Declining responsiveness of Plasmodium falciparum infections to artemisinin-based combination treatments on the Kenyan coast

Background

The emergence of artemisinin-resistant P. falciparum malaria in South-East Asia highlights the need for continued global surveillance of the efficacy of artemisinin-based combination therapies.

Methods

On the Kenyan coast we studied the treatment responses in 474 children 6–59 months old with uncomplicated P. falciparum malaria in a randomized controlled trial of dihydroartemisinin-piperaquine vs. artemether-lumefantrine from 2005 to 2008. (ISRCTN88705995)

Results

The proportion of patients with residual parasitemia on day 1 rose from 55% in 2005–2006 to 87% in 2007–2008 (odds ratio, 5.4, 95%CI, 2.7–11.1; P<0.001) and from 81% to 95% (OR, 4.1, 95%CI, 1.7–9.9; P = 0.002) in the DHA-PPQ and AM-LM groups, respectively. In parallel, Kaplan-Meier estimated risks of apparent recrudescent infection by day 84 increased from 7% to 14% (P = 0.1) and from 6% to 15% (P = 0.05) with DHA-PPQ and AM-LM, respectively. Coinciding with decreasing transmission in the study area, clinical tolerance to parasitemia (defined as absence of fever) declined between 2005–2006 and 2007–2008 (OR body temperature >37.5°C, 2.8, 1.9–4.1; P<0.001). Neither in vitro sensitivity of parasites to DHA nor levels of antibodies against parasite extract accounted for parasite clearance rates or changes thereof.

Conclusions

The significant, albeit small, decline through time of parasitological response rates to treatment with ACTs may be due to the emergence of parasites with reduced drug sensitivity, to the coincident reduction in population-level clinical immunity, or both. Maintaining the efficacy of artemisinin-based therapy in Africa would benefit from a better understanding of the mechanisms underlying reduced parasite clearance rates.

Trial Registration

Controlled-Trials.com ISRCTN88705995     

Vitamin E and selenium treatment of monocrotaline induced hepatotoxicity in rats

Monocrotaline (MCT) is a hepatotoxic pyrrolizidine alkaloid that is derived from plants; exposure may occur by consumption of contaminated grains, herbal teas and medicines. MCT can cause liver damage. We investigated the antioxidant effects of selenium (Se) and vitamin E against the toxic effects of MCT. Female Wistar albino rats were divided into four groups: a control group, an MCT group, an MCT + Se group, and an MCT + vitamin E group. Liver tissues were harvested, fixed, processed to paraffin and sections were cut. Anti-von Willebrand factor (vWF) immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL), and hematoxylin and eosin staining were performed. Serum and liver tissue glutathione (GSH), catalase (CAT), and glutathione peroxidase (GPx) levels were measured. Histopathological and TUNEL data showed significantly increased liver damage in the MCT group compared to controls. Histopathological and TUNEL staining indicated significant improvements in the MCT + vitamin E and MCT + Se groups compared to the MCT group. MCT significantly reduced the serum GSH level and GPx activity, and liver GPx activity. Biochemical data indicated a significant improvement in serum GSH level in the MCT + vitamin E group compared to the MCT group. We suggest that vitamin E and Se afford limited protection against MCT hepatotoxicity.     

Genotype and environment determine allocation to and costs of resistance in quaking aspen

Although genetic variability and resource availability both influence plant chemical composition, little is known about how these factors interact to modulate costs of resistance, expressed as negative correlations between growth and defense. We evaluated genotype × environment effects on foliar chemistry and growth of quaking aspen (Populus tremuloides) by growing multiple aspen genotypes under variable conditions of light and soil nutrient availability in a common garden. Foliage was analyzed for levels of nitrogen, phenolic glycosides and condensed tannins. Bioassays of leaf quality were conducted with fourth-stadium gypsy moth (Lymantria dispar) larvae. Results revealed strong effects of plant genotype, light availability and nutrient availability; the importance of each factor depended upon compound type. For example, tannin concentrations differed little among genotypes and across nutrient regimes under low light conditions, but markedly so under high light conditions. Phenolic glycoside concentrations, in contrast, were largely determined by genotype. Variation in phenolic glycoside concentrations among genotypes was the most important factor affecting gypsy moth performance. Gypsy moth biomass and development time were negatively and positively correlated, respectively, with phenolic glycoside levels. Allocation to phenolic glycosides appeared to be costly in terms of growth, but only under resource-limiting conditions. Context-dependent trade-offs help to explain why costs of allocation to resistance are often difficult to demonstrate.     

Relatedness severely impacts accuracy of marker-assisted selection for disease resistance in hybrid wheat

The accuracy of genomic selection depends on the relatedness between the members of the set in which marker effects are estimated based on evaluation data and the types for which performance is predicted. Here, we investigate the impact of relatedness on the performance of marker-assisted selection for fungal disease resistance in hybrid wheat. A large and diverse mapping population of 1739 elite European winter wheat inbred lines and hybrids was evaluated for powdery mildew, leaf rust and stripe rust resistance in multi-location field trials and fingerprinted with 9 k and 90 k SNP arrays. Comparison of the accuracies of prediction achieved with data sets from the two marker arrays revealed a crucial role for a sufficiently high marker density in genome-wide association mapping. Cross-validation studies using test sets with varying degrees of relationship to the corresponding estimation sets revealed that close relatedness leads to a substantial increase in the proportion of total genotypic variance explained by the identified QTL and consequently to an overoptimistic judgment of the precision of marker-assisted selection.     

Variability in host-plant quality for the larvae of a polyphagous insect folivore in midseason: the impact of light on three deciduous sapling species

We examined the effects of light availability on the suitability of foliage from red maple (Acer rubrum L.) (Aceraceae), black cherry (Prunus serotina Ehrhart) (Rosaceae), and sassafras [Sassafras albidum (Nuttall) Nees (Lauraceae)] for the larvae of the promethea moth, Callosamia promethea Drury (Lepidoptera: Saturniidae), in midseason. We identified replicate sun- and shade-grown saplings of red maple, black cherry, and sassafras from naturally growing populations in the field. Foliage collected from the experimental saplings was bioassayed using early instars of the promethea moth and assayed for nitrogen and carbon content. Promethea moth-larval performance and survivorship was highest on sassafras, intermediate on black cherry, and lowest on red maple. Larvae feeding on foliage from plants grown in the sun performed better than from those grown in the shade; the effect of light did not depend on sapling species. Foliar nitrogen content varied among the sapling species and was higher, overall, in foliage from plants grown in the sun. Nitrogen concentration related strongly and positively with larval performance and accounted for a great deal of the variation in performance both among the sapling species and between the sun and shade treatments. During midseason, foliar nitrogen content is determined by light availability, it varies among sapling species, and it is likely the primary constituent determining host quality for folivores on these sapling species.     

ALFRED: the ALelle FREquency Database. Update

Elaboration of ALFRED (http://alfred.med.yale.edu) is being continued in two directions. One of which is developing tools for efficiently annotating the entries and checking the integrity of the data already in the database while the other is to increase the quantity and accessibility of data. Information contained in ALFRED such as, polymorphic sites, number of populations and frequency tables (one sample typed for one site) has significantly increased.     

A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity

Variants of different Class I alcohol dehydrogenase (ADH) genes have been shown to be associated with an effect that is protective against alcoholism. Previous work from our laboratory has shown that the two sites showing the association are in linkage disequilibrium and has identified the ADH1B Arg47His site as causative, with the ADH1C Ile349Val site showing association only because of the disequilibrium. Here, we describe an initial study of the nature of linkage disequilibrium and genetic variation, in population samples from different regions of the world, in a larger segment of the ADH cluster (including the three Class I ADH genes and ADH7). Linkage disequilibrium across approximately 40 kb of the Class I ADH cluster is moderate to strong in all population samples that we studied. We observed nominally significant pairwise linkage disequilibrium, in some populations, between the ADH7 site and some Class I ADH sites, at moderate values and at a molecular distance as great as 100 kb. Our data indicate (1) that most ADH-alcoholism association studies have failed to consider many sites in the ADH cluster that may harbor etiologically significant alleles and (2) that the relevance of the various ADH sites will be population dependent. Some individual sites in the Class I ADH cluster show Fst values that are among the highest seen among several dozen unlinked sites that were studied in the same subset of populations. The high Fst values can be attributed to the discrepant frequencies of specific alleles in eastern Asia relative to those in other regions of the world. These alleles are part of a single haplotype that exists at high (>65%) frequency only in the eastern-Asian samples. It seems unlikely that this haplotype, which is rare or unobserved in other populations, reached such high frequency because of random genetic drift alone.     

DNA-DNA hybridization evidence of the rapid rate of muroid rodent DNA evolution

Single-copy nuclear DNAs (scnDNAs) of eight species of arvicoline and six species of murine rodents were compared using DNA-DNA hybridization. The branching pattern derived from the DNA comparisons is congruent with the fossil evidence and supported by comparative biochemical, chromosomal, and morphological studies. The recently improved fossil record for these lineages provides seven approximate divergence dates, which were used to calibrate the DNA-hybridization data. The average rate of scnDNA divergence was estimated as 2.5%/Myr. This is approximately 10 times the rate in the hominoid primates. These results agree with previous reports of accelerated DNA evolution in muroid rodents and extend the DNA-DNA hybridization data set of Brownell.