Association among Fas expression in leucocytes,serum Fas and Fas‐ligand concentrations and hepatic inflammation and fibrosis in chronic hepatitis C

Background: Replication of the hepatitis C virus (HCV) in peripheral blood mononuclear cells (PBMC) may impair immune functions and establish persistent infection. The aim of this study was to assess the influence of HCV on PBMC and their susceptibility to apoptosis in relation to liver inflammation and fibrosis. Methods: Eighty‐one patients with chronic hepatitis C (CHC) were enrolled in this study. Flow cytometry was used to determine the amount of T cells (CD4⁺, CD8⁺), B cells (CD19⁺), monocytes (CD14⁺) and natural killer cells (CD16⁺) in the peripheral blood and the expression of CD95⁺ (CD95/APO‐1) in each subset. Serum concentrations of sFas and sFasL were assessed by the enzyme‐linked immunosorbent assay method. Results: An increased expression of Fas was observed in CD4⁺ and CD8⁺ cells in CHC. There was a more prominent expression of Fas on CD4⁺ cells in HCV genotype 1b in contrast to 3a. Increased Fas expression on CD4⁺ cells was seen in advanced stages of liver disease. Fas expression on monocytes was lower in advanced stages of liver inflammation and fibrosis. Serum sFas concentration was higher in CHC compared with the control group. There was an association between sFasL concentration and inflammatory activity in the liver. Serum sFasL concentration correlated positively with the mean intensity of fluorescence of the Fas receptor in CD4⁺ and CD8⁺ cells, granulocytes and monocytes. Conclusion: These findings indicate that there is an increased susceptibility of PBMC to apoptosis, which can be attributed to the constant contact of leucocytes with the inflamed liver tissue, or from direct HCV influence.     

Blood Pressure-Lowering Response to Amlodipine as a Determinant of the Antioxidative Activity of Small, Dense HDL3

Background and Objective

High-density lipoproteins (HDLs) exert multiple antiatherogenic activities including protection of low-density lipoproteins (LDLs) from oxidative stress. Beneficial effects of calcium channel blockers on cardiovascular disease may in part be related to the reduction of oxidative stress, potentially enhancing the antioxidative activity (AOX) of HDLs. This study aimed to assess the effect of 1 month’s treatment with amlodipine on HDL AOX in hypertensive subjects.

Methods

This was a prospective trial of amlodipine 10 mg/day administered for 1 month in primary-care patients with hypertension (n = 28), 46% of whom were obese and 57% of whom displayed the metabolic syndrome. The main outcome measure was HDL AOX, assessed as the capacity of small, dense HDL3c particles to attenuate LDL oxidation induced in vitro by an azo initiator (AAPH).

Results

Mean (±SD) systolic (SBP) and diastolic (DBP) BP were reduced by amlodipine by 22.1mmHg (±13.2) and 10.4mmHg (±7.5), respectively (p<0.001). Body mass index, waist circumference, and plasma levels of triglycerides, cholesterol, and fasting blood glucose did not change significantly. Amlodipine treatment did not modify HDL3c AOX in the whole study population; changes in AOX were, however, positively correlated with SBP (r = 0.37, p = 0.05 for maximal diene concentration; r = 0.34, p = 0.08 for LDL oxidation rate). When the population was divided into two subgroups according to the BP response to amlodipine (change in SBP below or above the median), HDL3c AOX was significantly improved in hyperresponders (BP-lowering response >22/10 mmHg) as compared with hypo-responders (BP-lowering response <22/10mmHg: mean [± SD] change in the LDL oxidation rate in the presence of HDL3c, ?6.8% [± 11.2] vs +1.9% [±5.2], respectively, p = 0.04; maximal diene concentration, ?8.6% [±13.0] vs +1.9% [±8.2], respectively, p<0.05). By contrast, neither plasma concentrations of oxidized LDL, a marker of systemic oxidative stress, nor the chemical composition of HDL3c were modified between the subgroups.

Conclusions

In hypertensive patients, amlodipine treatment enhanced HDL AOX in subjects who had a BP reduction that exceeded the median response. This effect appears to be secondary to the hypotensive effect, rather than to the direct antioxidant properties, of the drug.     

Increased beta activity in dystonia patients after drug-induced dopamine deficiency

Several studies have confirmed that subthalamic and pallidal local field potential activity in the beta frequency band (13-30 Hz) is exaggerated in untreated patients with Parkinson's disease (PD) and is suppressed by dopaminergic treatment. This particular spectral pattern differs from that in patients with dystonia in whom pallidal activity is prominent at low frequencies (< 12 Hz). Here we demonstrate that tetrabenazine induced monoamine depletion and dopamine blockade is associated with increased activity in the low beta band (13-20 Hz) in the internal pallidum of patients with dystonia. Beta activity was elevated in six patients treated with tetrabenazine compared to six patients in whom this drug was not used. Our findings suggest that beta activity is enhanced in the chronically dopamine-depleted and blocked state irrespective of the underlying pathology, consistent with the idea that excessive synchrony in the beta band is directly related to dopaminergic hypofunction, rather than some degenerative disease-specific attribute of Parkinson's disease.     

Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity

A metabolic syndrome (MetS) phenotype is characterized by insulin-resistance, atherogenic dyslipidemia, oxidative stress, and elevated cardiovascular risk and frequently involves subnormal levels of high-density lipoprotein (HDL) cholesterol. We evaluated the capacity of physicochemically distinct HDL subfractions from MetS subjects to protect low-density lipoprotein against oxidative stress.MetS subjects presented an insulin-resistant phenotype, with central obesity and elevation in systolic blood pressure and plasma triglyceride, LDL-cholesterol, apolipoprotein B, glucose, and insulin levels. Systemic oxidative stress, assessed as plasma 8-isoprostanes, was significantly higher (3.7-fold) in MetS subjects (n = 10) compared with nonobese normolipidemic controls (n = 11). In MetS, small, dense HDL3a, 3b, and 3c subfractions possessed significantly lower specific antioxidative activity (up to -23%, on a unit particle mass basis) than their counterparts in controls. In addition, HDL2a and 3a subfractions from MetS patients possessed lower total antioxidative activity (up to -41%, at equivalent plasma concentrations). The attenuated antioxidative activity of small, dense HDL subfractions correlated with systemic oxidative stress and insulin resistance and was associated with HDL particles exhibiting altered physicochemical properties (core triglyceride enrichment and cholesteryl ester depletion).We conclude that antioxidative activity of small, dense HDL subfractions of altered chemical composition is impaired in MetS and associated with elevated oxidative stress and insulin resistance. Induction of selective increase in the circulating concentrations of dense HDL subfractions may represent an innovative therapeutic approach for the attenuation of high cardiovascular risk in MetS.