Geographical variation in the response of visceral leishmaniasis to paromomycin in East Africa: a multicentre, open-label, randomized trial

Background

Visceral leishmaniasis (VL) is a major health problem in developing countries. The untreated disease is fatal, available treatment is expensive and often toxic, and drug resistance is increasing. Improved treatment options are needed. Paromomycin was shown to be an efficacious first-line treatment with low toxicity in India.

Methods

This was a 3-arm multicentre, open-label, randomized, controlled clinical trial to compare three treatment regimens for VL in East Africa: paromomycin sulphate (PM) at 15 mg/kg/day for 21 days versus sodium stibogluconate (SSG) at 20 mg/kg/day for 30 days; and the combination of both dose regimens for 17 days. The primary efficacy endpoint was cure based on parasite-free tissue aspirates taken 6 months after treatment.

Findings

Overall, 135 patients per arm were enrolled at five centres in Sudan (2 sites), Kenya (1) and Ethiopia (2), when the PM arm had to be discontinued due to poor efficacy. The trial has continued with the higher dose of PM as well as the combination of PM and SSG arms. These results will be reported later. Baseline patient characteristics were similar among treatment arms. The overall cure with PM was significantly inferior to that with SSG (63.8% versus 92.2%; difference 28.5%, 95%CI 18.8% to 38.8%, p<0.001). The efficacy of PM varied among centres and was significantly lower in Sudan (14.3% and 46.7%) than in Kenya (80.0%) and Ethiopia (75.0% and 96.6%). No major safety issues with PM were identified.

Conclusion

The efficacy of PM at 15 mg/kg/day for 21 days was inadequate, particularly in Sudan. The efficacy of higher doses and the combination treatment warrant further studies.     

Lipid changes after leaf wounding in Arabidopsis thaliana: expanded lipidomic data form the basis for lipid co‐occurrence analysis

A direct‐infusion electrospray ionization triple–quadrupole mass spectrometry method with multiple reaction monitoring (MRM) was employed to measure 264 lipid analytes extracted from leaves of Arabidopsis thaliana subjected to mechanical wounding. The method provided precise measurements with an average coefficient of variation of 6.1%. Lipid classes analyzed comprised galactolipids and phospholipids (including monoacyl molecular species, molecular species with oxidized acyl chains, phosphatidic acids (PAs)), tri‐ and tetra‐galactosyldiacylglycerols (TrGDGs and TeGDGs), head‐group‐acylated galactolipids, and head‐group‐acylated phosphatidylglycerol (acPG), sulfoquinovosyldiacylglycerols (SQDGs), sphingolipids, di‐ and tri‐acylglycerols (DAGs and TAGs), and sterol derivatives. Of the 264 lipid analytes, 254 changed significantly in response to wounding. In general, levels of structural lipids decreased, whereas monoacyl molecular species, galactolipids and phosphatidylglycerols (PGs) with oxidized fatty acyl chains, PAs, TrGDGs, TeGDGs, TAGs, head‐group‐acylated galactolipids, acPG, and some sterol derivatives increased, many transiently. The observed changes are consistent with activation of lipid oxidizing, hydrolyzing, glycosylating, and acylating activities in the wounding response. Correlation analysis of the levels of lipid analytes across individual control and treated plants was used to construct a lipid dendrogram and to define clusters and sub‐clusters of lipid analytes, each composed of a group of lipids which occurred in a coordinated manner. Current knowledge of metabolism supports the notion that observed sub‐clusters comprise lipids generated by a common enzyme and/or metabolically downstream of a common enzyme. This work demonstrates that co‐occurrence analysis, based on correlation of lipid levels among plants, is a powerful approach to defining lipids generated in vivo by a common enzymatic pathway.     

A botanical inventory and diversity assessment of Mt. Marsabit forest, a sub-humid montane forest in the arid lands of northern Kenya

A botanical inventory and diversity of trees, shrubs (≥5 cm diameter at breast height [dbh]), herbs, climbers and lianas was assessed in plots (154) of 20 × 5 m in Mt. Marsabit forest, northern Kenya. We recorded 52 species of trees and shrubs, twelve species of herbs and six species of climbers and lianas. They belonged to 35 families and 64 genera. Rubiaceae was the richest family with nine species followed by Euphorbiaceae (six), Oleaceae (five), Rutaceae (four), Capparaceae, Labiatae and Leguminosae (three each). The rest of the families were represented by one or two species. Rinorea convallarioides (Bak.f.) Eyles ssp. marsabitensis Grey‐Wilson (Violaceae), an endemic species, and Drypetes gerrardii Hutch. (Euphorbiaceae), were the two most important species, accounting for more than third of the combined importance value. Species diversity indices were 2.735 (Shannon–Wiener), 0.88 (Simpson's) and 0.296 (Evenness). There was a strong evidence of disturbance arising from anthropogenic and wildlife foraging activities. This inventory has affirmed Mt. Marsabit forest as a unique habitat for several endemic, rare, threatened or vulnerable plant species, which should be conserved.     

Quantitative variation in seeds,seedling growth and biomass among Acacia senegal (L) Willd. provenances in Kenya

Conventionally, local seed sources are normally believed to perform better than introduced materials. However, studies show possibility of contrary results with many species such as Acacia senegal. The species is an economically and ecologically important tree of arid and semi‐arid lands of sub‐Saharan Africa. It produces gum arabic, used in land reclamation and agroforestry production. The species is however underutilized in Kenya due to lack of information on growth performance of different seed sources. Glasshouse provenance trial using seeds and soils from seven provenances in Kenya were used to evaluate interactions between seed sources and soils on growth and biomass. Seedling growth was assessed for 12 weeks in a randomized complete block design. Seed length, width, thickness and weight were measured. Seedlings height, root collar diameter, root dry weight, shoot dry weight and biomass were assessed and data subjected to univariate and multivariate analyses. No significant interaction between seed provenance and soils were evident; however, some provenances performed better across all the soils. Significant heritability and relationship between growth and environmental factors are reported. Overall, Ntumburi and Ngarendare provenances showed superior growth and plasticity. These provenances can be used tentatively as seed sources; however, field trials are recommended.     

Safety of over Twelve Hundred Infant Male Circumcisions Using the Mogen Clamp in Kenya

Background

Several sub-Saharan African countries plan to scale-up infant male circumcision (IMC) for cost-efficient HIV prevention. Little data exist about the safety of IMC in East and southern Africa. We calculated adverse event (AE) rate and risks for AEs associated with introduction of IMC services at five government health facilities in western Kenya.

Methods

AE data were analyzed for IMC procedures performed between September, 2009 and November, 2011. Healthy infants aged ≤2 months and weighing ≥2.5 kg were eligible for IMC. Following parental consent, trained clinicians provided IMC services free of charge under local anesthesia using the Mogen clamp. Odds ratios and 95% confidence intervals were used to explore AE risk factors.

Findings

A total of 1,239 IMC procedures were performed. Median age of infants was 4 days (IQR = 1, 16). The overall AE rate among infants reviewed post-operatively was 2.7% (18/678; 95%CI: 1.4, 3.9). There was one severe AE involving excision of a small piece of the lateral aspect of the glans penis. Other AEs were mild or moderate and were treated conservatively. Babies one month of age or older were more likely to have an AE (OR 3.20; 95%CI: 1.23, 8.36). AE rate did not differ by nurse versus clinical officer or number of previous procedures performed.

Conclusion

IMC services provided in Kenyan Government hospitals in the context of routine IMC programming have AE rates comparable to those in developed countries. The optimal time for IMC is within the first month of life.     

Sodium stibogluconate (SSG) & paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: a randomised controlled trial

Background

Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India.

Methods

A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SSG) combination (PM, 15 mg/kg/day and SSG, 20 mg/kg/day for 17 days) with SSG (20 mg/kg/day for 30 days) for treatment of VL in East Africa. Patients aged 4–60 years with parasitologically confirmed VL were enrolled, excluding patients with contraindications. Primary and secondary efficacy outcomes were parasite clearance at 6-months follow-up and end of treatment, respectively. Safety was assessed mainly using adverse event (AE) data.

Findings

The PM versus SSG comparison enrolled 205 patients per arm with primary efficacy data available for 198 and 200 patients respectively. The SSG & PM versus SSG comparison enrolled 381 and 386 patients per arm respectively, with primary efficacy data available for 359 patients per arm. In Intention-to-Treat complete-case analyses, the efficacy of PM was significantly lower than SSG (84.3% versus 94.1%, difference = 9.7%, 95% confidence interval, CI: 3.6 to 15.7%, p = 0.002). The efficacy of SSG & PM was comparable to SSG (91.4% versus 93.9%, difference = 2.5%, 95% CI: −1.3 to 6.3%, p = 0.198). End of treatment efficacy results were very similar. There were no apparent differences in the safety profile of the three treatment regimens.

Conclusion

The 17 day SSG & PM combination treatment had a good safety profile and was similar in efficacy to the standard 30 day SSG treatment, suggesting suitability for VL treatment in East Africa.

Clinical Trials Registration

www.clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00255567","term_id":"NCT00255567"}}NCT00255567     

How does metal soil pollution change the plant mycobiome?

Microorganisms play a key role in plant adaptation to the environment. The aim of this study was to evaluate the effect of toxic metals present in the soil on the biodiversity of plant-related, endophytic mycobiota. The mycobiome of plants and soil from a Zn–Pb heap and a metal-free ruderal area were compared via Illumina sequencing of the ITS1 rDNA. The biodiversity of plants and fungi inhabiting mine dump substrate was lower than that of the metal free site. In the endosphere of Arabidopsis arenosa from the mine dump the number of endophytic fungal taxa was comparable to that in the reference population, but the community structure significantly differed. Agaricomycetes was the most notably limited class of fungi. The results of plant mycobiota evaluation from the field study were verified in terms of the role of toxic metals in plant endophytic fungi community assembly in a reconstruction experiment. The results presented in this study indicate that metal toxicity affects the structure of the plant mycobiota not by changing the pool of microorganisms available in the soil from which the fungal symbionts are recruited but most likely by altering plant and fungi behaviour and the organisms' preferences towards associating in symbiotic relationships.     

Dispersal behaviour of African wild dogs in Kenya

Dispersal behaviour plays a key role in social organisation, demography and population genetics. We describe dispersal behaviour in a population of African wild dogs (Lycaon pictus) in Kenya. Almost all individuals, of both sexes, left their natal packs, with 45 of 46 reproductively active “alpha” individuals acquiring their status through dispersal. Dispersal age, group size and distance did not differ between males and females. However, only females embarked on secondary dispersal, probably reflecting stronger reproductive competition among females than males. When dispersing, GPS-collared wild dogs travelled further than when resident, both in daylight and by night, following routes an order of magnitude longer than the straight-line distance covered. Dispersers experienced a daily mortality risk three times that experienced by adults in resident packs. The detailed movement data provided by GPS-collars helped to reconcile differences between dispersal patterns reported previously from other wild dog populations. However, the dispersal patterns observed at this and other sites contrast with those assumed in published demographic models for this endangered species. Given the central role of dispersal in demography, models of wild dog population dynamics need to be updated to account for improved understanding of dispersal processes.