Synthesis of long-chain polyunsaturated fatty acids is inhibited in vivo in hypercholesterolemic rabbits and in vitro by oxysterols.

Plasma total lipids, total cholesterol (cholesterol esters and free cholesterol) and oxysterol (mainly 7 beta-hydroxycholesterol (7 beta OH)) concentrations were significantly elevated in New Zealand rabbits fed a 2% cholesterol-containing diet with respect to controls fed the same diet without cholesterol. In addition, linoleic (18:2 n-6) and alpha-linolenic acid (18:3 n-3) plasma concentrations were significantly elevated in hypercholesterolemic rabbits, while concentrations of long-chain n-6 and n-3 derivatives were reduced. Studies in monocytic cell line THP-1 revealed that 7 beta OH markedly inhibited the conversion of 18:2 to 20:4 n-6 and of 18:3 to 22:6 n-3, indicating depression of the desaturation steps; in particular the inhibition was greater for the Delta 5 desaturation step. Furthermore, experiments of Real-Time PCR showed that 5-10 microM 7 beta OH decreased the Delta 5 gene expression. In conclusion, atherogenic oxysterols interfere with the production of long-chain polyunsaturated fatty acids from their precursors both in hypercholesterolemic rabbits and in cultured cells.

Hyperhomocysteinemia in stable pediatric, adolescents, and young adult renal transplant recipients.

BACKGROUND: High total plasma homocysteine (tHcy) levels are accompanied by an increased risk for premature development of atherosclerosis and atherothrombosis. Adult renal transplant recipients have elevated tHcy levels. Corresponding data in pediatric, adolescent, and young adult renal transplant recipients are scarce. We investigated whether tHcy levels were elevated in stable renal transplant recipients who received kidney grafts before age 18. METHODS: This cross-sectional study was conducted during routine posttransplantation follow-up. Fasting tHcy levels, serum creatinine, and lipoprotein profile were measured in 38 clinically stable renal transplant recipients with different degrees of renal function. No patient was receiving B vitamin or folic acid supplementation. Estimated glomerular filtration rate (GFR) was assessed according to Schwartz's formula. All patients followed a triple-drug immunosuppressive regimen, with the exception of three patients (deflazacort and azathioprine). Forty-one apparently healthy subjects constituted the control group. tHcy levels were determined by fluorescence polarization immunoassay in an IMx analyzer. RESULTS: Mean tHcy levels in transplant recipients were significantly higher than in controls (16.8+/-8.7 micromol/L and 9.5+/-2.3 micromol/L, respectively; P<0.01). A significant positive correlation between tHcy and serum creatinine levels was observed for both transplant recipients (rS=0.70, P<0.01) and controls (rS=0.54, P<0.01). In transplant recipients, tHcy correlated negatively with estimated GFR (rS=[minus]0.47, P<0.05). Fasting tHcy levels in excess of 14.6 micromol/L (>95th percentile in controls) were present in 19 (50%) patients; 14 of these patients had an estimated GFR<60 ml/min per 1.73 m2. When the renal transplant recipients were analyzed by renal function, mean tHcy was significantly higher in patients with an estimated GFR<60 ml/min per 1.73 m2 compared with patients with an estimated GFR> or =60 ml/min per 1.73 m2 (20.5+/-9.9 vs. 13.2+/-5.8 micromol/L, P<0.01). Both groups were significantly different from controls (P<0.01). No relationship was found between tHcy level and either cumulative cyclosporine or cumulative methylprednisone doses. No differences were observed in tHcy levels or lipoprotein profile between patients who were receiving deflazacort and those on methylprednisone. CONCLUSIONS: Hyperhomocysteinemia in renal transplant recipients is a common condition. Testing for fasting tHcy level might be a useful tool to identify patients at increased risk for development of vascular disease.

Plasmatic homocysteine response to vitamin supplementation in elderly people.

Homocysteine (Hcy) increase is now widely accepted as a risk factor for vascular disease. The effects of folic acid (FA) and vitamins B12 and B6 in lowering Hcy have been extensively studied, but there is still little data on the response to FA dietary administration. Our purpose was to evaluate the impact of the diet and the degree of response to different doses of pharmacological FA supplementation. In a prospective, randomized, and simple blind study, 50 elderly subjects were given a 400-microg/day FA diet and were randomly assigned to one of the following treatments: Group I = placebo tablet; Group II = tablet containing 1-mg folic acid, 1-mg B12, and 25-mg B6; and Group III = tablet containing 2.5-mg folic acid and same B6 and B12 doses as Group II. Forty-four subjects completed the study, and their plasmas were evaluated. Hcy concentration significantly decreased even in patients with normal basal values, and there were no differences in the response between individuals receiving diet plus placebo and those receiving diet plus pharmacological supplementation. After the treatment, the mean decrease of plasmatic Hcy levels was 10.8 (9.4, 12.5) micromol/l, geometric mean [95% confidence interval (95% CI)], and particularly, the values for Group I were 10.6 (7.4, 14.8) micromol/l. In 31% of the subjects, the post-treatment Hcy levels were less than or = 5 micromol/l. These results show that a special diet, with or without pharmacological FA and B12 and B6 supplementation, significantly decreases the Hcy levels in elderly people. Therefore, a diet with high contents of FA might have an enormous impact on the morbidity and mortality of atherothrombosis.

Magnesium plus nifedipine: potentiation of hypotensive effect in preeclampsia?

Two women with preeclampsia treated unsuccessfully with alpha-methyldopa and magnesium sulfate became profoundly hypotensive when oral nifedipine was added. Blood pressure returned to previous levels without changes in fetal vitality. Awareness of this potentiation is important because nifedipine is being used increasingly in the treatment of pregnancy-related hypertension.