Muonium addition reactions in the gas phase: Quantum tunneling in Mu + C2H4 and Mu + C2D4

Copyright © 1990 American Institute of Physics.The reaction kinetics for the addition of the muonium (Mu=μ+e−) atom to C2H4 and C2D4 have been measured over the temperature range 150–500 K at (N2) moderator pressures near 1 atm. A factor of about 8 variation in moderator pressure was carried out for C2H4, with no significant change seen in the apparent rate constant kapp, which is therefore taken to be at the high pressure limit, yielding the bimolecular rate constant kMu for the addition step. This is also expected from the nature of the μSR technique employed, which, in favorable cases, gives kapp=kMu at any pressure. Comparisons with the H atom data of Lightfoot and Pilling, and Sugawara et al. and the D atom data of Sugawara et al. reveal large isotope effects. Only at the highest temperatures, near 500 K, is kMu/kH given by its classical value of 2.9, from the mean velocity dependence of the collision rate but at the lowest temperatures kMu/kH≳30/1 is seen, reflecting the pronounced tunneling of the much lighter Mu atom (mμ=1/9 mp). The present Mu results should provide accurate tests of reaction theories on currently available ab initio surfaces.NSERC (Canada), the Canada Council for their awarding of a Killam Research Fellowship and the Meson Science Institute, Faculty of Science, University of Tokyo

Surgical wound infection: epidemiology, pathogenesis, diagnosis and management

Surgical wound infection remains a significant problem following an operation, although surveillance for such infections remains a challenge exacerbated by early discharge and outpatient surgery. The riskof such infections isdetermined by technical problems with the operation, particularly bleeding, the amount of devitalized tissue created, and the need for drains within the wound, as well as such metabolic factors as obesity and diabetes. Perioperative antibiotic prophylaxis can decrease the incidence of such infections further, but a technically perfect operation is even more important

Human mass balance study of the novel anticancer agent ixabepilone using accelerator mass spectrometry

Ixabepilone (BMS-247550) is a semi-synthetic, microtubule stabilizing epothilone B analogue which is more potent than taxanes and has displayed activity in taxane-resistant patients. The human plasma pharmacokinetics of ixabepilone have been described. However, the excretory pathways and contribution of metabolism to ixabepilone elimination have not been determined. To investigate the elimination pathways of ixabepilone we initiated a mass balance study in cancer patients. Due to autoradiolysis, ixabepilone proved to be very unstable when labeled with conventional [14C]-levels (100 μCi in a typical human radio-tracer study). This necessitated the use of much lower levels of [14C]-labeling and an ultra-sensitive detection method, Accelerator Mass Spectrometry (AMS). Eight patients with advanced cancer (3 males, 5 females; median age 54.5 y; performance status 0–2) received an intravenous dose of 70 mg, 80 nCi of [14C]ixabepilone over 3 h. Plasma, urine and faeces were collected up to 7 days after administration and total radioactivity (TRA) was determined using AMS. Ixabepilone in plasma and urine was quantitated using a validated LC-MS/MS method. Mean recovery of ixabepilone-derived radioactivity was 77.3% of dose. Fecal excretion was 52.2% and urinary excretion was 25.1%. Only a minor part of TRA is accounted for by unchanged ixabepilone in both plasma and urine, which indicates that metabolism is a major elimination mechanism for this drug. Future studies should focus on structural elucidation of ixabepilone metabolites and characterization of their activities

Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis

Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) produce low levels of prostaglandin (PG) E(2), due to a limited capacity to up-regulate cyclooxygenase-2 (COX-2). This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood. In the present study, we examined whether the reduced level of COX-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5-aza-2′-deoxycytidine (5AZA) restored COX-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of PGE(2) production, collagen mRNA expression and sensitivity to apoptosis. COX-2 methylation assessed by bisulfite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, chromosome 8 open reading frame 4 (thyroid cancer protein 1, TC-1) (c8orf4), which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knockdown of c8orf4 in control fibroblasts down-regulated COX-2 and PGE(2) production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates COX-2 expression in lung fibroblasts through binding of the proximal promoter. We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate COX-2 expression and COX-2-derived PGE(2) synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4

Deciphering interplay between Salmonella invasion effectors

Bacterial pathogens have evolved a specialized type III secretion system (T3SS) to translocate virulence effector proteins directly into eukaryotic target cells. Salmonellae deploy effectors that trigger localized actin reorganization to force their own entry into non-phagocytic host cells. Six effectors (SipC, SipA, SopE/2, SopB, SptP) can individually manipulate actin dynamics at the plasma membrane, which acts as a ‘signaling hub’ during Salmonella invasion. The extent of crosstalk between these spatially coincident effectors remains unknown. Here we describe trans and cis binary entry effector interplay (BENEFIT) screens that systematically examine functional associations between effectors following their delivery into the host cell. The results reveal extensive ordered synergistic and antagonistic relationships and their relative potency, and illuminate an unexpectedly sophisticated signaling network evolved through longstanding pathogen–host interaction

Does Deworming Improve Growth and School Performance in Children?

Background The World Bank ranks soil-transmitted helminth infection as causing more ill health in children aged 5–15 years than any other infection. In light of this ranking, global agencies recommend regular, mass treatment with deworming drugs to children in developing countries. The World Health Organization (WHO) argues that “deworming helps meet the Millennium Development Goals”, in particular the six health-related goals:eradicate extreme poverty and hunger;achieve universal primary education;promote gender equality and empower women;reduce child mortality and improve maternal health; and combat HIV/AIDS, malaria, and other diseases. However, deworming campaigns cost money to deliver, and so we must be clear that WHO statements about the impact of these programmes are based on reliable evidence. In 2000, we systematically reviewed the reliable evidence from relevant controlled trials about the effects of anthelminth drugs for soil-transmitted helminth infection on child growth and cognition. This systematic review, published in The Cochrane Database and the BMJ, demonstrated uncertainty around the assumed benefit and concluded that it may be a potentially important intervention, but needed better evaluation. The BMJ published a large number of letters that criticised the findings, including from authors at the World Bank, the WHO, the United States Centers for Disease Control and Prevention, and the Pan American Health Organization. We do not feel that these criticisms were scientifically substantive enough to undermine the method or the conclusion. For example, several critics commented on the fact that the systematic review could not make any conclusions about the long-term effects of treatment—but, as we argued in our reply to these criticisms, “we were unable to find any randomised controlled trials that evaluated long term benefit, and the evidence of short term benefit was not, for us, convincing.” The research community quite correctly carried out further randomised controlled trials (RCTs) of repeated doses in community trials with longer follow-up compared with no intervention or placebo. In light of this additional research, we have now updated the original Cochrane review. An author of one of the trials included in the 2000 review, Ed Cooper, criticised the review for not taking into account heterogeneity in parasite burdens. Therefore, in the recently updated review, we conducted an additional subgroup analysis at trial level stratified by worm intensity and prevalence

Integration of length and curvature in haptic perception

We investigated if and how length and curvature information are integrated when an object is explored in one hand. Subjects were asked to explore four types of objects between thumb and index finger. Objects differed in either length, curvature, both length and curvature correlated as in a circle, or anti-correlated. We found that when both length and curvature are present, performance is significantly better than when only one of the two cues is available. Therefore, we conclude that there is integration of length and curvature. Moreover, if the two cues are correlated in a circular cross-section instead of in an anti-correlated way, performance is better than predicted by a combination of two independent cues. We conclude that integration of curvature and length is highly efficient when the cues in the object are combined as in a circle, which is the most common combination of curvature and length in daily life

The Cochrane Skin Group: a vanguard for developing and promoting evidence-based dermatology

Aim The Cochrane Skin Group (CSG) is part of the international Cochrane Collaboration (http://www.cochrane.org/). The CSG prepares, maintains and disseminates high quality evidence-based summaries on the prevention, diagnosis and treatment of skin diseases. We present a synopsis of the history, scope and priorities of the CSG. In addition, we report outcomes of CSG reviews and critically assess clinical value. Methods Descriptive analysis of systematic reviews published by the CSG since its inception including output, impact factor, associated methodological studies, and influence in clinical guidelines, promoting patient and public engagement and in triggering new primary research. Results The CSG started in 1997, and has published 61 reviews, 34 protocols and 31 registered titles by August 2013. The CSG scope includes 1000 skin diseases; 80% of reviews cover the top ten diagnoses and 40% of reviews provide clear guidance for clinical practice. CSG reviews had an impact factor of 6.1 in 2011 which places it alongside top dermatology journals. CSG reviews are typically broad in focus and have been shown to be of better quality than non-Cochrane reviews. They are highly cited in clinical guidelines. Several reviews have identified evidence gaps that have led to better primary research. Conclusions The CSG has emerged as a vanguard of evidence-based dermatology by growing a community interested in applying best external evidence to the care of skin patients and by identifying topics for research. CSG reviews are high impact, clinically relevant and have tangibly influenced international dermatology clinical practice guidelines and new research

A meta-analytic review of stand-alone interventions to improve body image

Objective Numerous stand-alone interventions to improve body image have been developed. The present review used meta-analysis to estimate the effectiveness of such interventions, and to identify the specific change techniques that lead to improvement in body image. Methods The inclusion criteria were that (a) the intervention was stand-alone (i.e., solely focused on improving body image), (b) a control group was used, (c) participants were randomly assigned to conditions, and (d) at least one pretest and one posttest measure of body image was taken. Effect sizes were meta-analysed and moderator analyses were conducted. A taxonomy of 48 change techniques used in interventions targeted at body image was developed; all interventions were coded using this taxonomy. Results The literature search identified 62 tests of interventions (N = 3,846). Interventions produced a small-to-medium improvement in body image (d+ = 0.38), a small-to-medium reduction in beauty ideal internalisation (d+ = -0.37), and a large reduction in social comparison tendencies (d+ = -0.72). However, the effect size for body image was inflated by bias both within and across studies, and was reliable but of small magnitude once corrections for bias were applied. Effect sizes for the other outcomes were no longer reliable once corrections for bias were applied. Several features of the sample, intervention, and methodology moderated intervention effects. Twelve change techniques were associated with improvements in body image, and three techniques were contra-indicated. Conclusions The findings show that interventions engender only small improvements in body image, and underline the need for large-scale, high-quality trials in this area. The review identifies effective techniques that could be deployed in future interventions

Common midwife toad ranaviruses replicate first in the oral cavity of smooth newts (Lissotriton vulgaris) and show distinct strain-associated pathogenicity

Ranavirus is the second most common infectious cause of amphibian mortality. These viruses affect caudates, an order in which information regarding Ranavirus pathogenesis is scarce. In the Netherlands, two strains (CMTV-NL I and III) were suspected to possess distinct pathogenicity based on field data. To investigate susceptibility and disease progression in urodeles and determine differences in pathogenicity between strains, 45 adult smooth newts (Lissotriton vulgaris) were challenged via bath exposure with these ranaviruses and their detection in organs and feces followed over time by PCR, immunohistochemistry and in situ hybridization. Ranavirus was first detected at 3 days post infection (p.i.) in the oral cavity and upper respiratory mucosa. At 6 days p.i, virus was found in connective tissues and vasculature of the gastrointestinal tract. Finally, from 9 days p.i onwards there was widespread Ranavirus disease in various organs including skin, kidneys and gonads. Higher pathogenicity of the CMTV-NL I strain was confirmed by higher correlation coefficient of experimental group and mortality of challenged animals. Ranavirus-exposed smooth newts shed virus in feces intermittently and infection was seen in the absence of lesions or clinical signs, indicating that this species can harbor subclinical infections and potentially serve as disease reservoirs