Perturbation of hyaluronan metabolism predisposes patients with type 1 diabetes mellitus to atherosclerosis.

AIMS/HYPOTHESIS: Cardiovascular disease contributes to mortality in type 1 diabetes mellitus, but the specific pathophysiological mechanisms remain to be established. We recently showed that the endothelial glycocalyx, a protective layer of proteoglycans covering the endothelium, is severely perturbed in type 1 diabetes, with concomitantly increased plasma levels of hyaluronan and hyaluronidase. In the present study, we evaluated the relationship between hyaluronan and hyaluronidase with carotid intima-media thickness (cIMT), an established surrogate marker for cardiovascular disease. SUBJECTS AND METHODS: Non-smoking type 1 diabetes patients without micro- or macrovascular complications and matched controls were recruited and cIMT of both carotid arteries was measured. To evaluate the relationship between cIMT and hyaluronan and hyaluronidase as well as other parameters, uni- or multivariate regression analyses were performed. RESULTS: We included 99 type 1 diabetes patients (age 10-72 years) and 99 age- and sex-matched controls. Mean cIMT, HbA(1c), high sensitivity C-reactive protein, hyaluronan and hyaluronidase were significantly increased in type 1 diabetes vs controls. Plasma hyaluronan and hyaluronidase were correlated in type 1 diabetes. In univariate regression analyses, mean IMT was associated with plasma hyaluronan, age and male sex, whereas after multivariate analysis only age and sex remained statistically significant. CONCLUSIONS/INTERPRETATION: We conclude that type 1 diabetes patients show structural changes of the arterial wall associated with increased hyaluronan metabolism. These data may lend further support to altered glycosaminoglycan metabolism in type 1 diabetes as a potential mechanism involved in accelerated atherogenesis.

No effect of folic acid on markers of endothelial dysfunction or inflammation in patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia.

BACKGROUND: Mild hyperhomocysteinaemia is a cardiovascular risk factor in patients with type 2 diabetes mellitus. Homocysteine may exert its detrimental effects through induction of endothelial dysfunction and/or chronic inflammation. In this study, we examined the effects of homocysteine-lowering therapy with folic acid on biochemical markers of endothelial dysfunction and low-grade inflammation in patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia (> or = 14 micromol/l). METHODS: In a randomised, double-blind, controlled trial, patients were treated with folic acid 5 mg or placebo for six months. At 0 and 6 months, albuminuria, von Willebrand factor, soluble cellular adhesion molecules, C-reactive protein, interleukin-6 and tumour necrosis factor-alpha were determined. RESULTS: Forty-one patients completed the study (folic acid 23, placebo 18). Baseline hyperhomocysteinaemia (median 17 micromol/l, range 14 to 30 micromol/l) was reduced by 29% in the folic-acid-treated group, and remained unchanged in patients receiving placebo. On average, folic acid treatment did not significantly affect any of the endothelial (e.g. von Willebrand factor: difference folic acid minus placebo +1%, confidence interval -3 to +16%) or inflammation (e.g. C-reactive protein: difference folic acid minus placebo +13%, confidence interval -42 to +52%) markers studied. Multiple regression analyses without and with adjustment for baseline differences in cardiovascular disease and ethnicity confirmed these results. An apparent beneficial effect of folic acid on albuminuria in crude analysis was attenuated by multiple adjustment (difference folic acid minus placebo -35%, confidence interval -178 to +32%, p=0.08, adjusted 0.26). CONCLUSION: The data indicate that, in this group of patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia, lowering homocysteine with folic acid for six months does not improve biochemical markers of endothelial dysfunction or low-grade inflammation.

Relationship between pernicious anaemia and gastric neuroendocrine cell disorders.

The incidence of gastric carcinoid tumours is increasing. This rise is probably due to the number of gastroscopies and improved histological techniques. The majority (65%) of these gastric tumours is associated with chronic atrophic gastritis and pernicious anaemia. In this article two patients are presented, one with pernicious anaemia and gastric neuroendocrine cell hyperplasia and one with pernicious anaemia and multiple gastric carcinoids. These neuroendocrine cell disorders have a relatively favourable prognosis. Therefore, a wait-and-see policy was preferred. The pathogenesis, clinical symptoms, diagnosis, prognosis and treatment of these different neuroendocrine cell manifestations are discussed. We recommend performing a gastroscopy at the time of diagnosis for young patients with pernicious anaemia, and whenever abdominal problems, unexplained weight loss or aggravation of the anaemia arise.

Risk factors for bleeding during treatment of acute venous thromboembolism.

OBJECTIVE: Identification of risk factors for bleeding and prospective evaluation of two bleeding risk scores in the treatment of acute venous thromboembolism. DESIGN: Secondary analysis of a prospective, randomized, assessorblind, multicenter clinical trial. SETTING: One university and 2 regional teaching hospitals. PATIENTS: 188 patients treated with heparin or danaparoid for acute venous thromboembolism. MEASUREMENTS: The presenting clinical features, the doses of the drugs, and the anticoagulant responses were analyzed using univariate and multivariate logistic regression analysis in order to evaluate prognostic factors for bleeding. In addition, the recently developed Utrecht bleeding risk score and Landefeld bleeding risk index were evaluated prospectively. RESULTS: Major bleeding occurred in 4 patients (2.1%) and minor bleeding in 101 patients (53.7%). For all (major and minor combined) bleeding, body surface area < or = 2 m2 (odds ratio 2.3, 95% CI 1.2-4.4; p = 0.01), and malignancy (odds ratio 2.4, 95% CI 1.1-4.9; p = 0.02) were confirmed to be independent risk factors. An increased treatment-related risk of bleeding was observed in patients treated with high doses of heparin, independent of the concomitant activated partial thromboplastin time ratios. Both bleeding risk scores had low diagnostic value for bleeding in this sample of mainly minor bleeders. CONCLUSIONS: A small body surface area and malignancy were associated with a higher frequency of bleeding. The bleeding risk scores merely offer the clinician a general estimation of the risk of bleeding. In patients with a small body surface area or in patients with malignancy, it may be of interest to study whether limited dose reduction of the anticoagulant drug may cause less bleeding without affecting efficacy.

Different postprandial metabolism of olive oil and soybean oil: a possible mechanism of the high-density lipoprotein conserving effect of olive oil.

The postprandial lipoprotein metabolism of two orally administered vitamin A-fat loads consisting of either 20% (wt:vol) soybean oil or 17% olive oil plus 3% soybean oil was studied in six normolipidemic young men according to a randomized crossover design. Mean (+/- SEM) retinyl palmitate concentrations (area under the 24-h curve) were higher in olive oil chylomicrons (97.3 +/- 5.5 mmol.L-1 x h-1), than in soybean-oil chylomicrons (84.0 +/- 10.5 mmol.L-1 x h-1; P < 0.02). Apolipoprotein B-48 concentrations were higher in the olive oil chylomicron remnants with densities (d) of 1.006-1.019 compared with soybean-oil remnants. The slower removal of olive oil chylomicron remnants was correlated to hepatic lipase activity (r = 0.84, P < 0.02). The initial HDL-cholesterol concentration (0.87 +/- 0.17 mmol/L--relatively low but within the normal range for young Dutch men) decreased significantly after ingestion of soybean oil to 0.66 +/- 0.10 mmol/L after 5 and 7 h, but no significant decrease was observed after olive oil ingestion. Soybean oil induced decreases in HDLs correlated inversely with hepatic lipase (r = -0.88, P < 0.02). The results suggested that competition between olive oil chylomicron remnants and HDL for hepatic lipase may have been the underlying mechanism that prevented the postprandial decrease in HDL cholesterol.

Different clearance of intravenously administered olive oil and soybean-oil emulsions: role of hepatic lipase.

The elimination of two intravenously administered fat emulsions consisting of either 20% (wt:vol) soybean oil or 17% olive oil plus 3% soybean oil was studied in six normolipidemic young men according to a randomized crossover protocol. Slower elimination was found with the olive oil emulsion. A significantly lower maximal removal capacity (K1) and fractional catabolic rate (K2) were measured with olive oil emulsion (P < 0.05). Removal of olive oil emulsion was inversely related to hepatic lipase activity (r = -0.85; P < 0.05). Removal of soybean-oil emulsion was related to the initial plasma triglyceride concentration (r = -0.84; P < 0.05) but not to lipolytic activity. In vivo apolipoprotein C-II binding was similar for both emulsions. Therefore, hepatic lipase activity is more important in the elimination of olive oil emulsions than soybean-oil emulsions. The faster elimination of soybean-oil emulsions suggests an additional elimination pathway, such as the reticuloendothelial system.