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Fatty acid profiles of various lipid fractions were determined in carefully selected insulin-dependent and non-insulin-dependent diabetics to assess relationships between serum fatty acid composition and type of diabetes. Clear-cut hypertriglyceridemia with slight hypercholesterolemia was found in both diabetic types. The decrease of lignoceric acid in sphingomyelin is the only alteration found in both types of diabetes. In the insulin-dependent diabetics, there were increases in levels of oleic acid and of alpha-linolenic acid in esterified cholesterol, and in levels of alpha-linolenic acid in the triglyceride fraction. In the non-insulin-dependent diabetics, there were increases in levels of oleic acid and total monounsaturated fatty acids in the triglyceride fraction and there was an increase in levels of saturated fatty acids and a decrease in levels of polyunsaturated acids in phosphatidylcholine; in sphingomyelin, dihomogamma-linoleic acid levels were enhanced. Arachidonic acid levels were normal in our patient population.

Patients infected with HIV are at increased risk of atherosclerosis, and have evidence of endothelium dysfunction. The hypothesis was tested that HIV-related endothelium dysfunction is related to loss of antioxidants. This was done by the supplementation of the antioxidants selenium and beta-carotene. We supplemented the diet of 10 HIV-seropositive subjects with 100 microg selenium daily, 11 subjects with 30 mg beta-carotene twice daily while 15 subjects were not supplemented. Plasma was obtained at outset and after a year, and tested by ELISA for endothelial cell, platelet and inflammatory markers. The non-supplemented patients experienced increases in von Willebrand factor and soluble thrombomodulin (both p0.01). There were no changes in any of the indices in the patients taking selenium or beta-carotene. Increased von Willebrand factor and soluble thrombomodulin in the non-supplemented patients imply increased damage to the endothelium over the year of the study. Therefore we interpret the lack of increase in the patients taking antioxidants as evidence of the protection of the endothelium by these agents.

We examined the relationship of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) with smoking and hypercholesterolaemia in peripheral artery disease (PAD). Serum samples were obtained from 119 patients with objectively-proven PAD, 39 patients with hypercholesterolaemia but asymptomatic for PAD, and 132 age and sex matched asymptomatic controls. Using ELISAs, we found increased sICAM-1 and sVCAM-1 (both p0.01) in the patients with PAD relative to the controls, but no significant change in patients with hypercholesterolaemia. However, the effect for sVCAM-1 was lost when smoking was entered as a covariate. Only sICAM-1 was higher in patients with PAD in the femoral/iliac arteries compared to the carotid arteries (p0.05). In a 39-month follow-up of 112 patients with PAD, increased ICAM-1 weakly (univariate p0.05) predicted those 57 whose disease progressed (i.e. to end points such as myocardial infarction and arterial surgery). However, high fibrinogen was a much better (univariate p = 0.001, multivariate p0.05) predictor of disease progression. We suggest (i) that increased levels of sVCAM-1 in atherosclerosis are due to smoking, (ii) that increased sICAM-1 is independent of this risk factor, (iii) that both these changes are independent of hypercholesterolaemia, and (iv) that increased sICAM-1 is a weak predictor of disease progression in peripheral atherosclerosis.

We investigated the possible role of antiphospholipid (APA) and anti-human 2-glycoprotein I (beta2-GPI) antibodies (Ab) in thrombosis and atherosclerosis in human immunodeficiency (HIV)-positive patients, in whom they seem to be more frequent.We measured APA and anti-beta2-GPI Ab in 58 HIV-positive patients together with markers of disease progression, circulating beta2-GPI, plasma lipids, biological markers of endothelial activation and integrity (plasma thrombomodulin, von Willebrand factor, vascular cell adhesion molecule 1) and with antimalonic dialdehyde antibodies (anti-MDA Ab).We found a 41% frequency of IgG APA in the HIV-positive patients. APA IgMs were rarely positive (7%), and anti-beta2-GPI IgGs were positive in 3-4% patients. There was no correlation between APA or anti-beta2-GPI Ab and the presence of opportunistic infections. Although plasma thrombomodulin, von Willebrand factor and vascular cell adhesion molecule 1 were significantly increased in the HIV-positive patients, APA was correlated only with vascular cell adhesion molecule 1, suggesting that APAs are correlated with endothelial activation but not with vascular endothelial lesions. A correlation between APA and anti-MDA IgG was demonstrated using multivariate analysis (r=0.542, P0.0001), suggesting a relationship between the targets of these antibodies. Finally, IgG APAs are frequent in HIV infection but are not correlated with biological markers of endothelial injury.Our results do not support a role for APA or anti-beta2-GPI in HIV-associated silent vascular endothelial damage. However, the role of these autoantibodies in clinically relevant thrombotic events should be investigated in HIV-positive patients.

Changes in endothelial cell activity are likely to play a role in the thrombotic complications of bone marrow transplantation (BMT) such as the development of veno-occlusive disease. Accordingly, we measured established plasma endothelial cell markers von Willebrand factor (vWf), soluble thrombomodulin (sTM), soluble ICAM-1 (sICAM-1), and possible inducers of these molecules, TNF alpha and elastase, in the plasma of 25 patients, 1 week before as well as 1 and 3 weeks after BMT. Compared to healthy age and sex-matched controls, patients exhibited increased vWf and sTM. One week after transplantation, there were significant increases in vWf and sICAM-1, with a significant fall in elastases. Three weeks after the transplantation, sICAM-1 and, to a lesser extent, vWf increased still further, whereas elastases were unchanged. There were no significant changes in sTM and in TNF alpha through the serial study. Our data suggest that before conditioning, vascular endothelium is damaged by both injury and activation, as seen by the variations of vWf and sTM. After transplantation, the enhancement of this damage seems to be more specifically related to activation, since we observed a strong subsequent increase in vWf and markedly in sICAM-1.

Circulating levels of the adhesion molecule P-selectin (CD62P) are increased in the plasma of patients with atherosclerosis, but its relationship to the anatomical location of symptomatic disease or extent of symptomatic disease is unknown. The influence of the risk factors for atherosclerosis on soluble P-selectin is also unclear. To clarify these questions we analysed plasma samples from 170 patients with symptomatic peripheral vascular disease and 119 asymptomatic controls who were, as a group, age- and sex-matched. Soluble P-selectin (ELISA) was increased in 83 patients with symptomatic disease of the iliac and/or femoral arteries alone (P0.05, ANOVA) but not in 37 patients with symptomatic carotid artery disease alone compared with controls. Soluble P-selectin was equally raised in 120 patients with disease at one arterial site and in 50 patients with disease at two or more arterial sites (both P0.05) compared with controls. Smoking and atherosclerosis were both independent predictors of raised soluble P-selectin. We conclude that increased soluble P-selectin may have value as a marker of peripheral vascular disease of the iliac and/or femoral arteries in group comparisons only, as the poor discrimination and wide variation of data make comparisons at the individual level difficult.

Objectives:To test the hypothesis that endothelial cell damage and hypoxia are related to the activity of neutrophil elastase in patients with peripheral atherosclerosis.Design:A cross-sectional serological study in a tertiary referral, University Hospital.Materials:Venous blood was obtained from 22 patients with peripheral vascular disease and an equal number of age and sex matched controls.Methods:Neutrophil elastase and two markers of endothelial cell damage (von Willebrand factor and soluble thrombomodulin) were measured in plasma by ELISA. Hypoxia was measured by percutaneous oxygen (by oximeter) at the dorsum of the foot.Results:Patients had higher von Willebrand factor, higher soluble thrombomodulin and higher elastase but lower percutaneous oxygen (all p < 0.001). In the patient's group, there were significant inverse correlates between von Willebrand factor and percutaneous oxygen (p = 0.004) and between soluble thrombomodulin and percutaneous oxygen (p = 0.011) while elastase correlated positively with soluble thrombomodulin (p = 0.023).Conclusions:Our data support the hypothesis that release of elastase from activated neutrophils relates to endothelial cell damage. This may contribute to hypoxia and may result in the deterioration in clinically assessed atherosclerosis.

In 34 patients with peripheral occlusive arterial disease, circulating levels of endothelial cell markers were compared with the ischemic status. Unlike tissue plasminogen activator and plasminogen activator inhibitor, plasma levels of thrombomodulin were closely related to both transcutaneous oxygen pressure (p = 0.01) and the graded clinical stages of disease (p = 0.02). Levels of von Willebrand factor were correlated only with the transcutaneous oxygen pressure (p = 0.04). Since thrombomodulin and von Willebrand factor constitute markers of endothelial cell damage, the extent of endothelial injury would appear to be determined by the ischemic status.

Thrombomodulin (TM) is a very efficient natural anti-thrombin glycoprotein expressed on the endothelial cell surface. Circulating soluble thrombomodulin is also detected by enzyme immunoassay in plasma and represents some fragments of membrane TM with various molecular weight. Plasma TM (TMp) levels are elevated in diseases associated with endothelium damage. We have explored TMp in patients with atheromatous disease and compared its level with others endothelial cell markers, particularly those who indicate cell activation, as tissue-type plasminogen activator (t-PA), inhibitor of plasminogen activator (PAI-1) and prostacyclin (PG12). Thirty seven patients with documented atheromatous artery disease were included in this study. They were not diabetics and their hepatic and renal functions were normal. Mean age was 71 +/- years. Routine serum parameters were checked out as well as others more specific for endothelium activation (TMp, PG12, PAI-1, t-PA) measured by enzyme immunoassay. Patients were classified according to three localizations of atheromatous involvement: - 15 patients with peripheral occlusive arteriopathy disease (POAD) - 6 with coronary artery disease (CAD); and 16 with polyvascular involvement (POLY). They were compared with 21 controls without any vascular lesions (mean age: 43 +/- 13 years). In controls TMp was 36 +/- 8 ng/ml without significant change according with age and sex. In patients whatever the localization of atheroma, TMp was found significantly higher: POAD = 51.3 +/- 19.7 ng/ml (p = 0.003); CAD = 49.2 +/- 15.4 ng/ml (p = 0.008); POLY = 49.6 +/- 17.2 ng/ml (p = 0.003). A positive correlation was pointed out in all patients between TMp and t-PA (p = 0.047), TMp and PG12 (p = 0.008). A positive correlation between TMp and t-PA (p = 0.034) was found only in the subgroup with POAD. In this study, there was no correlation between TMp and the following parameters: leucocytes, haemoglobin, cholesterol, HDL, LDL-cholesterol, Lp(a), fibrinogen.(ABSTRACT TRUNCATED AT 250 WORDS)