Genetic control of susceptibility to group A streptococcal infection in mice

The influence of genetic background on the ability to control infection with group A streptococci was investigated in different inbred strains of mice. Whereas BALB/c, C57BL/10, and DBA/2 mice were the most resistant strains, with lower bacteria loads and higher survival times, C3H/HeN and CBA/J mice exhibited substantially higher bacterial growth and 100% mortality. Differences in susceptibility were not dependent on the inoculum size. Resistance was influenced by sex, with males being much more susceptible than females. B cell- and T cell-deficient mice from the resistant background were as resistant to infection as were immunocompetent mice, which suggests that the effector mechanisms are independent of adaptive immunity. These results demonstrate for the first time the influence of genetic background and sex on susceptibility to infection with Streptococcus pyogenes in mice. The use of this mouse model of group A streptococcal infection will allow for a better definition of parameters involved in the outcome of the disease.     

Angiotensin and mineralocorticoid receptor antagonism attenuates cardiac oxidative stress in angiotensin II‐infused rats

Angiotensin II (Ang II) and aldosterone contribute to hypertension, oxidative stress and cardiovascular damage, but the contributions of aldosterone during Ang II‐dependent hypertension are not well defined because of the difficulty to assess each independently. To test the hypothesis that during Ang II infusion, oxidative and nitrosative damage is mediated through both the mineralocorticoid receptor (MR) and angiotensin type 1 receptor (AT1), five groups of Sprague–Dawley rats were studied: (i) control; (ii) Ang II infused (80 ng/min × 28 days); (iii) Ang II + AT1 receptor blocker (ARB; 10 mg losartan/kg per day × 21 days); (iv) Ang II + mineralocorticoid receptor (MR) antagonist (Epl; 100 mg eplerenone/day × 21 days); and (v) Ang II + ARB + Epl (Combo; × 21 days). Both ARB and combination treatments completely alleviated the Ang II‐induced hypertension, whereas eplerenone treatment only prolonged the onset of the hypertension. Eplerenone treatment exacerbated the Ang II‐mediated increase in plasma and heart aldosterone 2.3‐ and 1.8‐fold, respectively, while ARB treatment reduced both. Chronic MR blockade was sufficient to ameliorate the AT1‐mediated increase in oxidative damage. All treatments normalized protein oxidation (nitrotyrosine) levels; however, only ARB and Combo treatments completely reduced lipid peroxidation (4‐hydroxynonenal) to control levels. Collectively, these data suggest that receptor signalling, and not the elevated arterial blood pressure, is the principal culprit in the oxidative stress‐associated cardiovascular damage in Ang II‐dependent hypertension.     

Peripheral-type benzodiazepine receptors are highly concentrated in mitochondrial membranes of rat testicular interstitial cells

The binding of 3H-RO 5-4864 to the peripheral-type benzodiazepine receptors (PBZDR) in rat testicular interstitial cells (TIC) was characterized. The binding was saturable, reversible and showed a single high-affinity (Kd = 5.02 +/- 0.86 nM) class of binding sites. The maximal binding capacity (Bmax) in crude mitochondrial fractions (77.6 +/- 9.1 pmol/mg protein) represents the highest density of PBZDR in tissues thus far studied. In comparison with the crude mitochondrial fraction the subcellular fractionation of TIC revealed a 2-fold enrichment of 3H-RO 5-4864 binding sites to the purified mitochondria (Bmax = 140 +/- 23 pmol/mg protein). The ability of various drugs to displace 3H-RO 5-4864 from TIC binding sites was examined and the inhibition constants (Ki) for RO 5-4864, PK 11195, diazepam and flunitrazepam were 3.5, 4.4, 159, and 353 nM, respectively, whereas clonazepam and RO 15-1788 were inefficient in displacing 3H-RO 5-4864 (Ki greater than 10 microM). This pharmacological profile is characteristic of PBZDR described in other tissues. In conclusion, rat TIC possess a very high concentration of PBZDR primarily associated with mitochondrial membranes.     

Efficacy of folic acid when added to statin therapy in patients with hypercholesterolemia following acute myocardial infarction: a randomised pilot trial

BACKGROUND: Folic acid is assumed to have favourable effects on vascular endothelium, directly as well as indirectly through its effect on homocysteine metabolism. However, the clinical value of folic acid in secondary prevention after acute myocardial infarction (MI) has never been tested. Thus, a randomised, open-label, multicentre trial was performed in order to study the effect of folic acid 5 mg o.d. when added to statin therapy on the incidence of recurrent major clinical events up to 1 year post-MI. METHODS: A total of 283 patients with a total cholesterol >6.5 mmol/l (251 mg/dl) (mean 7.3 mmol/l) were included. All patients received 40 fluvastatin. In 140 of the 283 patients, folic acid (5 mg o.d.) was instituted at discharge, and the remaining 143 patients served as controls. Other secondary prevention measures for both groups were advocated. The primary endpoint was a composite consisting of all vascular events, including death, recurrent MI, strokes, and unplanned invasive coronary interventions. RESULTS: At baseline, the two groups were well-matched for all clinical and demographic parameters. After 1 year of treatment, no difference was noticed in the primary endpoint between the two groups. These endpoints occurred in 43 patients (31%) in the folic acid group, as opposed to 45 patients (31%) in the control group. All separate cardiovascular events were also equally distributed between both groups. Total cholesterol levels decreased to a similar extent in the two groups (to 5.5 and 5.7 mmol/l, in folic acid and control groups, respectively). CONCLUSIONS: In this medium-size pilot study, folic acid did not demonstrate any beneficial additive effects on cardiovascular mortality or morbidity in post-MI patients with hypercholesterolemia who were treated with statin therapy. Larger trials, possibly targeting at selected populations, must be awaited before definitive conclusions regarding the potentially favourable effects of folic acid supplementation in secondary prevention can be drawn.     

Influence of surgery on the natural history of rheumatic mitral and aortic valve disease

The rate of survival, the evolution of functional cardiac status and the incidence of major complications during a 5 year period were studied in 410 patients with rheumatic mitral or aortic valve disease, of whom 200 were treated medically and 210 by surgery. The 5 year survival rates in patients with various types of rheumatic mitral valve disease were similar (45 percent for those with mitral stenosis and 46 percent for those with mitral insufficiency or mixed mitral insufficiency and stenosis). The survival rate in patients with aortic valve disease was somewhat more favorable (64 percent).Mitral valvulotomy had the most positive influence on mortality. The 85 percent 5 year survival rate of patients who underwent this procedure was significantly higher than that of patients with medically treated mitral stenosis. In patients submitted to mitral and aortic valve replacement, the survival rate was also improved in comparison with data in the corresponding medically treated groups, but to a lesser degree (70 percent for aortic valve replacement and 60 percent for mitral valve replacement). In all surgically treated groups, initial operative mortality was the primary determinant of the rate of survival at the end of 5 years.Survivors of all surgical groups had appreciable improvement in cardiac functional classification and a remarkable reduction in the incidence of heart failure and atrial fibrillation. The incidence of infectious endocarditis was significantly reduced after mitral valvulotomy, as compared with the incidence in patients with medically treated mitral stenosis. Mitral and aortic valve replacement did not reduce the incidence of infectious endocarditis. The incidence of thromboembolic phenomena was favorably influenced by mitral valvulotomy and aortic valve replacement, but not by mitral valve replacement.     

Highly aggressive early prosthetic endocarditis by S. epidermidis

Prosthetic valve endocarditis is considered to be 15% of all infectious endocarditis in developed countries, more frequently during the first 45 days after surgery. Between 45 and 60% of patients with prosthetic valve endocarditis present periannular involve. The aortic valve injury and early symptoms onset after surgery are related with a higher power of aggressive prosthetic endocarditis invasion. We present the case of a patient affected with early aortic prosthetic valve endocarditis by S. epidermidis with a high aggressive and proliferating course, accompanied by fistula to left atrial, severe aortic regurgitation and left atrial roof rupture detected at the time of surgery, along with interventricular membranous septal defect.     

Plasma concentration of asymmetric dimethylarginine,an endogenous inhibitor of nitric oxide synthase,is elevated in hyperthyroid patients

Cardiovascular manifestations are frequent findings in patients with thyroid hormone disorders. Nitric oxide (NO) plays a key role in vascular, endothelial-mediated relaxation. NO is synthesized from L-arginine by NO synthase, an enzyme inhibited by endogenous compounds, mainly asymmetric dimethylarginine [asymmetric N(G),N(G)-dimethyl-L-arginine (ADMA)]. The aim of our work was to investigate whether plasma L-arginine and dimethylarginine concentrations and NO production are altered in hypo- and hyperthyroid patients, compared with control subjects. L-arginine, ADMA and symmetric dimethylarginine were analyzed by HPLC. NO was measured as plasma nitrite plus nitrate (NO(x)) concentration by a colorimetric method based on Griess reagent. L-arginine, ADMA, and symmetric dimethylarginine plasma levels in the hypothyroid group were similar to those of the control group; whereas in hyperthyroidism, these values were significantly increased. However, the L-arginine/ADMA ratio was decreased in hyperthyroid patients, resulting in diminished NO(x) production. When all subjects were analyzed together, free T(4) levels were directly correlated with ADMA and inversely correlated with NO(x).     

U-46619-induced potentiation of noradrenergic constriction in the human saphenous vein: antagonism by thromboxane receptor blockade.

OBJECTIVE: We investigated the potentiating effect of U-46619, a synthetic analogue of thromboxane A(2) (TXA(2)), on the adrenergic responses in human saphenous vein. METHODS: Saphenous vein rings were obtained from 35 patients undergoing coronary artery bypass surgery. The rings were suspended in organ bath chambers for isometric recording of tension. RESULTS: U-46619 (10(-10)-3 x 10(-7) mol/l) produced concentration-dependent and endothelium-independent contractile responses. U-46619 (10(-10) mol/l) potentiated the contractions elicited by electrical stimulation and potassium chloride, and produced leftward shifts of the concentration-response curve for noradrenaline. The TXA(2) receptor antagonist SQ-30741 (10(-8) mol/l) prevented the potentiation evoked by U-46619. The dihydropyridine calcium antagonist nifedipine (10(-6) mol/l) did not affect the potentiation of electrical stimulation and noradrenaline induced by U-46619, but abolished the potentiation of U-46619 on KCl-induced contractions. CONCLUSIONS: U-46619 facilitates sympathetic neurotransmission and potentiates constrictor effects of noradrenaline in human saphenous veins through stimulation of TXA(2) receptors. These effects are independent of calcium entry through dihydropyridine calcium channels.     

Use of erythropoietin in emergencies: massive intoxication by chloramines

Recombinant human Erythropoietin (rHuEPO) is normally used to correct anaemia in patients with End Stage Renal Disease (ESRD), that are in Regular Dialysis Treatment (RDT). This anaemia is usually due to the existence of two factors: A decrease in the erythropoiesis of the bone marrow and an increase in peripheral haemolysis and, consequently, a decrease in the life span of the red cells.