Effect of nutritional status on response to treatment with artemisinin-based combination therapy in young Ugandan children with malaria.

The relationship between malnutrition and malaria in young children is under debate, and no studies evaluating the association between malnutrition and response to artemisinin-based combination therapies (ACTs) have been published. We evaluated the association between malnutrition and response to antimalarial therapy in Ugandan children treated with ACTs for repeated episodes of malaria. Children aged 4 to 12 months diagnosed with uncomplicated malaria were randomized to dihydroartemisinin-piperaquine (DP) or artemether-lumefantrine (AL) and followed for up to 2 years. All HIV-exposed and HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis (TS). The primary exposure variables included height-for-age and weight-for-age z scores. Outcomes included parasite clearance at days 2 and 3 and risk of recurrent parasitemia after 42 days of follow-up. Two hundred ninety-two children were randomized to DP or AL, resulting in 2,013 malaria treatments. Fewer than 1% of patients had a positive blood smear by day 3 (DP, 0.2%; AL, 0.6% [P = 0.18]). There was no significant association between height-for-age or weight-for-age z scores and a positive blood smear 2 days following treatment. For children treated with DP but not on TS, decreasing height-for-age z scores of <-1 were associated with a higher risk of recurrent parasitemia than a height-for-age z score of >0 (hazard ratio [HR] for height-for-age z score of <-1 and ≥-2 = 2.89 [P = 0.039]; HR for height-for-age z score of <-2 = 3.18 [P = 0.022]). DP and AL are effective antimalarial therapies in chronically malnourished children in a high-transmission setting. However, children with mild to moderate chronic malnutrition not taking TS are at higher risk for recurrent parasitemia and may be considered a target for chemoprevention.

The effect of varying analytical methods on estimates of anti-malarial clinical efficacy.

BACKGROUND: Analytical approaches for the interpretation of anti-malarial clinical trials vary considerably. The aim of this study was to quantify the magnitude of the differences between efficacy estimates derived from these approaches and identify the factors underlying these differences. METHODS: Data from studies conducted in Africa and Thailand were compiled and the risk estimates of treatment failure, adjusted and unadjusted by genotyping, were derived by three methods (intention to treat (ITT), modified intention to treat (mITT) and per protocol (PP)) and then compared. RESULTS: 29 clinical trials (15 from Africa and 14 from Thailand) with a total of 65 treatment arms (38 from Africa and 27 from Thailand) were included in the analysis. Of the 15,409 patients enrolled, 2,637 (17.1%) had incomplete follow up for the unadjusted analysis and 4,489 (33.4%) for the adjusted analysis. Estimates of treatment failure were consistently higher when derived from the ITT or PP analyses compared to the mITT approach. In the unadjusted analyses the median difference between the ITT and mITT estimates was greater in Thai studies (11.4% [range 2.1-31.8]) compared to African Studies (1.8% [range 0-11.7]). In the adjusted analyses the median difference between PP and mITT estimates was 1.7%, but ranged from 0 to 30.9%. The discrepancy between estimates was correlated significantly with the proportion of patients with incomplete follow-up; p < 0.0001. The proportion of studies with a major difference (> 5%) between adjusted PP and mITT was 28% (16/57), with the risk difference greater in African (37% 14/38) compared to Thai studies (11% 2/19). In the African studies, a major difference in the adjusted estimates was significantly more likely in studies in high transmission sites (62% 8/13) compared to studies in moderate transmission sites (24% 6/25); p = 0.035. CONCLUSION: Estimates of anti-malarial clinical efficacy vary significantly depending on the analytical methodology from which they are derived. In order to monitor temporal and spatial trends in anti-malarial efficacy, standardized analytical tools need to be applied in a transparent and systematic manner.

Association between arsenic exposure from drinking water and plasma levels of soluble cell adhesion molecules.

BACKGROUND: Epidemiologic studies of cardiovascular disease risk factors and appropriate biomarkers in populations exposed to a wide range of arsenic levels are a public health research priority. OBJECTIVE: We investigated the relationship between inorganic arsenic exposure from drinking water and plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1), both markers of endothelial dysfunction and vascular inflammation, in an arsenic-exposed population in Araihazar, Bangladesh. METHODS: The study participants included 115 individuals with arsenic-related skin lesions participating in a 2 x 2 randomized, placebo-controlled, double-blind trial of vitamin E and selenium supplementation. Arsenic exposure status and plasma levels of sICAM-1 and sVCAM-1 were assessed at baseline and after 6 months of follow-up. RESULTS: Baseline well arsenic, a long-term measure of arsenic exposure, was positively associated with baseline levels of both sICAM-1 and sVCAM-1 and with changes in the two markers over time. At baseline, for every 1-mug/L increase in well arsenic there was an increase of 0.10 ng/mL [95% confidence interval (CI), 0.00-0.20] and 0.33 ng/mL (95% CI, 0.15-0.51) in plasma sICAM-1 and sVCAM-1, respectively. Every 1-microg/L increase in well arsenic was associated with a rise of 0.11 ng/mL (95% CI, 0.01-0.22) and 0.17 ng/mL (95% CI, 0.00-0.35) in sICAM-1 and sVCAM-1 from baseline to follow-up, respectively, in spite of recent changes in urinary arsenic as well as vitamin E and selenium supplementation during the study period. CONCLUSIONS: The findings indicate an effect of chronic arsenic exposure from drinking water on vascular inflammation that persists over time and also suggest a potential mechanism underlying the association between arsenic exposure and cardiovascular disease.

Changes in gene expression profiles in response to selenium supplementation among individuals with arsenic-induced pre-malignant skin lesions.

The molecular basis and downstream targets of oral selenium supplementation in individuals with elevated risk of cancer due to chronic exposure from environmental carcinogens has been largely unexplored. In this study, we investigated genome-wide differential gene expression in peripheral blood mononuclear cells (PBMC) from individuals with pre-malignant arsenic (As)-induced skin lesions before and after 6 months daily oral supplementation of 200 microg L-selenomethionine. The Affymetrix GeneChip Human 133A 2.0 array, containing probes for 22,277 gene transcripts, was used to assess gene expression. Three different normalization methods, RMA (robust multi-chip analysis), GC-RMA and PLIER (Probe logarithmic intensity error), were applied to explore differentially expressed genes. We identified a list of 28 biologically meaningful, significantly differentially expressed genes. Genes up-regulated by selenium supplementation included TNF, IL1B, IL8, SOD2, CXCL2 and several other immunological and oxidative stress-related genes. When mapped to a biological association network, many of the differentially expressed genes were found to regulate functional classes such as fibroblast growth factor, collagenase, matrix metalloproteinase and stromelysin-1, and thus, considered to affect cellular processes like apoptosis, proliferation and others. Many of the significantly up-regulated genes following selenium-supplementation were previously found by us to be down-regulated in a different set of individuals with As-induced skin lesions compared to those without. In conclusion, findings from this study may elucidate the biological effect of selenium supplementation in humans. Additionally, this study suggests that long-term selenium supplementation may revert some of the gene expression changes presumably induced by chronic As exposure in individuals with pre-malignant skin lesions.

A randomized, double-blind placebo-controlled trial evaluating the effects of vitamin E and selenium on arsenic-induced skin lesions in Bangladesh.

OBJECTIVE: We sought to determine whether supplementation of vitamin E (alpha-tocopherol), selenium (L-selenomethionine), or their combination improves arsenical skin lesions. METHODS: A 2 x 2 randomized, placebo-controlled, double-blind trial among 121 men and women chronically exposed to arsenic in drinking water was conducted in rural Bangladesh. Participants were randomized to one of four treatment arms: vitamin E, selenium, vitamin E and selenium (combination), or placebo and were treated for 6 months. RESULTS: At baseline, the average skin lesion scores were 2.23, 2.26, and 2.63 and at follow-up, the average skin lesion scores went down to 2.00, 2.06, and 2.47 in those receiving vitamin E, selenium, and the combination, respectively. CONCLUSIONS: Supplementation with vitamin E and selenium, either alone or in combination, slightly improved skin lesion status, although the improvement was not statistically significant.