Salem Medical Center

Roanoke, VA, United States

Salem Medical Center

Roanoke, VA, United States
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Seitz H.K.,Salem Medical Center | Stickel F.,University of Bern
Genes and Nutrition | Year: 2010

Chronic ethanol consumption is a strong risk factor for the development of certain types of cancer including those of the upper aerodigestive tract, the liver, the large intestine and the female breast. Multiple mechanisms are involved in alcohol-mediated carcinogenesis. Among those the action of acetaldehyde (AA), the first metabolite of ethanol oxidation is of particular interest. AA is toxic, mutagenic and carcinogenic in animal experiments. AA binds to DNA and forms carcinogenic adducts. Direct evidence of the role of AA in alcohol-associated carcinogenesis derived from genetic linkage studies in alcoholics. Polymorphisms or mutations of genes coding for AA generation or detoxifying enzymes resulting in elevated AA concentrations are associated with increased cancer risk. Approximately 40% of Japanese, Koreans or Chinese carry the AA dehydrogenase 2*2 (ALDH2*2) allele in its heterozygous form. This allele codes for an ALDH2 enzyme with little activity leading to high AA concentrations after the consumption of even small amounts of alcohol. When individuals with this allele consume ethanol chronically, a significant increased risk for upper alimentary tract and colorectal cancer is noted. In Caucasians, alcohol dehydrogenase 1C*1 (ADH1C*1) allele encodes for an ADH isoenzyme which produces 2.5 times more AA than the corresponding allele ADH1C*2. In studies with moderate to high alcohol intake, ADH1C*1 allele frequency and rate of homozygosity was found to be significantly associated with an increased risk for cancer of the upper aerodigestive tract, the liver, the colon and the female breast. These studies underline the important role of acetaldehyde in ethanol-mediated carcinogenesis. © Springer-Verlag 2009.


Hafen C.A.,University of Virginia | Spilker A.,University of Virginia | Chango J.,University of Virginia | Marston E.S.,Salem Medical Center | Allen J.P.,University of Virginia
Journal of Research on Adolescence | Year: 2014

Successfully navigating entry into romantic relationships is a key task in adolescence, which sensitivity to rejection can make difficult to accomplish. This study uses multi-informant data from a community sample of 180 adolescents assessed repeatedly from age 16 to 22. Individuals with elevated levels of rejection sensitivity at age 16 were less likely to have a romantic partner at age 22, reported more anxiety and avoidance when they did have relationships, and were observed to be more negative in their interactions with romantic partners. In addition, females whose rejection sensitivity increased during late adolescence were more likely to adopt a submissive pattern within adult romantic relationships, further suggesting a pattern in which rejection sensitivity forecasts difficulties. © 2014 Society for Research on Adolescence.


Kovesdy C.P.,Salem Medical Center | Kovesdy C.P.,University of Virginia
Clinical Journal of the American Society of Nephrology | Year: 2010

The introduction of calcitriol followed by several of its analogs in the 1990s made vitamin D receptor activators (VDRA) the cornerstone of therapy for secondary hyperparathyroidism. The 2003 publication of the first major epidemiologic study describing the association of VDRAs with survival in ESRD has raised the awareness of the nephrology community about the potential impact of these agents on morbidity and mortality. This study was followed by numerous other epidemiologic studies which attempted to address the inherent shortcomings of observational studies by using sophisticated statistical methods. The complex nature of the statistical designs applied by some of these studies has led to some confusion about how to interpret the results, and how to use the results in a way that offers the most help for patients, but does not impede future scientific research. This report presents a discussion of relevant studies examining the association between VDRA and survival, with the goal to examine shortcomings that still exist in the knowledge on this subject. Special emphasis is placed on the discussion of studies with discrepant results to highlight remaining controversies and to emphasize areas in need of further research. Not withstanding all of the limitations of epidemiologic studies, the preponderance of evidence favors a survival benefit for ESRD patients treated with VDRA. This should provide a powerful impetus to investigate in clinical trials the risks and benefits of VDRA administration as a means to prolong survival. Copyright © 2010 by the American Society of Nephrology.


Ricks J.,University of California at Los Angeles | Molnar M.Z.,University of California at Los Angeles | Molnar M.Z.,Semmelweis University | Kovesdy C.P.,Salem Medical Center | And 6 more authors.
Diabetes | Year: 2012

Previous observational studies using differing methodologies have yielded inconsistent results regarding the association between glycemic control and outcomes in diabetic patients receiving maintenance hemodialysis (MHD). We examined mortality predictability of A1C and random serum glucose over time in a contemporary cohort of 54,757 diabetic MHD patients (age 63 ± 13 years, 51% men, 30% African Americans, 19% Hispanics). Adjusted all-cause death hazard ratio (HR) for baseline A1C increments of 8.0-8.9, 9.0-9.9, and ≥10%, compared with 7.0-7.9% (reference), was 1.06 (95% CI 1.01-1.12), 1.05 (0.99-1.12), and 1.19 (1.12-1.28), respectively, and for time-averaged A1C was 1.11 (1.05-1.16), 1.36 (1.27-1.45), and 1.59 (1.46-1.72). A symmetric increase in mortality also occurred with time-averaged A1C levels in the low range (6.0-6.9%, HR 1.05 [95% CI 1.01-1.08]; 5.0-5.9%, 1.08 [1.04-1.11], and ≤5%, 1.35 [1.29-1.42]) compared with 7.0-7.9% in fully adjusted models. Adjusted all-cause death HR for time-averaged blood glucose 175-199, 200-249, 250-299, and ≥300 mg/dL, compared with 150-175 mg/dL (reference), was 1.03 (95% CI 0.99-1.07), 1.14 (1.10-1.19), 1.30 (1.23-1.37), and 1.66 (1.56-1.76), respectively. Hence, poor glycemic control (A1C ≥8% or serum glucose ≥200 mg/dL) appears to be associated with high all-cause and cardiovascular death in MHD patients. Very low glycemic levels are also associated with high mortality risk. © 2012 by the American Diabetes Association.


Kovesdy C.P.,Salem Medical Center | Kovesdy C.P.,University of Virginia | Kuchmak O.,Carilion Clinic | Lu J.L.,Salem Research Institute | Kalantar-Zadeh K.,University of California at Los Angeles
American Journal of Kidney Diseases | Year: 2010

Background Phosphorus binders are used to treat hyperphosphatemia in maintenance dialysis patients, in whom the use of these medications has been associated with lower mortality in some observational studies. It is not clear whether similar benefits can be seen in patients with nondialysis-dependent chronic kidney disease (CKD). Study Design Historical cohort. Setting & Participants 1,188 men with moderate and advanced nondialysis-dependent CKD at a single medical center. Predictor Administration of any phosphorus binder. Outcomes & Measurements We examined associations of any phosphorus-binder administration with all-cause mortality and the slopes of estimated glomerular filtration rate using time-varying Cox models and mixed-effects models. Associations also were examined in intention-to-treat analyses and in 133 patient-pairs matched according to propensity scores. Results 344 patients were treated with a phosphorus binder; 658 patients died (mortality rate, 141 deaths/1,000 patient-years; 95% CI, 131-153) during a median follow-up of 3.1 years. Treatment with phosphorus binders was associated with significantly lower mortality (adjusted HR, 0.61; 95% CI, 0.45-0.81; P < 0.001). Results were similar when exposure was modeled in intention-to-treat analyses and examining propensity-matched patients. Phosphorus-binder use was not associated with significant changes in kidney function loss. Limitations Results may not apply to all patients with nondialysis-dependent CKD. Conclusions Administration of phosphorus binders is associated with lower mortality in men with moderate and advanced nondialysis-dependent CKD. Clinical trials are needed to determine the risks and benefits of phosphorus-binder use in this patient population. © 2010 National Kidney Foundation, Inc.


Seitz H.K.,University of Heidelberg | Seitz H.K.,Salem Medical Center | Mueller S.,University of Heidelberg
Advances in Experimental Medicine and Biology | Year: 2015

The mechanisms by which chronic alcohol consumption enhances carcinogenesis include acetaldehyde (AA) generated by alcohol dehydrogenase and reactive oxygen species (ROS) generated predominantly by cytochrome P450 2E1 (CYP2E1), but also by other factors during infl ammation. In addition, ethanol also alters epigenetics by changing DNA and histone methylation and acetylation. A loss of retinoic acid due to a CYP2E1-related enhanced degradation results in enhanced cellular proliferation and decreased cell differentiation. Changes in cancer genes and in signaling pathways (MAPK, RAS, Rb, TGFβ, p53, PTEN, ECM, osteopontin, Wnt) may also contribute to ethanol-mediated mechanisms in carcinogenesis. Finally, immunosuppression may facilitate tumor spread. In the present review major emphasis is led on AA and ROS. While AA binds to proteins and DNA generating carcinogenic DNA adducts and inhibiting DNA repair and DNA methylation, ROS results in lipid peroxidation with the generation of lipid peroxidation products such as 4-hydoxynonenal which binds to DNA-forming highly carcinogenic exocyclic DNA adducts. ROS production correlates signifi cantly with CYP2E1 in the liver but also in the esophagus, and its generation can be signifi - cantly reduced by the specifi c CYP2E1 inhibitor clomethiazole. Finally, CMZ also inhibits alcohol-mediated nitrosamine-induced hepatocarcinogenesis. © 2015, Springer International Publishing Switzerland.


Molnar M.Z.,University of California at Los Angeles | Ojo A.O.,University of Michigan | Bunnapradist S.,University of California at Los Angeles | Kovesdy C.P.,Salem Medical Center | Kalantar-Zadeh K.,University of California at Los Angeles
Nature Reviews Nephrology | Year: 2012

Over the past two decades, most guidelines have advocated early initiation of dialysis on the basis of studies showing improved survival in patients starting dialysis early. These recommendations led to an increase in the proportion of patients initiating dialysis with an estimated glomerular filtration rate (eGFR) >10 ml/min/1.73 m 2, from 20% in 1996 to 52% in 2008. During this period, the percentage of patients starting dialysis with an eGFR ≥15 ml/min/1.73 m 2 increased from 4% to 17%. However, recent studies have failed to substantiate a benefit of early dialysis initiation and some data have suggested worse outcomes for patients starting dialysis with a higher eGFR. Several reasons for this seemingly paradoxical observation have been suggested, including the fact that patients requiring early dialysis are likely to have more severe symptoms and comorbidities, leading to confounding by indication, as well as biological mechanisms that causally relate early dialysis therapy to adverse outcomes. Patients with a failing renal allograft who reinitiate dialysis encounter similar problems. However, unique factors associated with a failed allograft means that the optimal timing of dialysis initiation in failed transplant patients might differ from that in transplant-naive patients with chronic kidney disease. In this Review, we discuss studies of dialysis initiation and compare risks and benefits of early versus late initiation and reinitiation of dialysis therapy. © 2012 Macmillan Publishers Limited. All rights reserved.


Linhart K.,University of Heidelberg | Bartsch H.,Salem Medical Center | Seitz H.K.,German Cancer Research Center
Redox Biology | Year: 2014

Exocyclic etheno-DNA adducts are mutagenic and carcinogenic and are formed by the reaction of lipidperoxidation (LPO) products such as 4-hydoxynonenal or malondialdehyde with DNA bases. LPO products are generated either via inflammation driven oxidative stress or via the induction of cytochrome P-450 2E1 (CYP2E1). In the liver CYP2E1 is induced by various compounds including free fatty acids, acetone and ethanol. Increased levels of CYP2E1 and thus, oxidative stress are observed in the liver of patients with non-alcoholic steatohepatitis (NASH) as well as in the chronic alcoholic. In addition, chronic ethanol ingestion also increases CYP2E1 in the mucosa of the oesophagus and colon. In all these tissues CYP2E1 correlates significantly with the levels of carcinogenic etheno-DNA adducts. In contrast, in patients with non-alcoholic steatohepatitis (NASH) hepatic etheno-DNA adducts do not correlate with CYP2E1 indicating that in NASH etheno-DNA adducts formation is predominately driven by inflammation rather than by CYP2E1 induction. Since etheno-DNA adducts are strong mutagens producing various types of base pair substitution mutations as well as other types of genetic damage, it is strongly believed that they are involved in ethanol mediated carcinogenesis primarily driven by the induction of CYP2E1. © 2014 The Authors.


Kou Z.,Wayne State University | VandeVord P.J.,Virginia Polytechnic Institute and State University | VandeVord P.J.,Salem Medical Center
GLIA | Year: 2014

An improved understanding and characterization of glial activation and its relationship with white matter injury will likely serve as a novel treatment target to curb post injury inflammation and promote axonal remyelination after brain trauma. Traumatic brain injury (TBI) is a significant public healthcare burden and a leading cause of death and disability in the United States. Particularly, traumatic white matter (WM) injury or traumatic axonal injury has been reported as being associated with patients' poor outcomes. However, there is very limited data reporting the importance of glial activation after TBI and its interaction with WM injury. This article presents a systematic review of traumatic WM injury and the associated glial activation, from basic science to clinical diagnosis and prognosis, from advanced neuroimaging perspective. It concludes that there is a disconnection between WM injury research and the essential role of glia which serve to restore a healthy environment for axonal regeneration following WM injury. Particularly, there is a significant lack of non-invasive means to characterize the complex pathophysiology of WM injury and glial activation in both animal models and in humans. An improved understanding and characterization of the relationship between glia and WM injury will likely serve as a novel treatment target to curb post injury inflammation and promote axonal remyelination. © 2014 Wiley Periodicals, Inc.


Sajja V.S.S.S.,University of Virginia | Ereifej E.S.,University of Virginia | VandeVord P.J.,University of Virginia | VandeVord P.J.,Salem Medical Center
Neuroscience Letters | Year: 2014

Clinical outcomes from blast neurotrauma are associated with higher order cognitive functions such as memory, problem solving skills and attention. Current literature is limited to a single overpressure exposure or repeated exposures at the same level of overpressure and is focused on the acute response (<3 days). In an attempt to expand the understanding of neuropathological and molecular changes of the subacute response (7 days post injury), we used an established rodent model of blast neurotrauma. Three pressure magnitudes (low, moderate and high) were used to evaluate molecular injury thresholds. Immunohistochemical analysis demonstrated increased cleaved caspase-3 levels and loss of neuronal population (NeuN. +.) within the hippocampus of all pressure groups. On the contrary, selective activation of microglia was observed in the low blast group. In addition, increased astrocytes (GFAP), membrane signal transduction protein (Map2k1) and calcium regulator mechanosensitive protein (Piezo 2) were observed in the moderate blast group. Results from gene expression analysis suggested ongoing neuroprotection, as brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF) and Mn and CuZn superoxide dismutases (SOD) all increased in the low and moderate blast groups. Ongoing neuroprotection was further supported by increased SOD levels observed in the moderate group using immunohistochemistry. The gene expression level of glutamate aspartate transporter (GLAST) was upregulated in the low, but downregulated in the high blast group, while no changes were found in the moderate group. Overall, the data shown here provides evidence of a diverse neuroprotective and glial response to various levels of blast exposure. This mechanistic role of neuroprotection is vital in understanding ongoing cellular stress, both at the gene and protein levels, in order to develop interventional studies for the prognosis of injury. © 2014 Elsevier Ireland Ltd.

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