The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

Genetic differences in omega-gliadins involved in two different immediate food hypersensitivities to wheat

Background: Anti-gliadin IgE are expressed in patients with food allergy associated to skin immediate hypersensitivity to hydrolyzed wheat proteins (IHHWP). It is not known if they react with omega 5-gliadins, the major allergens in wheat dependant exercise-induced food anaphylaxis (WDEIA), encoded on wheat chromosomes 1B. Methods: Unmodified gliadins from 14 wheat varieties expressing most of the 1B omega-gliadin alleles, were immunoprobed after SDS-PAGE and blotting, with four sera from patients with IHHWP, and two with WDEIA. Gliadins reacting with IgE were visualized using chemiluminescence and identified according to their mobility and typical SDS-PAGE pattern. The resulting signal was also measured to compare their IgE reactivity. Results: IHHWP and WDEIA sera exhibited distinct patterns of reactivity. IgE of patients with IHHWP reacted mainly with all omega-gliadins alleles and one gamma-gliadin encoded respectively on chromosomes 1D and 1B, but not with any omega 5-gliadins alleles as for WDEIA. A few other reactive alleles of omega-gliadins were encoded on chromosomes 1A. Unassigned additional bands of the whole gliadin pattern were also reactive. The four patients with IHHWP exhibited almost the same pattern of reactivity. Main differences concerned band reactivity which modulated the overall reactivity of each wheat variety. Conclusions: The IgE epitopes involved in IHHWP and WDEIA are different. This suggests that the protein state and the route of exposure to very similar gluten structures, probably orientate the pattern of epitope reactivity and the wheat food allergy manifestations

Implantation-induced structural defects in highly activated USJs: Boron precipitation and trapping in pre-Amorphised silicon

International audienceToday, most of the state-of-the-art USJs fabrication processes involve the formation of an amorphous surface layer before or during the dopant implant step. In this paper, we present a review of some recent experimental studies on the Boron precipitation and trapping in pre-amorphised USJs. These studies suggest that the physical mechanism governing the Boron trapping mainly depends on the Boron concentration left below the a/c interface after the implant. In addition to providing a contribution to the understanding of the Boron trapping phenomenon, these results clearly indicate that physical models for the formation of large Boron precipitates need to be implemented in TCAD simulators for a comprehensive description of the USJ fabrication process

A comparison of systematic stenting and conventional balloon angioplasty during primary percutaneous transluminal coronary angioplasty for acute myocardial infarction

AbstractOBJECTIVESIn a multicenter, randomized trial, systematic stenting using the Wiktor stent was compared to conventional balloon angioplasty with provisional stenting for the treatment of acute myocardial infarction (AMI).BACKGROUNDPrimary angioplasty in AMI is limited by in-hospital recurrent ischemia and a high restenosis rate.METHODSA total of 211 patients with AMI <12 h from symptom onset, with an occluded native coronary artery, were randomly assigned to systematic stenting (n = 101) or balloon angioplasty (n = 110). The primary end point was the binary six-month restenosis rate determined by core laboratory quantitative angiographic analysis.RESULTSAngiographic success (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3 and residual diameter stenosis <50%) was achieved in 86% of the patients in the stent group and in 82.7% of those in the balloon angioplasty group (p = 0.5). Compared with the 3% cross-over in the stent group, cross-over to stenting was required in 36.4% of patients in the balloon angioplasty group (p = 0.0001). Six-month binary restenosis (≥50% residual stenosis) rates were 25.3% in the stent group and 39.6% in the balloon angioplasty group (p = 0.04). At six months, the event-free survival rates were 81.2% in the stent group and 72.7% in the balloon angioplasty group (p = 0.14), and the repeat revascularization rates were 16.8% and 26.4%, respectively (p = 0.1). At one year, the event-free survival rates were 80.2% in the stent group and 71.8% in the balloon angioplasty group (p = 0.16), and the repeat revascularization rates were 17.8% and 28.2%, respectively (p = 0.1).CONCLUSIONSIn the setting of primary angioplasty for AMI, as compared with a strategy of conventional balloon angioplasty, systematic stenting using the Wiktor stent results in lower rates of angiographic restenosis

Évolution de la sensibilité de Streptococcus pneumoniae aux antibiotiques : résultats de l&apos;observatoire du pneumocoque Alsace (année 2005) Evolution of antibiotic resistance of Streptococcus pneumoniae: results of Alsace observatory in 2005 Author&apos;s perso

Résumé But de l&apos;étude. -Entre le 1 er janvier et le 31 décembre 2005, les participants à l&apos;Observatoire régional du pneumocoque (ORP) Alsace (un centre hospitalier universitaire, sept centres hospitaliers non universitaires et 12 laboratoires privés) ont collecté 232 souches supposées pathogènes et non redondantes de Streptococcus pneumoniae pour étudier leur sensibilité vis-à-vis des bêtalactamines. Méthode. -Les concentrations minimales inhibitrices (CMI) de la pénicilline G, de l&apos;amoxicilline et du céfotaxime ont été déterminées par la méthode E-test et par la méthode de dilution en milieu gélosé (Steers). Les résultats ont été interprétés selon les recommandations du CA-SFM. Les sensibilités à d&apos;autres molécules ont été étudiées. Abstract Objectives. -Between 1st January 2005 and 31st December 2005, 232 strains of Streptococcus pneumoniae were collected in the Alsace county from participating laboratories (one from university hospital, 7 from general hospitals and 12 private laboratories) to assess their susceptibility to penicillin and evaluated serogroups of strains. Method. -The coordinating centre performed MICs by the reference agar dilution test, interpreted according to CA-SFM breakpoints. Others antibiotics (erythromycin, cotrimoxazole, tetracycline…) were tested by agar diffusion, ATB-PNEUMO gallery or VITEK gallery (BioMérieux, France) by each participating laboratory. Data were processed, using 4th dimension software. Results. -Strains were collected from 151 blood samples, 38 ear pus, 11 cerebrospinal fluids, 8 pleural liquids and 24 representative pulmonary samples. The prevalence of pneumococci with decreased susceptibility to penicillin G (PDSP) is 35.1% (pulmonary samples excluded). The rate of PNSP decreases for all types of samples compared with other years of surveillance 2003 (44.0%). The rate of blood samples decreases for first time between the creation of Pneumococcal Observatory. The high-level resistance tend to decrease and began low. The PDSP are rather resistant to erythromycin, cotrimoxazole and fosfomycin. Among the PDSP, the most prevalent serotypes were 14, 19, 6 and 9. Conclusion. -Among pneumococcal strains, the rate of PDSP tend however to decrease in 2005 compared with 2003. The rate stays inferior to the observed rates in other French counties where the same decreasing is described