How much would low- and middle-income countries benefit from addressing the key risk factors of road traffic injuries?

Despite strong advocacy, the UN Decade of Action for Road Safety (2011-2020) is ending with most low- and middle-income countries (LMICs) no closer to the Sustainable Development Goals target of reducing traffic mortality by half. In contrast, most high-income countries (HICs) have seen large benefits in recent decades from large-scale safety interventions. We aimed to assess how much LMICs would benefit from interventions that address six key risk factors related to helmet use, seatbelt use, speed control, drink driving, and vehicle design for safety of occupants and pedestrians. We use a comparative risk assessment framework to estimate mortality and health loss (disability adjusted life years lost, DALYs) that would be averted if these risks were reduced through intervention. We estimate effects for six countries that span all developing regions: China, Colombia, Ethiopia, India, Iran, and Russia. We find relatively large benefits (27% reductions in road traffic deaths and DALYs) from speed control in all countries, and about 5%-20% reductions due to other interventions depending on who is at risk in each country. To achieve larger gains, LMICs would need to move beyond simply learning from HICs and undertake new research to address risk factors particularly relevant to their context.

Insulin/IGF1 signalling mediates the effects of ß2 -adrenergic agonist on muscle proteostasis and growth.

BACKGROUND: Stimulation of ß2 -adrenoceptors can promote muscle hypertrophy and fibre type shift, and it can counteract atrophy and weakness. The underlying mechanisms remain elusive. METHODS: Fed wild type (WT), 2-day fasted WT, muscle-specific insulin (INS) receptor (IR) knockout (M-IR-/- ), and MKR mice were studied with regard to acute effects of the ß2 -agonist formoterol (FOR) on protein metabolism and signalling events. MKR mice express a dominant negative IGF1 receptor, which blocks both INS/IGF1 signalling. All received one injection of FOR (300 µg kg-1 subcutaneously) or saline. Skeletal muscles and serum samples were analysed from 30 to 240 min. For the study of chronic effects of FOR on muscle plasticity and function as well as intracellular signalling pathways, fed WT and MKR mice were treated with formoterol (300 µg kg-1  day-1 ) for 30 days. RESULTS: In fed and fasted mice, one injection of FOR inhibited autophagosome formation (LC3-II content, 65%, P ≤ 0.05) that was paralleled by an increase in serum INS levels (4-fold to 25-fold, P ≤ 0.05) and the phosphorylation of Akt (4.4-fold to 6.5-fold, P ≤ 0.05) and ERK1/2 (50% to two-fold, P ≤ 0.05). This led to the suppression (40-70%, P ≤ 0.05) of the master regulators of atrophy, FoxOs, and the mRNA levels of their target genes. FOR enhanced (41%, P ≤ 0.05) protein synthesis only in fed condition and stimulated (4.4-fold to 35-fold, P ≤ 0.05) the prosynthetic Akt/mTOR/p70S6K pathway in both fed and fasted states. FOR effects on Akt signalling during fasting were blunted in both M-IR-/- and MKR mice. Inhibition of proteolysis markers by FOR was prevented only in MKR mice. Blockade of PI3K/Akt axis and mTORC1, but not ERK1/2, in fasted mice also suppressed the acute FOR effects on proteolysis and autophagy. Chronic stimulation of ß2 -adrenoceptors in fed WT mice increased body (11%, P ≤ 0.05) and muscle (15%, P ≤ 0.05) growth and downregulated atrophy-related genes (30-40%, P ≤ 0.05), but these effects were abolished in MKR mice. Increases in muscle force caused by FOR (WT, 24%, P ≤ 0.05) were only partially impaired in MKR mice (12%, P ≤ 0.05), and FOR-induced slow-to-fast fibre type shift was not blocked at all in these animals. In MKR mice, FOR also restored the lower levels of muscle SDH activity to basal WT values and caused a marked reduction (57%, P ≤ 0.05) in the number of centrally nucleated fibers. CONCLUSIONS: NS/IGF1 signalling is necessary for the anti-proteolytic and hypertrophic effects of in vivo ß2 -adrenergic stimulation and appears to mediate FOR-induced enhancement of protein synthesis. INS/IGF1 signalling only partially contributes to gain in strength and does not mediate fibre type transition induced by FOR.

A naturally occurring single amino acid replacement in multiple gene regulator of group A Streptococcus significantly increases virulence.

Single-nucleotide polymorphisms (SNPs) are the most common source of genetic variation within a species; however, few investigations demonstrate how naturally occurring SNPs may increase strain virulence. We recently used group A Streptococcus as a model pathogen to study bacteria strain genotype-patient disease phenotype relationships. Whole-genome sequencing of approximately 800 serotype M59 group A Streptococcus strains, recovered during an outbreak of severe invasive infections across North America, identified a disproportionate number of SNPs in the gene encoding multiple gene regulator of group A Streptococcus (mga). Herein, we report results of studies designed to test the hypothesis that the most commonly occurring SNP, encoding a replacement of arginine for histidine at codon 201 of Mga (H201R), significantly increases virulence. Whole transcriptome analysis revealed that the H201R replacement significantly increased expression of mga and 54 other genes, including many proven virulence factors. Compared to the wild-type strain, a H201R isogenic mutant strain caused significantly larger skin lesions in mice. Serial quantitative bacterial culture and noninvasive magnetic resonance imaging also demonstrated that the isogenic H201R strain was significantly more virulent in a nonhuman primate model of joint infection. These findings show that the H201R replacement in Mga increases the virulence of M59 group A Streptococcus and provide new insight to how a naturally occurring SNP in bacteria contributes to human disease phenotypes.

Biópsia estereotáxica para linfomas primários do sistema nervoso central / Stereotaxic biopsy for primary lymphomas of the central nervous system

Os linfomas primários do SNC säo ratos, mas sua incidência tem aumentado nos últimos anos. Estes tumores frequentemente se localizaram nos gânglios de base e tálamo ou se apresentam de forma multifocal. O tratamento atual para eles é a radioterapia, associada ou näo a quimioterapia. Devido à sua extremamente baixa morbidade, a biópsia estereotáxica é o método ideal para determinar o diagnóstico histológico em pacientes com suspeita de linfomas do SNC. Os autoes apresentam estudo de 49 casos de linfomas primários do SNC, diagnosticado por biópsia esterotáxica