Effect of preventive supplementation with zinc and other micronutrients on non-malarial morbidity in Tanzanian pre-school children: a randomized trial.

BACKGROUND: The efficacy of preventive zinc supplementation against diarrhea and respiratory illness may depend on simultaneous supplementation with other micronutrients. We aimed to assess the effect of supplementation with zinc and multiple micronutrients on diarrhea and other causes of non-malarial morbidity. METHODS AND FINDINGS: Rural Tanzanian children (n = 612) aged 6-60 months and with height-for-age z-score < -1.5 SD were randomized to daily supplementation with zinc (10 mg) alone, multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Children were followed for an average of 45 weeks. During follow-up, we recorded morbidity episodes. We found no evidence that concurrent supplementation with multi-nutrients influenced the magnitude of the effect of zinc on rates of diarrhea, respiratory illness, fever without localizing signs, or other illness (guardian-reported illness with symptoms involving skin, ears, eyes and abscesses, but excluding trauma or burns). Zinc supplementation reduced the hazard rate of diarrhea by 24% (4%-40%). By contrast, multi-nutrients seemed to increase this rate (HR; 95% CI: 1.19; 0.94-1.50), particularly in children with asymptomatic Giardia infection at baseline (2.03; 1.24-3.32). Zinc also protected against episodes of fever without localizing signs (0.75; 0.57-0.96), but we found no evidence that it reduced the overall number of clinic visits. CONCLUSIONS: We found no evidence that the efficacy of zinc supplements in reducing diarrhea rates is enhanced by concurrent supplementation with other micronutrients. By reducing rates of fever without localizing signs, supplementation with zinc may reduce inappropriate drug use with anti-malarial medications and antibiotics. TRIAL REGISTRATION: ClinicalTrials.gov NCT00623857.

Effect of supplementation with zinc and other micronutrients on malaria in Tanzanian children: a randomised trial.

BACKGROUND: It is uncertain to what extent oral supplementation with zinc can reduce episodes of malaria in endemic areas. Protection may depend on other nutrients. We measured the effect of supplementation with zinc and other nutrients on malaria rates. METHODS AND FINDINGS: In a 2×2 factorial trial, 612 rural Tanzanian children aged 6-60 months in an area with intense malaria transmission and with height-for-age z-score≤-1.5 SD were randomized to receive daily oral supplementation with either zinc alone (10 mg), multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Intervention group was indicated by colour code, but neither participants, researchers, nor field staff knew who received what intervention. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. The primary outcome, an episode of malaria, was assessed among children reported sick at a primary care clinic, and pre-defined as current Plasmodium infection with an inflammatory response, shown by axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥ 8 mg/L. Nutritional indicators were assessed at baseline and at 251 days (median; 95% reference range: 191-296 days). In the primary intention-to-treat analysis, we adjusted for pre-specified baseline factors, using Cox regression models that accounted for multiple episodes per child. 592 children completed the study. The primary analysis included 1,572 malaria episodes during 526 child-years of observation (median follow-up: 331 days). Malaria incidence in groups receiving zinc, multi-nutrients without zinc, multi-nutrients with zinc and placebo was 2.89/child-year, 2.95/child-year, 3.26/child-year, and 2.87/child-year, respectively. There was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Neither zinc nor multi-nutrients influenced malaria rates (marginal analysis; adjusted HR, 95% CI: 1.04, 0.93-1.18 and 1.10, 0.97-1.24 respectively). The prevalence of zinc deficiency (plasma zinc concentration <9.9 µmol/L) was high at baseline (67% overall; 60% in those without inflammation) and strongly reduced by zinc supplementation. CONCLUSIONS: We found no evidence from this trial that zinc supplementation protected against malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT00623857

Determinants of red cell distribution width (RDW) in cardiorenal patients: RDW is not related to erythropoietin resistance.

BACKGROUND: Studies have shown that red cell distribution width (RDW) is related to outcome in chronic heart failure (CHF). The pathophysiological process is unknown. We studied the relationship between RDW and erythropoietin (EPO) resistance, and related factors such as erythropoietic activity, functional iron availability and hepcidin. METHODS AND RESULTS: In the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome (EPOCARES) study, which investigates the role of EPO in 54 iron-supplemented anemic patients with CHF and chronic kidney disease (CKD) (n = 35 treated with 50 IU/kg/wk Epopoetin beta, n = 19 control), RDW was not associated with EPO resistance. We defined EPO resistance by EPO levels (r = 0.12, P = .42), the observed/predicted log EPO ratio (r = 0.12, P = .42), the increase in reticulocytes after 2 weeks of EPO treatment (r = -0.18, P = .31), and the increase of hemoglobin after 6 months of EPO treatment (r = 0.26, P = .35). However, RDW was negatively correlated with functional iron availability (reticulocyte hemoglobin content, r = -0.48, P < .001, and transferrin saturation, r = -0.39, P = .005) and positively with erythropoietic activity (soluble transferrin receptor, r = 0.48, P < .001, immature reticulocyte fraction, r = 0.36, P = .01) and positively with interleukin-6 (r = 0.48, P < .001). No correlation existed between hepcidin-25 and RDW. CONCLUSIONS: EPO resistance was not associated with RDW. RDW was associated with functional iron availability, erythropoietic activity, and interleukin-6 in anemic patients with CHF and CKD.

Polyphenolic grape extract inhibits platelet activation through PECAM-1: an explanation for the French paradox.

BACKGROUND: Moderate and prolonged consumption of red wine is associated with decreased cardiovascular morbidity and mortality. Inhibition of platelet functions by ingredients in red wine is thought to be one of the causes. However, the molecular mechanism of this inhibition has remained unexplained. MATERIALS AND METHODS: We measured aggregation, changes in cytosolic Ca(2+) and tyrosine phosphorylation of the inhibitory receptor platelet endothelial cell adhesion molecule-1 (PECAM-1) in platelets stimulated with thrombin receptor (PAR-1) activating peptide (TRAP) and ADP and investigated the effects of alcohol-free polyphenolic grape extract (PGE), alcohol, and the polyphenols catechin, epi-catechin, resveratrol, trans-resveratrol, and gallic acid. RESULTS: Polyphenolic grape extract induced dose-dependent inhibition of TRAP-induced and ADP-induced platelet aggregation and Ca(2+) mobilization. Inhibition was accompanied by activation of PECAM-1. Apart from a slight inhibition by catechin, ethanol or other individual polyphenols failed to inhibit aggregation or activate PECAM-1. CONCLUSIONS: Red wine inhibits platelet functions through its PGE content, which stimulates the inhibitory receptor PECAM-1, thereby attenuating platelet activation.