Intravenous intralipid-induced blood pressure elevation and endothelial dysfunction in obese African-Americans with type 2 diabetes.

OBJECTIVE: Increased free fatty acids (FFAs) are leading candidates in the pathogenesis of insulin resistance and hypertension in obese subjects. We evaluated the effect of sustained elevations of FFA on blood pressure, endothelial function, insulin secretion, inflammatory markers, and renin-angiotensin system. RESEARCH DESIGN AND METHODS: Twenty-four obese, African-American, normotensive diabetic subjects received a sequential 48-h infusion of Intralipid (20%, 40 ml/h) plus heparin (250 units/h) or normal saline (40 ml/h) plus heparin (250 units/h). RESULTS: Blood pressure was significantly increased within 4 h of lipid infusion and reached a peak increment of 13 mm Hg in systolic and 5 mm Hg in diastolic blood pressure at 24 h (P < 0.01). Compared to baseline, lipid infusion reduced flow-mediated dilatation by 11% at 24 h and 18% at 48 h (P < 0.001). FFA and triglyceride levels increased from a baseline of 0.5 +/- 0.2 mmol/liter and 135 +/- 76 mg/dl to 1.8 +/- 1.0 mmol/liter and 376 +/- 314 mg/dl at 48 h, respectively (P < 0.01). C-Reactive protein increased by 35% at 24 h and by 110% at 48 h of lipid infusion. There were no significant changes in plasma renin and aldosterone levels during lipid or saline infusions. CONCLUSION: Increased FFA levels result in a rapid and sustained elevation in blood pressure, impaired endothelial function, and increased inflammatory markers in obese subjects with type 2 diabetes. The model of FFA-induced hypertension may be useful in examining disease mechanisms associated with the development of hypertension in obese subjects.

Practice of therapy acquired regulatory skills and depressive relapse/recurrence prophylaxis following cognitive therapy or mindfulness based cognitive therapy.

BACKGROUND: To investigate whether usage of treatment-acquired regulatory skills is associated with prevention of depressive relapse/recurrence. METHOD: Remitted depressed outpatients entered a 24-month clinical follow up after either 8 weekly group sessions of cognitive therapy (CT; N = 84) or mindfulness-based cognitive therapy (MBCT; N = 82). The primary outcome was symptom return meeting the criteria for major depression on Module A of the SCID. RESULTS: Factor analysis identified three latent factors (53% of the variance): decentering (DC), distress tolerance (DT), and residual symptoms (RS), which were equivalent across CT and MBCT. Latent change score modeling of factor slopes over the follow up revealed positive slopes for DC (ß = .177), and for DT (ß = .259), but not for RS (ß = -.017), indicating posttreatment growth in DC and DT, but no change in RS. Cox regression indicated that DC slope was a significant predictor of relapse/recurrence prophylaxis, Hazard Ratio (HR) = .232 90% Confidence Interval (CI) [.067, .806], controlling for past depressive episodes, treatment group, and medication. The practice of therapy-acquired regulatory skills had no direct effect on relapse/recurrence (ß = .028) but predicted relapse/recurrence through an indirect path (ß = -.125), such that greater practice of regulatory skills following treatment promoted increases in DC (ß = .462), which, in turn, predicted a reduced risk of relapse/recurrence over 24 months (ß = -.270). CONCLUSIONS: Preventing major depressive disorder relapse/recurrence may depend upon developing DC in addition to managing residual symptoms. Following the acquisition of therapy skills during maintenance psychotherapies, DC is strengthened by continued skill utilization beyond treatment termination. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

In the elderly, interleukin-6 plasma levels and the -174G>C polymorphism are associated with the development of cardiovascular disease.

OBJECTIVE: Interleukin (IL)-6-mediated inflammation is involved in cardiovascular disease (CVD). We assessed IL-6 levels and the -174G>C genotype in a case-control study of men and women (average age 73 years) within the Cardiovascular Health Study. METHODS AND RESULTS: Cases included incident angina, myocardial infarction (MI), and stroke (5-year follow-up), prevalent MI, and MRI-detectable infarcts. A control group and a group free of subclinical CVD were used for comparison. The -174C allele was associated with higher C-reactive protein (11% higher, P=0.02), fibrinogen (3% higher, P=0.02), and IL-6 (5% higher; P=0.16). IL-6 was associated with increased atherosclerosis when the control group was compared with the group free of subclinical CVD. No further association with CVD events was found when case groups were compared with the control group. Compared with its absence, presence of the -174C allele was associated with risk of MRI infarcts (odds ratio 1.5). CONCLUSIONS: IL-6 levels differentiated those with subclinical CVD from those without. Although the -174C allele was not associated with incident events, associations of the genotype with inflammation and MRI infarcts, combined with the plasma IL-6 results, suggest that IL-6 may chronically predispose an individual to develop atherosclerosis.

Oligonucleotides blocking glucosylceramide synthase expression selectively reverse drug resistance in cancer cells.

High glucosylceramide synthase (GCS) activity is one factor contributing to multidrug resistance (MDR) in breast cancer. Enforced GCS overexpression has been shown to disrupt ceramide-induced apoptosis and to confer resistance to doxorubicin. To examine whether GCS is a target for cancer therapy, we have designed and tested the effects of antisense oligodeoxyribonucleotides (ODNs) to GCS on gene expression and chemosensitivity in multidrug-resistant cancer cells. Here, we demonstrate that antisense GCS (asGCS) ODN-7 blocked cellular GCS expression and selectively increased the cytotoxicity of anticancer agents. Pretreatment with asGCS ODN-7 increased doxorubicin sensitivity by 17-fold in MCF-7-AdrR (doxorubicin-resistant) breast cancer cells and by 10-fold in A2780-AD (doxorubicin-resistant) ovarian cancer cells. In MCF-7 drug-sensitive breast cancer cells, asGCS ODN-7 only increased doxorubicin sensitivity by 3-fold, and it did not influence doxorubicin cytotoxicity in normal human mammary epithelial cells. asGCS ODN-7 was shown to be more efficient in reversing drug resistance than either the GCS chemical inhibitor d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol or the P-glycoprotein blocking agents verapamil and cyclosporin A. Experiments defining drug transport and lipid metabolism parameters showed that asGCS ODN-7 overcomes drug resistance mainly by enhancing drug uptake and ceramide-induced apoptosis. This study demonstrates that a 20-mer asGCS oligonucleotide effectively reverses MDR in human cancer cells.