Nutraceutical approaches to homocysteine lowering in hypertensive subjects at low cardiovascular risk: a multicenter, randomized clinical trial.

Although the role of homocysteine (HCys) in secondary cardiovascular prevention has been scaled down, hyper-homocysteinemia remains a risk factor for cerebrovascular events. The aim of this study was to investigate the efficacy of nutraceuticals in lowering HCys serum levels versus a conventional vitamin supplementation in hypertensive subjects at low cardiovascular risk. One-hundred and four patients (mean age 62.8±14.5 years, 63.5% males), 52 for each treatment group, were enrolled. The study recruited patients with stage 1 essential hypertension and hyper-homocysteinemia (HCys ≥15 µmol/L), without a history of cardiovascular and cerebrovascular disease. They were sequentially randomized to receive a combined nutraceutical containing 400 µg folate-6-5-methyltetrahydrofolate, 3 mg vitamin B6, 5 µg vitamin B12, 2.4 mg vitamin B2, 12.5 mg zinc and 250 mg betaine (Normocis400®) once daily for two months, or supplementation with highly dosed folic acid (5 mg/day) (control group). Differences in serum HCys values were compared by ANOVA for repeated measures. A significant HCys reduction in comparison to baseline was found in both groups at the end of the study treatment, from 21.5±8.7 to 10.0±1.7 µmol/L for Normocis400® subjects (p less than 0.0001), and from 22.6±6.2 to 14.3±2.8 µmol/L for controls (p less than 0.0001). HCys reduction was significantly higher among patients treated with Normocis400® (p less than 0.035). The ideal HCys level (i.e. less than 10 µmol/L) was reached in 55.8% of cases in theNormocis400® group, and it was significantly higher than in controls. No side effects were observed in either treatment group. Randomized clinical trials are ongoing to test the effect of folate, B6, and B12 supplementation in primary prevention of cardiovascular and cerebrovascular events. In the meantime, especially when the ideal HCys level is far from being reached, Normocis400® appears to be safe, well tolerated and effective in reducing HCys levels.

Increased stimulation threshold in a patient with autoimmune disease: successful management with oral prednisolone and azathioprine.

We report a patient with a systemic vasculitis and heart involvement with complete atrio-ventricular block. After pacemaker implantation, the stimulation threshold significantly increased resulting in exit block. Two adjunctive ventricular leads were implanted with temporary threshold improvement. Oral glucocorticoids decreased the stimulation threshold with a transient, dose-dependent efficacy but with remarkable side effects. Azathioprine, an immunosuppressive agent, obtained a sustained decrease of the stimulation threshold.

Single amino acid mutations in transmembrane domain 5 confer to the plasma membrane Ca2+ pump properties typical of the Ca2+ pump of endo(sarco)plasmic reticulum.

Conserved residues in some of the transmembrane domains are proposed to mediate ion translocation by P-type pumps. The plasma membrane Ca(2+) pump (PMCA) lacks 2 of these residues in transmembrane domains (TM) 5 and 8. In particular, a glutamic acid (Glu-771) residue in TM5, which is proposed to be involved in the binding and transport of Ca(2+) by the sarcoplasmic reticulum Ca(2+) pump (SERCA), is replaced by an alanine (Ala-854) in the PMCA pump. Ala-854 has been mutated to Glu, Asp, or Gln; Glu-975 in TM8, which is an Ala in the SERCA pump, has been mutated to Gln, Asp, or Ala. The mutants have been expressed in three cell systems, with or without the help of viruses. When expressed in large amounts in Sf9 cells, the mutated pumps were isolated and analyzed in the purified state. Two of the three TM8 mutants were correctly delivered to the plasma membrane and were active. All the TM5 mutants were retained in the endoplasmic reticulum; two of them (A854Q and A854E) retained activity. Their properties (La(3+) sensitivity and decay of the phosphorylated intermediate, higher cooperativity of Ca(2+) binding with a Hill's coefficient approaching 2) differed from those of the expressed wild type PMCA pump, and resembled those of the SERCA pump.

Homocysteine and arterial occlusive disease: a concise review.

Many cross-sectional and prospective studies have shown that raised serum/plasma levels of total homocysteine increase the risk of coronary, cerebral, and peripheral artery disease. The risk associated with hyperhomocysteinemia appears to be concentration-dependent and not attributable to traditional risk factors. The odds ratio for ischemic heart disease has been estimated to be 1.4 for every 5 mumol/l increase of total plasma homocysteine. Median fasting total plasma homocysteine in adult males is approximately 10 mumol/l. Mild hyperhomocysteinemia is estimated to occur in 5-10% of the general population. Plasma concentrations are increased as a result of age, male gender, impaired renal function, low vitamin B intake, and genetically-determined defects of the enzymes involved in homocysteine metabolism. Folate supplements can reduce total homocysteine levels by approximately 25%. Studies in vitro and in vivo indicate that homocysteine can impair endothelial function. Despite increasing recognition of hyperhomocysteinemia as a risk factor for arterial occlusive disease, irrefutable proof that mild hyperhomocysteinemia contributes directly to the pathogenesis of atherothrombosis will come if interventions to lower total homocysteine reduce cardiovascular events. Family studies may also provide evidence of causality if genetic causes of hyperhomocysteinemia are found to segregate with disease.

Effects of caffeine on glucose tolerance: a placebo-controlled study.

OBJECTIVE: The investigation was performed to study the effects of 200 mg oral caffeine on glucose tolerance. DESIGN: Single-blind Latin square with active treatment (caffeine) and placebo. SETTING: The University of Padova, Department of Internal Medicine. SUBJECTS: 30 nonsmoking healthy subjects aged 26-32 years who abstained not only from coffee but also from tea, chocolate and cola for 4 weeks and who had given their informed consent. INTERVENTIONS: A 75 g oral glucose tolerance test (OGTT) was performed after giving caffeine or placebo (highly decaffeinated coffee). RESULTS: The glycaemic curve was normal in all subjects and was similar in the two groups until the second hour; in subjects taking caffeine a shift towards the right was detected at the 2nd, 3rd and 4th hours in comparison to those taking the placebo. Blood insulin levels were comparable after caffeine and after placebo along the entire OGTT. CONCLUSIONS: The data suggest that caffeine intake induces a rise in blood glucose levels that is insulin independent.

Hemodynamics following real and hypnosis-simulated phlebotomy.

Forearm arterial flow was measured in 22 healthy first-time blood donors during a 300-ml. blood letting and during the subsequent recovery. Blood pressure (BP) was also taken simultaneously and forearm peripheral resistance calculated. Following a transient BP and flow increase due to tachycardia related to needle insertion, both systolic BP and flow progressively and significantly decreased, while resistance increased. In a further 22 sex- and aged-matched highly hypnotizable subjects, blood donation was simulated by means of verbal hypnotic suggestions. The BP, flow and resistance curves were similar to those obtained with the real blood letting, without any between-subject difference or group/time interaction. Mere hypnosis without suggestion of phlebotomy and the simple bed resting did not produce any effect. These results indicate that the hemodynamic changes observed during and after a blood loss are partly due to mental involvement rather than merely to the hydraulic effects of the removal of blood.

Effect of two different therapeutic approaches on total and cardiovascular mortality in a Cardiovascular Study in the Elderly (CASTEL).

Although limited numbers of elderly subjects have occasionally been included in population-based studies, only a few studies have been conducted specifically on elderly hypertensives, and practically none at a population level. We studied 655 hypertensive subjects from a cohort of 2,254 elderly subjects. The intervention consisted of the creation of a Hypertension Outpatients' Clinic under our auspices but with complete co-operation from general practitioners, randomizing the identified hypertensive patients into pre-established therapeutic drug regimens, and early follow-up recording of mortality for 7 years. The drugs used were clonidine (n = 61), nifedipine (n = 146) and the fixed combination of atenolol+chlorthalidone (n = 144); 304 subjects underwent "free therapy" by their personal physicians without any special intervention. There were 1,404 normotensive subjects. Overall 7-year follow-up mortality was 34.9% in the hypertensive subjects receiving "free therapy", 22.5% in those receiving "special care", and 24.2% in the normotensives. Cardiovascular mortality was respectively 23.7%, 12.2%, and 12.0%. Overall and cardiovascular annual cumulative mortality were significantly lower in the << special therapy >> than in the << free therapy >> group. The fixed combination of atenolol and chlorthalidone reduced mortality below that of the normotensives, independent of other cardiovascular risk factors.

Uranyl-formol: a simple and reliable stain for routine electron microscope observation of ultrathin sections.

A new, highly stable uranium stain, which allows very simple, ultra rapid staining procedures for routine electron microscopy of ultrathin sections, is presented. The advantages of the new staining procedures, in comparison with the most conventional ones, employing lead citrate, are illustrated and discussed.