Ilex paraguariensis Attenuates Changes in Mortality,Behavioral and Biochemical Parameters Associated to Methyl Malonate or Malonate Exposure in Drosophila melanogaster

Methylmalonic acidemia is a genetic disease characterized by accumulation of organic acids, such as methylmalonic (MMA) and malonic (MA) acids. Considering that the accumulation of MMA and MA causes several damages due to oxidative stress, antioxidants are thought to play a pivotal role in preventing deleterious effects associated with exposure to such compounds. Ilex paraguariensis (IP) was used here to test the hypothesis that supplementation with the aqueous extract of this plant could exert protective effect against MMA or MA induced mortality, behavioral and/or biochemical changes in Drosophila melanogaster (DM). Initially, a curve time- and dose–response to MMA (1–10 mM), MA (1–10 mM) and IP (63–500 μM) was performed. Thereafter, flies were concomitantly exposed to MA (5 mM), MMA (5 mM) and/or IP (250 μg/mL) during 15 days for survival assay, and for 48 hs to MA (1 or 5 mM), MMA (1 or 5 mM) and/or IP (250 μg/mL) for subsequent investigations. Both MMA and MA exposure resulted in higher incidence of mortality, a worse performance in the negative geotaxis assay and increased locomotion in open-field test as compared with control group. Furthermore, a marked increase in non-protein thiol (NPSH) and in thiobarbituric acid reactive substances (TBARS) levels, decrease in superoxide dismutase (SOD), catalase and acetylcholinesterase (AChE) activities, and decrease in MTT and resazurin reduction were noted in MMA or MA treated groups. IP treatment offered significant protection against all alterations associated to MMA or MA exposure. This study confirm the hypothesis that supplementation with IP offers protection against changes associated to MMA or MA exposure in DM, due, at least in part, to its antioxidant effect.

     

Resequencing the susceptibility gene,ITGAM, identifies two functionally deleterious rare variants in systemic lupus erythematosus cases

Introduction

The majority of the genetic variance of systemic lupus erythematosus (SLE) remains unexplained by the common disease-common variant hypothesis. Rare variants, which are not detectable by genome-wide association studies because of their low frequencies, are predicted to explain part of this ”missing heritability.” However, recent studies identifying rare variants within known disease-susceptibility loci have failed to show genetic associations because of their extremely low frequencies, leading to the questioning of the contribution of rare variants to disease susceptibility. A common (minor allele frequency = 17.4% in cases) nonsynonymous coding variant rs1143679 (R77H) in ITGAM (CD11b), which forms half of the heterodimeric integrin receptor, complement receptor 3 (CR3), is robustly associated with SLE and has been shown to impair CR3-mediated phagocytosis.

Methods

We resequenced ITGAM in 73 SLE cases and identified two previously unidentified, case-specific nonsynonymous variants, F941V and G1145S. Both variants were genotyped in 2,107 and 949 additional SLE cases, respectively, to estimate their frequencies in a disease population. An in vitro model was used to assess the impact of F941V and G1145S, together with two nonsynonymous ITGAM polymorphisms, A858V (rs1143683) and M441T (rs11861251), on CR3-mediated phagocytosis. A paired two-tailed t test was used to compare the phagocytic capabilities of each variant with that of wild-type CR3.

Results

Both rare variants, F941V and G1145S, significantly impair CR3-mediated phagocytosis in an in vitro model (61% reduction, P = 0.006; 26% reduction, P = 0.0232). However, neither of the common variants, M441T and A858V, had an effect on phagocytosis. Neither rare variant was observed again in the genotyping of additional SLE cases, suggesting that there frequencies are extremely low.

Conclusions

Our results add further evidence to the functional importance of ITGAM in SLE pathogenesis through impaired phagocytosis. Additionally, this study provides a new example of the identification of rare variants in common-allele-associated loci, which, because of their extremely low frequencies, are not statistically associated. However, the demonstration of their functional effects adds support to their contribution to disease risk, and questions the current notion of dismissing the contribution of very rare variants on purely statistical analyses.     

Increasing the Use of Skilled Health Personnel Where Traditional Birth Attendants Were Providers of Childbirth Care: A Systematic Review

Background

Improved access to skilled health personnel for childbirth is a priority strategy to improve maternal health. This study investigates interventions to achieve this where traditional birth attendants were providers of childbirth care and asks what has been done and what has worked?

Methods and Findings

We systematically reviewed published and unpublished literature, searching 26 databases and contacting experts to find relevant studies. We included references from all time periods and locations. 132 items from 41 countries met our inclusion criteria and are included in an inventory; six were intervention evaluations of high or moderate quality which we further analysed. Four studies report on interventions to deploy midwives closer to communities: two studies in Indonesia reported an increase in use of skilled health personnel; another Indonesian study showed increased uptake of caesarean sections as midwives per population increased; one study in Bangladesh reported decreased risk of maternal death. Two studies report on interventions to address financial barriers: one in Bangladesh reported an increase in use of skilled health personnel where financial barriers for users were addressed and incentives were given to skilled care providers; another in Peru reported that use of emergency obstetric care increased by subsidies for preventive and maternity care, but not by improved quality of care.

Conclusions

The interventions had positive outcomes for relevant maternal health indicators. However, three of the studies evaluate the village midwife programme in Indonesia, which limits the generalizability of conclusions. Most studies report on a main intervention, despite other activities, such as community mobilization or partnerships with traditional birth attendants. Many authors note that multiple factors including distance, transport, family preferences/support also need to be addressed. Case studies of interventions in the inventory illustrate how different countries attempted to address these complexities. Few high quality studies that measure effectiveness of interventions exist.     

Analysis of a genome-wide association study-linked locus (CCR6) in Asian rheumatoid arthritis

A genome-wide association study in Japan identified the C-C chemokine receptor type 6 gene (CCR6) as associated with rheumatoid arthritis (RA). This finding has not been validated in other Asian populations. A case-control study involving 996 subjects, comprising 440 controls and 556 RA patients, was done to determine their anticyclic citrullinated peptide (anti-CCP) antibody status and CCR6 polymorphism (rs3093024) genotype. Three hundred eighty-seven patients were anti-CCP positive and 153 anti-CCP negative. Logistic regression showed that allele A was likely to increase the risk of developing RA among females via a recessive model (odds ratio [OR]=1.55, 95% confidence interval [CI]=1.01, 2.39), whereas the risk effect appeared to be reduced among males via an additive model (OR=0.60, 95% CI=0.42, 0.85). Considering only subjects who are anti-CCP positive, allele A increased RA risk among females via a recessive model (OR=1.68, 95% CI=1.07, 2.64) but decreased the risk among males via an additive model (OR=0.59, 95% CI=0.39, 0.89). We showed that CCR6 polymorphism was a risk factor among females but a protective factor among males. Functional studies are warranted to unravel the pathophysiological relevance of the gene variant and other linked variants with RA.     

Tratamiento de la hiperglucemia en el hospital. Impresiones y conocimientos del médico residente

Background and objectiveIn many hospitals, adequate glycemic control is not achieved despite implementation of new insulin therapy protocols. Our aim was to assess resident physician’ attitudes toward inpatient hyperglycemia, barriers to achieve optimum control, and impact on them of an insulin training programMaterial and methodsA questionnaire was used to assess understanding and standard management of hyperglycemia before and six months after implementation of an inpatient insulin treatment program.ResultsTwenty-five interns completed the questionnaire. Glycemic control was considered “very important” in all admission situations, but was only considered “very important” in conventional hospitalization by 36% of interns. Most of these felt “comfortable” using sliding scales, but not with the basal/bolus regimen, which was the least commonly used. Perception of number of well-controlled patients and comfort and use of basal/bolus therapy increased at six months, but use of “sliding scales” remained high. The greatest difficulty reported for adequate management of hyperglycemia was the lack of knowledge.ConclusionsMost residents are aware of the importance of adequate glycemic control, but cannot achieve it because of inadequate knowledge. The insulin training program led to an improved perception and applicability of basal-bolus insulin regimens. However, despite all efforts, use of sliding scales remains high. Training programs should emphasize management of hyperglycemia.     

Trypanosome lytic factors: novel mediators of human innate immunity

A novel trypanosome lytic factor (TLF) has been characterized that protects humans from infection by Trypanosoma brucei brucei. The mechanism of trypanolysis is unknown; contrary to one hypothesis, TLF does not kill trypanosomes by generating oxygen radicals. However, these trypanosomes become human-infective when they express a serum-resistance-associated gene.     

Virulence in murine model shows the existence of two distinct populations of Brazilian Vaccinia virus strains

Brazilian Vaccinia virus had been isolated from sentinel mice, rodents and recently from humans, cows and calves during outbreaks on dairy farms in several rural areas in Brazil, leading to high economic and social impact. Some phylogenetic studies have demonstrated the existence of two different populations of Brazilian Vaccinia virus strains circulating in nature, but little is known about their biological characteristics. Therefore, our goal was to study the virulence pattern of seven Brazilian Vaccinia virus strains. Infected BALB/c mice were monitored for morbidity, mortality and viral replication in organs as trachea, lungs, heart, kidneys, liver, brain and spleen. Based on the virulence potential, the Brazilian Vaccinia virus strains were grouped into two groups. One group contained GP1V, VBH, SAV and BAV which caused disease and death in infected mice and the second one included ARAV, GP2V and PSTV which did not cause any clinical signals or death in infected BALB/c mice. The subdivision of Brazilian Vaccinia virus strains into two groups is in agreement with previous genetic studies. Those data reinforce the existence of different populations circulating in Brazil regarding the genetic and virulence characteristics.