In falciparum malaria sequestration of erythrocytes containing mature forms of Plasmodium falciparum in the microvasculature of vital organs is central to pathology, but quantitation of this hidden ...sequestered parasite load in vivo has not previously been possible. The peripheral blood parasite count measures only the circulating, relatively non-pathogenic parasite numbers. P. falciparum releases a specific histidine-rich protein (PfHRP2) into plasma. Quantitative measurement of plasma PfHRP2 concentrations may reflect the total parasite biomass in falciparum malaria.
We measured plasma concentrations of PfHRP2, using a quantitative antigen-capture enzyme-linked immunosorbent assay, in 337 adult patients with falciparum malaria of varying severity hospitalised on the Thai-Burmese border. Based on in vitro production rates, we constructed a model to link this measure to the total parasite burden in the patient. The estimated geometric mean parasite burden was 7 x 10(11) (95% confidence interval CI 5.8 x 10(11) to 8.5 x 10(11)) parasites per body, and was over six times higher in severe malaria (geometric mean 1.7 x 10(12), 95% CI 1.3 x 10(12) to 2.3 x 10(12)) than in patients hospitalised without signs of severity (geometric mean 2.8 x 10(11), 95% CI 2.3 x 10(11) to 3.5 x 10(11); p < 0.001). Parasite burden was highest in patients who died (geometric mean 3.4 x 10(12), 95% CI 1.9 x 10(12) to 6.3 x 10(12); p = 0.03). The calculated number of sequestered parasites increased with disease severity and was higher in patients with late developmental stages of P. falciparum present on peripheral blood smears. Comparing model and laboratory estimates of the time of sequestration suggested that admission to hospital with uncomplicated malaria often follows schizogony-but in severe malaria is unrelated to stage of parasite development.
Plasma PfHRP2 concentrations may be used to estimate the total body parasite biomass in acute falciparum malaria. Severe malaria results from extensive sequestration of parasitised erythrocytes.
Because of their sequestration in the microcirculation, the pathogenic late stages of
Plasmodium falciparum are under-represented in peripheral blood samples from patients with falciparum malaria. ...Excreted products of the parasite might help to estimate this sequestered biomass. We quantified the stage-dependent production and release per parasite of
P. falciparum histidine-rich protein 2 (PfHRP2) with the objective of measuring the sequestered biomass. A simple method to relate parasite stage to parasite age was developed to facilitate this. In four isolates of
P. falciparum, the median (range) PfHRP2 content was 2.0
fg (0.5–4.3
fg) for a young ring stage infected erythrocyte, and 5.4
fg (2.1–10.2
fg) for the schizont stage. The amount of PfHRP2 in the parasitized erythrocyte increased most during development to the mature trophozoite stage. The median (range) amount of PfHRP2 secreted per parasite per entire erythrocytic cycle was 5.2
fg (1.1–13.0
fg). A median of 89% of the total PfHRP2 was excreted at the moment of schizont rupture. This assessment of the stage-dependent release of PfHRP2 is an essential prerequisite for future studies aimed at estimating the total patient parasite mass from the peripheral blood PfHRP2 concentration.
The introduction of the bacterium Wolbachia (wMel strain) into Aedes aegypti mosquitoes reduces their capacity to transmit dengue and other arboviruses. Evidence of a reduction in dengue case ...incidence following field releases of wMel-infected Ae. aegypti has been reported previously from a cluster randomised controlled trial in Indonesia, and quasi-experimental studies in Indonesia and northern Australia.
Following pilot releases in 2015-2016 and a period of intensive community engagement, deployments of adult wMel-infected Ae. aegypti mosquitoes were conducted in Niterói, Brazil during 2017-2019. Deployments were phased across four release zones, with a total area of 83 km2 and a residential population of approximately 373,000. A quasi-experimental design was used to evaluate the effectiveness of wMel deployments in reducing dengue, chikungunya and Zika incidence. An untreated control zone was pre-defined, which was comparable to the intervention area in historical dengue trends. The wMel intervention effect was estimated by controlled interrupted time series analysis of monthly dengue, chikungunya and Zika case notifications to the public health surveillance system before, during and after releases, from release zones and the control zone. Three years after commencement of releases, wMel introgression into local Ae. aegypti populations was heterogeneous throughout Niterói, reaching a high prevalence (>80%) in the earliest release zone, and more moderate levels (prevalence 40-70%) elsewhere. Despite this spatial heterogeneity in entomological outcomes, the wMel intervention was associated with a 69% reduction in dengue incidence (95% confidence interval 54%, 79%), a 56% reduction in chikungunya incidence (95%CI 16%, 77%) and a 37% reduction in Zika incidence (95%CI 1%, 60%), in the aggregate release area compared with the pre-defined control area. This significant intervention effect on dengue was replicated across all four release zones, and in three of four zones for chikungunya, though not in individual release zones for Zika.
We demonstrate that wMel Wolbachia can be successfully introgressed into Ae. aegypti populations in a large and complex urban setting, and that a significant public health benefit from reduced incidence of Aedes-borne disease accrues even where the prevalence of wMel in local mosquito populations is moderate and spatially heterogeneous. These findings are consistent with the results of randomised and non-randomised field trials in Indonesia and northern Australia, and are supportive of the Wolbachia biocontrol method as a multivalent intervention against dengue, chikungunya and Zika.
Seismic inversion is applied to generate physical property models (P-wave velocity and numerical attenuation) for four profiles in the Nechako-Chilcotin plateau region of south-central British ...Columbia, Canada. A newly developed method that combines three-dimensional (3-D) travel-time inversion and 2.5-dimensional (2.5-D) viscoacoustic full-waveform inversion was applied to generate the geophysical models from vibroseis data acquired along the preexisting crooked roads. These models are useful for the characterization of rock types in terms of their positions and thicknesses, which may be used in conjunction with geological ground truth to infer the extent of lithostratigraphic units in the subsurface. The velocity structures also may be used for future reprocessing of the seismic reflection data to derive improved images based on the better near-surface velocity models. The subsurface geology of the Nechako-Chilcotin plateau region is complex, resulting from multiple stages of tectonic compression and extension, contemporaneous with the deposition of sediments and volcanic material. Several basin structures are identified from the joint interpretation of the waveform tomography velocity models and post-stack time migration images. The combination of these results enables the extrapolation and characterization of geological structures to ∼3 km depth, particularly within the Cenozoic volcanic units that dominate near-surface stratigraphy. Based on the seismic profiles, a fence-diagram geological interpretation that extends to ∼3 km depth illustrates the complex structure of the Jurassic to Neogene stratigraphic sequence.
Abstract
In previous studies with dairy cattle, methionine supply during late-gestation enhanced cow feed intake and affected calf growth in utero and postnatally. Our objective was to investigate ...how methionine supply during mid-gestation, phase where the secondary myogenesis occurs, alters heifers’ plasma concentration of amino acids and offspring’ birth weight in beef cattle. Forty purebred Angus heifers were blocked by expected parturition day and blocks were balanced by sire, body weight, and body condition score. Heifers were randomly assigned to a basal diet with no added methionine (Control) or the basal diet plus a commercial source of rumen-protected methionine (Methionine). The methionine source was dosed to deliver 6 grams of metabolizable methionine daily. Heifers received the treatments from day 90 to 180 of gestation, and all heifers were pair-feed during early- and late-gestation. Heifers’ plasma samples were collected on day 180 of gestation. Data were analyzed using mixed models. The model for plasma samples included the fixed effect of treatment and the random effect of block, while the birth weight model included the fixed effect of treatment, sex, and its interaction and the random effect of block. Plasma concentrations of insulin, glucose, and urea were not affected by treatments (P ≥ 0.20). Dietary supply of methionine increased plasma concentration of methionine (P < 0.01), and decreased glycine and serine (P < 0.01). None of the other essential and non-essential amino acids were affected by treatments (P ≥ 0.12). Heifers supplemented with methionine had a greater plasma concentration of the antioxidant taurine than control heifers (P = 0.04). A treatment × sex interaction was observed for calf birth weight; methionine-fed heifers delivered heavier male calves than control-fed heifers (P = 0.03). No treatment or sex effect was observed for calf birth weight (P ≥ 0.18). Our preliminary results indicate that methionine supply during mid-gestation affects fetal growth in beef cattle in a sex-dependent manner.
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