Immunogenicity and efficacy of oral vaccines in developing countries: lessons from a live cholera vaccine

Oral vaccines, whether living or non-living, viral or bacterial, elicit diminished immune responses or have lower efficacy in developing countries than in developed countries. Here I describe studies with a live oral cholera vaccine that include older children no longer deriving immune support from breast milk or maternal antibodies and that identify some of the factors accounting for the lower immunogenicity, as well as suggesting counter-measures that may enhance the effectiveness of oral immunization in developing countries. The fundamental breakthrough is likely to require reversing effects of the 'environmental enteropathy' that is often present in children living in fecally contaminated, impoverished environments

Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial

<div><p>Background</p><p>Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension.</p><p>Methods and findings</p><p>To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 μg/kg/d and then 60 min at 30 μg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow.</p><p>Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; <i>p <</i> 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study’s main limitations were the relatively small sample size and stable, well-compensated population.</p><p>Conclusions</p><p>Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01640964" target="_blank">NCT01640964</a></p></div

Sensitivity of South American tropical forests to an extreme climate anomaly

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: Publicly available climate data used in this paper are available from ERA5 (ref. 64), CRU ts.4.03 (ref. 65), WorldClim v2 (ref. 66), TRMM product 3B43 V7 (ref. 67) and GPCC, Version 7 (ref. 68). The input data are available on ForestPlots42.Code availability R code for graphics and analyses is available on ForestPlots42.The tropical forest carbon sink is known to be drought sensitive, but it is unclear which forests are the most vulnerable to extreme events. Forests with hotter and drier baseline conditions may be protected by prior adaptation, or more vulnerable because they operate closer to physiological limits. Here we report that forests in drier South American climates experienced the greatest impacts of the 2015–2016 El Niño, indicating greater vulnerability to extreme temperatures and drought. The long-term, ground-measured tree-by-tree responses of 123 forest plots across tropical South America show that the biomass carbon sink ceased during the event with carbon balance becoming indistinguishable from zero (−0.02 ± 0.37 Mg C ha−1 per year). However, intact tropical South American forests overall were no more sensitive to the extreme 2015–2016 El Niño than to previous less intense events, remaining a key defence against climate change as long as they are protected

Measurement of low dietary fiber intake as a risk factor for chronic constipation in children

Background: Scarce information exists regarding dietary fiber intake in children with chronic constipation. the objective of this case-control study was to evaluate the intake of fiber as a risk factor for chronic constipation.Methods: Fifty-two children with a mean age of 6.8 +/- 3.2 years who had chronic constipation were age and gender matched with 52 children with normal intestinal habits. the fiber content of the diet was evaluated with a 24-hour dietary recall. Two tables of fiber composition in foods were used: a Brazilian table, and a table based on the method of the Association of Official Agricultural Chemists (AOAC).Results: According to the Brazilian table, the median intake of fiber (in grams per day) by the constipated and the control groups was 13.8 and 17.3, respectively, for total fiber (p = 0.020), 6.8 and 9.7 for insoluble fiber (p = 0.004), and 6.5 and 7.6 for soluble fiber (p = 0.104). According to the AOAC table, the constipation group (9.7 g/day) also had lower (p = 0.0022) intake of total fiber than the control group (12.6 g/day). the coefficient of correlation between the two tables on fiber content of food was +0.82 (p < 0.001) in the constipation group and +0.86 (p < 0.001) in the control group. the intake of fiber was less than the minimum recommendation (age + 5 g) and statistically associated (p = 0.001) with the constipation group (75.0%) in comparison with the controls (42.5%). the odds ratio was 4.1 (95% confidence limits, 1.64-10.32).Conclusion: Intake of fiber below the minimum recommendation is a risk factor for chronic constipation in children.Universidade Federal de São Paulo, Escola Paulista Med, Div Pediat Gastroenterol, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Div Nutr & Metab, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Div Pediat Gastroenterol, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Div Nutr & Metab, São Paulo, BrazilWeb of Scienc