RAD52 (RAD52 homolog (S. cerevisiae))

Review on RAD52, with data on DNA/RNA, on the protein encoded and where the gene is implicated

Inhaled magnesium sulfate in the treatment of acute asthma.

BACKGROUND: Asthma exacerbations can be frequent and range in severity from mild to life-threatening. The use of magnesium sulfate (MgSO₄) is one of numerous treatment options available during acute exacerbations. While the efficacy of intravenous MgSO₄ has been demonstrated, the role of inhaled MgSO₄ is less clear. OBJECTIVES: To determine the efficacy and safety of inhaled MgSO₄ administered in acute asthma. SPECIFIC AIMS: to quantify the effects of inhaled MgSO₄ I) in addition to combination treatment with inhaled β₂-agonist and ipratropium bromide; ii) in addition to inhaled β₂-agonist; and iii) in comparison to inhaled β₂-agonist. SEARCH METHODS: We identified randomised controlled trials (RCTs) from the Cochrane Airways Group register of trials and online trials registries in September 2017. We supplemented these with searches of the reference lists of published studies and by contact with trialists. SELECTION CRITERIA: RCTs including adults or children with acute asthma were eligible for inclusion in the review. We included studies if patients were treated with nebulised MgSO₄ alone or in combination with β₂-agonist or ipratropium bromide or both, and were compared with the same co-intervention alone or inactive control. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial selection, data extraction and risk of bias. We made efforts to collect missing data from authors. We present results, with their 95% confidence intervals (CIs), as mean differences (MDs) or standardised mean differences (SMDs) for pulmonary function, clinical severity scores and vital signs; and risk ratios (RRs) for hospital admission. We used risk differences (RDs) to analyse adverse events because events were rare. MAIN RESULTS: Twenty-five trials (43 references) of varying methodological quality were eligible; they included 2907 randomised patients (2777 patients completed). Nine of the 25 included studies involved adults; four included adult and paediatric patients; eight studies enrolled paediatric patients; and in the remaining four studies the age of participants was not stated. The design, definitions, intervention and outcomes were different in all 25 studies; this heterogeneity made direct comparisons difficult. The quality of the evidence presented ranged from high to very low, with most outcomes graded as low or very low. This was largely due to concerns about the methodological quality of the included studies and imprecision in the pooled effect estimates. Inhaled magnesium sulfate in addition to inhaled β₂-agonist and ipratropiumWe included seven studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, results were inconsistent overall and the largest study reporting this outcome found no between-group difference at 60 minutes (MD -0.3 % predicted peak expiratory flow rate (PEFR), 95% CI -2.71% to 2.11%). Admissions to hospital at initial presentation may be reduced by the addition of inhaled magnesium sulfate (RR 0.95, 95% CI 0.91 to 1.00; participants = 1308; studies = 4; I² = 52%) but no difference was detected for re-admissions or escalation of care to ITU/HDU. Serious adverse events during admission were rare. There was no difference between groups for all adverse events during admission (RD 0.01, 95% CI -0.03 to 0.05; participants = 1197; studies = 2). Inhaled magnesium sulfate in addition to inhaled β₂-agonistWe included 13 studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, none of the pooled results showed a conclusive benefit as measured by FEV1 or PEFR. Pooled results for hospital admission showed a point estimate that favoured the combination of MgSO₄ and β₂-agonist, but the confidence interval includes the possibility of admissions increasing in the intervention group (RR 0.78, 95% CI 0.52 to 1.15; participants = 375; studies = 6; I² = 0%). There were no serious adverse events reported by any of the included studies and no between-group difference for all adverse events (RD -0.01, 95% CI -0.05 to 0.03; participants = 694; studies = 5). Inhaled magnesium sulfate versus inhaled β₂-agonistWe included four studies in this comparison. The evidence for the efficacy of β₂-agonists in acute asthma is well-established and therefore this could be considered a historical comparison. Two studies reported a benefit of β₂-agonist over MgSO₄ alone for PEFR and two studies reported no difference; we did not pool these results. Admissions to hospital were only reported by one small study and events were rare, leading to an uncertain result. No serious adverse events were reported in any of the studies in this comparison; one small study reported mild to moderate adverse events but the result is imprecise. AUTHORS' CONCLUSIONS: Treatment with nebulised MgSO₄ may result in modest additional benefits for lung function and hospital admission when added to inhaled β₂-agonists and ipratropium bromide, but our confidence in the evidence is low and there remains substantial uncertainty. The recent large, well-designed trials have generally not demonstrated clinically important benefits. Nebulised MgSO₄ does not appear to be associated with an increase in serious adverse events. Individual studies suggest that those with more severe attacks and attacks of shorter duration may experience a greater benefit but further research into subgroups is warranted.Despite including 24 trials in this review update we were unable to pool data for all outcomes of interest and this has limited the strength of the conclusions reached. A core outcomes set for studies in acute asthma is needed. This is particularly important in paediatric studies where measuring lung function at the time of an exacerbation may not be possible. Placebo-controlled trials in patients not responding to standard maximal treatment, including inhaled β₂-agonists and ipratropium bromide and systemic steroids, may help establish if nebulised MgSO₄ has a role in acute asthma. However, the accumulating evidence suggests that a substantial benefit may be unlikely

Comparison of new and primary production models using SeaWiFS data in contrasting hydrographic zones of the northern North Atlantic.

The accuracy of two satellite models of marine primary (PP) and new production (NP) were assessed against 14C and 15N uptake measurements taken during six research cruises in the northern North Atlantic. The wavelength resolving model (WRM) was more accurate than the Vertical General Production Model (VGPM) for computation of both PP and NP. Mean monthly satellite maps of PP and NP for both models were generated from 1997 to 2010 using SeaWiFS data for the Irminger basin and North Atlantic. Intra- and inter-annual variability of the two models was compared in six hydrographic zones. Both models exhibited similar spatio-temporal patterns: PP and NP increased from April to June and decreased by August. Higher values were associated with the East Greenland Current (EGC), Iceland Basin (ICB) and the Reykjanes Ridge (RKR) and lower values occurred in the Central Irminger Current (CIC), North Irminger Current (NIC) and Southern Irminger Current (SIC). The annual PP and NP over the SeaWiFS record was 258 and 82 gC m-2 yr-1 respectively for the VGPM and 190 and 41 gC m-2 yr-1 for the WRM. Average annual cumulative sum in the anomalies of NP for the VGPM were positively correlated with the North Atlantic Oscillation (NAO) in the EGC, CIC and SIC and negatively correlated with the multivariate ENSO index (MEI) in the ICB. By contrast, cumulative sum of the anomalies of NP for the WRM were significantly correlated with NAO only in the EGC and CIC. NP from both VGPM and WRM exhibited significant negative correlations with Arctic Oscillation (AO) in all hydrographic zones. The differences in estimates of PP and NP in these hydrographic zones arise principally from the parameterisation of the euphotic depth and the SST dependence of photo-physiological term in the VGPM, which has a greater sensitivity to variations in temperature than the WRM. In waters of 0 to 5C PP using the VGPM was 43% higher than WRM, from 5 to 10C the VGPM was 29% higher and from 10 to 15C the VGPM was 27% higher

The gut microbiota and metabolome are associated with diminished COVID-19 vaccine-induced antibody responses in immunosuppressed inflammatory bowel disease patients

Background: Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients. Methods: Faecal and serum samples were prospectively collected from infliximab-treated patients with IBD in the CLARITY-IBD study undergoing vaccination against SARS-CoV-2. Antibody responses were measured following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Patients were classified as having responses above or below the geometric mean of the wider CLARITY-IBD cohort. 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) were performed on faecal samples. Univariate, multivariable and correlation analyses were performed to determine gut microbial and metabolomic predictors of response to vaccination. Findings: Forty-three infliximab-treated patients with IBD were recruited (30 Crohn's disease, 12 ulcerative colitis, 1 IBD-unclassified; 26 with concomitant thiopurine therapy). Eight patients had evidence of prior SARS-CoV-2 infection. Seventeen patients (39.5%) had a serological response below the geometric mean. Gut microbiota diversity was lower in below average responders (p = 0.037). Bilophila abundance was associated with better serological response, while Streptococcus was associated with poorer response. The faecal metabolome was distinct between above and below average responders (OPLS-DA R2X 0.25, R2Y 0.26, Q2 0.15; CV-ANOVA p = 0.038). Trimethylamine, isobutyrate and omega-muricholic acid were associated with better response, while succinate, phenylalanine, taurolithocholate and taurodeoxycholate were associated with poorer response. Interpretation: Our data suggest that there is an association between the gut microbiota and variable serological response to vaccination against SARS-CoV-2 in immunocompromised patients. Microbial metabolites including trimethylamine may be important in mitigating anti-TNF-induced attenuation of the immune response. Funding: JLA is the recipient of an NIHR Academic Clinical Lectureship (CL-2019-21-502), funded by Imperial College London and The Joyce and Norman Freed Charitable Trust. BHM is the recipient of an NIHR Academic Clinical Lectureship (CL-2019-21-002). The Division of Digestive Diseases at Imperial College London receives financial and infrastructure support from the NIHR Imperial Biomedical Research Centre (BRC) based at Imperial College Healthcare NHS Trust and Imperial College London. Metabolomics studies were performed at the MRC-NIHR National Phenome Centre at Imperial College London; this work was supported by the Medical Research Council (MRC), the National Institute of Health Research (NIHR) (grant number MC_PC_12025) and infrastructure support was provided by the NIHR Imperial Biomedical Research Centre (BRC). The NIHR Exeter Clinical Research Facility is a partnership between the University of Exeter Medical School College of Medicine and Health, and Royal Devon and Exeter NHS Foundation Trust. This project is supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care

Core outcome domains for early-phase clinical trials of sound-, psychology-, and pharmacology-based interventions to manage chronic subjective tinnitus in adults: the COMIT'ID study protocol for using a Delphi process and face-to-face meetings to establish consensus

Background: The reporting of outcomes in clinical trials of subjective tinnitus indicates that many different tinnitus-related complaints are of interest to investigators, from perceptual attributes of the sound (e.g. loudness) to psychosocial impacts (e.g. quality of life). Even when considering one type of intervention strategy for subjective tinnitus, there is no agreement about what is critically important for deciding whether a treatment is effective. The main purpose of this observational study is therefore to develop Core Outcome Domain Sets for the three different intervention strategies (sound, psychological, and pharmacological) for adults with chronic subjective tinnitus that should be measured and reported in every clinical trial of these interventions. Secondary objectives are to identify the strengths and limitations of our study design for recruiting and reducing attrition of participants, and to explore uptake of the core outcomes. Methods: The ‘Core Outcome Measures in Tinnitus: International Delphi’ (COMIT’ID) study will use a mixed methods approach that incorporates input from healthcare users at the pre-Delphi stage, a modified three round Delphi survey and final consensus meetings (one for each intervention). The meetings will generate recommendations by stakeholder representatives on agreed Core Outcome Domain Sets specific to each intervention. A subsequent step will establish a common cross-cutting Core Outcome Domain Set by identifying the common outcome domains included in all three intervention-specific Core Outcome Domain Sets. To address the secondary objectives, we will gather feedback from participants about their experience of taking part in the Delphi process. We aspire to conduct an observational cohort study to evaluate uptake of the core outcomes in published studies at 7 years following core outcome set publication. Discussion: The COMIT’ID study aims to develop a Core Outcome Domain Set that are agreed as critically important for deciding whether a treatment for subjective tinnitus is effective. Such a recommendation would help to standardise future clinical trials worldwide and so we will determine if participation increases use of the core outcome set in the long term. Trial registration: This project has been registered in the database of the Core Outcome Measures in Effectiveness Trials (COMET) initiative

The genetic basis of DOORS syndrome: an exome-sequencing study.

Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals

Homeostatic regulation of the endoneurial microenvironment during development, aging and in response to trauma, disease and toxic insult

The endoneurial microenvironment, delimited by the endothelium of endoneurial vessels and a multi-layered ensheathing perineurium, is a specialized milieu intérieur within which axons, associated Schwann cells and other resident cells of peripheral nerves function. The endothelium and perineurium restricts as well as regulates exchange of material between the endoneurial microenvironment and the surrounding extracellular space and thus is more appropriately described as a blood–nerve interface (BNI) rather than a blood–nerve barrier (BNB). Input to and output from the endoneurial microenvironment occurs via blood–nerve exchange and convective endoneurial fluid flow driven by a proximo-distal hydrostatic pressure gradient. The independent regulation of the endothelial and perineurial components of the BNI during development, aging and in response to trauma is consistent with homeostatic regulation of the endoneurial microenvironment. Pathophysiological alterations of the endoneurium in experimental allergic neuritis (EAN), and diabetic and lead neuropathy are considered to be perturbations of endoneurial homeostasis. The interactions of Schwann cells, axons, macrophages, and mast cells via cell–cell and cell–matrix signaling regulate the permeability of this interface. A greater knowledge of the dynamic nature of tight junctions and the factors that induce and/or modulate these key elements of the BNI will increase our understanding of peripheral nerve disorders as well as stimulate the development of therapeutic strategies to treat these disorders

Differentiation of embryonic stem cells into fibroblast-like cells in three-dimensional type I collagen gel cultures

Fibroblasts are heterogeneous mesenchymal cells that play important roles in the production and maintenance of extracellular matrix. Although their heterogeneity is recognized, progenitor progeny relationships among fibroblasts and the factors that control fibroblast differentiation are poorly defined. The current study was designed to develop a reliable method that would permit in vitro differentiation of fibroblast-like cells from human and murine embryonic stem cells (ESCs). Undifferentiated ESCs were differentiated into embryoid bodies (EBs) with differentiation media. EBs were then cast into type I collagen gels and cultured for 21 d with basal media. The spindle-shaped cells that subsequently grew from the EBs were released from the gels and subsequently cultured as monolayers in basal media supplemented with serum. Differentiated cells showed a characteristic spindle-shaped morphology and had ultrastructural features consistent with fibroblasts. Immunocytochemistry showed positive staining for vimentin and alpha-smooth muscle actin but was negative for stage-specific embryonic antigens and cytokeratins. Assays of fibroblast function, including proliferation, chemotaxis, and contraction of collagen gels demonstrated that the differentiated cells, derived from both human and murine ESCs, responded to transforming growth factor-β1 and prostaglandin E2 as would be expected of fibroblasts, functions not expected of endothelial or epithelial cells. The current study demonstrates that cells with the morphologic and functional features of fibroblasts can be reliably derived from human and murine ESCs. This methodology provides a means to investigate and define the mechanisms that regulate fibroblast differentiation

Diarrhoea in a large prospective cohort of European travellers to resource-limited destinations

BACKGROUND: Incidence rates of travellers' diarrhoea (TD) need to be updated and risk factors are insufficiently known. METHODS: Between July 2006 and January 2008 adult customers of our Centre for Travel Health travelling to a resource-limited country for the duration of 1 to 8 weeks were invited to participate in a prospective cohort study. They received one questionnaire pre-travel and a second one immediately post-travel. First two-week incidence rates were calculated for TD episodes and a risk assessment was made including demographic and travel-related variables, medical history and behavioural factors. RESULTS: Among the 3100 persons recruited, 2800 could be investigated, resulting in a participation rate of 89.2%. The first two-weeks incidence for classic TD was 26.2% (95%CI 24.5-27.8). The highest rates were found for Central Africa (29.6%, 95% CI 12.4-46.8), the Indian subcontinent (26.3%, 95%CI 2.3-30.2) and West Africa (21.5%, 95%CI 14.9-28.1). Median TD duration was 2 days (range 1-90). The majority treated TD with loperamide (57.6%), while a small proportion used probiotics (23.0%) and antibiotics (6.8%). Multiple logistic regression analysis on any TD to determine risk factors showed that a resolved diarrhoeal episode experienced in the 4 months pre-travel (OR 2.03, 95%CI 1.59-2.54), antidepressive comedication (OR 2.11, 95%CI 1.17-3.80), allergic asthma (OR 1.67, 95%CI 1.10-2.54), and reporting TD-independent fever (OR 6.56, 95%CI 3.06-14.04) were the most prominent risk factors of TD. CONCLUSIONS: TD remains a frequent travel disease, but there is a decreasing trend in the incidence rate. Patients with a history of allergic asthma, pre-travel diarrhoea, or of TD-independent fever were more likely to develop TD while abroad