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    ABSTRACT: Severe malaria manifests as several overlapping syndromes with high mortality. Interaction of parasites with endothelial protein C receptors and high parasite biomass have recently been identified as key determinants of severe disease. However, gaps in our understanding of severe malaria might hinder translation of these findings into new therapies.
    Science translational medicine 11/2013; 5(211):211ps18.
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    ABSTRACT: Severe malaria defines individuals at increased risk of death from their infection. Proposed pathogenic mechanisms include parasite sequestration, inflammation, and endothelial dysfunction. Severe malaria is not a single entity, manifesting with distinct syndromes such as severe anemia, severe respiratory distress or coma, each characterized by differences in epidemiology, underlying biology, and risk of death. The relative contribution of the various pathogenic mechanisms may differ between syndromes, and this is supported by accumulating evidence, which challenges sequestration as the initiating event. Here we propose that high parasite biomass is the common initiating feature, but subtle variations in the interaction between the host and parasite exist, and understanding these differences may be crucial to improve outcomes in patients with severe malaria.
    Trends in Parasitology 11/2013;
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    ABSTRACT: Heat shock proteins are classified into six main families, of which HSP70 is the best studied. HSP70 is postulated to modulate the immune/inflammatory response in critical illness. Glutamine promotes HSP70 release, however, little is known about the relationship between glutamine and HSP70 in paediatric critical illness. We therefore aimed to describe plasma levels of HSP70, inflammatory mediators and glutamine in critically ill children. A clinical audit identified 143 children with severe meningococcal disease, 78 convalescent children, in addition to 35 healthy paediatric controls. Stored plasma was used to measure plasma concentrations of HSP70, inflammatory mediators and glutamine. HSP70 was significantly increased on admission (n = 143, mean 26.7 ng/ml; ±SD 79.95) compared with convalescence (n = 78, mean 3.16 ng/ml; ±SD 5.67). Glutamine levels were low (n = 132, mean 0.31 mmol/l; ±SD 0.13), which continued in convalescence (n = 65, mean 0.40 mmol/l; ±SD 0.14). Enteral glutamine provided only 28% of the recommendations. Glutamine was inversely correlated with length-of-stay (n = 98, r = -0.520, p < 0.001), ventilation (n = 98, r = -0.513, p < 0.001), lactate (n = 98, r = -0.41, p < 0.001) and CRP (n = 98, r = -0.51, p < 0.001). HSP70 was correlated with length-of-stay (n = 99, r = 0.30, p < 0.001), ventilation (n = 99, r = 0.31, p < 0.001), lactate (n = 99, r = 0.26, p < 0.001) and CRP (n = 99, r = 0.29, p < 0.001) and inflammatory mediators. There was no relationship between glutamine and HSP70 or inflammatory mediators. During acute illness HSP70/inflammatory mediators are significantly increased, and glutamine is significantly depleted. However, glutamine and HSP70 were not correlated. Enteral feeds only provided a small proportion of the ASPEN/ESPEN recommendations for glutamine.
    Clinical nutrition (Edinburgh, Scotland) 10/2013;
  • Allergy 10/2013; 68(10):1341-2.
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    ABSTRACT: To determine whether antepartum factors alone, intrapartum factors alone, or both in combination, are associated with term neonatal hypoxic-ischemic encephalopathy (HIE).METHODS:A total of 405 infants ≥35 weeks' gestation with early encephalopathy, born between 1992 and 2007, were compared with 239 neurologically normal infants born between 1996 and 1997. All cases met criteria for perinatal asphyxia, had neuroimaging findings consistent with acute hypoxia-ischemia, and had no evidence for a non-hypoxic-ischemic cause of their encephalopathy.RESULTS:Both antepartum and intrapartum factors were associated with the development of HIE on univariate analysis. Case infants were more often delivered by emergency cesarean delivery (CD; 50% vs 11%, P < .001) and none was delivered by elective CD (vs 10% of controls). On logistic regression analysis only 1 antepartum factor (gestation ≥41 weeks) and 7 intrapartum factors (prolonged membrane rupture, abnormal cardiotocography, thick meconium, sentinel event, shoulder dystocia, tight nuchal cord, failed vacuum) remained independently associated with HIE (area under the curve 0.88; confidence interval 0.85-0.91; P < .001). Overall, 6.7% of cases and 43.5% of controls had only antepartum factors; 20% of cases and 5.8% of controls had only intrapartum factors; 69.5% of cases and 31% of controls had antepartum and intrapartum factors; and 3.7% of cases and 19.7% of controls had no identifiable risk factors (P < .001).CONCLUSIONS:Our results do not support the hypothesis that HIE is attributable to antepartum factors alone, but they strongly point to the intrapartum period as the necessary factor in the development of this condition.
    PEDIATRICS 09/2013;
  • The Journal of allergy and clinical immunology 08/2013;
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    ABSTRACT: Neisseria meningitidis is a commensal of humans that can colonise the nasopharyngeal epithelium for weeks to months, and occasionally invades to cause life-threatening septicaemia and meningitis. Comparatively little is known about meningococcal gene expression during colonisation beyond those first few hours. In this study, the transcriptome of adherent serogroup B N. meningitidis strain MC58 was determined at intervals during prolonged co-cultivation with confluent monolayers of the human respiratory epithelial cell line 16HBE14. At different time points up to 21 days, 7 - 14% of the meningococcal genome was found to be differentially regulated. The transcriptome of adherent meningococci obtained after 4 hours of co-culture was markedly different from that obtained after prolonged co-cultivation (24 hours, 96 hours and 21 days). Genes persistently up-regulated during prolonged co-cultivation included three (hfq, misR/phoP and lrp) encoding global regulatory proteins. Many genes encoding known adhesins involved in epithelial adherence were up-regulated, including those of a novel locus encoding epithelial adhesive function (NMB0342 - NMB0348). Sixteen genes (including porA, porB, rmpM and fbpA) encoding proteins previously identified by their immunoreactivity to sera from individuals colonised long term with serogroup B meningococci were also up-regulated during prolonged co-cultivation, indicating that our system models growth conditions in vivo during the commensal state. Surface-expressed proteins down-regulated in the nasopharynx (and so less subject to selection pressure) but upregulated in the bloodstream (and so vulnerable to antibody-mediated bactericidal activity) should be interesting candidate vaccine antigens, and in this study three new proteins fulfilling these criteria have been identified - NMB0497, NMB0866 and NMB1882.
    Infection and immunity 08/2013;
  • Current opinion in pediatrics 08/2013; 25(4):549-50.
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    ABSTRACT: Observational studies suggest high prenatal vitamin D intake may be associated with reduced childhood wheezing. We examined the effect of prenatal vitamin D on childhood wheezing in an interventional study. We randomised 180 pregnant women at 27 weeks gestation to either no vitamin D, 800 IU ergocalciferol daily until delivery or single oral bolus of 200,000 IU cholecalciferol, in an ethnically stratified, randomised controlled trial. Supplementation improved but did not optimise vitamin D status. Researchers blind to allocation assessed offspring at 3 years. Primary outcome was any history of wheeze assessed by validated questionnaire. Secondary outcomes included atopy, respiratory infection, impulse oscillometry and exhaled nitric oxide. Primary analyses used logistic and linear regression. We evaluated 158 of 180 (88%) offspring at age 3 years for the primary outcome. Atopy was assessed by skin test for 95 children (53%), serum IgE for 86 (48%), exhaled nitric oxide for 62 (34%) and impulse oscillometry of acceptable quality for 51 (28%). We found no difference between supplemented and control groups in risk of wheeze [no vitamin D: 14/50 (28%); any vitamin D: 26/108 (24%) (risk ratio 0.86; 95% confidence interval 0.49, 1.50; P = 0.69)]. There was no significant difference in atopy, eczema risk, lung function or exhaled nitric oxide between supplemented groups and controls. Prenatal vitamin D supplementation in late pregnancy that had a modest effect on cord blood vitamin D level, was not associated with decreased wheezing in offspring at age three years. Controlled-Trials.com ISRCTN68645785.
    PLoS ONE 06/2013; 8(6):e66627.
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    ABSTRACT: The development of vaccines against tuberculosis continues to be hindered by the lack of correlates of protection. Immunity to Mycobacterium tuberculosis (M.tb) infection relies predominantly on cell mediated response, which are routinely measured using a read-out of host cytokine profiles, However, to date none of the cytokine profiles have been found to predict protection. A number of functional in vitro approaches have been developed that measure growth of mycobacteria pre and post vaccination as a potential functional surrogate marker for vaccine take. The use of a reporter-gene tagged BCG-lux assay measuring the viability of mycobacteria in whole blood samples has previously been described by our group to assess vaccine immunogenicity. Since only very small blood samples are usually available in paediatric studies, we now report a modification of the BCG-lux assay to reduce the volume required and make it more field-friendly. Our results show that a 2-fold reduction in blood volume made no significant difference to bacterial growth ratios, used as the main read-out. These results confirm the suitability of the BCG-lux assay for functional studies of vaccine immunogenicity and immunopathogenesis in young children and could play a role in late-phase TB vaccine trials of novel candidates.
    Journal of immunological methods 05/2013;
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