment significantly reduced the analgesic effects of real rTMS. These results demonstrate that left DLPFC rTMS-induced analgesia requires opioid activity and suggest that rTMS drives endogenous opioidergic pain relief in the human brain. Further studies with chronic dosing regimens of drugs that block or augment the actions of opiates are needed to determine whether TMS can augment opiates in chronic or postoperative pain management. © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.


George M.S.,Institute of Psychiatry | George M.S.,Medical University of South Carolina | George M.S.,Ralph hnson Va Medical Center | Aston-Jones G.,Medical University of South Carolina
Neuropsychopharmacology | Year: 2010

Although the preceding chapters discuss much of the new knowledge of neurocircuitry of neuropsychiatric diseases, and an invasive approach to treatment, this chapter describes and reviews the noninvasive methods of testing circuit-based theories and treating neuropsychiatric diseases that do not involve implanting electrodes into the brain or on its surface. These techniques are transcranial magnetic stimulation, vagus nerve stimulation, and transcranial direct current stimulation. Two of these approaches have FDA approval as therapies. © 2010 Nature Publishing Group All rights reserved.


Lopes-Virella M.F.,Medical University of South Carolina | Lopes-Virella M.F.,Ralph hnson Va Medical Center | Virella G.,Medical University of South Carolina
Clinical Immunology | Year: 2010

Human low density lipoprotein (LDL) undergoes oxidation and glycation in vivo. By themselves, oxidized LDL (oxLDL) and AGE-LDL have proinflammatory properties and are considered atherogenic. But the atherogenicity of these lipoproteins are significantly increased as a consequence of the formation of immune complexes (IC) involving specific autoantibodies. OxLDL and AGE antibodies have been shown to be predominantly of the IgG1 and IgG3 isotypes. OxLDL antibodies are able to activate the complement system by the classical pathway and to induce FcR-mediated phagocytosis. In vitro and ex vivo studies performed with modified LDL-IC have proven their pro-inflammatory and atherogenic properties. Clinical studies have demonstrated that the levels of circulating modified LDL-IC correlate with parameters indicative of cardiovascular and renal disease in diabetic patients and other patient populations. The possibility that spontaneously formed or induced modified LDL antibodies (particularly IgM oxLDL antibodies) may have a protective effect has been suggested, but the data is unclear and needs to be further investigated. © 2009 Elsevier Inc.


Lopes-Virella M.F.,Medical University of South Carolina | Lopes-Virella M.F.,Ralph hnson Va Medical Center | Virella G.,Medical University of South Carolina
Journal of Atherosclerosis and Thrombosis | Year: 2013

There is strong evidence supporting a key role of the adaptive immune response in atherosclerosis, given that both activated Th cells producing predominantly interferon-γ and oxidized LDL (oxLDL) and the corresponding antibodies have been isolated from atheromatous plaques. Studies carried out using immune complexes (IC) prepared with human LDL and rabbit antibodies have demonstrated proatherogenic and pro-inflammatory properties, mostly dependent on the engagement of Fcγ receptors I and II in macrophages and macrophage-like cell lines. Following the development of a methodology for isolating modified LDL (mLDL) antibodies from serum and isolated IC, it was confirmed that antibodies reacting with oxLDL and advanced glycation end product-modified LDL are predominantly IgG of subtypes 1 and 3 and that mLDL IC prepared with human reagents possesses pro-inflammatory and proatherogenic properties. In previous studies, LDL separated from isolated IC has been analyzed for its modifications, and the reactivity of antibodies isolated from the same IC with different LDL modifications has been tested. Recently, we obtained strong evidence suggesting that the effects of mLDL IC on phagocytic cells are modulated by the composition of the mLDL. Clinical studies have shown that the level of mLDL in circulating IC is a strong predictor of cardiovascular disease (CVD) and, in diabetic patients, other significant complications, such as nephropathy and retinopathy. In conclusion, there is convincing ex vivo and clinical data supporting the hypothesis that, in humans, the humoral immune response to mLDL is pathogenic rather than protective.


Oates J.C.,Ralph hnson Va Medical Center | Oates J.C.,Medical University of South Carolina
Autoimmunity | Year: 2010

Systemic lupus erythematosus (SLE) is an autoimmune syndrome marked by autoantibody production. Innate immunity is essential to transform humoral autoimmunity into the clinical lupus phenotype. Nitric oxide (NO) is a membrane- permeable signaling molecule involved in a broad array of biologic processes through its ability to modify proteins, lipids, and DNA and alter their function and immunogenicity. The literature regarding mechanisms through which NO regulates inflammation and cell survival is filled with contradictory findings. However, the effects of NO on cellular processes depend on its concentration and its interaction with reactive oxygen. Understanding this interaction will be essential to determine mechanisms through which reactive intermediates induce cellular autoimmunity and contribute to a sustained innate immune response and organ damage in SLE. © 2010 Informa UK Ltd.


Snider A.J.,Medical University of South Carolina | Alexa Orr Gandy K.,Medical University of South Carolina | Obeid L.M.,Medical University of South Carolina | Obeid L.M.,Ralph hnson Va Medical Center
Biochimie | Year: 2010

Sphingolipids and their synthetic enzymes are emerging as important mediators in inflammatory responses and as regulators of immune cell functions. In particular, sphingosine kinase (SK) and its product sphingosine-1-phosphate (S1P) have been extensively implicated in these processes. SK catalyzes the phosphorylation of sphingosine to S1P and exists as two isoforms, SK1 and SK2. SK1 has been shown to be activated by cytokines including tumor necrosis factor-alpha (TNF-α) and interleukin1-β (IL1-β). The activation of SK1 in this pathway has been shown to be, at least in part, required for mediating TNF-α and IL1-β inflammatory responses in cells, including induction of cyclo-oxygenase 2 (COX2). In addition to their role in inflammatory signaling, SK and S1P have also been implicated in various immune cell functions including, mast cell degranulation, migration of neutrophils, and migration and maturation of lymphocytes. The involvement of sphingolipids and sphingolipid metabolizing enzymes in inflammatory signaling and immune cell functions has implicated these mediators in numerous inflammatory disease states as well. The contribution of these mediators, specifically SK1 and S1P, to inflammation and disease are discussed in this review. © 2010.


Spampinato M.V.,Medical University of South Carolina | Rumboldt Z.,Medical University of South Carolina | Hosker R.J.,Medical University of South Carolina | Mintzer J.E.,Medical University of South Carolina | Mintzer J.E.,Ralph hnson Va Medical Center
Radiology | Year: 2011

Purpose: To examine the influence of apoliprotein E ε4 allele(APOE 4) carrier status on disease progression by evaluating the rate of regional gray matter (GM) volume loss and disease severity in patients with newly diagnosed Alzheimer disease (AD) and stable amnestic mild cognitive impairment (MCI). Materials and Methods: This study was approved by the institutional review board and was HIPAA compliant. All subjects or their legal representatives gave informed consent for participation. Ninety-five subjects (63 male; average age, 77.1 years; age range, 58-91 years; 51 APOE4 carriers; 44 noncarriers) with either documented MCI to AD conversion or stable amnestic MCI underwent three yearly magnetic resonance imaging examinations. Voxel-based morphometry for image postprocessing and Clinical Dementia Rating (CDR) scale for cognitive assessment were used. Results: In APOE 4 carriers, GM volume loss affected the hippocampi, temporal and parietal lobes, right caudate nucleus, and insulae in patients with MCI to AD conversion and the insular and temporal lobes in patients in whom MCI was stable. In subjects who were not APOE 4 carriers, there was no significant GM volume change. There were no differences in CDR scores between APOE 4 carriers and noncarriers. Conclusion: APOE 4 carriers with cognitive decline undergo faster GM atrophy than do noncarriers. The involvement of APOE 4 in the progression of hippocampal atrophy, neocortical atrophy, or both has potential important implications for diagnosis and therapeutic approaches in patients with AD and should be considered in clinical trials. The present results and the results of prior studies indicate that the rate of hippocampal and neocortical atrophy is greater in association with APOE 4 in nondemented elderly subjects, subjects with MCI, and those with AD. © RSNA, 2010.


Basile J.,Ralph hnson Va Medical Center | Neutel J.,Orange County Research Center
Therapeutic Advances in Cardiovascular Disease | Year: 2010

The treatment of hypertension should cause blood pressure (BP) changes that reduce the long-term risks of cardiovascular morbidity and mortality. There are considerable clinical benefits to be gained by promptly treating patients to recognized BP goals, particularly for those at high risk. This may be achieved by the use of combination therapy as first-line treatment. However, despite widely acknowledged therapeutic guidelines, there are significant gaps between current treatment recommendations and their implementation in clinical practice. One important explanation for inadequate treatment and subsequent poor BP control is clinical inertia. Undertreatment and clinical inertia may sometimes be mistaken for treatment-resistant hypertension, as is often the case in specific patient populations whose disease is often considered a challenge to treat because of a greater risk of cardiovascular complications (e.g. Blacks, obese patients, and those with diabetes). The availability of fixed-dose drug combinations may address some of the common misconceptions thought to promote clinical inertia. Few studies have specifically focused on subpopulations with difficult-to-treat hypertension that is uncontrolled on monotherapies. One example is an ongoing 20-week, multicenter, prospective, blinded endpoint, dose-titration, treat-to-goal study evaluating the efficacy and safety of initial fixed-dose combination therapy with amlodipine/olmesartan medoxomil, and further up-titration with hydrochlorothiazide, in patients with hypertension who are uncontrolled on antihypertensive monotherapy. This study may demonstrate the benefits of treating patients with hypertension to goal using initial fixed-dose combination therapy, even in patients considered to be at a higher risk of cardiovascular complications. © The Author(s), 2010.

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