Postexposure Treatment of Marburg Virus Infection

Rhesus monkeys are protected from disease when a recombinant vesicular stomatitis virus–based vaccine is administered 20–30 min after infection with Marburg virus. We protected 5/6 monkeys when this vaccine was given 24 h after challenge; 2/6 animals were protected when the vaccine was administered 48 h postinfection

Rosette-Disrupting Effect of an Anti-Plasmodial Compound for the Potential Treatment of Plasmodium falciparum Malaria Complications

The spread of artemisinin-resistant parasites could lead to higher incidence of patients with malaria complications. However, there are no current treatments that directly dislodge sequestered parasites from the microvasculature. We show that four common antiplasmodial drugs do not disperse rosettes (erythrocyte clusters formed by malaria parasites) and therefore develop a cell-based high-throughput assay to identify potential rosette-disrupting compounds. A pilot screen of 2693 compounds identified Malaria Box compound MMV006764 as a potential candidate. Although it reduced rosetting by a modest 20%, MMV006764 was validated to be similarly effective against both blood group O and A rosettes of three laboratory parasite lines. Coupled with its antiplasmodial activity and drug-likeness, MMV006764 represents the first small-molecule compound that disrupts rosetting and could potentially be used in a resource-limited setting to treat patients deteriorating rapidly from malaria complications. Such dual-action drugs that simultaneously restore microcirculation and reduce parasite load could significantly reduce malaria morbidity and mortality

Report of AAPM Therapy Physics Committee Task Group 74: Inâ air output ratio, Sc, for megavoltage photon beams

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134830/1/mp7367.pd

Early Gadolinium Enhancement for Area at Risk Determination: A Preclinical Validation Study

Objectives—The aim of this study was to determine if early gadolinium enhancement (EGE) by cardiovascular magnetic resonance (CMR) imaging in a canine model of reperfused myocardial infarction depicts the area at risk (AAR) as determined by microsphere blood flow analysis. Background—It remains controversial whether only the irreversibly injured myocardium enhances when performing CMR imaging in the setting of acute myocardial infarction. Recently, EGE has been proposed as a measure of the AAR in acute myocardial infarction as it correlates well with T2-weighted imaging of the AAR, but still requires pathological validation. Methods—Eleven dogs underwent 2 hours of coronary artery occlusion and 48 hours of reperfusion prior to imaging at 1.5T. EGE imaging was performed 3 minutes after contrast administration with coverage of the entire left ventricle. Late gadolinium enhancement (LGE) imaging was performed between 10 and 15 minutes after contrast injection. AAR was defined as myocardium with blood flow (mL/min/g) \u3c 2SD from remote myocardium determined by microspheres during occlusion. The size of infarction was determined using triphenyltetrazolium chloride (TTC). Results—There was no significant difference in the size of enhancement by EGE compared to the size of AAR by microspheres (44.1± 15.8% vs. 42.7± 9.2%, p=0.61) with good correlation (r=0.88, p \u3c 0.001) and good agreement by Bland-Altman analysis (mean bias 1.4± 17.4%). There was no difference in the size of enhancement by EGE compared to enhancement on native T1 and T2 maps. The size of EGE was significantly greater than the infarct by TTC, (44.1± 15.8% vs. 20.7± 14.4%, p \u3c 0.001) and LGE (44.1± 15.8% vs. 23.5± 12.7%, p \u3c 0.001). Conclusion—At three minutes post-contrast, EGE correlated well with the AAR by microspheres and CMR, and was greater than infarct size. Thus, EGE enhances both reversibly and irreversibly injured myocardium

Can We Possibly Derive Sediment Quality Guidelines for Chemical Mixtures ?

for their great contribution to this work. Concluding Remarks: • Chemical mixtures do matter as reflected by the fact that 78% cases for mixtures of antifouling biocides would result in additive or synergistic effects to marine organisms. • It is possible to use TEQ-based approach to derive SQGs for mixtures consisting chemicals with a similar mode of toxic action. • For mixtures containing chemicals with different modes of toxic action, the multidimensional SSD approach maybe adopted. But this method is time-consuming and not cost-effective. • Field based approaches such as f-SSD and f-CSD potentially serve as an alternative way to derive SQGs and account for interacting effects of chemicals and biological interaction. • There is no perfect solution but we can always find a better one

The impact of albendazole treatment on the incidence of viral- and bacterial-induced diarrhea in school children in southern Vietnam: study protocol for a randomized controlled trial

Anthelmintics are one of the more commonly available classes of drugs to treat infections by parasitic helminths (especially nematodes) in the human intestinal tract. As a result of their cost-effectiveness, mass school-based deworming programs are becoming routine practice in developing countries. However, experimental and clinical evidence suggests that anthelmintic treatments may increase susceptibility to other gastrointestinal infections caused by bacteria, viruses, or protozoa. Hypothesizing that anthelmintics may increase diarrheal infections in treated children, we aim to evaluate the impact of anthelmintics on the incidence of diarrheal disease caused by viral and bacterial pathogens in school children in southern Vietnam.This is a randomized, double-blinded, placebo-controlled trial to investigate the effects of albendazole treatment versus placebo on the incidence of viral- and bacterial-induced diarrhea in 350 helminth-infected and 350 helminth-uninfected Vietnamese school children aged 6-15 years. Four hundred milligrams of albendazole, or placebo treatment will be administered once every 3 months for 12 months. At the end of 12 months, all participants will receive albendazole treatment. The primary endpoint of this study is the incidence of diarrheal disease assessed by 12 months of weekly active and passive case surveillance. Secondary endpoints include the prevalence and intensities of helminth, viral, and bacterial infections, alterations in host immunity and the gut microbiota with helminth and pathogen clearance, changes in mean z scores of body weight indices over time, and the number and severity of adverse events.In order to reduce helminth burdens, anthelmintics are being routinely administered to children in developing countries. However, the effects of anthelmintic treatment on susceptibility to other diseases, including diarrheal pathogens, remain unknown. It is important to monitor for unintended consequences of drug treatments in co-infected populations. In this trial, we will examine how anthelmintic treatment impacts host susceptibility to diarrheal infections, with the aim of informing deworming programs of any indirect effects of mass anthelmintic administrations on co-infecting enteric pathogens.ClinicalTrials.gov: NCT02597556 . Registered on 3 November 2015

Cosmic-ray ionization of molecular clouds

Low-energy cosmic rays are a fundamental source of ionization for molecular clouds, influencing their chemical, thermal and dynamical evolution. The purpose of this work is to explore the possibility that a low-energy component of cosmic-rays, not directly measurable from the Earth, can account for the discrepancy between the ionization rate measured in diffuse and dense interstellar clouds. We collect the most recent experimental and theoretical data on the cross sections for the production of H2+ and He+ by electron and proton impact, and we discuss the available constraints on the cosmic-ray fluxes in the local interstellar medium. Starting from different extrapolations at low energies of the demodulated cosmic-ray proton and electron spectra, we compute the propagated spectra in molecular clouds in the continuous slowing-down approximation taking into account all the relevant energy loss processes. The theoretical value of the cosmic-ray ionization rate as a function of the column density of traversed matter is in agreement with the observational data only if either the flux of cosmic-ray electrons or of protons increases at low energies. The most successful models are characterized by a significant (or even dominant) contribution of the electron component to the ionization rate, in agreement with previous suggestions. However, the large spread of cosmic-ray ionization rates inferred from chemical models of molecular cloud cores remains to be explained. Available data combined with simple propagation models support the existence of a low-energy component (below about 100 MeV) of cosmic-ray electrons or protons responsible for the ionization of molecular cloud cores and dense protostellar envelopes.Comment: 14 pages, 15 figure

Randomized Controlled Ferret Study to Assess the Direct Impact of 2008–09 Trivalent Inactivated Influenza Vaccine on A(H1N1)pdm09 Disease Risk

During spring-summer 2009, several observational studies from Canada showed increased risk of medically-attended, laboratory-confirmed A(H1N1)pdm09 illness among prior recipients of 2008–09 trivalent inactivated influenza vaccine (TIV). Explanatory hypotheses included direct and indirect vaccine effects. In a randomized placebo-controlled ferret study, we tested whether prior receipt of 2008–09 TIV may have directly influenced A(H1N1)pdm09 illness. Thirty-two ferrets (16/group) received 0.5 mL intra-muscular injections of the Canadian-manufactured, commercially-available, non-adjuvanted, split 2008–09 Fluviral or PBS placebo on days 0 and 28. On day 49 all animals were challenged (Ch0) with A(H1N1)pdm09. Four ferrets per group were randomly selected for sacrifice at day 5 post-challenge (Ch+5) and the rest followed until Ch+14. Sera were tested for antibody to vaccine antigens and A(H1N1)pdm09 by hemagglutination inhibition (HI), microneutralization (MN), nucleoprotein-based ELISA and HA1-based microarray assays. Clinical characteristics and nasal virus titers were recorded pre-challenge then post-challenge until sacrifice when lung virus titers, cytokines and inflammatory scores were determined. Baseline characteristics were similar between the two groups of influenza-naïve animals. Antibody rise to vaccine antigens was evident by ELISA and HA1-based microarray but not by HI or MN assays; virus challenge raised antibody to A(H1N1)pdm09 by all assays in both groups. Beginning at Ch+2, vaccinated animals experienced greater loss of appetite and weight than placebo animals, reaching the greatest between-group difference in weight loss relative to baseline at Ch+5 (7.4% vs. 5.2%; p = 0.01). At Ch+5 vaccinated animals had higher lung virus titers (log-mean 4.96 vs. 4.23pfu/mL, respectively; p = 0.01), lung inflammatory scores (5.8 vs. 2.1, respectively; p = 0.051) and cytokine levels (p>0.05). At Ch+14, both groups had recovered. Findings in influenza-naïve, systematically-infected ferrets may not replicate the human experience. While they cannot be considered conclusive to explain human observations, these ferret findings are consistent with direct, adverse effect of prior 2008–09 TIV receipt on A(H1N1)pdm09 illness. As such, they warrant further in-depth investigation and search for possible mechanistic explanations

MicroRNA 10a Marks Regulatory T Cells

MicroRNAs (miRNAs) are crucial for regulatory T cell (Treg) stability and function. We report that microRNA-10a (miR-10a) is expressed in Tregs but not in other T cells including individual thymocyte subsets. Expression profiling in inbred mouse strains demonstrated that non-obese diabetic (NOD) mice with a genetic susceptibility for autoimmune diabetes have lower Treg-specific miR-10a expression than C57BL/6J autoimmune resistant mice. Inhibition of miR-10a expression in vitro leads to reduced FoxP3 expression levels and miR-10a expression is lower in unstable “exFoxP3” T cells. Unstable in vitro TGF-ß-induced, iTregs do not express miR-10a unless cultured in the presence of retinoic acid (RA) which has been associated with increased stability of iTreg, suggesting that miR-10a might play a role in stabilizing Treg. However, genetic ablation of miR-10a neither affected the number and phenotype of natural Treg nor the capacity of conventional T cells to induce FoxP3 in response to TGFβ, RA, or a combination of the two. Thus, miR-10a is selectively expressed in Treg but inhibition by antagomiRs or genetic ablation resulted in discordant effects on FoxP3