Analysis 9.1. Comparison 9 Mortality stratum for children and adults in the countries where trials were undertaken (children/ adults), Outcome

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Background Pulmonary arterial hypertension (PAH) is a proliferative disease of the pulmonary vasculature which preferentially affects females. Estrogens, such as the metabolite 16α-hydroxyestrone (16αOHE), may contribute to PAH pathogenesis; and, alterations in cellular energy metabolism associate with PAH. We hypothesized that 16αOHE promotes heritable PAH (HPAH) via miR-29 family upregulation, and that antagonism of miR-29 would attenuate pulmonary hypertension in transgenic mouse models of Bmpr2 mutation. Methods and Results MicroRNA (miR) array profiling of human lung tissue found elevation of miRs associated with energy metabolism, including the miR-29 family, among HPAH patients. miR-29 expression was 2-fold higher in Bmpr2 mutant mice lungs at baseline compared to controls, and 4 to 8-fold higher in Bmpr2 mice exposed to 16αOHE 1.25 μg/hr for 4 weeks. Blot analyses of Bmpr2 mouse lung protein showed significant reductions in PPARγ and CD36 in those mice exposed to 16αOHE, as well as from protein derived from HPAH lungs compared to controls. Bmpr2 mice treated with anti-miR-29 (α-miR29) (20mg/kg injections for 6 weeks) had improvements in hemodynamic profile, histology, and markers of dysregulated energy metabolism compared to controls. PASMCs derived from Bmpr2 murine lungs demonstrated mitochondrial abnormalities, which improved with α-miR29 transfection in vitro; endothelial-like cells derived from HPAH patient iPS cell lines were similar, and improved with α-miR29 treatment. Conclusions 16αOHE promotes the development of HPAH via upregulation of miR-29, which alters molecular and functional indices of energy metabolism. Antagonism of miR-29 improves in vivo and in vitro features of HPAH, and reveals a possible novel therapeutic target.

BACKGROUND: Probiotics may offer a safe intervention in acute infectious diarrhoea to reduce the duration and severity of the illness.OBJECTIVES: To assess the effects of probiotics in proven or presumed acute infectious diarrhoea.SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group's trials register (July 2010), the Cochrane Controlled Trials Register (The Cochrane Library Issue 2, 2010), MEDLINE (1966 to July 2010, EMBASE (1988 to July 2010), and reference lists from studies and reviews. We also contacted organizations and individuals working in the field, and pharmaceutical companies manufacturing probiotic agents.SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing a specified probiotic agent with a placebo or no probiotic in people with acute diarrhoea that is proven or presumed to be caused by an infectious agent. DATA COLLECTION AND ANALYSIS:Two reviewers independently assessed the methodological quality of the trial and extracted data. Primary outcomes were the mean duration of diarrhoea, stool frequency on day 2 after intervention and ongoing diarrhoea on day 4. A random-effects model was used.MAIN RESULTS: Sixty-three studies met the inclusion criteria with a total of 8014 participants. Of these, 56 trials recruited infants and young children. The trials varied in the definition used for acute diarrhoea and the end of the diarrhoeal illness, as well as in the risk of bias. The trials were undertaken in a wide range of different settings and also varied greatly in organisms tested, dosage, and participants' characteristics. No adverse events were attributed to the probiotic intervention. Probiotics reduced the duration of diarrhoea, although the size of the effect varied considerably between studies. The average of the effect was significant for mean duration of diarrhoea (mean difference 24.76 hours; 95% confidence interval 15.9 to 33.6 hours; n = 4555, trials = 35) diarrhoea lasting ≥ 4 days (risk ratio 0.41; 0.32 to 0.53; n = 2853, trials = 29) and stool frequency on day 2 (mean difference 0.80; 0.45 to 1.14; n = 2751, trials = 20). The differences in effect size between studies was not explained by study quality, probiotic strain, the number of different strains, the viability of the organisms, dosage of organisms, the causes of diarrhoea, or the severity of the diarrhoea, or whether the studies were done in developed or developing countries.AUTHORS' CONCLUSIONS: Used alongside rehydration therapy, probiotics appear to be safe and have clear beneficial effects in shortening the duration and reducing stool frequency in acute infectious diarrhoea. However, more research is needed to guide the use of particular probiotic regimens in specific patient groups.