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Abstract: To investigate a potential molecular basis for a link between diabetes and atherosclerosis, experiments were performed to determine the role of NAD(P)H oxidase in the enhanced proliferative capacity of vascular smooth muscle cells (VSMC) from OLETF rat, an animal model of type 2 diabetes. An enhanced proliferative response to 10% fetal bovine serum with an increased cell cycle progression from G1 to S phase as well as an augmented superoxide generation with an increased NAD(P)H oxidase activity were observed in diabetic versus control VSMC. Both the enhanced proliferation and superoxide generation in diabetic VSMC were significantly attenuated not only by diphenyleneiodonium (10 μM) and apocynin (100 μM), NAD(P)H oxidase inhibitors but also by protein tyrosine kinase inhibitors such as genistein (100 μM) and AG 112 (100 μM). Furthermore, the enhanced NAD(P)H oxidase activity in diabetic VSMC was significantly attenuated by genistein and AG112, but not by daidzein (100 μM), a genistein analogue devoid of protein tyrosine kinase inhibitory properties. Based on these results, it is suggested that the enhanced proliferative capacity of diabetic VSMC is closely related to the activation of NAD(P)H oxidase that is induced through activation of protein tyrosine kinase. [Copyright &y& Elsevier]

Reactive oxygen species (ROS) have been implicated in the pathogenesis of vascular dysfunction in diabetes mellitus, and NAD(P)H oxidase is known as the most important source of ROS in the vasculatures. To determine whether NAD(P)H oxidase is a major participant in the critical intermediary signaling events in high glucose (HG, 25 mM)-induced proliferation of vascular smooth muscle cells (VSMC), we investigated in explanted aortic VSMC from rats the role of NAD(P)H oxidase on the HG-related cellular proliferation and superoxide production. VSMC under HG condition had increased proliferative capacity that was inhibited by tiron (1 mM), a cell membrane permeable superoxide scavenger, but not by SOD, which is not permeable to cell membrane. The nitroblue tetrazolium staining in the HG-exposed VSMC was more prominent than that of VSMC under normal glucose (5.5 mM) condition, which was significantly inhibited by DPI (10 μM), an NAD(P)H oxidase inhibitor, but not by inhibitors for other oxidases such as NADH dehydrogenase, xanthine oxidase, and nitric oxide synthase. In the VSMC under HG condition, the enhanced NAD(P)H oxidase activity with increased membrane translocation of Rac1 was observed, but the protein expression of p22phox and gp91phox was not increased. These data suggest that HG-induced changes in VSMC proliferation are related to the intracellular production of superoxide through enhanced activity of NAD(P)H oxidase. [Copyright &y& Elsevier]

Abstract: Macrovascular and microvascular diseases are currently the principal causes of morbidity and mortality in patients with diabetes. Oxidative stress has been postulated to be a major contributor to the pathogenesis of these events. There is considerable evidence that many biochemical pathways adversely affected by hyperglycemia and other substances that are found at elevated levels in diabetic patients are associated with the generation of reactive oxygen species, ultimately leading to increased oxidative stress in a variety of tissues. In the absence of an appropriate compensation by the endogenous antioxidant defense network, increased oxidative stress leads to the activation of stress-sensitive intracellular signaling pathways and the formation of gene products that cause cellular damage and contribute to the late complications of diabetes. It has recently been suggested that diabetic subjects with vascular complications may have a defective cellular antioxidant response against the oxidative stress generated by hyperglycemia. This raises the concept that antioxidant therapy may be of great interest in these patients. Although our understanding of how hyperglycemia-induced oxidative stress ultimately leads to tissue damage has advanced considerably in recent years, effective therapeutic strategies to prevent or delay the development of this damage remain limited. Thus, further investigations of therapeutic interventions to prevent or delay the progression of diabetic vascular complications are needed. [Copyright &y& Elsevier]

Abstract: The metabolic syndrome (MS) is a cluster of risk factors for cardiovascular disease related to insulin resistance. Recently, serum gamma glutamyltransferase (GGT) has been proposed as a marker of oxidative stress and is associated with a marked increase in the risk of cardiovascular disease. So, we investigated the association between serum GGT and components of the metabolic syndrome in the Korean adults. A total 3246 adults (aged 20–70 years, 1622 men and 1624 women) who visited Center for Health Promotion in Pusan National University Hospital for a medical checkup were included. We measured serum GGT and lipid profiles, fasting glucose, fasting insulin and blood pressure. As the quartile of serum GGT increased, the number of components of MS and prevalence of MS were increased. Serum GGT was also increased according as the number of components of MS was increased. A significant correlation (r =0.200, p <0.001 in men and r =0.133, p <0.001 in women) was noted between the numbers of the components of the MS and serum GGT. In addition, serum GGT was correlated significantly (r =0.266, p <0.001 in men and r =0.264, p <0.001 in women) with homeostasis model assessment of insulin resistance (HOMA-IR). In linear regression model, serum GGT was mainly influenced by the concentration of triglycerides and fasting glucose. In conclusion, serum GGT is closely related with insulin resistance and the increased number of components of MS. Among components of MS, serum GGT may be more associated with dyslipidemia and abnormal glucose tolerance, suggesting that serum GGT has more relationship with hepatic insulin resistance regardless of non-alcoholic fatty liver disease. [Copyright &y& Elsevier]

Background: Serum cystatin C has been known as a novel marker of preclinical renal dysfunction, and higher cystatin C levels are associated with increased risks of hip and nonvertebral fractures. However, there are few reports on the association between serum cystatin C and bone mineral density (BMD), especially in the Asian population. We evaluated the association between cystatin C levels and BMD of the spine and hip in Korean adults.Methods: A cross-sectional study was performed in 865 Korean adults (325 men and 540 women) who participated in a comprehensive medical examination program and underwent bone densitometry. Renal function was assessed by the estimated glomerular filtration rate (eGFR), which was calculated using an equation based on creatinine (eGFRcre) and cystatin C (eGFRcys).Results: The serum cystatin C level was negatively correlated with different types of BMD, including the lowest lumbar, total lumbar, femoral neck, and total femur BMD, in women, but not in men. Higher cystatin C levels were associated with a higher prevalence of osteoporosis in women (odds ratio [OR], 3.68; 95% confidence interval [CI], 1.69-8.03; P=0.001), but not in men (OR, 0.85; 95% CI, 0.30-2.38; P=0.761). However, this association was attenuated in the multivariable model adjusted for age, body mass index, serum 25-hydroxyvitamin D3, and creatinine (OR, 1.01; 95% CI, 0.38-2.71) in women. In addition, the eGFRcys showed a stronger positive correlation with BMD than the eGFRcre.Conclusion: Our findings suggest that serum cystatin C levels might help identify women with osteoporosis who are susceptible to fractures. [ABSTRACT FROM AUTHOR]

ConclusionLoco-regional recurrence-free survival was significantly decreased in the papillary thyroid cancer patients with > 6 metastatic lymph nodes and a lymph node ratio > 0.22. Also, the risk of lung metastasis was significantly increased in cases with bilateral neck node metastases. ObjectiveThis study focused on the metastatic lymph node status of the lateral neck compartment to understand its prognostic significance for loco-regional recurrence and distant metastasis. MethodsBetween January 2004 and December 2009, 1040 patients were diagnosed with papillary thyroid cancer and underwent treatment. ResultsIn a multivariate analysis, sex, the number of metastatic lymph nodes, and the lymph node ratio was significantly associated with loco-regional recurrence. The sensitivity/specificity of > 6 metastatic lymph nodes for predicting recurrence was 64.0%/69.7%. The 5-year loco-regional recurrence-free survival of patients with 0–6 metastatic lymph nodes and > 6 metastatic lymph nodes were 93.4% and 79.2%, respectively. The 5-year loco-regional recurrence-free survival of patients with a lymph node ratio ≤ 0.22 and a lymph node ratio > 0.22 were 97.1% and 78.8%, respectively. In the multivariate analysis, only bilateral neck node metastases were significantly associated with lung metastasis. [ABSTRACT FROM PUBLISHER]

Background TNF-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor receptor superfamily and its serum level is known to be closely associated with future cardiovascular events and prognosis of various cardiovascular diseases. We investigated whether serum TRAIL levels are associated with the severity of acute ischemic stroke and specific stroke subtype. Methods We used an enzyme-linked immunosorbent assay to measure the serum TRAIL levels of 293 patients with acute ischemic stroke within 7 days of onset. Stroke subtype was classified as large artery atherosclerosis, cardioembolism, small vessel occlusion and other determined etiology. We used National Institute of Health Stroke Scale (NIHSS) score of first hospital day and stroke volume on diffusion-weighted imaging within 7 days of stroke onset for measuring the severity of acute ischemic stroke. Results The level of serum TRAIL showed significant negative correlations with NIHSS score and stroke volume. Serum TRAIL levels significantly decreased as the tertile of NIHSS score and stroke volume increased. The relative risk of patients with serum TRAIL < 64.0 pg/mL for the presence of highest tertile of NIHSS score was significantly increased (adjusted OR [95%CI]; 7.07 [3.64–13.74]). Regarding stroke volume, the relative risk of patients with serum TRAIL < 71.5 pg/mL for the presence of highest tertile of stroke volume was also significantly increased (adjusted OR [95%CI]; 2.81 [1.61–4.92]). There are no significant differences of serum TRAIL level among stroke subtypes. Conclusions Low serum TRAIL levels were significantly associated with the acute ischemic stroke severity. This finding suggests that serum TRAIL might also have a role in acute ischemic stroke as well as other cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Abstract: Endothelial expression of E-selectin is enhanced in diabetic patients with retinopathy, however, the underlying mechanisms are unclear. Therefore, this study was aimed to determine if endothelial expression of E-selectin is stimulated with serum from type 2 diabetic patients with retinopathy, and whether this process is related to NAD(P)H oxidase-derived oxidative stress. Serum was obtained from type 2 diabetic patients with (T2DR) or without (T2DM) retinopathy, and age-matched non-diabetic healthy person (Control). Serum was added to in vitro-grown human coronary artery endothelial cells (HCAEC), after which E-selectin expression, reactive oxygen species (ROS) production, and NAD(P)H oxidase activity were measured. Serum from T2DR induced a significantly higher expression of E-selectin than serum from T2DM and control in association with an enhanced production of ROS in HCAEC. T2DR serum enhanced E-selectin expression in a ROS-dependent manner since this process was significantly attenuated not only by tiron (1 mM), a superoxide scavenger, but also by DPI (10 μmol/L) and apocynin (100 μmol/L), inhibitors of NAD(P)H oxidase. Furthermore, the activity of NADH oxidase was markedly increased by T2DR serum, and this was accompanied by the enhanced membrane translocation of p47phox, a cytosolic subunit of NAD(P)H oxidase. These findings suggest that serum from T2DR induced up-regulation of E-selectin expression in HCAEC, and this process might be dependent on activation of endothelial NADH oxidase via an enhanced membrane translocation of p47phox. [Copyright &y& Elsevier]