T cell responses to the RTS,S/AS01(E) and RTS,S/AS02(D) malaria candidate vaccines administered according to different schedules to Ghanaian children

Background

The Plasmodium falciparum pre-erythrocytic stage candidate vaccine RTS,S is being developed for protection of young children against malaria in sub-Saharan Africa. RTS,S formulated with the liposome based adjuvant AS01_E or the oil-in-water based adjuvant AS02_D induces P. falciparum circumsporozoite (CSP) antigen-specific antibody and T cell responses which have been associated with protection in the experimental malaria challenge model in adults.

Methods

This study was designed to evaluate the safety and immunogenicity induced over a 19 month period by three vaccination schedules (0,1-, 0,1,2- and 0,1,7-month) of RTS,S/AS01_E and RTS,S/AS02_D in children aged 5–17 months in two research centers in Ghana. Control Rabies vaccine using the 0,1,2-month schedule was used in one of two study sites.

Results

Whole blood antigen stimulation followed by intra-cellular cytokine staining showed RTS,S/AS01_E induced CSP specific CD4 T cells producing IL-2, TNF-α, and IFN-γ. Higher T cell responses were induced by a 0,1,7-month immunization schedule as compared with a 0,1- or 0,1,2-month schedule. RTS,S/AS01_E induced higher CD4 T cell responses as compared to RTS,S/AS02_D when given on a 0,1,7-month schedule.

Conclusions

These findings support further Phase III evaluation of RTS,S/AS01_E. The role of immune effectors and immunization schedules on vaccine protection are currently under evaluation.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00360230","term_id":"NCT00360230"}}NCT00360230     

Acne and anticonvulsants.

The severity of acne and rate of excretion of sebum were assessed in 243 patients with epilepsy taking various anticonvulsants who were in hospital long term and in matched controls derived from a normal population of 2176 people. Neither the prevalence of acne nor the sebum excretion rate significantly increased in the patients compared with the controls or in patients taking phenytoin compared with those not. It is concluded that anticonvulsant treatment does not cause acne.     

An investigation of the ligand-binding properties of Pseudomonas aeruginosa nitrite reductase.

The low-temperature e.p.r. and m.c.d. (magnetic-circular-dichroism) spectra of Pseudomonas aeruginosa nitrite reductase, together with those of its partially and fully cyanide-bound derivatives, were investigated. The m.c.d. spectra in the range 600-2000 nm indicate that the native axial ligands to haem c are histidine and methionine, and furthermore that it is the methionine ligand that must be displaced before cyanide binding at this haem. The m.c.d. spectra in the range 1000-2000 nm contain no charge-transfer bands arising from low-spin ferric haem d1, a chlorin. New optical transitions in the region 700-850 nm were found for the cyanide adduct of haem d1. The g-values of haem d1 in the native enzyme are 2.51, 2.43 and 1.71, suggesting co-ordination by two histidine ligands in the oxidized state. There is clear evidence in the e.p.r. data of an interaction between the c and d1 haem groups. This is not apparent in the optical spectra. The results are interpreted in terms of haem groups that are remote from each other, their interaction being mediated through protein conformational changes. The possible implications of this in relation to reduction processes catalysed by the enzyme are considered.     

Mechanics of tether formation in liposomes

It is well-known that a "tether" may be drawn out from a pressurized liposome by means of a suitably applied radial-outward force applied locally to the lipid bilayer. The tether is a narrow, uniform cylindrical tube, which joins the main vesicle in a short "transition region." A first-order energy analysis establishes the broad relationship between the force F needed to draw the tether, the radius R0 of the tether, the bending-stiffness constant B for the lipid bilayer and the membrane tension T in the pressurized liposome. The aim of the present paper is to study in detail the "transition region" between the tether and the main vesicle, by means of a careful application of the engineering theory of axisymmetric shell structures. It turns out that the well-known textbook "thin-shell" theory is inadequate for this purpose, because the tether is evidently an example of a thick-walled shell; and a novel ingredient of the present study is the introduction of elastic constitutive relations that are appropriate to the thick-shell situation. The governing equations are set up in dimensionless form, and are solved by means of a "shooting" technique, starting with a single disposable parameter at a point on the meridian in the tether, which can be adjusted until the boundary conditions at the far "equator" of the main vessel are satisfied. It turns out that the "transition region" between the tether and the main vessel is well characterized by only a few parameters, while the tether and main vessel themselves are described by very simple equations. Introduction of the thick-shell constitutive relation makes little difference to the conformation of and stress-resultants in, the main vessel; but it makes a great deal of difference in the tether itself Indeed, a kind of phase-change appears to take place in the "transition region" between these two zones of the liposome.     

Adolescent Self-Organization and Adult Smoking and Drinking over Fifty Years of Follow-Up: The British 1946 Birth Cohort

Variations in markers of adolescent self-organization predict a range of economic and health-related outcomes in general population studies. Using a population-based birth cohort study we investigated associations between adolescent self-organization and two common factors over adulthood influencing health, smoking and alcohol consumption. The MRC National Survey of Health and Development (the British 1946 birth cohort) was used to test associations between a dimensional measure of adolescent self-organization derived from teacher ratings, and summary longitudinal measures of smoking and alcohol consumption over the ensuing five decades. Multinomial regression models were adjusted for sex, adolescent emotional and conduct problems, occupational social class of origin, childhood cognition, educational attainment and adult occupational social class. With all covariates adjusted, higher adolescent self-organization was associated with fewer smoking pack years, although not with quitting; there was no association with alcohol consumption across adulthood (none or heavy compared with light to moderate). Adolescent self-organization appears to be protective against smoking, but not against heavy alcohol consumption. Interpretation of this differential effect should be embedded in an understanding of the social and sociodemographic context in which these health behaviours occur over time.     

The electron-transfer reaction between azurin and the cytochrome c oxidase from Pseudomonas aeruginosa.

A stopped-flow investigation of the electron-transfer reaction between oxidized azurin and reduced Pseudomonas aeruginosa cytochrome c-551 oxidase and between reduced azurin and oxidized Ps. aeruginosa cytochrome c-551 oxidase was performed. Electrons leave and enter the oxidase molecule via its haem c component, with the oxidation and reduction of the haem d1 occurring by internal electron transfer. The reaction mechanism in both directions is complex. In the direction of oxidase oxidation, two phases assigned on the basis of difference spectra to haem c proceed with rate constants of 3.2 X 10(5)M-1-S-1 and 2.0 X 10(4)M-1-S-1, whereas the haem d1 oxidation occurs at 0.35 +/- 0.1S-1. Addition of CO to the reduced enzyme profoundly modifies the rate of haem c oxidation, with the faster process tending towards a rate limit of 200S-1. Reduction of the oxidase was similarly complex, with a fast haem c phase tending to a rate limit of 120S-1, and a slower phase with a second-order rate of 1.5 X 10(4)M-1-S-1; the internal transfer rate in this direction was o.25 +/- 0.1S-1. These results have been applied to a kinetic model originally developed from temperature-jump studies.     

Multiple regression methods show great potential for rare variant association tests

The investigation of associations between rare genetic variants and diseases or phenotypes has two goals. Firstly, the identification of which genes or genomic regions are associated, and secondly, discrimination of associated variants from background noise within each region. Over the last few years, many new methods have been developed which associate genomic regions with phenotypes. However, classical methods for high-dimensional data have received little attention. Here we investigate whether several classical statistical methods for high-dimensional data: ridge regression (RR), principal components regression (PCR), partial least squares regression (PLS), a sparse version of PLS (SPLS), and the LASSO are able to detect associations with rare genetic variants. These approaches have been extensively used in statistics to identify the true associations in data sets containing many predictor variables. Using genetic variants identified in three genes that were Sanger sequenced in 1998 individuals, we simulated continuous phenotypes under several different models, and we show that these feature selection and feature extraction methods can substantially outperform several popular methods for rare variant analysis. Furthermore, these approaches can identify which variants are contributing most to the model fit, and therefore both goals of rare variant analysis can be achieved simultaneously with the use of regression regularization methods. These methods are briefly illustrated with an analysis of adiponectin levels and variants in the ADIPOQ gene.     

Expression and function of potassium channels in the human placental vasculature

In the placental vasculature, where oxygenation may be an important regulator of vascular reactivity, there is a paucity of data on the expression of potassium (K) channels, which are important mediators of vascular smooth muscle tone. We therefore addressed the expression and function of several K channel subtypes in human placentas. The expression of voltage-gated (Kv)2.1, KV9.3, large-conductance Ca2+-activated K channel (BKCa), inward-rectified K+ channel (KIR)6.1, and two-pore domain inwardly rectifying potassium channel-related acid-sensitive K channels (TASK)1 in chorionic plate arteries, veins, and placental homogenate was assessed by RT-PCR and Western blot analysis. Functional activity of K channels was assessed pharmacologically in small chorionic plate arteries and veins by wire myography using 4-aminopyridine, iberiotoxin, pinacidil, and anandamide. Experiments were performed at 20, 7, and 2% oxygen to assess the effect of oxygenation on the efficacy of K channel modulators. KV2.1, KV9.3, BKCa, KIR6.1, and TASK1 channels were all demonstrated to be expressed at the message level. KV2.1, BKCa, KIR6.1, and TASK1 were all demonstrated at the protein level. Pharmacological manipulation of voltage-gated and ATP-sensitive channels produced the most marked modifications in vascular tone, in both arteries and veins. We conclude that K channels play an important role in controlling placental vascular function.