Morphine activates neuroinflammation in a manner parallel to endotoxin

Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.Xiaohui Wang, Lisa C. Loram, Khara Ramos, Armando J. de Jesus, Jacob Thomas, Kui Cheng, Anireddy Reddy, Andrew A. Somogyi, Mark R. Hutchinson, Linda R. Watkins and Hang Yi

A security proof of continuous-variable QKD using three coherent states

We introduce a ternary quantum key distribution (QKD) protocol and asymptotic security proof based on three coherent states and homodyne detection. Previous work had considered the binary case of two coherent states and here we nontrivially extend this to three. Our motivation is to leverage the practical benefits of both discrete and continuous (Gaussian) encoding schemes creating a best-of-both-worlds approach; namely, the postprocessing of discrete encodings and the hardware benefits of continuous ones. We present a thorough and detailed security proof in the limit of infinite signal states which allows us to lower bound the secret key rate. We calculate this is in the context of collective eavesdropping attacks and reverse reconciliation postprocessing. Finally, we compare the ternary coherent state protocol to other well-known QKD schemes (and fundamental repeaterless limits) in terms of secret key rates and loss.Comment: Close to the published versio

Structure modifications of hydrolytically degradable polymer flocculant for improved water recovery from mature fine tailings

Oil sands mining operations in Canada produce large volumes of waste tailings that are difficult to dewater using commercial polyacrylamide-based flocculants. Recently, we have developed a novel hydrolytically-degradable polymer synthesized through micellar radical polymerization of short-chain polyester cationic macromonomers. Poly(PCL2ChMA), made of polycaprolactone choline iodide ester methacrylate with two polyester units, effectively treated mature fine tailings (MFT) solutions as evaluated by measuring initial settling rate, supernatant turbidity, and capillary suction time (CST) of the sediments[1]. Please download the file below for full content

Prognostically controlled comparison of dialysis and renal transplantation

Prognostically controlled comparison of dialysis and renal transplantation. Because the comparison of survival in patients with renal failure treated by dialysis and transplantation may be biased by pretreatment prognostic differences in the patients who receive these two therapies, we quantified the pretreatment prognosis of all 430 dialysis and transplant patients who began therapy for end-stage renal disease at two hospitals from 1970 to 1980. Five pretreatment factors had a statistically significant adverse effect on survival: age, duration of diabetes, left ventricular failure, myocardial infarction, and other serious comorbid illness. Dialysis patients had a worse pretreatment prognosis than transplant patients did. When we controlled for these pretreatment differences, the actuarial 5-year patient survivals were 80% for dialysis (D), 79% for cadaver transplantation (CT), and 91% for living donor transplantation (LDT), (P = 0.9 for CT vs. D, and P = 0.05 for LDT vs. D). This similarity in survival with dialysis and cadaver transplantation was quite different from the results obtained when pretreatment prognosis was not controlled; the uncontrolled 5-year patient survivals were 43% for D, 77% for CT, and 89% for LDT (P < 0.001 for CT vs. D, and P < 0.001 for LDT vs. D). Our data suggest that the major factor determining differences in survival with dialysis and renal transplantation is not the relative efficacy of the two treatments but the pretreatment prognostic status of the patients chosen to receive them.Une comparaison contrôlée de façon pronostique entre la dialyse et la transplantation rénale. Puisque la comparaison de la survie des malades en insuffisance rénale traités par dialyse ou par transplantation peut être biaisée par des différences pronostiques pré-thérapeutiques entre les malades qui reçoivent ces deux traitements, nous avons quantifié le pronostic pré-thérapeutique de l'ensemble des 430 malades dialysés et transplantés qui ont commencé le traitement de leur insuffisance rénale dans deux hôpitaux de 1970 à 1980. Cinq facteurs préthérapeutiques possédaient un effet adverse statistiquement significatif sur la survie: l'âge, la durée du diabète, une insuffisance ventriculaire gauche, un infarctus du myocarde, et une autre maladie sérieuse associée. Les dialysés avaient un pronostic pré-thérapeutique plus mauvais que les transplantés. Lorsque nous avons contrôlé ces différences pré-thérapeutiques, la survie actuarielle à 5 ans des malades était de 80% pour la dialyse (D), 79% pour la transplantation cadavérique (CT), et 91% pour la transplantation avec donneur vivant (LDT) (P = 0,9 pour CT contre D, et P = 0,05 pour LDT contre D). Cette similitude de survie en dialyse ou après transplantation cadavérique était très différente des résultats obtenus lorsque le pronostic pré-thérapeutique n'était pas contrôlé; les survies non contrôlées à 5 ans des malades étaient de 43% pour D, 77% pour CT, et 89% pour LDT (P < 0,001 pour CT contre D, et P < 0,001 pour LDT contre D). Nos données suggèrent que le facteur principal déterminant les différences de survie en dialyse ou après transplantation rénale n'est pas l'efficacité relative des deux traitements, mais l'état pronostique pré-thérapeutique des malades choisis pour les recevoir

Differential Performance of Traumatic Brain Injury Subjects and Non-Brain-Injured Peers on Cognitive Tasks

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Remote sensing and modeling of mosquito abundance and habitats in Coastal Virginia, USA

The increase in mosquito populations following extreme weather events poses a major threat to humans because of mosquitoes’ ability to carry disease-causing pathogens, particularly in low-lying, poorly drained coastal plains vulnerable to tropical cyclones. In areas with reservoirs of disease, mosquito abundance information can help to identify the areas at higher risk of disease transmission. Using a Geographic Information System (GIS), mosquito abundance is predicted across the City of Chesapeake, Virginia. The mosquito abundance model uses mosquito light trap counts, a habitat suitability model, and dynamic environmental variables (temperature and precipitation) to predict the abundance of the species Culiseta melanura, as well as the combined abundance of the ephemeral species, Aedes vexans and Psorophora columbiae, for the year 2003. Remote sensing techniques were used to quantify environmental variables for a potential habitat suitability index for the mosquito species. The goal of this study was to produce an abundance model that could guide risk assessment, surveillance, and potential disease transmission. Results highlight the utility of integrating field surveillance, remote sensing for synoptic landscape habitat distributions, and dynamic environmental data for predicting mosquito vector abundance across low-lying coastal plains. Limitations of mosquito trapping and multi-source geospatial environmental data are highlighted for future spatial modeling of disease transmission risk

Insights into antitrypanosomal drug mode-of-action from cytology-based profiling

Chemotherapy continues to have a major impact on reducing the burden of disease caused by trypanosomatids. Unfortunately though, the mode-of-action (MoA) of antitrypanosomal drugs typically remains unclear or only partially characterised. This is the case for four of five current drugs used to treat Human African Trypanosomiasis (HAT); eflornithine is a specific inhibitor of ornithine decarboxylase. Here, we used a panel of T. brucei cellular assays to probe the MoA of the current HAT drugs. The assays included DNA-staining followed by microscopy and quantitative image analysis, or flow cytometry; terminal dUTP nick end labelling to monitor mitochondrial (kinetoplast) DNA replication; antibody-based detection of sites of nuclear DNA damage; and fluorescent dye-staining of mitochondria or lysosomes. We found that melarsoprol inhibited mitosis; nifurtimox reduced mitochondrial protein abundance; pentamidine triggered progressive loss of kinetoplast DNA and disruption of mitochondrial membrane potential; and suramin inhibited cytokinesis. Thus, current antitrypanosomal drugs perturb distinct and specific cellular compartments, structures or cell cycle phases. Further exploiting the findings, we show that putative mitogen-activated protein-kinases contribute to the melarsoprol-induced mitotic defect, reminiscent of the mitotic arrest associated signalling cascade triggered by arsenicals in mammalian cells, used to treat leukaemia. Thus, cytology-based profiling can rapidly yield novel insight into antitrypanosomal drug MoA

Impact of previous hepatitis B infection on the clinical outcomes from chronic hepatitis C? A population-level analysis

Chronic coinfection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is associated with adverse liver outcomes. The clinical impact of previous HBV infection on liver disease in HCV infection is unknown. We aimed at determining any association of previous HBV infection with liver outcomes using antibodies to the hepatitis B core antigen (HBcAb) positivity as a marker of exposure. The Scottish Hepatitis C Clinical Database containing data for all patients attending HCV clinics in participating health boards was linked to the HBV diagnostic registry and mortality data from Information Services Division, Scotland. Survival analyses with competing risks were constructed for time from the first appointment to decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver‐related mortality. Records of 8513 chronic HCV patients were included in the analyses (87 HBcAb positive and HBV surface antigen [HBsAg] positive, 1577 HBcAb positive and HBsAg negative, and 6849 HBcAb negative). Multivariate cause‐specific proportional hazards models showed previous HBV infection (HBcAb positive and HBsAg negative) significantly increased the risks of decompensated cirrhosis (hazard ratio [HR]: 1.29, 95% CI: 1.01‐1.65) and HCC (HR: 1.64, 95% CI: 1.09‐2.49), but not liver‐related death (HR: 1.02, 95% CI: 0.80‐1.30). This is the largest study to date showing an association between previous HBV infection and certain adverse liver outcomes in HCV infection. Our analyses add significantly to evidence which suggests that HBV infection adversely affects liver health despite apparent clearance. This has important implications for HBV vaccination policy and indications for prioritization of HCV therapy

Examination of the risk of reinfection with hepatitis C among injecting drug users who have been tested in Glasgow

Unsafe injecting practices put injecting drug users (IDUs) at repeat exposure to infection with the hepatitis C virus (HCV). It has not yet been determined if spontaneously clearing one's primary infection influences the risk of reinfection; our aim was to estimate the relative risk of reinfection in IDUs who have cleared the virus. We conducted a retrospective study using a large database of HCV test results covering Greater Glasgow Health Board during 1993–2007 to calculate rates of infection and reinfection in current/former IDUs. The relative risk of (re)infection in previously infected compared with never-infected IDUs was estimated using Poisson regression, adjusting for age at study entry, sex, and calendar period of test. Although the rate of reinfection in IDUs who were HCV antibody-positive, RNA-negative at baseline was lower (7/100 person-years, 95% CI: 5–9) than the rate of acute infection in IDUs who were HCV antibody-negative at baseline (10/100 person-years, 95% CI: 9–12), the risk of reinfection was not significantly different than the risk of initial infection (adjusted rate ratio = 0.78, 95% CI: 0.57–1.08). We found only weak evidence for a reduced risk of HCV reinfection in IDUs who had cleared their previous infection. Further research among those who have cleared infection through antiviral therapy is needed to help inform decisions regarding treatment of IDUs