Artesunate-mefloquine combination therapy in acute Plasmodium falciparum malaria in young children: a field study regarding neurological and neuropsychiatric safety

BACKGROUND: Mefloquine-artesunate combination therapy for uncomplicated falciparum malaria is one of the treatments used in African children. Data concerning neurological safety in adults and children treated with mefloquine and artesunate combination therapy is well documented in Asia. Safety data for neurological and neuropsychiatric side effects of mefloquine and artesunate combination therapy in African children are scarce, although WHO recommends this therapy in Africa. METHODS: A phase IV, open label, single arm study was conducted among African children between 10 and 20 kg with acute uncomplicated falciparum malaria. They were treated over three consecutive days with a paediatric fixed-dose combination of artesunate (50 mg/d) and mefloquine (125 mg/d). Parasitological, clinical and neurological examinations and standardized questions about neuropsychiatric symptoms were carried out on days 0, 4, 7, 28 and 63. The primary objective was to assess the neurological and neuropsychiatric safety of artesunate-mefloquine combination therapy in young children. RESULTS: From December 2007 to March 2009, 220 children with uncomplicated Plasmodium falciparum malaria were treated with artesunate and mefloquine. 213 children were analysed according to study protocol. 50 neurological and neuropsychiatric adverse events occurred in 28 patients. Eleven drug-related neurological and neuropsychiatric adverse events occurred in eight patients. Sleeping disorders were present in 2.3%, neurological disorders in 1.4%, neuropsychiatric disorders in 1% and eating disorders in 0.5% of the patients. Adverse events were of mild to moderate intensity and resolved spontaneously. CONCLUSION: African children showed a low percentage of self-limited neurological and neuropsychiatric adverse events, confirming studies on neurological safety in Asian children treated with artesunate and mefloquine. Sleeping disorders were most frequently observed

Mechanochemical modeling of dynamic microtubule growth involving sheet-to-tube transition

Microtubule dynamics is largely influenced by nucleotide hydrolysis and the resultant tubulin configuration changes. The GTP cap model has been proposed to interpret the stabilizing mechanism of microtubule growth from the view of hydrolysis effects. Besides, the microtubule growth involves the closure of a curved sheet at its growing end. The curvature conversion also helps to stabilize the successive growth, and the curved sheet is referred to as the conformational cap. However, there still lacks theoretical investigation on the mechanical-chemical coupling growth process of microtubules. In this paper, we study the growth mechanisms of microtubules by using a coarse-grained molecular method. Firstly, the closure process involving a sheet-to-tube transition is simulated. The results verify the stabilizing effect of the sheet structure, and the minimum conformational cap length that can stabilize the growth is demonstrated to be two dimers. Then, we show that the conformational cap can function independently of the GTP cap, signifying the pivotal role of mechanical factors. Furthermore, based on our theoretical results, we describe a Tetris-like growth style of microtubules: the stochastic tubulin assembly is regulated by energy and harmonized with the seam zipping such that the sheet keeps a practically constant length during growth.Comment: 23 pages, 7 figures. 2 supporting movies have not been uploaded due to the file type restriction

Maternal common mental disorders and infant development in Ethiopia : the P-MaMiE Birth Cohort

Background: Chronicity and severity of early exposure to maternal common mental disorders (CMD) has been associated with poorer infant development in high-income countries. In low- and middle-income countries (LAMICs), perinatal CMD is inconsistently associated with infant development, but the impact of severity and persistence has not been examined. Methods: A nested population-based cohort of 258 pregnant women was identified from the Perinatal Maternal Mental Disorder in Ethiopia (P-MaMiE) study, and 194 (75.2%) were successfully followed up until the infants were 12 months of age. Maternal CMD was measured in pregnancy and at two and 12 months postnatal using the WHO Self-Reporting Questionnaire, validated for use in this setting. Infant outcomes were evaluated using the Bayley Scales of Infant Development. Results: Antenatal maternal CMD symptoms were associated with poorer infant motor development ( β ^ -0.20; 95% CI: -0.37 to -0.03), but this became non-significant after adjusting for confounders. Postnatal CMD symptoms were not associated with any domain of infant development. There was evidence of a dose-response relationship between the number of time-points at which the mother had high levels of CMD symptoms (SRQ ≥ 6) and impaired infant motor development ( β ^ = -0.80; 95%CI -2.24, 0.65 for ante- or postnatal CMD only, β ^ = -4.19; 95%CI -8.60, 0.21 for ante- and postnatal CMD, compared to no CMD; test-for-trend χ213.08(1), p < 0.001). Although this association became non-significant in the fully adjusted model, the β ^ coefficients were unchanged indicating that the relationship was not confounded. In multivariable analyses, lower socio-economic status and lower infant weight-for-age were associated with significantly lower scores on both motor and cognitive developmental scales. Maternal experience of physical violence was significantly associated with impaired cognitive development. Conclusions: The study supports the hypothesis that it is the accumulation of risk exposures across time rather than early exposure to maternal CMD per se that is more likely to affect child development. Further investigation of the impact of chronicity of maternal CMD upon child development in LAMICs is indicated. In the Ethiopian setting, poverty, interpersonal violence and infant undernutrition should be targets for interventions to reduce the loss of child developmental potential.Peer Reviewe

Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial

Diana Gibb and colleagues investigate the effect of in utero tenofovir exposure by analyzing the pregnancy and infant outcomes of HIV-infected women enrolled in the DART trial

Socioeconomic Status (SES) and Children's Intelligence (IQ): In a UK-Representative Sample SES Moderates the Environmental, Not Genetic, Effect on IQ

The environment can moderate the effect of genes - a phenomenon called gene-environment (GxE) interaction. Several studies have found that socioeconomic status (SES) modifies the heritability of children's intelligence. Among low-SES families, genetic factors have been reported to explain less of the variance in intelligence; the reverse is found for high-SES families. The evidence however is inconsistent. Other studies have reported an effect in the opposite direction (higher heritability in lower SES), or no moderation of the genetic effect on intelligence