In vivo activity of aryl ozonides against Schistosoma species

We evaluated the in vivo antischistosomal activities of 11 structurally diverse synthetic peroxides. Of all compounds tested, ozonide (1,2,4-trioxolane) OZ418 had the highest activity against adult Schistosoma mansoni, with total and female worm burden reductions of 80 and 90% (P < 0.05), respectively. Furthermore, treatment of S. haematobium-infected mice with OZ418 reduced the total worm burden by 86%. In conclusion, OZ418 is a promising antischistosomal lead compound.     

Peut-on améliorer la notification des effets indésirables dans les établissements hospitaliers ? Bilan de 5 ans d’activité du réseau PharmacoMIP

Background. Spontaneous reporting of adverse drug reactions (ADR) is fundamental to drug safety surveillance (pharmacovigilance) and assessment of benefit/risk ratio. However, under-reporting remains the limit of the system. Objective. The aim of this study was to assess the effect of regular visits of an Assistant in Clinical Research (CRA) on the improvement of ADR reporting in non-university hospitals. Methods. We set up an ADR report collecting system that involved regular visits in non-university hospitals, We began the visits in 2006 in 2 areas (Haute Garonne and Gers), extended to 4 other areas in 2009. We compared the reporting rate (number of reports/number of beds) of total ADRs reported by non-university hospitals in these areas before (one year) and after the start of CRA visits. Results. A total 2831 of reports were collected by the CRA: 40% were "serious" including two deaths. The results suggest an increase of 100% of the rate of reporting of ADRs. Conclusion. This study shows that regular visits increases the number of ADRs reported by non-university hospitals. Further assessment of this procedure is necessary for long term evaluation of its effectiveness.     

Population Pharmacokinetic and Pharmacodynamic Modeling of Amodiaquine and Desethylamodiaquine in Women with Plasmodium vivax Malaria during and after Pregnancy

Amodiaquine is effective for the treatment of Plasmodium vivax malaria, but there is little information on the pharmacokinetic and pharmacodynamic properties of amodiaquine in pregnant women with malaria. This study evaluated the population pharmacokinetic and pharmacodynamic properties of amodiaquine and its biologically active metabolite, desethylamodiaquine, in pregnant women with P. vivax infection and again after delivery. Twenty-seven pregnant women infected with P. vivax malaria on the Thai-Myanmar border were treated with amodiaquine monotherapy (10 mg/kg/day) once daily for 3 days. Nineteen women, with and without P. vivax infections, returned to receive the same amodiaquine dose postpartum. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic and pharmacodynamic properties of amodiaquine and desethylamodiaquine. Amodiaquine plasma concentrations were described accurately by lagged first-order absorption with a two-compartment disposition model followed by a three-compartment disposition of desethylamodiaquine under the assumption of complete in vivo conversion. Body weight was implemented as an allometric function on all clearance and volume parameters. Amodiaquine clearance decreased linearly with age, and absorption lag time was reduced in pregnant patients. Recurrent malaria infections in pregnant women were modeled with a time-to-event model consisting of a constant-hazard function with an inhibitory effect of desethylamodiaquine. Amodiaquine treatment reduced the risk of recurrent infections from 22.2% to 7.4% at day 35. In conclusion, pregnancy did not have a clinically relevant impact on the pharmacokinetic properties of amodiaquine or desethylamodiaquine. No dose adjustments are required in pregnancy.     

The type I interferon response bridles rabies virus infection and reduces pathogenicity

Rabies virus (RABV) is a neurotropic virus transmitted by the bite of an infected animal that triggers a fatal encephalomyelitis. During its migration in the nervous system (NS), RABV triggers an innate immune response, including a type I IFN response well known to limit viral infections. We showed that although the neuroinvasive RABV strain CVS-NIV dampens type I IFN signaling by inhibiting IRF3 phosphorylation and STAT2 translocation, an early and transient type I IFN response is still triggered in the infected neuronal cells and NS. This urged us to investigate the role of type I IFN on RABV infection. We showed that primary mouse neurons (DRGs) of type I IFN(α/β) receptor deficient mice (IFNAR^−/− mice) were more susceptible to RABV than DRGs of WT mice. In addition, exogenous type I IFN is partially efficient in preventing and slowing down infection in human neuroblastoma cells. Intra-muscular inoculation of type I IFNAR deficient mice [IFNAR^−/− mice and NesCre (^+/−) IFNAR (^flox/flox) mice lacking IFNAR in neural cells of neuroectodermal origin only] with RABV reveals that the type I IFN response limits RABV dissemination in the inoculated muscle, slows down invasion of the spinal cord, and delays mortality. Thus, the type I IFN which is still produced in the NS during RABV infection is efficient enough to reduce neuroinvasiveness and pathogenicity and partially protect the host from fatal infection.     

Ineligibility for renal transplantation: prevalence,causes and survival in a consecutive cohort of 445 patients

Kianda MN, Wissing KM, Broeders NE, Lemy A, Ghisdal L, Hoang AD, Mikhalski D, Donckier V, Vereerstraeten P, Abramowicz D. Ineligibility for renal transplantation: prevalence, causes and survival in a consecutive cohort of 445 patients.
Clin Transplant 2011: 25: 576–583. © 2010 John Wiley & Sons A/S. Abstract: Little is known about the proportion of renal transplant candidates who are considered ineligible by the transplant center, the reasons of their ineligibility and their survival during dialysis. In this retrospective, single‐center study of 445 adult patients referred between 2001 and 2006, 36 (8%) were deemed ineligible for medical contraindications. The leading reason was cardiovascular (CV) (75%), specifically aorto‐iliac, and/or limb vessels atheromatosis or calcifications; ischemic heart disease; or a combination thereof. Nine patients had other contraindications that were absolute for three of them; six patients displayed a combination of relative contraindications. When compared to eligible patients (N = 409), those ineligible were significantly older (60 yr vs. 48), more often diabetics (50% vs. 15%), obese (39% vs. 17%) suffering from coronary artery disease (53% vs. 11%) and peripheral arterial disease (86% vs. 11%). Their primary nephropathy was more often diabetic and/or hypertensive/nephroangiosclerosis (61% vs. 23%), and their median dialysis vintage prior to evaluation was longer (29 months vs. 10, p < 0.0001). The actuarial survival of ineligible patients was significantly lower than that of eligible patients (at five yr: 53% vs. 88%). Adequate control of CV risk factors before dialysis and early referral for transplantation might help to improve eligibility of renal transplant candidates.     

Audiological findings in 100 USH2 patients

Abadie C, Blanchet C, Baux D, Larrieu L, Besnard T, Ravel P, Biboulet R, Hamel C, Malcolm S, Mondain M, Claustres M, Roux A-F. Audiological findings in 100 USH2 patients. Bilateral sensorineural hearing loss (HL), classically described as mild to severe with a typically down-sloping audiometric configuration, is the earliest symptom occurring in Usher syndrome type II (USH2). Audiological findings were analyzed in a total of 100 USH2 patients (92 families) divided into three groups according to the gene involved: 88 USH2A, 10 GPR98 and 2 DFNB31 patients. A fine analysis of audiograms was performed (pure tone average, degree of severity, configuration). The median age of HL diagnosis was 5 years (range 8 months-31 years) although the median age at USH2 diagnosis was 34.5 (range 8-76). Moderate HL was predominant (76%) and a gently down-sloping configuration characterized most audiograms (66%). No statistically significant difference was found between USH2A and GPR98 patients but a tendency was clearly noted for more GPR98 patients to present with severe hearing loss. It is not possible to predict the mutated gene from audiograms.     

Age-related prevalence of Methanomassiliicoccus luminyensis in the human gut microbiome

A 16S rDNA sequence-based investigation of methanogenic Archaea in the human stools found Methanobrevibacter smithii in 99.2% and Methanosphaera stadtmanae in 32.6%. The recently described Methanomassiliicoccus luminyensis found by others to be representative of a new order of methanogenic Archaea was found in 4% of stool specimens. The prevalence of M. luminyensis significantly increased with age, contrary to M. smithii and M. stadtmanae.     

Geographical differentiation of the molecular diversity of cacao swollen shoot virus in Togo

The variability of cacao swollen shoot virus (CSSV) was studied in two areas of Togo with distinct epidemiological backgrounds, Kloto and Litimé. This molecular study was based on 120 sequence comparisons of the first part of ORF3 of the viral genome. The phylogenetic study distinguished three groups of CSSV isolates, A, B, and C, with clear geographical differentiation between the Kloto and Litimé areas. The only group detected in Kloto was group C, whereas the Litimé area only contained isolates from groups A and B, which most probably originated from Ghana. The divergence between the three groups strongly suggests a different origin for each of the groups.