In-hospital safety in field conditions of Nifurtimox Eflornithine Combination Therapy (NECT) for T. B. Gambiense Sleeping Sickness

Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease. Until 2009, available treatments for 2(nd) stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic, and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT) demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World Health Organisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support its wider use

The Relation of Lime and Phosphoric Acid to the Growth and Bone Development of White Rats.

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A mathematical model for LH release in response to continuous and pulsatile exposure of gonadotrophs to GnRH

In a previous study, a model was developed to investigate the release of luteinizing hormone (LH) from pituitary cells in response to a short pulse of gonadotropin-releasing hormone (GnRH). The model included: binding of GnRH to its receptor (R), dimerization and internalization of the hormone receptor complex, interaction with a G protein, production of inositol 1,4,5-trisphosphate (IP(3)), release of calcium from the endoplasmic reticulum (ER), entrance of calcium into the cytosol via voltage gated membrane channels, pumping of calcium out of the cytosol via membrane and ER pumps, and release of LH. The extended model, presented in this paper, also includes the following physiologically important phenomena: desensitization of calcium channels; internalization of the dimerized receptors and recycling of some of the internalized receptors; an increase in G(q )concentration near the plasma membrane in response to receptor dimerization; and basal rates of synthesis and degradation of the receptors. With suitable choices of the parameters, good agreement with a variety of experimental data of the LH release pattern in response to pulses of various durations, repetition rates, and concentrations of GnRH were obtained. The mathematical model allows us to assess the effects of internalization and desensitization on the shapes and time courses of LH response curves

Accretion Disc Wind Variability in the States of the Microquasar GRS 1915+105

Continuing our study of the role and evolution of accretion disc winds in the microquasar GRS 1915+105, we present high-resolution spectral variability analysis of the beta and gamma states with the Chandra High Energy Transmission Grating Spectrometer. By tracking changes in the absorption lines from the accretion disc wind, we find new evidence that radiation links the inner and outer accretion discs on a range of time-scales. As the central X-ray flux rises during the high-luminosity gamma state, we observe the progressive over-ionization of the wind. In the beta state, we argue that changes in the inner disc leading to the ejection of a transient 'baby jet' also quench the highly-ionized wind from the outer disc. Our analysis reveals how the state, structure, and X-ray luminosity of the inner accretion disc all conspire to drive the formation and variability of highly-ionized accretion disc winds.Comment: Accepted for publication in MNRAS. 11 pages, 7 figures, uses mn2e.cls. Comments welcom

Accuracy of five algorithms to diagnose gambiense human African trypanosomiasis.

Algorithms to diagnose gambiense human African trypanosomiasis (HAT, sleeping sickness) are often complex due to the unsatisfactory sensitivity and/or specificity of available tests, and typically include a screening (serological), confirmation (parasitological) and staging component. There is insufficient evidence on the relative accuracy of these algorithms. This paper presents estimates of the accuracy of five algorithms used by past Médecins Sans Frontières programmes in the Republic of Congo, Southern Sudan and Uganda

RNA Sequencing Identifies Transcriptionally Viable Gene Fusions in Esophageal Adenocarcinomas

Esophageal adenocarcinoma (EAC) is a deadly cancer with increasing incidence in the U.S., but mechanisms underlying pathogenesis are still mostly elusive. In addressing this question, we assessed gene-fusion landscapes by comprehensive RNA sequencing (RNAseq) of 55 pre-treatment EAC and 49 non-malignant biopsy tissues from patients undergoing endoscopy for Barrett’s esophagus. In this cohort, we identified 21 novel candidate EAC-associated fusions occurring in 3.33%-11.67% of EACs. Two candidate fusions were selected for validation by PCR and Sanger sequencing in an independent set of pre-treatment EAC (N=115) and non-malignant (N=183) biopsy tissues. In particular, we observed RPS6KB1–VMP1 gene fusion as a recurrent event occurring in ~10% of EAC cases. Notably, EAC cases harboring RPS6KB1–VMP1 fusions exhibited significantly poorer overall survival as compared to fusion-negative cases. Mechanistic investigations established that the RPS6KB1–VMP1 transcript coded for a fusion protein which significantly enhanced the growth rate of non-dysplastic Barrett’s esophagus cells. Compared to the wild-type VMP1 protein, which mediates normal cellular autophagy, RPS6KB1–VMP1 fusion exhibited aberrant subcellular localization and was relatively ineffective in triggering autophagy. Overall, our findings identified RPS6KB1–VMP1 as a genetic fusion that promotes EAC by modulating autophagy-related processes, offering new insights into the molecular pathogenesis of esophageal adenocarcinomas

Microfabricated wire arrays for Z-pinch.

Microfabrication methods have been applied to the fabrication of wire arrays suitable for use in Z. Self-curling GaAs/AlGaAs supports were fabricated as an initial route to make small wire arrays (4mm diameter). A strain relief structure that could be integrated with the wire was designed to allow displacements of the anode/cathode connections in Z. Electroplated gold wire arrays with integrated anode/cathode bus connections were found to be sufficiently robust to allow direct handling. Platinum and copper plating processes were also investigated. A process to fabricate wire arrays on any substrate with wire thickness up to 35 microns was developed. Methods to handle and mount these arrays were developed. Fabrication of wire arrays of 20mm diameter was demonstrated, and the path to 40mm array fabrication is clear. With some final investment to show array mounting into Z hardware, the entire process to produce a microfabricated wire array will have been demonstrated

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal

Structural studies of thermally stable, combustion-resistant polymer composites

Composites of the industrially important polymer, poly(methyl methacrylate) (PMMA), were prepared by free-radical polymerization of MMA with varying amounts (1–30 wt. %) of sodium dioctylsulfosuccinate (Aerosol OT or AOT) surfactant added to the reaction mixture. The composites with AOT incorporated show enhanced resistance to thermal degradation compared to pure PMMA homopolymer, and micro-cone combustion calorimetry measurements also show that the composites are combustion-resistant. The physical properties of the polymers, particularly at low concentrations of surfactant, are not significantly modified by the incorporation of AOT, whereas the degradation is modified considerably for even the smallest concentration of AOT (1 wt. %). Structural analyses over very different lengthscales were performed. X-ray scattering was used to determine nm-scale structure, and scanning electron microscopy was used to determine μm-scale structure. Two self-assembled species were observed: large phase-separated regions of AOT using electron microscopy and regions of hexagonally packed rods of AOT using X-ray scattering. Therefore, the combustion resistance is observed whenever AOT self-assembles. These results demonstrate a promising method of physically incorporating a small organic molecule to obtain a highly thermally stable and combustion-resistant material without significantly changing the properties of the polymer

The Synthetic Plasmodium falciparum Circumsporozoite Peptide PfCS102 as a Malaria Vaccine Candidate: A Randomized Controlled Phase I Trial

BACKGROUND: Fully efficient vaccines against malaria pre-erythrocytic stage are still lacking. The objective of this dose/adjuvant-finding study was to evaluate the safety, reactogenicity and immunogenicity of a vaccine candidate based on a peptide spanning the C-terminal region of Plasmodium falciparum circumsporozoite protein (PfCS102) in malaria naive adults. METHODOLOGY AND PRINCIPAL FINDINGS: Thirty-six healthy malaria-naive adults were randomly distributed into three dose blocks (10, 30 and 100 microg) and vaccinated with PfCS102 in combination with either Montanide ISA 720 or GSK proprietary Adjuvant System AS02A at days 0, 60, and 180. Primary end-point (safety and reactogenicity) was based on the frequency of adverse events (AE) and of abnormal biological safety tests; secondary-end point (immunogenicity) on P. falciparum specific cell-mediated immunity and antibody response before and after immunization. The two adjuvant formulations were well tolerated and their safety profile was good. Most AEs were local and, when systemic, involved mainly fatigue and headache. Half the volunteers in AS02A groups experienced severe AEs (mainly erythema). After the third injection, 34 of 35 volunteers developed anti-PfCS102 and anti-sporozoite antibodies, and 28 of 35 demonstrated T-cell proliferative responses and IFN-gamma production. Five of 22 HLA-A2 and HLA-A3 volunteers displayed PfCS102 specific IFN-gamma secreting CD8(+) T cell responses. Responses were only marginally boosted after the 3(rd) vaccination and remained stable for 6 months. For both adjuvants, the dose of 10 microg was less immunogenic in comparison to 30 and 100 microg that induced similar responses. AS02A formulations with 30 microg or 100 microg PfCS102 induced about 10-folds higher antibody and IFN-gamma responses than Montanide formulations. CONCLUSIONS/SIGNIFICANCE: PfCS102 peptide was safe and highly immunogenic, allowing the design of more advanced trials to test its potential for protection. Two or three immunizations with a dose of 30 microg formulated with AS02A appeared the most appropriate choice for such studies. TRIAL REGISTRATION: Swissmedic.ch 2002 DR 1227