Prevention of islet allograft rejection in diabetic mice by targeting Janus Kinase 3 with 4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (JANEX-1)

Janus kinase (JAK) 3-deficient mice were not able to reject allogeneic islet allografts. The JAK3 inhibitor 4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (CAS 202475-60-3, JANEX-1, WHI-P131) prevented the rejection of islet allografts in mice with a normal JAK3 expression status. The combination of JANEX-1 and cyclosporin A (CAS 59865-13-3) was more effective than either agent alone.     

Azasterols as inhibitors of sterol 24-methyltransferase in Leishmania species and Trypanosoma cruzi

This paper describes the synthesis of some novel azasterols based on (20R,22xi)-5alpha-pregnan-20-(piperidin-2-yl)-3beta,20-diol. These compounds are potential inhibitors of the enzyme sterol 24-methyltransferase (24-SMT), which is a vital enzyme in the biosynthesis of ergosterol and related 24-alkyl sterols. Structure-activity studies were undertaken to understand the important features for activity against the enzyme, with the aim of increasing activity and selectivity. The compounds were evaluated for inhibition of recombinant Leishmania major 24-SMT and the effect of compounds on sterol composition and parasite proliferation. Essentially, compounds which showed good activity against the recombinant enzyme had a significant effect on the sterol composition and growth of parasites. The activity of compounds was found to be related to the basicity and stereochemical location of the nitrogen. Also, presence of an unprotected 3beta-OH seemed to be important for activity. However, some azasterols which were not good inhibitors of 24-SMT also showed antiproliferative activity, suggesting that there may be other modes of actions of these compounds.     

Lack of effect of aprepitant on digoxin pharmacokinetics in healthy subjects

Aprepitant is a highly selective neurokinin-1 receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine3 (5HT3) receptor antagonist, has been shown to be efficacious in the prevention of highly emetogenic chemotherapy-induced nausea and vomiting. In vitro data suggest that aprepitant is a substrate and a weak inhibitor of P-glycoprotein. Thus, the effect of aprepitant on the pharmacokinetics of digoxin, a P-glycoprotein substrate, was examined in a double-blind, placebo-controlled, randomized, two-period crossover study in 12 healthy subjects. Each subject received daily oral doses of digoxin 0.25 mg on Days 1 through 13 during both treatment periods. Aprepitant 125 mg (or matching placebo) was coadministered orally with digoxin on Day 7, and aprepitant 80 mg (or matching placebo) was coadministered orally with digoxin on Days 8 to 11. Aprepitant did not affect the pharmacokinetics of digoxin. The geometric mean ratios (90% confidence interval [CI]) for plasma AUC0-24 h of digoxin (with/without aprepitant) were 0.99 (0.91, 1.09) and 0.93 (0.83, 1.05) on Days 7 and 11, respectively, and the geometric mean ratios (90% CI) for the 24-hour urinary excretion of immunoreactive digoxin (with/without aprepitant) were 0.91 (0.80, 1.04) and 1.00 (0.91, 1.09) on Days 7 and 11, respectively. Thus, aprepitant, when dosed as a 5-day regimen, did not interact with a known substrate of the P-glycoprotein transporter.     

Effects of sildenafil (viagra) on human myocardial contractility,in vitro arrhythmias,and tension of internal mammaria arteries and saphenous veins

Sildenafil (Viagra) has been proved effective in the therapy for erectile dysfunction. Cardiovascular adverse effects are a matter of continuous debate. The aim of the study was to investigate effects of sildenafil on isolated human cardiovascular tissue directly. Isometric force of contraction was determined in isolated, electrically stimulated (1 Hz, 37 degrees C) human right atrial and left ventricular muscle strips. Vascular tension was determined in rings of human internal mammaria arteries and saphenous veins. Sildenafil (0.0001-10 microM) neither in human atrium (n = 12) nor in failing (n = 8) or nonfailing (n = 5) ventricle exerted a significant inotropic response. Furthermore, no effect on isoprenaline-elicited arrhythmias was observed. Neither addition of isoprenaline (0.1 microM) nor addition of the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) (100 microM) affected myocardial contractility in the presence of sildenafil (10 microM). In precontracted arteries and veins, addition of sildenafil (0.1-10 microM) led to pronounced vasorelaxation (maximal 35.5 +/- 2.2% and 45.6 +/- 6.3%, respectively, in the presence of 10 microM sildenafil). In the presence of SNAP (0.03 microM), this effect was markedly increased in arteries (72.4 +/- 10.1%, n = 4, P < 0.02) as well as in veins (73.5 +/- 6.3%, n = 6, P < 0.02). Sildenafil exerts potent vasodilatory actions but has no direct influence on human myocardial contractility or proarrhythmic effects in vitro.     

Use of a purified Trypanosoma cruzi antigen and CpG oligodeoxynucleotides for immunoprotection against a lethal challenge with trypomastigotes

The crucial role played by Ag163B6/cruzipain, the major cystein proteinase of Trypanosoma cruzi, in the process of parasite internalization into mammalian cells and IgG hydrolysis, signals this antigen as a potential target for raising a protective immune response against Chagas' disease. On the other hand, synthetic oligodeoxynucleotides containing CpG-motifs (CpG-ODN) are capable of driving immunity toward a Th1 bias. Considering the importance of Th1 mechanisms in resistance against this intracellular parasite, we analyzed the ability of Ag163B6/cruzipain plus CpG-ODN to induce immunoprotection against a lethal challenge with trypomastigotes. Mice were immunized with Ag163B6+CpG-ODN showing high specific antibody titers, mostly IgG2a. Spleen cells from these mice strongly proliferated and presented significant increase of IL-2 and IFN-gamma concentrations in their supernatant upon antigen stimulation. Trypomastigote challenge rendered elevated parasitemia and mortality in all control groups, meanwhile Ag163B6+CpG-ODN mice displayed the lowest level of blood parasites and 100% survival to acute infection. Besides, we demonstrated that other parasite antigens introduced into mice when challenged, and consequently never seen before by the immune system, also elicited a Th1 immune response. Taken together, these results plus others provide the basis for the design of a multicomponent anti-T. cruzi vaccine which may ultimately be used not only to protect humans at risk of infection, but also may alleviate or prevent the pathogenic responses characteristic of chronic Chagas' disease by reducing or perhaps eliminating tissue parasites from infected patients.     

Opinions of students and educators concerning health: the public school perspective in a peripheral area of the city of São Paulo

This study focused on prevailing concepts in society concerning adolescents' health problems and needs. Based on concerns in the field of Collective Health in relation to public policies for social protection, the study attempted to grasp the public school perspective concerning these issues. The study's theoretical reference was the social determination of the health-disease process and the view that health needs are translated into demands for changes in the harmful processes resulting from relations in the production process. Data were gathered through interviews with pedagogical coordinators and focus groups with adolescents in public schools from the Raposo Tavares School District (Municipality of S o Paulo). The results showed that the participants recognized: (1) the sphere of social determinants at the base of adolescents' health problems and (2) in addition to disease processes, a set of social problems impacting the health-disease process, highlighting drug use and violence. Health needs are translated as demands for cross-sector public social policies.     

Distance learning in the nursing area: report of an experience

This study aims at reporting an experience of offering a course in the master program of the Universidad Nacional de Rosário. The purpose is to offer elements for a reflection on a conception of long-distance education, as an adequate and efficient modality of education, aiming at enabling a teaching with quality to a determined clientele. The course was developed in three moments: video-conference, long-distance didactic activities and a seminar. The tutoring was shared by establishing the challenge of having a dialogic relation with the students. Authors believe that long-distance education is an adequate pedagogical tool to qualify nurses who have no access to traditional graduate studies. Therefore it enables the qualification of a greater number of nurses, geographically dispersed, who are unable to scape from the routine of their personal and professional lives. Facing the need to form the country's nursing workers and qualify nurses to act as teachers, long-distance learning is an effective and possible pedagogical strategy.     

Importance of LDL/HDL cholesterol ratio as a predictor for coronary heart disease events in patients with heterozygous familial hypercholesterolaemia: a 15-year follow-up (1987-2002)

This study evaluated the prognostic significance of several risk factors on the outcome of coronary heart disease (CHD) in 639 cardiovascular disease-free subjects with heterozygous familial hypercholesterolaemia (FH). During the 15-year follow-up, 53 (18%) men and 34 (9.8%) women had a CHD event (men vs women, p < 0.001). The age-adjusted 15-year event rate was 3% (87 events/2915 person-years). Smoking increased the CHD risk (hazard ratio = 2.45, p < 0.001), women had a 74% lower risk of a vascular event, compared to men, after controlling for the postmenopausal status (hazard ratio = 0.26, p < 0.001). A one-unit difference in low density lipoprotein (LDL)/high density lipoprotein cholesterol (HDL) cholesterol ratio was associated with a 17% higher risk (hazard ratio = 1.17, p < 0.05); hypertension increased the risk for an adverse event (hazard ratio = 3.02, p < 0.05) and a 1 mg/dl increase in plasma fibrinogen level was associated with a 4% higher CHD risk (hazard ratio = 1.04, p < 0.05). With the power of the 15 years of prospective evaluation, the study shows that increased smoking, hypertension and LDL cholesterol levels eight times more than HDL cholesterol predicts an adverse CHD event, in patients with FH.     

Statins in coronary bypass surgery: rationale and clinical use

Statin therapy prevents the first occurrence and recurrence of coronary events and reduces cardiovascular and general mortality in patients with coronary artery disease. These compounds modulate a variety of processes involved in the pathophysiology of arteriosclerosis and vascular graft disease by lipid-dependent and lipid-independent (pleiotropic) mechanisms. As a result, statins produce angiographic and clinical benefits in patients undergoing coronary bypass surgery. We review the present knowledge about the effects of statins on this pathologic condition and the evidence supporting an early treatment initiation.