Imbalance of peptidoglycan biosynthesis alters the cell surface charge of Listeria monocytogenes

The bacterial cell wall is composed of a thick layer of peptidoglycan and cell wall polymers, which are either embedded in the membrane or linked to the peptidoglycan backbone and referred to as lipoteichoic acid (LTA) and wall teichoic acid (WTA), respectively. Modifications of the peptidoglycan or WTA backbone can alter the susceptibility of the bacterial cell towards cationic antimicrobials and lysozyme. The human pathogen Listeria monocytogenes is intrinsically resistant towards lysozyme, mainly due to deacetylation and O-acetylation of the peptidoglycan backbone via PgdA and OatA. Recent studies identified additional factors, which contribute to the lysozyme resistance of this pathogen. One of these is the predicted ABC transporter, EslABC. An eslB mutant is hyper-sensitive towards lysozyme, likely due to the production of thinner and less O-acetylated peptidoglycan. Using a suppressor screen, we show here that suppression of eslB phenotypes could be achieved by enhancing peptidoglycan biosynthesis, reducing peptidoglycan hydrolysis or alterations in WTA biosynthesis and modification. The lack of EslB also leads to a higher negative surface charge, which likely stimulates the activity of peptidoglycan hydrolases and lysozyme. Based on our results, we hypothesize that the portion of cell surface exposed WTA is increased in the eslB mutant due to the thinner peptidoglycan layer and that latter one could be caused by an impairment in UDP-N-acetylglucosamine (UDP-GlcNAc) production or distribution

Depressive disorders in caregivers of dementia patients: a systematic review.

Although depressive symptomatology has been well studied in caregivers of patients with dementia, depressive disorders have been examined much less. We conducted a systematic literature search in major bibliographical databases (Medline, Psychinfo, Dissertation Abstracts), and included studies examining caregivers of dementia patients that reported the prevalence of major depressive disorder, according to diagnostic criteria as assessed with a standardized psychiatric diagnostic interview. Ten studies with a total of 790 caregivers were identified (sample sizes: 22–147). In only one of the studies, a representative community sample was used. A total of 176 subjects (22.3%) had a depressive disorder (prevalence range from 0.15–0.32). In the three studies reporting differential prevalence rates for men and women somewhat smaller prevalence rates were found for men than for women. In six studies caregivers were compared to a (mostly matched) control group. The relative risks of having a depressive disorder in caregivers ranged from 2.80–38.68 (all RR’s were significant). In the three prospective studies relatively high incidence rates were found (0.48). This study made it clear that prevalence and incidence of depressive disorders are increased in caregivers of dementia patients. More research is clearly needed in this population

Safety and efficacy of cerliponase alfa in children with neuronal ceroid lipofuscinosis type 2 (CLN2 disease): an open-label extension study

Background: Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 (TPP1) enzyme replacement therapy for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2 disease), which is caused by mutations in the TPP1 gene. We aimed to determine the long-term safety and efficacy of intracerebroventricular cerliponase alfa in children with CLN2 disease. Methods: This analysis includes cumulative data from a primary 48-week, single-arm, open-label, multicentre, dose-escalation study (NCT01907087) and the 240-week open-label extension with 6-month safety follow-up, conducted at five hospitals in Germany, Italy, the UK, and the USA. Children aged 3–16 years with CLN2 disease confirmed by genetic analysis and enzyme testing were eligible for inclusion. Treatment was intracerebroventricular infusion of 300 mg cerliponase alfa every 2 weeks. Historical controls with untreated CLN2 disease in the DEM-CHILD database were used as a comparator group. The primary efficacy outcome was time to an unreversed 2-point decline or score of 0 in the combined motor and language domains of the CLN2 Clinical Rating Scale. This extension study is registered with ClinicalTrials.gov, NCT02485899, and is complete. Findings: Between Sept 13, 2013, and Dec 22, 2014, 24 participants were enrolled in the primary study (15 female and 9 male). Of those, 23 participants were enrolled in the extension study, conducted between Feb 2, 2015, and Dec 10, 2020, and received 300 mg cerliponase alfa for a mean of 272·1 (range 162·1–300·1) weeks. 17 participants completed the extension and six discontinued prematurely. Treated patients were significantly less likely than historical untreated controls to have an unreversed 2-point decline or score of 0 in the combined motor and language domains (hazard ratio 0·14, 95% CI 0·06 to 0·33; p<0·0001). All participants experienced at least one adverse event and 21 (88%) experienced a serious adverse event; nine participants experienced intracerebroventricular device-related infections, with nine events in six participants resulting in device replacement. There were no study discontinuations because of an adverse event and no deaths. Interpretation: Cerliponase alfa over a mean treatment period of more than 5 years was seen to confer a clinically meaningful slowing of decline of motor and language function in children with CLN2 disease. Although our study does not have a contemporaneous control group, the results provide crucial insights into the effects of long-term treatment. Funding: BioMarin Pharmaceutical

Investigating young women’s motivations to engage in early mammography screening in Switzerland: results of a cross-sectional study

The scientific and public debate concerning organized mammography screening is unprecedentedly strong. With research evidence concerning its efficacy being ambiguous, the recommendations pertaining to the age-thresholds for program inclusion vary between - and even within - countries. Data shows that young women who are not yet eligible for systematic screening, have opportunistic mammograms relatively often and, moreover, want to be included in organized programs. Yet, to date, little is known about the precise motivations underlying young women's desire and intentions to go for, not medically indicated, mammographic screening. A cross-sectional online survey was carried out among women aged 30-49 years (n = 918) from Switzerland. The findings show that high fear (β = .08, p ≤ .05), perceived susceptibility (β = .10, p ≤ .05), and ego-involvement (β = .34, p ≤ .001) are the main predictors of screening intentions among women who are not yet eligible for the systematic program. Also, geographical location (Swiss-French group: β = .15, p ≤ .001; Swiss-Italian group: β = .26, p ≤ .001) and age (β = .11, p ≤ .001) play a role. In turn, breast cancer knowledge, risk perceptions, and educational status do not have a significant impact. Young women seem to differ inherently from those who are already eligible for systematic screening in terms of the factors underlying their intentions to engage in mammographic screening. Thus, when striving to promote adherence to systematic screening guidelines - whether based on unequivocal scientific evidence or policy decisions - and to allow women to make evidence-based, informed decisions about mammography, differential strategies are needed to reach different age-group

Evidence at a glance: error matrix approach for overviewing available evidence

Contains fulltext : 88651.pdf (publisher's version ) (Open Access)BACKGROUND: Clinical evidence continues to expand and is increasingly difficult to overview. We aimed at conceptualizing a visual assessment tool, i.e., a matrix for overviewing studies and their data in order to assess the clinical evidence at a glance. METHODS: A four-step matrix was constructed using the three dimensions of systematic error, random error, and design error. Matrix step I ranks the identified studies according to the dimensions of systematic errors and random errors. Matrix step II orders the studies according to the design errors. Matrix step III assesses the three dimensions of errors in studies. Matrix step IV assesses the size and direction of the intervention effect. RESULTS: The application of this four-step matrix is illustrated with two examples: peri-operative beta-blockade initialized in relation to surgery versus placebo for major non-cardiac surgery, and antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. When clinical evidence is deemed both internally and externally valid, the size of the intervention effect is to be assessed. CONCLUSION: The error matrix provides an overview of the validity of the available evidence at a glance, and may assist in deciding which interventions to use in clinical practice

Perspective from a Younger Generation -- The Astro-Spectroscopy of Gisbert Winnewisser

Gisbert Winnewisser's astronomical career was practically coextensive with the whole development of molecular radio astronomy. Here I would like to pick out a few of his many contributions, which I, personally, find particularly interesting and put them in the context of newer results.Comment: 14 pages. (Co)authored by members of the MPIfR (Sub)millimeter Astronomy Group. To appear in the Proceedings of the 4th Cologne-Bonn-Zermatt-Symposium "The Dense Interstellar Medium in Galaxies" eds. S. Pfalzner, C. Kramer, C. Straubmeier, & A. Heithausen (Springer: Berlin

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

X-Ray Spectroscopy of Stars

(abridged) Non-degenerate stars of essentially all spectral classes are soft X-ray sources. Low-mass stars on the cooler part of the main sequence and their pre-main sequence predecessors define the dominant stellar population in the galaxy by number. Their X-ray spectra are reminiscent, in the broadest sense, of X-ray spectra from the solar corona. X-ray emission from cool stars is indeed ascribed to magnetically trapped hot gas analogous to the solar coronal plasma. Coronal structure, its thermal stratification and geometric extent can be interpreted based on various spectral diagnostics. New features have been identified in pre-main sequence stars; some of these may be related to accretion shocks on the stellar surface, fluorescence on circumstellar disks due to X-ray irradiation, or shock heating in stellar outflows. Massive, hot stars clearly dominate the interaction with the galactic interstellar medium: they are the main sources of ionizing radiation, mechanical energy and chemical enrichment in galaxies. High-energy emission permits to probe some of the most important processes at work in these stars, and put constraints on their most peculiar feature: the stellar wind. Here, we review recent advances in our understanding of cool and hot stars through the study of X-ray spectra, in particular high-resolution spectra now available from XMM-Newton and Chandra. We address issues related to coronal structure, flares, the composition of coronal plasma, X-ray production in accretion streams and outflows, X-rays from single OB-type stars, massive binaries, magnetic hot objects and evolved WR stars.Comment: accepted for Astron. Astrophys. Rev., 98 journal pages, 30 figures (partly multiple); some corrections made after proof stag