Statins reduce oxidized low-density lipoprotein levels,but do not alter soluble intercellular cell-adhesion molecule-1 and vascular cell-adhesion molecule-1 levels in subjects with hypercholesterolaemia

ICAM-1 (intercellular cell-adhesion molecule-1) and VCAM-1 (vascular cell-adhesion molecule-1) are cell-adhesion molecules that have an essential role in monocyte recruitment. In the present study we have investigated (i) whether statins reduce soluble levels of ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1), and the relationship between resistance of LDL (low-density lipoprotein) to in vitro oxidation and sICAM-1 and sVCAM-1 levels. Whole blood samples were obtained from 55 healthy non-smoking adults (aged 35-65 years) with moderate (LDL-cholesterol, 3.4-4.9 mmol/l) hypercholesterolaemia participating in a randomized double-blinded, 8-week trial comparing pravastatin (40 mg), simvastatin (20 and 80 mg) and placebo. sICAM-1 levels (means+/-S.D.) increased slightly from 12.2+/-4.2 to 13.6+/-4.2 ng/ml with statin therapy, whereas, among placebo-assigned subjects, levels were unchanged (11.8+/-5.0 and 11.8+/-3.9 ng/ml). sVCAM-1 increased from 18.9+/-10.1 to 21.1+/-7.4 ng/ml among those on active therapy and slightly declined with placebo assignment (19.8+/-8.8 to 19.4+/-6.4 ng/ml). Lag times increased with statin therapy from 74.3+/-39.8 min to 98.3+/-57.8 min ( P =0.003), and were unchanged in the placebo group (from 103.1+/-61.1 to 90.8+/-65.9 min; P =0.48). There were no significant changes between statin and placebo therapy for sICAM-1, sVCAM-1 or lag times ( P =0.09, 0.16 and 0.067 respectively). Changes in sICAM-1 and sVCAM-1 were not correlated with the change in lag times. In contrast with the known effects of oxidized LDL on gene activation of ICAM-1 and VCAM-1, lag times did not correlate with sICAM-1 and sVCAM-1. Statin therapy improved lag times, but has no effect on sICAM-1 or sVCAM-1 levels.     

Circulating soluble adhesion molecules ICAM-1 and VCAM-1 and their association with clinical outcome, troponin T and C-reactive protein in patients with acute coronary syndromes

OBJECTIVES: The aim of this study was to compare concentrations of soluble intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) in patients with coronary artery disease and healthy control and to evaluate the usefulness of the inflammatory markers as predictors of adverse prognosis in patients with acute coronary syndromes (ACS). DESIGN AND METHODS: ELISA was used to measure sICAM-1 and sVCAM-1 levels in 75 patients with ACS, 36 patients with stable angina pectoris (SAP) and 25 healthy subjects. hsCRP was measured with immunoturbidimetric assay, cardiac troponin T-with electrochemiluminescence immunoassay. RESULTS: All soluble ICAM-1 and VCAM-1 significantly discriminated between patients with ACS and SAP (p=0.014 and 0.05, respectively) and control subjects (p<0.001 and 0.05). During the 6-month follow-up of the patients with ACS, there were 28 major cardiac events (37.3%). The odds ratio associated with the highest value of sVCAM-1 was 4.62 (95% CI 1.8-11.4, p=0.0009) without adjustment and remained significantly elevated after adjustment for cTnT (RR 3.93, 1.5-10, p=0.04) and hsCRP (RR 2.22, 0.8-5.7, p=0.05). In contrast, an elevated level of sICAM-1 was not associated with future coronary risk after adjustment for cTnT and hsCRP. CONCLUSIONS: In patients with acute coronary syndromes, VCAM-1 serum levels powerfully predict an increased risk for subsequent cardiovascular events and extend the prognostic information gained from traditional biochemical markers.     

Intercellular adhesion molecule 1 (ICAM-1) gene variant is associated with coronary artery calcification independent of soluble ICAM-1 levels.

BACKGROUND: Although circulating levels of soluble intercellular adhesion molecule 1 (sICAM-1) predict cardiovascular events, no studies have examined intercellular adhesion molecule 1 (ICAM-1) gene variants, plasma sICAM-1 levels, and atherosclerosis in the same sample. METHODS: We examined the association of the ICAM-1 K469E gene variant and plasma sICAM-1 with coronary artery calcification (CAC) in 632 asymptomatic subjects, recruited on the basis of a family history of premature cardiovascular disease. RESULTS: In age-adjusted ordinal regression, sICAM-1 levels were associated with CAC (odds ratio [OR] [95% confidence interval (CI)] 1.30 [1.04-1.6] per 100 ng/dL sICAM-1; p = .02), but this association was lost after adjusting for traditional risk factors (OR [95% CI] 0.9 [0.69-1.16]). In men, but not women (interaction p = .018), the ICAM-1 K469E GG genotype predicted lower CAC after adjusting for traditional risk factors (OR [95% CI] 0.33 [0.17-0.61]; p = .001) and further controlling for plasma sICAM-1 (OR [95% CI] 0.27 [0.14-0.52]; p < .001). CONCLUSIONS: In a study sample specifically selected for the characteristic of a family history of premature coronary heart disease, ICAM K469E GG was associated with lower CAC scores in men but not women even after controlling for plasma levels of sICAM-1. These studies suggest that ICAM-1 variants may modulate atherosclerosis in humans and provide support for the concept that inflammatory gene polymorphisms may influence atherosclerosis independent of plasma levels of their gene products.     

Adhesion molecules in untreated inflammatory arthritis: synovial expression and levels in synovial fluid and serum [corrected] [published erratum appears in QJM 1996 Jul;89(7):559]

Adhesion molecules play a critical role in regulating leucocyte migration at sites of inflammation. The relationship of soluble forms in serum or synovial fluid (SF) to synovial membrane expression in inflammatory arthritis is controversial. We examined soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin levels in matched serum and SF, and their relationship to expression in synovium obtained at the same time in 13 patients with previously untreated inflammatory arthritis. Serum- soluble (s)ICAM-1 correlated with sedimentation rate (T = 0.45), Ritchie articular index (T = 0.47) and SF sICAM-1 (T = 0.48), and SF sICAM-1 correlated with membrane ICAM-1 expression (p < 0.02). sE- selectin and sVCAM-1 levels were unrelated to disease activity or membrane expression. Membrane E-selectin expression correlated inversely with ICAM-1 expression (T = -0.57) and serum sICAM-1 (T = - 0.54). Serum sE-selectin correlated inversely with membrane ICAM-1 expression (T = -0.55). The correlations observed between ICAM-1 in serum, SF, synovium and disease activity suggest that ICAM-1 could be a useful target for immunotherapy. The inverse relationship of ICAM-1 and E-selectin suggest important differences in regulation and pathogenetic roles.      

Effect of nicotine replacement and quitting smoking on circulating adhesion molecule profiles (sICAM-1, sCD44v5, sCD44v6)

BACKGROUND: Soluble ICAM-1 (sICAM-1; sCD54), sCD44v5 and sCD44v6 are circulating adhesion molecules, with immunomodulatory potential, that have been frequently attributed diagnostic, prognostic and aetiological significance in a number of inflammatory and malignant diseases. We have previously shown that systemic concentrations of these molecules are increased significantly in tobacco smokers, but reduce to within normal levels at 12 months following successful quitting. MATERIALS AND METHODS: We have been able to extend these observations by measuring levels before and 4, 8, 22 and 52 weeks after smoking cessation in subjects receiving high-dose nicotine replacement therapy (25 mg of nicotine; n = 34) or placebo patches (n = 34) for 26 weeks. Smoking cessation was confirmed by regular measurement of expired-air CO levels and by plasma cotinine analysis. RESULTS: Plasma sICAM-1, sCD44v5 and sCD44v6 concentrations all declined rapidly within 4 weeks of smoking cessation (P < 0.001 for all declines). Additionally, no differences were observed between those using nicotine replacement and those who were not for sICAM-1, sCD44v5, or sCD44v6. CONCLUSIONS: The recovery in smoking-associated adhesion molecule profiles represents an almost immediate beneficial effect of smoking cessation. Nicotine replacement therapy is an effective aid to quitting and does not affect these recoveries. The elevated levels of these important risk factors in smokers (sICAM-1, sCD44v5 and sCD44v6) are linked to noxious element(s) in tobacco smoke other than nicotine or nicotine metabolites.     

Decreased endogenous secretory advanced glycation end product receptor in type 1 diabetic patients: its possible association with diabetic vascular complications

OBJECTIVE: The binding of advanced glycation end products (AGEs) to their receptor (RAGE) plays an important role in the development of diabetic vascular complications. In the present study, we examined circulating endogenous secretory RAGE (esRAGE) levels in subjects with type 1 diabetes and explored the possible association between esRAGE levels and the severity of diabetic vascular complications. RESEARCH DESIGN AND METHODS: Circulating esRAGE levels in serum were examined in 67 Japanese type 1 diabetic patients (22 men and 45 women, age 24.0 +/- 4.4 years [means +/- SD]) and 23 age-matched healthy nondiabetic subjects (10 men and 13 women aged 24.9 +/- 1.4 years). Daily urinary albumin excretion, the presence of retinopathy, and intima-media thickness (IMT) of the carotid artery were also evaluated. We further explored the association between esRAGE levels and severity of diabetic vascular complications. RESULTS: Circulating esRAGE levels were significantly lower in subjects with type 1 diabetes than in nondiabetic subjects (0.266 +/- 0.089 vs. 0.436 +/- 0.121 ng/ml, respectively, P < 0.0001) and was inversely correlated with HbA(1c) (A1C) levels (r = -0.614, P < 0.0001). In addition, multivariate regression analysis demonstrated that A1C was an independent risk factor for a low esRAGE value. Furthermore, circulating esRAGE levels were inversely correlated with carotid IMT (r = -0.325, P = 0.0017) and was one of the independent risk factors for IMT thickening. Furthermore, there was a significant difference (P = 0.0124) in esRAGE levels between patients without retinopathy (0.286 +/- 0.092 ng/ml) and those with retinopathy (0.230 +/- 0.074 ng/ml). CONCLUSIONS: Circulating esRAGE levels were significantly lower in type 1 diabetic patients than in nondiabetic subjects and were inversely associated with the severity of some diabetic vascular complications.     

High redox thioredoxin but low thioredoxin reductase activities in the serum of patients with rheumatoid arthritis

BACKGROUND: Thioredoxin (Trx)/thioredoxin reductase (TrxR) is a redox-active system induced by oxidative stress. We investigated its status as a function of RA disease activity. METHODS: 64 consecutive RA patients and 27 healthy subjects were enrolled in the study. Serum Trx protein levels were evaluated using an immunoassay and immunoblot, while redox Trx and TrxR activities and oxidative stress markers (carbonyl groups, thiols), were determined using spectrophotometric methods. RESULTS: Redox Trx activity and Trx protein concentrations were significantly higher in RA patients than in controls (redox Trx activity: 37.7+/-22.6 versus 21.1+/-7.9 ng/mL, p<0.01; Trx protein: 25.5+/-12.0 versus 12.3+/-5.1 ng/mL, p<0.0001). Redox Trx activity correlated with the DAS score (r=0.45, p=0.004) and with the tender joint count (r=0.49, p=0.002) whereas there was no correlation with Trx protein concentrations. Immunoblot analysis showed that circulating Trx was partially aggregated. TrxR activity was lower in the serum of RA patients than in healthy subjects (197+/-70 versus 263+/-56 U/L, p=0.002). TrxR activity was correlated with the DAS score (r=0.53, p<0.001) and with the tender joint count (r=0.36, p<0.01). There were no correlations between oxidative stress marker levels and redox Trx activity, Trx protein concentrations or TrxR activity. CONCLUSION: Redox Trx and TrxR activities correlated with the disease activity of RA patients consistent with the hypothesis that Trx/TrxR activities may contribute to disease activity in RA.     

Contribution of insulin resistance to reduced antioxidant enzymes and vitamins in nonobese Korean children

BACKGROUND: The prevalence of insulin resistance has been reported in nonobese, nondiabetic healthy individuals. We examined the relationship between insulin resistance and the reduced antioxidant systems of plasma lipid soluble vitamins and antioxidant enzymes in erythrocytes and to determine the contributing factors to the antioxidant systems in nonobese children. METHODS: We measured blood lipid profiles, glucose, insulin concentrations, plasma antioxidant vitamins and erythrocytic antioxidant enzyme activities of 103 Korean children in the absence of obesity. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: A significant inverse relationships between HOMA-IR and lipid corrected beta-carotene (r=-0.233, p<0.05), alpha-tocopherol (r=-0.370, p<0.0001) were observed. In addition, increased HOMA-IR was significantly related to the decreased activities of superoxide dismutase (r=-0.226, p<0.05) and catalase (r=-0.261, p<0.05). Stepwise multiple linear regression analyses showed that HOMA-IR was the independent factor to determine the antioxidant status such as plasma alpha-tocopherol (beta=-0.379, p<0.0001), beta-carotene (beta=-0.243, p<0.05), SOD (beta=-0.230, p<0.05), and catalase activity (beta=-0.255, p<0.05) after adjusting percent ideal body weight, waist circumference, gender, blood lipids and leptin levels in nonobese children. CONCLUSION: The reduced antioxidant status in insulin resistance state even in nonobese children suggests the importance of early nutritional intervention with features of insulin resistance.     

Elevation of serum cerebral injury markers correlates with serum choline decline after coronary artery bypass grafting surgery.

The aims of this study were to determine circulating choline status and its relationship to circulating levels of S-100beta protein and neuron-specific enolase, biochemical markers of cerebral injury and cognitive decline, after coronary artery bypass grafting (CABG) surgery. Preoperatively, patients scheduled for off-pump or on-pump CABG surgery had serum concentrations of 12.0+/-0.2 and 11.7+/-0.4 micromol/L free choline and 2640+/-65 and 2675+/-115 micromol/L phospholipid-bound choline, respectively. Serum free and bound choline levels decreased by 22-37% or 34-47% and 16-36% or 31-38% at 48 h after off-pump or on-pump surgery, respectively. Serum S-100beta and neuron-specific enolase increased from preoperative values of 0.083+/-0.009 and 6.3+/-0.2 microg/L to 0.405+/-0.022 and 11.4+/-0.8 microg/L, respectively, at 0 h postoperatively and remained elevated for 48 h after off-pump surgery. Serum free and bound choline concentrations were inversely correlated with the concentrations of S-100beta (r=-0.798; p<0.001 and r=-0.734; p<0.001) and neuron-specific enolase (r=-0.840; p<0.001 and r=-0.728; p<0.001). In conclusion, CABG surgery induces a decline in serum free and phospholipid-bound choline concentrations. The decreased serum choline concentrations were inversely correlated with the elevated levels of circulating cerebral injury markers. Thus, a decline in circulating choline may be involved in postoperative cognitive decline.     

Circulating intercellular adhesion molecule-1 in chronic hepatitis C patients with normal or elevated aminotransferase before and after alpha-interferon treatment

OBJECTIVES: Intercellular adhesion molecule-1 (ICAM-1) plays a fundamental role during liver inflammation. In fact, weak ICAM-1 expression is physiologically restricted to the endothelium of portal vessels and to sinusoidal lining cells, but it becomes markedly evident on sinusoidal lining cells and at the surface of hepatocytes during inflammatory liver diseases. The aim of this study was to evaluate the behaviour of soluble ICAM-1 (sICAM-1) in chronic hepatitis C (CH-C) patients with persistently normal aminotransferase in comparison with patients with CH-C and elevated aminotransferase, and its changes during alpha-interferon (IFN) therapy. Immunohistochemical localization of ICAM-1 was also performed on liver tissue specimens of both groups. METHODS: Sixty subjects were divided into 3 groups: group A included 19 patients with CH-C and persistently normal aminotransferase; group B included 21 patients with CH-C and persistently elevated aminotransferase levels, and group C included 20 healthy subjects representing the control group. The first two groups were treated with recombinant alpha-IFN 2b at a dose of 6 MU 3 times a week for 3 months and followed up with 3 MU 3 times a week for another 3 months. RESULTS: Baseline values of serum ICAM-1 in groups A and B were significantly higher than those in group C (p < 0.0001). The median baseline value of sICAM-1 in group A (525.0 ng/ml) was lower than that of group B (561.0 ng/ml), but the difference was not statistically significant. Furthermore, there was a trend toward higher ICAM-1 values as histological severity increased (Mantel-Haenszel chi(2) 8.8, p < 0.003). Post-treatment sICAM-1 serum values showed a marked decrease in both groups, but only among responder patients, while ICAM-1 levels were unchanged in non-responders. Immunohistochemical localization showed no staining for ICAM-1 in normal liver specimens, while there was a quite similar staining for ICAM-1 in the two groups of patients, consistent with an inflammatory process. CONCLUSIONS: This study shows that circulating ICAM-1 levels in most patients with CH-C and persistently normal aminotransferase are higher than those in a control group and the fact that ICAM-1 molecules are also expressed on the hepatocyte membrane suggests that they could play an important role, in association with other molecules, in the intercellular adhesion processes during the induction and maintenance phases of the immune response. In both groups, only patients responding to alpha-IFN therapy showed a marked decrease in serum ICAM-1 below baseline values.     

鼻内应用肾上腺皮质激素治疗鼻息肉后ICAM-1及sICAM-1的表达及意义

目的:检测鼻内应用肾上腺皮质激素(激素)治疗鼻息肉前后鼻息肉组织中的细胞间黏附分子-1(intercellular adhesion molecule-1,ICAM-1)和鼻分泌物中的可溶性细胞间黏附分子-1(soluble intercellular adhesion molecule-1,sICAM-1)表达水平的变化,探讨ICAM-1、sICAM-1两者间关系及其在鼻息肉发展过程中的作用及鼻内应用激素治疗鼻息肉的可能机制.方法:选择19例未用药的鼻息肉患者(未用药组)、14例经鼻内应用激素(氟替卡松)治疗后的鼻息肉患者(激素治疗组)、12名正常人(正常对照组),取其鼻息肉或鼻黏膜组织及鼻分泌物,用ELISA法检测其鼻息肉或鼻黏膜组织匀浆中ICAM-1和鼻分泌物中sICAM-1的含量并作比较.结果:未用药组鼻息肉组织匀浆中ICAM-1的含量及鼻分泌物中sICAM-1的含量,较激素治疗组及正常对照组为高(均为P＜0.01),而激素治疗组与正常对照组鼻黏膜组织匀浆中ICAM-1的含量和鼻分泌物中sICAM-1的含量比较差异无统计学意义(P＞0.05).未用药组鼻息肉组织匀浆中ICAM-1及鼻分泌物sICAM-1含量呈线性相关(r=0.843,P=0.000).结论:鼻内应用激素的治疗效果可能与其抑制ICAM-1的表达有关.在未受药物干扰的情况下,鼻分泌物中 sICAM-1的含量也能很好的反映鼻息肉组织中ICAM-1的表达情况.     

Effects of repeated infliximab therapy on serum lipid profile in patients with refractory rheumatoid arthritis

BACKGROUND: Patients with rheumatoid arthritis (RA) frequently display an atherogenic lipid profile which has been linked with inflammation. Tumor necrosis factor-alpha (TNF-alpha), a pivotal pro-inflammatory cytokine in RA may be involved in the development of the disturbed lipid metabolism. We investigated whether infliximab, an anti-TNF-alpha therapy, may modify the lipid profile. METHODS: 56 consecutive RA patients were treated with infliximab (3 mg/kg at weeks 0, 2, 6, 14, 22, 30). Lipid profile and CRP were assayed at baseline and before infusion at weeks 6 and 30. Baseline values were compared with those in 56 healthy volunteers. RESULTS: At baseline, the concentrations of HDL-cholesterol were lower in RA patients than in the controls (1.3+/-0.4 vs. 1.5+/-0.2 mmol/L; p<0.01). The triglyceride concentrations (1.6+/-0.8 vs. 1.3+/-0.4 mmol/L, p<0.01), the ratio of total cholesterol/HDL-cholesterol (4.3+/-1.6 vs. 3.2+/-0.5, p<0.001) and LDL-cholesterol/HDL-cholesterol (2.6+/-1.2 vs. 1.7+/-0.5, p<0.001) were significantly higher in RA patients than in controls. After 6 weeks of infliximab therapy, the mean total cholesterol concentration increased by 25% (p<0.001), LDL-cholesterol by 24% (p<0.001) and HDL-cholesterol by 30% (p<0.001). The decrease in CRP levels to 30 week inversely correlated with the increase in HDL-cholesterol (r=-0.47, p=0.005). CONCLUSIONS: Infliximab administration is associated with important increases in cholesterol levels in all its forms but as no significant beneficial effect on the atherogenic ratio.     

Soluble adhesion molecules in acute ischemic stroke

BACKGROUND: Inflammatory adhesion molecules play a key role in the development of ischemic lesions. Elevated plasma concentrations of soluble adhesion molecules are reported in stroke patients, but data are still controversial. Our aim was to explore the potential association of plasma levels of soluble (s) intercellular and vascular cellular adhesion molecules-1 (sICAM-1 and sVCAM-1), sE-selectin and sL-selectin with acute ischemic stroke. METHODS: At our university hospital in Zagreb, Croatia, we prospectively enrolled 67 subjects with acute ischemic stroke, as well as 76 consecutive healthy individuals as controls who were visiting the centre for reasons unrelated to stroke. Serum concentrations of the molecules of interest were determined by means of quantitative sandwich enzyme immunoassay. RESULTS: Mean levels of sICAM-1 (p < 0.001), sVCAM-1 (p < 0.034) and sE-selectin (p < 0.002) were higher in patients than in controls, whereas sL-selectin was lower in patients (p = 0.043). In patients, levels of soluble adhesion molecules were independent of age and sex except for sL-selectin, which was inversely correlated with age (r = -0.260, p = 0.034) and higher in women (p = 0.006) and diabetics (n = 14; p = 0.004). Serum levels did not differ significantly with respect to carotid atherosclerotic disease, smoking status, hypertension or hypercholesterolemia. As well as correlating with each other, concentrations of soluble adhesion molecules in patients correlated with traditional biochemical markers of inflammation: total leukocyte count, erythrocyte sedimentation rate (ESR) and C-reactive protein level. Concentrations of sICAM-1 and high-density lipoprotein-cholesterol and ESR were identified as significant independent predictors/indicators of acute ischemic stroke. CONCLUSIONS: Acute ischemic stroke is associated with elevated plasma levels of sICAM-1, sVCAM-1 and sE-selectin, independent of age, sex and other recognized risk factors for stroke. Decreased levels of sL-selectin are associated with acute stroke. The observed changes in serum concentrations of adhesion molecules indicate inflammatory process occurring during acute cerebral ischemia.     

The circulating levels of cardiac natriuretic hormones in healthy adults: effects of age and sex.

In order to study the relationships between sex hormones, aging, and circulating levels of cardiac natriuretic peptides and to define reference values for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) assays, we measured the plasma levels of cardiac natriuretic peptides in a large group of healthy adults divided according to age and sex. We studied 216 healthy subjects of both sexes (109 men and 107 women) with age ranging from 20 to 77 years (mean 43.2+/-14.8 years). All subjects were non-obese and had normal arterial blood pressure; they were free from acute diseases, including asymptomatic heart disease. Highly sensitive and specific IRMA methods were used to measure plasma ANP and BNP. The mean ANP value in healthy adult subjects of both sexes was 17.8+/-10.9 pg/ml with no significant difference between men (16.7+/-10.0 pg/ml) and women (18.8+/-11.7 pg/ml). The mean BNP value in healthy adult subjects of both sexes was 9.9+/-9.0 pg/ml with a significant difference (p<0.0001) between men (7.7+/-7.1 pg/ml) and women (12.2+/-10.2 pg/ml). There was a weak linear relationship between age and either ANP (r=0.350, p<0.0001) or BNP (r=0.254, p=0.0002) values. When the circulating levels of cardiac natriuretic hormones, and age and sex were analyzed by multiple stepwise regression analysis, both age and sex significantly and independently contributed to the regression. Our study indicates independent positive effects of aging and female sex hormones on ANP and BNP levels in healthy adult subjects. These effects should be taken into account in the calculation of appropriate reference values for cardiac natriuretic hormones.     

Serum protein oxidation in patients with rheumatoid arthritis and effects of infliximab therapy

OBJECTIVE: To examine protein oxidation in rheumatoid arthritis (RA) and evaluate its evolution after infliximab therapy in a subgroup of patients. METHODS: Seventy-one consecutive patients with RA were included. Among them, 30 patients refractory to conventional therapy were treated with infliximab. Serum markers of oxidative stress were determined at baseline and before the infusions of infliximab at weeks 6 and 30. Baseline values were compared with those in 30 healthy volunteers. RESULTS: Mean levels of serum carbonyl groups were significantly higher in RA patients than in controls (1.29+/-0.76 versus 0.58+/-0.39 nmol/mg of protein, p<0.0001), whereas thiol levels were found to be lower (238.3+/-61.6 versus 316.5+/-54.8 micromol/L, p<0.0001). Thiol levels inversely correlated with the disease activity score (r=-0.42, p=0.004), and with CRP values (r=-0.45, p=0.001). Immunoblots showed that albumin and heavy chain immunoglobulin were oxidized more markedly than in healthy volunteers. Significantly lower levels of thiol groups were detected in patients with refractory RA disease (208.9+/-66.8 versus 264.2+/-43.0 micromol/L, p<0.0004) but concentrations of carbonyl groups were similar. Short-term treatment with infliximab significantly decreased carbonyl groups (0.97+/-0.47 nmol/mg protein, p=0.02) and increased thiol (231.2+/-48.7 micromol/L, p=0.02) levels. CONCLUSION: Our results highlight free radical protein damage in RA and a link with inflammation, as underlined by the beneficial effects of infliximab.     

Fat distribution and endothelial function in normal-overweight menopausal women

BACKGROUND: Adipose tissue is not an inert deposit of fat; in the truncal area, it seems to be metabolically active, due to the adipokines produced locally. These substances are related to insulin resistance, inflammation and atherosclerotic damage to the vascular system. The development of ultrasound methodologies enable better estimation of fat distribution and more detailed investigation of the metabolic aspects of the fat depots and their impact on the initial stages of atherosclerosis. AIM OF THE STUDY: To investigate the influence of abdominal fat on endothelial function, the initial stages of atherosclerotic vascular damage and its relationship with inflammatory status in normal-overweight subjects [n. 162, body mass index (BMI) >25 kg/m(2) to <30 kg/m(2)]. METHODS: A total of 162 Caucasian postmenopausal women (mean age 54 +/- 4 years, menopausal age 8 +/- 4 years) were subdivided on the basis of the median value of the visceral fat distribution and associations with brachial flow-mediated vasoactivity (FMV), BMI, intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), total and LDL cholesterol investigated. RESULTS: Subjects with lower levels of visceral fat had a higher brachial FMV (7.9 +/- 4.3 vs. 5.1 +/- 3.2%, P < 0.05) and lower BMI, waist, sICAM-1, sVCAM-1, total and LDL cholesterol. In univariate analyses, abdominal visceral fat showed a direct correlation with sICAM-1 (r = 0.43, P < 0.001), and an inverse correlation with FMV (r = -0.49, P < 0.01). Moreover an indirect relationship emerged between brachial FMV and sICAM-levels (r = -0.36, P < 0.05). In a multivariate analysis the predictive variables for brachial FMV were LDL cholesterol (beta = -0.22, P < 0.05), visceral fat (beta = -0.32, P < 0.05), sICAM-1 (beta = -0.18, P < 0.05), HDL cholesterol (beta = 0.25, P < 0.05) and brachial diameter (beta = -0.27, P < 0.05). Subcutaneous fat and triglycerides were also included in the model. CONCLUSIONS: In Caucasian normal-overweight women, visceral fat thickness was directly associated with the level of soluble ICAM-1 and inversely with FMV, thereby showing its relevance to endothelial function and the inflammatory state.     

Plasmatic antioxidant capacity due to ascorbate using TEMPO scavenging and electron spin resonance

BACKGROUND: Ascorbate is the most effective water-soluble antioxidant and its plasma concentration is usually measured by different methods including colorimetric assays, HPLC or capillary electrophoresis. Plasma antioxidant capacity is determined by indexes such as total reactive antioxidant potential, total antioxidant reactivity, oxygen radical absorbance capacity, etc. We developed an alternative method for the evaluation of the plasma antioxidant status due to ascorbate. METHODS: TEMPO kinetics scavenging analyzed by ESR spectroscopy was performed on plasma samples in different antioxidant situations. Plasma ascorbate concentrations were determined by capillary electrophoresis. Ascorbyl radical levels were measured by ESR. RESULTS: Plasma reactivity with TEMPO (PR-T) reflected plasma ascorbate levels. Average PR-T for normal plasmas resulted 85+/-27 micromol/l (n=43). PR-T during ascorbic acid intake (1 g/day) increased to an average value of 130+/-20 micromol/l (p<0.001, n=20). PR-T correlated with the plasmatic ascorbate levels determined by capillary electrophoresis (r=0.92), presenting as an advantage the avoiding of the deproteination step. Plasma ascorbyl radical levels increase from 16+/-2 to 24+/-3 nmol/l (p<0.005, n=14) after ascorbate intake. CONCLUSIONS: PR-T could be considered as a measure of the plasmatic antioxidant capacity due to the plasma ascorbate levels and could be useful to investigate different antioxidant situations.     

Metabolic syndrome aggravates the increased endothelial activation and low-grade inflammation in subjects with familial low HDL

BACKGROUND: Inhibition of cytokine-induced expression of adhesion molecules is one of the atheroprotective mechanisms of high-density lipoprotein (HDL). AIM: We investigated whether increased endothelial activation and low-grade inflammation are present in Finnish subjects with familial low HDL, and which factors contribute to the inflammatory parameters. METHOD: High-sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and sE-selectin were measured in 91 subjects with low HDL-cholesterol from 41 low-HDL families and in 112 normolipidemic controls with comparable age- and gender distribution. Presence of the features of the metabolic syndrome (MetS) was recorded. RESULTS: sVCAM-1, sICAM-1, sE-selectin, and hsCRP were significantly higher in low-HDL subjects than in the controls (sVCAM-1: 560+/-147 ng/mL versus 496+/-95 ng/mL, P = 0.001; sICAM-1: 247+/-60 ng/mL versus 215+/-47 ng/mL, P<0.001; sE-selectin: 52+/-20 ng/mL versus 44+/-16 ng/mL, P = 0.022; and hsCRP: 1.73+/-2.05 mg/L versus 0.85+/-1.10 mg/L, P<0.001). Low-HDL subjects had increased body mass index (BMI) and waist, and elevated insulin and triglyceride levels. Adhesion molecules and hsCRP increased according to the number of the features of the MetS. CONCLUSIONS: The presence of the MetS in subjects with familial low HDL-cholesterol aggravates the low-grade inflammation and endothelial activation, and ultimately may add to the higher susceptibility for atherosclerotic disease in these individuals.     

Soluble intracellular adhesion molecule-1 is associated with cardiovascular disease risk and mortality in older adults

BACKGROUND: Intracellular adhesion molecule-1 (ICAM-1) regulates leukocyte-endothelial attachment, a process crucial to atherosclerosis. Circulating soluble ICAM-1 (sICAM-1) may serve as a marker of cardiovascular disease (CVD) progression. OBJECTIVES: We examined the association of sICAM-1 with measures of subclinical CVD and risk of incident CVD events and death in older men and women (age > or = 65 years) from the Cardiovascular Health Study. METHODS: Selected participants were free of clinical CVD at baseline. Non-exclusive incident case groups were angina (n = 534), myocardial infarction (n = 304), stroke (n = 327), and death (n = 842; CVD death = 310). A total 643 subjects were free of events during follow-up. RESULTS: sICAM-1 was positively associated with C-reactive protein, interleukin-6 and fibrinogen and measures of subclinical CVD in these older men and women. In Cox regression models adjusted for age, gender, and race, increasing levels of sICAM-1 were associated with increased risk of all cause mortality in men and women. Hazard ratios (95% confidence intervals) for a one standard deviation increase in sICAM-1 (89.7 ng mL(-1)) were 1.3 (1.1-1.4) in men and 1.2 (1.1-1.3) in women. sICAM-1 was associated with increased risk of CVD death in women (1.2; 1.0-1.5), but not men (1.1; 0.9-1.3). There were no associations of sICAM-1 with non-fatal CVD events. CONCLUSIONS: While sICAM-1 was associated with death in older men and women, there was a more marked association between sICAM-1 and CVD death in women.     

Correlation between plasma total homocysteine and copper in patients with peripheral vascular disease

BACKGROUND: Increased concentrations of both plasma total homocysteine and copper are separately associated with cardiovascular disease. Correlations between plasma total homocysteine, trace elements, and vitamins in patients with peripheral vascular disease have not been investigated. METHODS: The concentrations of trace elements in plasma were determined by the multielement analytical technique of total-reflection x-ray fluorescence spectrometry. Plasma total homocysteine was determined by HPLC. RESULTS: In the univariate and multivariate regression analyses, copper was positively correlated with plasma total homocysteine in all subjects (coefficient +/- SE, 0.347 +/- 0.113; P = 0.0026 and coefficient +/- SE, 0.422 +/- 0.108; P = 0.0002, respectively), and in patients with peripheral vascular disease (coefficient +/- SE, 0.370 +/- 0.150; P = 0.016; and coefficient +/- SE, 0.490 +/- 0.151; P = 0.0025, respectively). Correlation between copper and plasma total homocysteine was not detected in healthy control subjects. The concentration of calcium in plasma (67.5 vs 80. 8 microg/g) was significantly lower in the patients than in the control subjects (P = 0.02). When the patients were divided into groups, the patients with suprainguinal lesions had significantly higher copper concentrations (P = 0.04) and significantly lower selenium and calcium concentrations (P = 0.01 and 0.008, respectively) than the healthy subjects. Patients had higher concentrations of autoantibodies against oxidized LDL and concentrations of thiobarbituric acid-reactive substance than the healthy subjects (P <0.0001 and P = 0.001, respectively). The concentrations of plasma total homocysteine and alpha-tocopherol were significantly higher, and the concentrations of vitamin B(6) and beta-carotene were lower in the patients than the healthy subjects. CONCLUSION: Our findings suggest that the atherogenicity of homocysteine may be related to copper-dependent interactions.