Patterns of Schistosoma haematobium infection, impact of praziquantel treatment and re-infection after treatment in a cohort of schoolchildren from rural KwaZulu-Natal/South Africa

BACKGROUND: Schistosomiasis is one of the major health problems in tropical and sub-tropical countries, with school age children usually being the most affected group. In 1998 the Department of Health of the province of KwaZulu-Natal established a pilot programme for helminth control that aimed at regularly treating primary school children for schistosome and intestinal helminth infections. This article describes the baseline situation and the impact of treatment on S. haematobium infection in a cohort of schoolchildren attending grade 3 in a rural part of the province. METHODS: Primary schoolchildren from Maputaland in northern KwaZulu-Natal were examined for Schistosoma haematobium infection, treated with praziquantel and re-examined four times over one year after treatment in order to assess the impact of treatment and patterns of infection and re-infection. RESULTS: Praziquantel treatment was highly efficacious at three weeks after treatment when judged by egg reduction rate (95.3%) and cure rate of heavy infections (94.1%). The apparent overall cure rate three weeks after treatment (57.9%) was much lower but improved to 80.7% at 41 weeks after treatment. Re-infection with S. haematobium was low and appeared to be limited to the hot and rainy summer. Analysis of only one urine specimen per child considerably underestimated prevalence when compared to the analysis of two specimens, but both approaches provided similar estimates of the proportion of heavy infections and of average infection intensity in the population. CONCLUSION: According to WHO guidelines the high prevalence and intensity of S. haematobium infection necessitate regular treatment of schoolchildren in the area. The seasonal transmission pattern together with the slow pace of re-infection suggest that one treatment per year, applied after the end of summer, is sufficient to keep S. haematobium infection in the area at low levels

Patterns of geohelminth infection, impact of albendazole treatment and re-infection after treatment in schoolchildren from rural KwaZulu-Natal/South-Africa

BACKGROUND: Geohelminth infection is a major health problem of children from rural areas of developing countries. In an attempt to reduce this burden, the Department of Health of the province of KwaZulu-Natal (KZN) established in 1998 a programme for helminth control that aimed at regularly treating primary school children for schistosomiasis and intestinal helminths. This article describes the baseline situation and the effect of treatment on geohelminth infection in a rural part of the province. METHODS: Grade 3 schoolchildren from Maputaland in northern KZN were examined for infections with hookworm, Ascaris lumbricoides, and Trichuris trichiura, treated twice with 400 mg albendazole and re-examined several times over one year after the first treatment in order to assess the impact of treatment and patterns of infection and re-infection. RESULTS: The hookworm prevalence in the study population (83.2%) was considerably higher than in other parts of the province whereas T. trichiura and especially A. lumbricoides prevalences (57.2 and 19.4%, respectively) were much lower than elsewhere on the KZN coastal plain. Single dose treatment with albendazole was very effective against hookworm and A. lumbricoides with cure rates (CR) of 78.8 and 96.4% and egg reduction rates (ERR) of 93.2 and 97.7%, respectively. It was exceptionally ineffective against T. trichiura (CR = 12.7%, ERR = 24.8%). Re-infection with hookworm and A. lumbricoides over 29 weeks after treatment was considerable but still well below pre-treatment levels. CONCLUSION: High geohelminth prevalences and re-infection rates in the study population confirm the need for regular treatment of primary school children in the area. The low effectiveness of single course albendazole treatment against T. trichiura infection however demands consideration of alternative treatment approaches

Corticosteroid-Induced Immunosuppression ultimately does not compromise the efficacy of antibiotherapy in murine mycobacterium ulcerans Infection

Buruli ulcer (BU) is a necrotizing disease of the skin, subcutaneous tissue and bone caused by Mycobacterium ulcerans. It has been suggested that the immune response developed during the recommended rifampicin/streptomycin (RS) antibiotherapy is protective, contributing to bacterial clearance. On the other hand, paradoxical reactions have been described during or after antibiotherapy, characterized by pathological inflammatory responses. This exacerbated inflammation could be circumvented by immunosuppressive drugs. Therefore, it is important to clarify if the immune system contributes to bacterial clearance during RS antibiotherapy and if immunosuppression hampers the efficacy of the antibiotic regimen. METHODOLOGY/PRINCIPAL FINDINGS: We used the M. ulcerans infection footpad mouse model. Corticosteroid-induced immunosuppression was achieved before experimental infection and maintained during combined RS antibiotherapy by the administration of dexamethasone (DEX). Time-lapsed analyses of macroscopic lesions, bacterial burdens, histology and immunohistochemistry were performed in M. ulcerans-infected footpads. We show here that corticosteroid-immunosuppressed mice are more susceptible to M. ulcerans, with higher bacterial burdens and earlier ulceration. Despite this, macroscopic lesions remised during combined antibiotic/DEX treatment and no viable bacteria were detected in the footpads after RS administration. This was observed despite a delayed kinetics in bacterial clearance, associated with a local reduction of T cell and neutrophil numbers, when compared with immunocompetent RS-treated mice. In addition, no relapse was observed following an additional 3 month period of DEX administration. CONCLUSIONS/SIGNIFICANCE: These findings reveal a major role of the RS bactericidal activity for the resolution of M. ulcerans experimental infections even during immunosuppression, and support clinical investigation on the potential use of corticosteroids or other immunosuppressive/anti-inflammatory drugs for the management of BU patients undergoing paradoxical reactions.This work was supported by a grant from the Health Services of Fundação Calouste Gulbenkian, and the Portuguese Science and Technology Foundation (FCT) fellowships SFRH/BD/41598/2007, SFRH/BPD/64032/2009, SFRH/BPD/68547/2010 and SFRH/BD/33573/2009 to TGM, GT, AGF, and JBG, respectively. MS is a Ciência 2007 fello

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

The MSX1 allele 4 homozygous child exposed to smoking at periconception is most sensitive in developing nonsyndromic orofacial clefts

Nonsyndromic orofacial clefts (OFC) are common birth defects caused by certain genes interacting with environmental factors. Mutations and association studies indicate that the homeobox gene MSX1 plays a role in human clefting. In a Dutch case-control triad study (mother, father, and child), we investigated interactions between MSX1 and the parents' periconceptional lifestyle in relation to the risk of OFC in their offspring. We s

Saccadic Eye Movements Minimize the Consequences of Motor Noise

The durations and trajectories of our saccadic eye movements are remarkably stereotyped. We have no voluntary control over these properties but they are determined by the movement amplitude and, to a smaller extent, also by the movement direction and initial eye orientation. Here we show that the stereotyped durations and trajectories are optimal for minimizing the variability in saccade endpoints that is caused by motor noise. The optimal duration can be understood from the nature of the motor noise, which is a combination of signal-dependent noise favoring long durations, and constant noise, which prefers short durations. The different durations of horizontal vs. vertical and of centripetal vs. centrifugal saccades, and the somewhat surprising properties of saccades in oblique directions are also accurately predicted by the principle of minimizing movement variability. The simple and sensible principle of minimizing the consequences of motor noise thus explains the full stereotypy of saccadic eye movements. This suggests that saccades are so stereotyped because that is the best strategy to minimize movement errors for an open-loop motor system

Heparanase expression is a prognostic indicator for postoperative survival in pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma has a median survival of less than 6 months from diagnosis. This is due to the difficulty in early diagnosis, the aggressive biological behaviour of the tumour and a lack of effective therapies for advanced disease. Mammalian heparanase is a heparan-sulphate proteoglycan cleaving enzyme. It helps to degrade the extracellular matrix and basement membranes and is involved in angiogenesis. Degradation of extracellular matrix and basement membranes as well as angiogenesis are key conditions for tumour cell spreading. Therefore, we have analysed the expression of heparanase in human pancreatic cancer tissue and cell lines. Heparanase is expressed in cell lines derived from primary tumours as well as from metastatic sites. By immunohistochemical analysis, it is preferentially expressed at the invading edge of a tumour at both metastatic and primary tumour sites. There is a trend towards heparanase expression in metastasising tumours as compared to locally growing tumours. Postoperative survival correlates inversely with heparanase expression of the tumour reflected by a median survival of 34 and 17 month for heparanase negative and positive tumours, respectively. Our results suggest, that heparanase promotes cancer cell invasion in pancreatic carcinoma and could be used as a prognostic indicator for postoperative survival of patients

Genome wide linkage study, using a 250K SNP map, of Plasmodium falciparum infection and mild malaria attack in a Senegalese population

Multiple factors are involved in the variability of host's response to P. falciparum infection, like the intensity and seasonality of malaria transmission, the virulence of parasite and host characteristics like age or genetic make-up. Although admitted nowadays, the involvement of host genetic factors remains unclear. Discordant results exist, even concerning the best-known malaria resistance genes that determine the structure or function of red blood cells. Here we report on a genomewide linkage and association study for P. falciparum infection intensity and mild malaria attack among a Senegalese population of children and young adults from 2 to 18 years old. A high density single nucleotide polymorphisms (SNP) genome scan (Affimetrix GeneChip Human Mapping 250K-nsp) was performed for 626 individuals: i.e. 249 parents and 377 children out of the 504 ones included in the follow-up. The population belongs to a unique ethnic group and was closely followed-up during 3 years. Genome-wide linkage analyses were performed on four clinical and parasitological phenotypes and association analyses using the family based association tests (FBAT) method were carried out in regions previously linked to malaria phenotypes in literature and in the regions for which we identified a linkage peak. Analyses revealed three strongly suggestive evidences for linkage: between mild malaria attack and both the 6p25.1 and the 12q22 regions (empirical p-value = 5 x 10(-5) and 96 x 10(-5) respectively), and between the 20p11q11 region and the prevalence of parasite density in asymptomatic children (empirical p-value = 1.5 x 10(-4)). Family based association analysis pointed out one significant association between the intensity of plasmodial infection and a polymorphism located in ARHGAP26 gene in the 5q31-q33 region (p-value = 3.7 x 10(-5)). This study identified three candidate regions, two of them containing genes that could point out new pathways implicated in the response to malaria infection. Furthermore, we detected one gene associated with malaria infection in the 5q31-q33 region

Optimization of Muscle Activity for Task-Level Goals Predicts Complex Changes in Limb Forces across Biomechanical Contexts

Optimality principles have been proposed as a general framework for understanding motor control in animals and humans largely based on their ability to predict general features movement in idealized motor tasks. However, generalizing these concepts past proof-of-principle to understand the neuromechanical transformation from task-level control to detailed execution-level muscle activity and forces during behaviorally-relevant motor tasks has proved difficult. In an unrestrained balance task in cats, we demonstrate that achieving task-level constraints center of mass forces and moments while minimizing control effort predicts detailed patterns of muscle activity and ground reaction forces in an anatomically-realistic musculoskeletal model. Whereas optimization is typically used to resolve redundancy at a single level of the motor hierarchy, we simultaneously resolved redundancy across both muscles and limbs and directly compared predictions to experimental measures across multiple perturbation directions that elicit different intra- and interlimb coordination patterns. Further, although some candidate task-level variables and cost functions generated indistinguishable predictions in a single biomechanical context, we identified a common optimization framework that could predict up to 48 experimental conditions per animal (n = 3) across both perturbation directions and different biomechanical contexts created by altering animals' postural configuration. Predictions were further improved by imposing experimentally-derived muscle synergy constraints, suggesting additional task variables or costs that may be relevant to the neural control of balance. These results suggested that reduced-dimension neural control mechanisms such as muscle synergies can achieve similar kinetics to the optimal solution, but with increased control effort (≈2×) compared to individual muscle control. Our results are consistent with the idea that hierarchical, task-level neural control mechanisms previously associated with voluntary tasks may also be used in automatic brainstem-mediated pathways for balance